Diagnosis and Treatment of Uveitis

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_rioperative inflammation is essential for riP ~lC surgical cases. Efforts to establish a pa.Jgic mechanism and the design of medical regilO contl'ol or eliminate the intraocular inflamma...1 before elective surgery is required for a successful outcome. In certain circumstances, this dictum cannot be realized. Endophthalmitis, lens-induced uveitis, and vitreous surgery designed to control medically unresponsive uveitis, by definition, must be performed while the eye is still inflamed. Surgery under these circumstances (in the presence of active intraocular inflammation) carries a much higher potential for surgical complications.

Vitreous surgery is performed using a standard threeport vitrectomyprocedure. A longer infusion tip is often required in uveitis patients to accommodate scleral thickening, choroidal edema, or retinal separation that is freluently encounteted in an eye with uveitis. Special care 'Juld be taken to ensure proper location of the infusion lla within the vitreous cavity before turning on the ,n in these patients. A bimanual technique of vitrecembranectomy, or lensectomy can be performed .~ vitreous cells and debris, epiretinal melTIvascular tissue, or lens material. 'th intermediate or diffuse uveitis may bene')my simply as a result of the removal of .c-Iacities and vitreous debris. 24 A clear vitreous J facilitates the ophthalmologist in conducting ..:cessary postoperative fundus examinations and in Lecting cystoid macular edema (CME). The debridement of inflammatory cells and mediators is also believed to have a curative or moderating effect on the clinical course in patients with pars planitis, juvenile rheumatoid arthritis, and sarcoidosis (Fig. 14-13).25-29 In addition to removing inflammatory cells, it is possible that vitrectomy removes any inciting foreign or autologous antigenic material. Type II collagen is an autoantigen found only in the vitreous cavity and injoints. 30 It is an immunoreactive protein that can produce arthritis and uveitis in animal models. Patients with several uveitis syndromes have T cells in their blood that are reactive to type II collagen,31 Vitrectomy removes this "autoantigen," and much like removing lens proteins in a phacogenic uveitis patient, may thereby moderate the inflammation. VitrectOlTIY may also remove autoreactive helper T cells from the eye that are recruiting other nonspecific inflammatory cells. Transplantation research has shown that graft rejection is mediated by only a few antigen specific helper T cells found at the rejection site. 32 These cells are responsible for recruiting other nonspecific inflammatory cells into the foreign tissue, resulting in graft rejection. Vitrectomy may therefore remove these isolated, helper T-cell populations responsible for promoting and maintaining the uveitis. Finally, vitrectomy and lensectomy alters the imlTIunologic milieu of the eye. Converting the eye to a

FIGURE 14-13. A, Fundus photograph of the right eye from a 17-year-old girl with chronic, medically unresponsive, pars planitis and CME' receiving maximal medical therapy and visual acuity of 20/200. B, Fundus photograph of the left eye from the same patient showing clear media, and resolution of the vitritis and cystoid macular edema (CME) following therapeutic vitrectomy. Vision returned to 20/20 and remained quiet for 7 years. The right eye continued to have recurrent uveitis and ultimately required vitrectomy surgery.

CHAPTER 14: THERAPEUTIC SURGERY: CORNEA, IRIS,

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FIGURE 14-14. A, Fundus photograph of a 39-year-old woman with persistent, nonclearing inflammatory membranes in the vitreous and a traction macular detachment following retinal toxoplasmosis. Visual acuity is 20/400. B, Fundus photograph of the same patient following therapeutic vitrectomy and membranectomy showing successful removal of the membranes and return of 20/20 visual acuity.

unicameral state may allow for a more immunologically tolerant environment to be established. 33 Each of these postulated mechanisms may play a role in lessening the uveitis, and by that, reduce the severity of CME. The beneficial effects of vitrectomy, however, are not universal for all patients with uveitis. 34, 35 Patients with intermediate forms of uveitis may respond better than those with predominantly anterior or posterior uveitis. 25- 29 Membrane removal can be done at the same time as the vitrectomy to repair many ~f the complications of uveitis. 34 Intraocular picks, spatulas, scissors, needle knifes, and various forceps can be used to remove inflammatory membranes from the retina and ciliary body (Fig" 14-14). Anteroposterior, vitreomacular tractions from an inflamed vitreous body may playa role in maintaining chronic CME or create a shallow macular detachment. Eliminating this traction through vitrectomy and membranectomy surgery may improve macular function. Epiretinal membrane (ERM) formation frequently occurs in eyes with uveitis. Tangential traction caused by epiretinal membranes cause decreased vision via wrinkling of the macula and secondary CME. These membranes can be successfully removed at the time of the vitrectomy via delamination or en bloc techniques. One of the mechanisms for hypotony in patients with uveitis is the formation of a cyclitic membrane. Chronic traction of the ciliary body results in ciliary body detachment and reduced aqueous humor formation.Vitrectomy and cyclitic membrane removal can be performed to reattach the ciliary body. A skilled assistant is required to assist in scleral depression in the region of the ciliary body, so that the surgeon can dissect and remove the inflammatory membrane or surgically segment it to reduce traction. Lens-induced uveitis occurs when lens material is retained in the eye following cataract surgery or ocular trauma. If a significant amount of nuclear material is dropped into the vitreous cavity during cataract surgery, a lens-induced uveitis is likely (Fig. 14-15). Vitrectomy combined with pars plana lensectomy should be performed to remove inciting autoantigenic lens material. Following a standard vitrectomy, a fragmentation handpiece is used to phacoemulsify the retained lens material.

Care should be taken not to injure the macula during the fragmentation process. At the end of any vitreoretinal surgery, the eye should be inspected for any iatrogenic retinal breaks; if breaks are present, they should be treated with retinal laser or cryopexy. Unless contraindicated, all uveitic vitrectomized eyes receive 400 I+g of dexamethasone in the vitre'ous cavity and 40 mg of triamcinolone in the sub-Tenon space. This greatly assists in controlling excessive postoperative inflammation and fibrin formation. Regional and intraocular corticosteroids are contraindicated or are to be used with extreme caution in a patient with a possible infectious etiology (e.g., toxoplasmosis or viral diseases). A rapid and severe retinal necrosis can occur as a result of the potent immunosuppressive effect of these drugs (Fig. 14-16). Appropriate antimicrobial agents need to be used in conjunction with corticosteroid drug delivery in these settings.

RETINAL Retinal detachment, ischemia, necrosis, and subretinal neovascular membrane formation are common complica-

FIGURE 14-15. Fundus photograph of a patient with Marfan's syndrome showing mild vitritis and a lens that became dislocated during cataract surgery. Vitrectomy and pars plana lensectomy was successful at removing the dislocated lens and controlling the lens-induced uveitis.

CHAPTER 14: THERAPEUTIC SURGERY: CORNEA,

CATARACT,

- VITREOUS, RETINAL

FIGURE 14-16. A, Fundus photograph of a patient with a rapidly progressing, multifocal, necrotizing retinitis following a sub-Tenon's injection of 40 mg triamcinolone. B, Retinal biopsy shows toxoplasma organisms in the areas of retinal necrosis. The infectious retinitis was facilitated by the profound, immunosuppressive effects of regional corticosteroids.

tions of uveitis. 35- 39 Many of these sequelae can be addressed by laser, retinal cryopexy or retinal surgical techniques. As with other surgical endeavors, control of perioperative inflammation is an important goal prior to elective retinal surgery. These patients frequently have cataract, posterior syn.echiae and vitreous opacification that need to be addressed either prior to, or at the time of the vitreoretinal surgery. Retinal detachment can occur i,l1. uveitis patients through various mechanisms. Retinal tears may occur unrelated to the uveitis or as a result of the intraocular inflammation. Often these tears can be treated with standard retinal laser or cryopexy. Inflammatory membranes create traction on the retina. and result in retinal tears and detachment. Cytomegalovirus, varicella zoster virus, and toxoplasmosis can cause retinal necrosis and create multiple, posterior retinal breaks. 37,38 Prophylactic laser photocoagulation can be performed at the boundary of healthy retina and the areas of retinal necrosis to reduce the risk for retinal detachment (Fig. 14-17). Toxocariasis, cyclitic membranes in juvenile rheumatoid arthritis and

anterior vitreous scarring in pars planitis can produce giant retinal tears and detachment. 35 ,39 Myopic patients who develop exudative retinal detachment from syphilis or Vogt-Koyanagi-Harada syndrome (VKH) may have a rhegmatogenous component that needs to be addressed for successful retinal repair. Regardless of the mechanism, the principles of the repair are the same: (1) relieve vitreous tractions, (2) seal the breaks, and (3) attach the sensory retina to the underlying retinal pigment epithelium (RPE). Although standard scleral buckle surgery or pneumatic retinopexy can accomplish these goals in simple detachments associated with uveitis (Fig. 14-18), many patients have more complex detachments that cannot be repaired by scleral buckle alone. Diseases such as acute retinal necrosis/ bilateral acute retinal necrosis (ARN/BARN) or cytomegalovirus retinitis produce multiple and posterior breaks that cannot be sealed by scleral buckles (Fig. 14-19). Instead, internal repair is required through vitrectomy and long-acting gas or silicon oil tamponade. 37 , 38 Vitrectomy can mOre efficiently remove complex, lTIultilaminar

FIGURE 14-17. Fundus photograph of a patient with resolving acute retinal necrosis (ARN) and peripheral retinal necrosis. Prophylactic laser retinopexy was performed in healthy non-necrotic retina to prevent retinal detachment. Note the areas of peripheral retinal necrosis.

FIGURE 14-18. Fundus photograph of a patient with birdshot chorioretinitis and a rhegmatogenous retinal detachment repaired via scleral buckle surgery. Note the cream-colored retinal lesions and the attached retina on the buckle.

14: THERAPEUTIC SURGERY: CORNEA, IRIS, CATARACT, ..... II-_""""-....pg~u.... _

~IGUR~ 14-19. Fundus photograph of a patient with multiple, postenor, retmal breaks following resolution of bilateral acute retinal necrosis (BARN).

tractional membranes that are often present in pars planitis, sarcoidosis, and ARN/BARN. Posterior tears can be sealed through endolaser photocoagulation more effectively than through external cryopexy. Multiple tears can be supported more efficiently through the surface tension created by gas or silicon oil tamponade (Fig. 14-20). Therefore, internal repair is more often used to repair the retina in uveitis than in patients with routine rhegmatogenous detachments. Retinal detachment in patient~ with uveitis can have an exudative component. Both the rhegmatogenous component and the exudative aspect of the detachment need to be addressed simultaneously. Repair of a retinal break in a patient with high myopia and a bilateral syphilitic exudative retinal detachment without controlling the uveitis will not be successful (Fig. 14-21). Likewise, an exudative retinal detachment from posterior scleritis or VKH syndrome will not respond to medical therapy if there is an undetected retinal break. Anatomic and visual success are greatly influenced by the underlying uveitis syndrome and the health of the

FI?~~E 14-20: .Fundl~s photograph of a patient with cytomegalovirus ret1l11tls and a sIlICon OIl-filled eye, following internal repair of a retinal detachment. Note the inactive viral retinitis and the laser reaction surrounding the posterior retinal breaks.

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FIGURE 14-21. Fundus photograph of a patient with both a rhegmatogenous and exudative retinal detachment from syphilitic uveitis and high myopia. The retina was repaired by both scleral buckle and medical therapy, including penicillin and oral prednisone.

optic nerve and macula. Choroidal thickening and retinal edema may lessen the effect of cryopexy and laser in creating a permanent adhesion at the site of the retinal tear. Both laser and retinal cryopexy are destructive procedures and may incite aggressive postoperative inflammation. Post-operative fibrin formation may be enhanced in eyes with uveitis and fibrin formation may promote cyclitic membrane formation and proliferative vitreoretinopathy (PVR). In patients with excessive postoperative fibrin, tissue plasminogen activator (tPA) can be injected into the eye to assist in clearing of the fibrin and prevent these complications (Fig. 14-22). Ultimately, visual prognosis is predicated on whether the macula was detached and on the pre-existing maculopathy. Final visual acuity will be greatly influenced by presence of fixed macular cysts, macular scarring, subfoveal neovascularization, ischemia, CME, or retinal necrosis. Finally, patients have a better visual prognosis if the macula is not involved than those who present with a macula-off detachment. Many forms of posterior uveitis are associated with retinal or subretinal neovascular membranes. 4o Patients with Adamantiades-Beh<;;:et disease, systemic lupus erythematosus (SLE) , and sarcoidosis may develop large areas of retinal capillary nonperfusion and secondary retinal neovascularization (Fig. 14-23). Fluorescein angiography can define the areas of ischemia and help direct panretinal laser photocoagulation when indicated (Fig. 14-24). Efforts to control the underlying disease and halt the progressive microvascular disease should be attempted. Retinal neovascularization may progress in patients with sarcoidosis by medical therapy alone (Fig. 14-25). Persistent ischemia and retinal neovascularization can be treated with panretinal photocoagulation to the areas of ischemia. Successful laser can reduce the risk of recurrent vitreous hemorrhages. Patients with ocular histoplasmosis, punctate inner choroiditis, serpiginous choroiditis, VKH, birdshot chorioretinitis, sympathetic ophthalmia, and many other forms of posterior uveitis may develop subretinal neovascular membranes (SRNVMs) , resulting in loss of macular function due to serous or hemorrhagic exudation. If

14: THERAPEUTIC

CORNEA, IRIS, CATARACT, GLAUCOMA, VITREOUS, RETINAL

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i:t patient 24 hours following Moltenq tube implantation for glaucoma in an eye with· severe 13, Photograph of the same eye 5 minutes following the injection of 10 I-1g of tPAinto the anterior of the fibrin in the anterior chamber. The eye remained quiet without worsening uveitis or additional _L

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FIGURE 14-23. A, Fundus photograph of a patient with systemic lupus erythematosus showing vitreous hemorrhage, preretinal hemorrhage, and retinal arteriolitis. B, Fluorescein angiogram of the same· patient showing areas of capillary nonperfusion, retinal ischemia, and retinal neovascularization.

FIGURE 14-24. A, Fundus photograph of a patient with Adamantiades-Beh~etdisease and retinal vasculitis, hemorrhage, and cotton-wool spots. B, Fluorescein angiogram of the same patient showing laser photocoagulation to the areas of retinal ischemia.

CHAPTER 14: THERAPEUTIC SURGERY: CORNEA, IRIS, CATARAC-r, ..... 1l..._>..IJ ..... "-'O·U"I..

FIGURE 14-25. A, Fundus photograph from a patient with sarcoidosis and vitritis with neovascularization of the disc (NVD). Visual acuity was 20/100. B, Fluorescein angiogram of the same patient showing cystoid macular edema (CME) and NVD. C, Fundus photograph of the same patient 6 weeks following oral corticosteroid therapy and control of the uveitis. Note the resolution of the NVD. Vision improved to 20/20. D, Fluorescein angiogram of the same patient showing resolution of the CME and NVD.

these are extrafoveal (200 to 2500 /-Lm from the fovea) or juxtafoveal (1 to 200 /-Lm from the center of the fovea) laser photocoagulation can reduce the risk of visual loss. The multicenter Macular Photocoagulation Study Group demonstrated a six line loss of vision in 50% of untreated patients over a 24-month period as compared with a 22% loss of 6 lines in the laser-treated group in patients with

ocular histoplasmosis syndrome. The membrane is typically outlined with laser using 100 /-Lm spots for 0.1 second. The power is determined by observing the tissue reaction and obtaining the desired whitish yellow burn. The lesion is then filled in with 200 /-Lm laser spot for 0.2 second and then overlapped by 200 to 500 /-Lm burns for 0.5 second (Fig. 14-26). The underlying choroiditis may

FIGURE 14-26. A, Fluorescein angiogram from a patient with juxtafoveal subretinal neovascular membrane (SRNVM) from presumed ocular histoplasmosis syndrome (POHS) with vision of 20/400. B, Fluorescein angiogram from the same patient following laser photocoagulation of the SRNVM and return of 20/25 vision. Note the destruction of the neovascular membrane.

CHAPTER'14: THERAPEUTIC SURGERY: CORNEA, IRIS, ............

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FIGURE 14-27. A, Fundus photograph of a patient with subfoveal SRNVM and 20/400 visual acuity. Note the subfoveal serous fluid hemorrhage. B, Fundus photograph of the same patient following submacular surgery and surgical removal of the SRNVM. Note the resolution of the subretinal fluid and hemorrhage. Vision improved to 20/20 following removal of the neovascular complex.

be aggravated by laser photocoagulation, thereby promoting further neovascularization. Control of the underlying uveitis is recommended before laser treatment to prevent this complication. Oral or regional corticosteroids should be considered before laser surgery in patients with an inflammatory etiology for the subretinal neovascularization. If the neovascularization membrane is in a subfoveal location (less than 1 /-Lm from the foveal center) , laser photocoagulation may reduce vision'~by destruction of the foveal photoreceptors. Submacular surgery can be performed to excise these lesions surgically. A vitrectomy is performed and a needle knife is used to perform a retinotomy adjacent to the SRNVM. The membrane is mobilized and subretinal forceps are then used to grasp the membrane and remove it through the small retinotomy (Fig. 14-27). The vitreous cavity is filled with air. Laser photocoagulation is not typically required. Postoperative visual acuity can stabilize or improve in 83% of all eyes, but recurrent neovascularization may occur in 30% to 50% of patients. Retinal cryopexy has been advocated for the treatment of peripheral retinal neovascularization in patients with pars planitis. Laser photocoagulation of the peripheral retina can accomplish similar results by ablating the retina and causing involution of vitreous base neovascularization. Such treatment can reduce the frequency of vitreous hemorrhage and may reduce the severity of the intermediate uveitis and moderate CME. Although the mechanism of this form of therapy is unknown, cryopexy may destroy the helper T cells in the vitreous gel that are responsible for recruiting other inflammatory cells into the vitreous cavity. Alternatively, it may re-establish the blood-eye barrier or ablate ischemic tissues. A double freeze-thaw cycle is delivered to the area of inflammatory debris.

References 1. Breinin GM, DeVoe AG: Chelation of calcium with edathamil calcium-disodium in band keratopathy and corneal calcium affections. Arch Ophthalmol 1954;52:840-851. 2. Ridley H: Cataract surgery in chronic uveitis. Trans Ophthalmol Soc UK 1965;85:519-525.

3. Key SN III, Kimura SJ: Iridocyclitis associated with juvenile rheumatoid arthritis. AmJ Ophthalmol 1975;80:425-429. 4. Smiley WI\.: The eye in juvenile rheumatoid arthritis. Trans Ophthalmol Soc UK 1974;94:817-829. 5. Kanski lJ, Shun-Shin GA: Systemic uveitis syndromes in childhood: an analysis of 340 cases. Ophthalmology 1984;91:1247-1252. 6. Foster CS, Fong LP, Singh G: Cataract surgery and intraocular lens implantation in patients rvith uveitis. Ophthalmology 1989;96:281288. 7. Tabbara K, Chavis P: Cataract extraction in patients with chronic postoperative uveitis. Int Ophthalmol Clin 1995;35:121-131. 8. O'Neill D, Murray P, Patel B, Hamilton A: Extracapsular cataract surgery with and without intraocular lens implantation in Fuchs' heterochromic iridocyclitis. Ophthalmology 1995;102:1362-1368. 9. Foster RE, Lowder CY, Meisler DM, Zakov ZN: Extracapsular cataract extraction and posterior chamber intraocular lens implantation in uveitis patients. Ophthalmology 1992;99:1234-1241. 10. Foster CS, Stavrou P, Zafirakis P, et al: Intraocular lens explantation in patients with uveitis. AmJ Ophthalmol 1999;128:31-37. 11. Foster CS: Cataract surgery and intraocular lens implantation in patients with pars planitis. Recent Advances in Uveitis. Proceedings of the Third International Symposium on Uveitis. Brussels, Belgium, Kugler Publishers, 1993, pp 593-595. 12. Akova YA, Foster CS: Cataract surgery in patients with sarcoidosisassociated uveitis. Ophthalmology 1994;101:473-479. 13. Foster CS, Barrett F: Cataract development and cataract surgery in patients with juvenile rheumatoid arthritis associated iridocyclitis. Ophthalmology 1993;100:809-817. 14. Panek WC, Holland GN, Lee DA, Christensen RE: Glaucoma in patients with uveitis. Br J Ophthalmol 1990;74:223-227. 15. Foster CS, Havrilikova K, Tugal-Tutkun I, et al: Secondary glaucoma in patients with juvenile rheumatoid arthlitis. Acta Ophthalmol 2000;78:576. 16. Hoskins HD Jr, HetheringtonJ Jr, Shaffer RN: Surgical management of the inflammatory glaucomas. Perspect Ophthalmol 1977;1:173181. 17. Hill RA, Nguyen QH, Baerveldt G, et al: Trabeculectomy and Molteno implantation for glaucomas associated with uveitis. Ophthalmology 1993;100:903-908. 18. Stavrou P, Mission GP, Rowson NJ, Murray PI: Trabeculectomy in uveitis. Oc Immunol Inflamm 1995;3:209-215. 19. Towler HMA, Bates AK, Broadway DC, Lightman S: Primary trabeculectomy with 5-fluorouracil for glaucoma secondary to uveitis. Oc Immunol Inflamm 1995;3:163-170. 20. Patitsas C, Rockwood EJ, Meisler DM, Lowder CY: Glaucoma filtering surgery with postoperative 5-fluorouracil in patients with intraocular inflammatory disease. Ophthalmology 1992;99:594-599. 21. Jampel HD, Jabs DA, Quigley HA: Trabeculectomy with 5-fluorouracil for adult inflammatory glaucoma. Am J Ophthalmol 1990;109:168-173. 22. Gil-Carrasco F, Salinas-VanOrman E, Recillas-Gispert C, et al:

CHAPTER 14: THERAPEUTIC SURGERY: CORNEA,

23.

24. 25.

26. 27.

28. 29. 30.

31.

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Ahmed valve implant for uncontrolled uveitic glaucoma. Oc Immu32. Bishop KB, Orosz CG: Limiting dilution analysis for alloreactive nol Inflamm 1998;6:27-37. TCGF-secretory T cells: Two related LDA methods that can discrimiDaMata A, Burk SE, Netland PA, et al: Management of uveitic nate between unstimulated precursor T cells and in vivo alloactiglaucoma with Ahmed Glaucoma Valve implantation. Ophthalmolvated T cells. Transplantation 1989;47:671-677. ogy 1999;106:2168-2172. 33. Michels RG: Vitrectomy for macular pucker. Ophthalmology Fitzgerald CR: Pars plana vitrectomy for vitreous opacity secondary 1984;91:54-61. to presumed toxoplasmosis. Arch Ophthalmol 1980;98:321-323. 34. Streilein]W: Anterior chamber associated immune deviation: the Algvere P, Alanko H, Dickhoff K, et al: Pars plana vitrectomy in privilege of immunity in the eye. Surv Ophthalmol 1990;35:67-73. the management of intraocular inflammation. Acta Ophthalmol 35. Michelson JB, Nozik RA: Inflammatory retinal detachment. In: 1981;59:727-736. Michelson JB, Nozik RA, eds: Surgical Treatment. of Ocular InDiamond JG, Kaplan HJ: Uveitic effect of vitrectomy combined with flammatory Disease. Philadelphia, JB Lippincott, 1988. lensectomy. Ophthalmology 1979;86:1320-1329. . 36. Smith RE, Nozik RA: Retinal detachment in uveitis. In: Smith RE, Diamond JG, Kaplan HJ: Lensectomy and vitrectomy for compliNozik RA: Uveitis: A Clinical Approach to Diagnosis and Managecated cataract secondary to uveitis. Arch OphthalmoI1978;96:1798ment, 2nd ed. Baltimore, Williams & Wilkins, 1998. 1804. 37. Clarkson JG, Blumenkranz MS, Culbertson WW, et al: Retinal deBacskulin A, Eckardt C: Results of pars plana vitrectomy in chronic tachment following the acute retinal necrosis syndrome. Ophthaluveitis in children. Ophthalmologie 1993;90:434-439. mology 1984;91:1665-1668. Kaplan HJ: Surgical treatment of intermediate uveitis. In: Boke 38. Jabs DA, Enger C, Haller L, et al: Retinal detachments in patients WRF, Manthey KF, Nussenblatt RB, eds: Intermediate uveitis, Vol with cytomegalovirus retinitis. Arch Ophtl1almol 1991;109:794-799. 23. Basel, Karger Basel, 1992, pp 185-189. 39. Kreiger AE: Management of combined inflammatory and rhegmatoStuart JM, Cremer MA, Dixit SN, et al: Collagen-induced arthritis genous retinal detachments (AIDS and ARN). In: Ryan SJ, ed: in rats. Comparison of vitreous and cartilage derived collagens. Retina, 2nd ed, Vol III. St. Louis, Mosby, 1994, P 2489. Arhritis Rheum 1979;22:347-352. 40. Nussenblatt RB, Whitcup SM, Palestine AG: Surgical treatment in Opremcak EM, Scales DK, Cowans AB. Cell mediated autoimmune uveitis. In: Uveitis: Fundamentals and Clinical Practice, 2nd ed. St mechanisms in uveitis. Association for Research in Vision and OphLouis, Mosby, 1996, P 148. thalmology 1993;34/4:1104.

I c.

Michael Samson and C. Stephen Foster

NITION Syphilis is an infection by the spirochete bacterium Treponema pallidum. It is a sexually transmitted disease, entering the body through the genitals, mouth, or tiny breaks in the skin. If the condition is left untreated, it will progress through four stages, with the potential to cause morbidity to any of the major body organs. It can persist in the infected individual for an entire lifetime and reveal itself in various manifestations, its symptoms capable of mimicking a great variety of diseases. Because of this, it has been called the Great Imitator, and despite increased public awareness, sensitive laboratory tests, and effective treatment, it remains in the differential of many diseases to this day.

HISTORY The disease acquired its name 'from the work of the Italian poet Hiero Fracastor. The title of his poem, Syphilis, sive Morbo Gallico, referred not only to the disease but also to the main character, Syphilis, a shepherd who carried the affliction. Although the poem was written in 1530, the disease did not become widely known as syphilis until many years thereafter. Previous to this, it was known as the "French Pox," a name given to it (by Italians) owing to its spread through Europe accompanying the armies of King Charles VII of France, whose ranks included infected Spanish mercenaries recently returned from ventures to the New World. It struck many soldiers in King Charles' camps during his siege of Naples and allowed the French the opportunity to coin a name they found less offensive: "the Neapolitan POX."l In 1905, Schaudin and Hoffman isolated the spirochete T. pallidum from skin lesions of infected patients. 2 Soon afterward, studies revealed that patients infected with syphilis created antibodies against extracts of normal mammalian tissues, like cardiolipin. 3 This allowed for the development of a blood test that could detect infected individuals, and Wasserman introduced a test to detect these antibodies in 1910. 4 This test became an essential tool in diagnosing the disease. Despite the ability to detect infected individuals, successful treatment of syphilis did not come until 1943, with the discovery of penicillin, which has been the mainstay of treatment to this day.5

EPIDEMIOLOGY The most common presentation of syphilis in the eye is uveitis. Before the 1940s, syphilis was considered one of the leading causes of all cases of uveitis, second only to tuberculosis. In current times, it is considered a rare

cause of uveitis. This apparent decrease in uveitis cases attributed to the spirochetal infection is most likely a result of two factors. First, the discovery of penicillin gave physicians an effective treatment. Especially when treated during the initial stages, antibiotic treatment allows for a reliable cure with little risk to the patient; previously, the mainstay treatment consisted of arsenic derivatives, which caused significant morbidity to individuals owing to its toxicity, and its effectiveness in treating syphilis wasquestionable. Since the introduction of penicillin, cases. of syphilis dropped worldwide, especially in industrialized countries. The second reason syphilis was seen less often as a cause of uveitis was the discovery of tests for other entities that could also cause uveitis. Blood tests for toxoplasmosis and histoplasmosis became available, with a concomitant increase in uveitis diagnosed secondary to these entities.. Sarcoidosis was also found to be associated with ocular inflammation. In conjunction with reliable tests for syphi-· lis, it was found that many cases of uveitis were in fact caused by these newer entities, whereas decades earlier, they would have been attributed to "the Great Imitator." Syphilis is believed to currently comprise less than 1 % to 2% of all uveitis cases. 6 It is the authors' belief that there is little importance in establishing the incidence of syphilis among the causes of uveitis for several reasons. First, there are very specific and sensitive serologic tests that are universally available that can easily establish the diagnosis. Second, it is one of the few uveitic entities for which a treatment exists that can exact a long-term cure. Third, one of every three untreated patients with latent stage syphilis will progress to tertiary stage syphilis, resulting in significant risk of neurologic or cardiologic morbidity. Finally, one can never rule out syphilis as a cause of uveitis based solely on clinical presentation. Most reported case series state that the majority of patients in whom syphilitic uveitis is diagnosed were patients in whom the ocular disease was the only manifestation of syphilis infection. Schlaegel wrote in the 1970s that he had "never seen a case of uveitis in secondary syphilis-most cases were picked up on routine FTA testing."6 We believe that it is unethical not to rule out syphilis in almost all cases of uveitis, or .in any case of unexplained ocular inflammation.

CLINICAL

Syphilis Because syphilis had been described for 500 years before a successful treatment was available, much is known about

CHAPTER 15: SYPHILIS TABLE 15-1. THE STAGES OF UNTREATED STAGE

MANifESTATIONS

Primary Secondary Latent Tertiary

Chancre Rash, lymphadenopathy No evident systemic disease Cardiovascular syphilis, neuros)1Jhilis, benign tertiary

DOES UVEITIS PRESENT?

No Yes Yes, lllOSt con11llon Yes

its natural history. Surprisingly, detailed descriptions of its signs and clinical course are not different from our experiences to this day, with the exception that late manifestations of syphilis are becoming rarer. The progression of untreated syphilis has been categorized into four stages (Table 15-1). The first stage, primary syphilis, is characterized by the chancre, which initiates at the inoculation site. Chancres usually appear about 3 weeks after infection, although this period can range from 2 to 6 weeks. They usually develop in the genitalia but have been reported to initially occur in the mouth or skin. They have also been reported to present on the conjunctiva or the lids. These lesions are painless papules, which eventually ulcerate. They are filled with numerous spirochetes and usually resolve without treatment roughly 4 weeks after their appearance. If the condition is left untreated, patients progress to secondary syphilis 4 to 10 weeks after the initial manifestation of the disease. Secondary syphilis denotes the stage during which spirochetes are disseminated in the blood. The symptoms are characterized by generalized rash and lymphadenopathy. The rash is maculopapular, and may appear quite prominent on the palms and soles. Other symptoms may include fever, malaise, headache, nausea, anorexia, hair loss, mouth ulcers, and joint pains. Many different organs can be involved during secondary syphilis, including the liver, kidneys, and the gastrointestinal tract. The eyes are affected in approximately 10% of cases. 7 Eye involvement, including uveitis, usually presents much later than the other systemic manifestations, up to 6 months after initial infection. Like the primary stage, these symptoms are transient, and usually resolve spontaneously over several weeks. The following stage is called the latent stage, a time in which clinical disease is not detectable, nor is the infection contagious. This stage can last for the individuals' entire lifetime. The latent stage is divided into early latent (up to 1 year after initial infection) and late latent (after 1 year) periods. One third of patients progress to tertiary syphilis. Tertiary syphilis represents an obliterative endarteritis that can affect most body systems. It is divided into three major groups: benign tertiary syphilis, cardiovascular syphilis, and neurosyphilis. The characteristic lesion of benign tertiary syphilis is the gumma. Histologically, the gumma is a granuloma. This lesion is usually found in the skin and mucous membranes but can occur anywhere in the body, and it has been found in the choroid and iris. Cardiovascular syphilis includes aortitis, aortic aneurysms, aortic valve insufficiency, and narrowing of the coronary

ostia. Neurosyphilis includes meningovascular syphilis, parenchymatous neurosyphilis, and tabes dorsalis. Unlike benign tertiary syphilis, cardiovascular and neurosyphilis carry severe risks of morbidity and mortality.

Syphilitic Anterior Uveitis Syphilitic uveitis can occur as soon as 6 weeks after infection. Presentation during secondary syphilis is usually delayed and can appear approximately 6 months after other secondary signs (e.g., generalized rash) have resolved. Syphilitic uveitis may also first. manifest in late latent syphilis, many years after initial infection. This is probably characteristic of most patients who dev~lop syphilitic uveitis, since in the majority of reported cases, affected patients present without systemic signs of syphilis at or near the time of initial presentations. This delay may allow clinicians to overlook syphilis as a potential cause of uveitis if the patient is not specifically questi011.ed. Alternatively, patients may not recall having been infected or may not recall if or what kind of treatment they received in the past. Syphilitic uveitis may affect the anterior segment, posterior segment, or both. Anterior uveitis may present with an associated vitritis, or remain confined to the anterior segment only (Table 15-2). Recent case series suggest that anterior uveitis with vitritis is more common than isolated anterior inflammation. I It may present unilaterally or bilaterally, with bilateral disease reported in 44% to 71 % of cases. I, 2, 8 Additionally, syphilitic uveitis is one of the few types of uveitis that commonly presents as granulomatous inflammation 9 and can present with iris nodules similar in appearance to those seen in other granulomatous diseases. Barile and Flynn 2 reported that 67% of cases in their series of syphilitic anterior uveitis were granulomatous in nature. Another finding in syphilitic uveitis involving the anterior chamber is roseolae of the iris. 6 These roseolae result from engorgement of the superficial vessels of the iris, usually in the middle third of the iris. They usually occur in secondary stage, around 6 weeks after initial infection. According to Duke-Elder lo , they are very rare but may present without other signs of ocular inflammation and may represent the first eye finding in syphilis infection. Schwartz and O'Connor reported a patient with syphilitic uveitis who presented with roseolae, who later had areas evolving into iris papules.u Iris angiogram revealed leakage of the dilated vessels, and those in the region of the papules. Leakage persisted even after the papules and roseolae resolved. Interstitial keratitis, posterior synechiae, lens disloca-

TABLE 15-2. CLINICAL CHARACTERISTICS OR SIGNS OF SYPHILITIC ANTERIOR UVEITIS Unilateral or bilateral Granulomatous or nongranulomatous Iris nodules Anterior with or without anterior vitritis Interstitial keratitis Dilated iris vessels (roseolae of the iris) Lens dislocation Iris atrophy

m

CHAPTER 15: SYPHILIS

tion, and iris atrophy are other signs that can be seen in the anterior segment in association with syphilitic uveitis.

Syphilitic Posterior Uveitis Syphilis can affect the posterior segment (Table 15-3). In the series of patients with ocular syphilis reported from our center, 65% had involvement of the posterior segment. Barile and Flynn 2 found posterior involvement in only 36% of their patients. The posterior involvement can take on many different forms. The most common posterior segment involvement is chorioretinitis. The fundus initially displays several active lesions, which are typically grayish yellow in color. These lesions can number from a few to numerous, and they can be seen anywhere in the fundus, although there isa preference for the posterior pole or near the equator. The lesions are small, perhaps from one half to a full disk diameter in size but can coalesce to become confluent. Serous retinal detachment (SRD) , disk edema, and vasculitis are occasional associated signs. The amount of vitreal cells varies, although most case series report a significant degree of vitreal involvement. Syphilis can present as a focal chorioretinitis. 12 There are several case reports describing acute central chorioretinitis as an initial manifestation of syphilis. Initially, the patient complains of blurred vision or a central scotoma. There is neurosensory detachment of the retina, which is associated with small retinal hemorrhages and exudate. Deep chorioretinal lesions are localized under the area of detachment. An uncommol1t'i'presentation is that of a macular pseudohypopyon: Ouano and colleagues 13 described a case that presented as a vitritis with SRD of the macula. In their patient, there was turbid yellow fluid in the inferior one third of the SRD, appearing with a meniscus level, and hence the name "pseudohypopyon."13 Retinitis without choroidal involvement is yet another potential clinical presentation of syphilis in the posterior segment. H , 15 Syphilitic neuroretinitis presents with focal areas of retinal edema, usually in the posterior pole, and an associated papillitis with retinal edema around the optic disk. Vasculitis is commonly associated, and vitritis is often present, while anterior inflammation is mild or absent. Fluorescein angiography shows intraretinal lesions in the areas of retinitis, disk leakage, and vessel wall staining. Another variation of posterior segment involvement is a process localized at the level of the retinal pigment epithelium (RPE).16 In 1990, Gass coined the term "syphilitic posterior placoid chorioretinitis," and he described six patients with secondary syphilis who showed one or more macular or juxtapapillary placoid lesions at the level of the RPE. According to the authors, the biomicroTABLE 15-3. THE MANifESTATIONS Of SYPHILITIC POSTERIOR UVEITIS DiffUSE CHORIORETINITIS

NECROTIZING RETINITIS

Focal chorioretinitis Retinitis/neuroretinitis "Posterior placoid chorioretinitis"

Retinal vasculitis Intermediate uveitis Panuveitis

scopic and fluorescein angiographic findings .of those localized placoid lesions of syphilitic chorioretinitis may represent one of the most specific findings in secondary syphilis described to date. Syphilis can present as a necrotizing retinitis. 17 Clinically, this form presents with patches of retinitis in the midperiphery and peripheral retina, which can become confluent. These lesions may be accompanied by vasculitis and vascular occlusions. Clinically, it can be indistinguishablefrom acute retinal necrosis (ARN), herpes simplex retinitis, or cytomegalovirus retinitis. However, it differs by its dramatic response to intravenous penicillin and can have a good visual outcome without the complications associated with the aforementioned entitiesY Isolated retinal vasculitis has also been associated with syphilis infection. 18-2o One such entity, retinal arteriolitis, presents with yellow exudates adjacent to the artery. These exudates may present diffusely or focally, resembling emboli or plaques as seen in central or branch retinal artery occlusion. However, fluorescein angiography demonstrates no filling defects, and the lesions are stable over time, suggesting they are focal areas of perivascular exudate. 7 Other forms of vasculitis can affect the larger arterial branches, the venous branches l3 , or both. The clinical appearance depends on the severity of the disease process, ranging from increased vessel girth and tortuosity to extensive perivascular exudate and fibrosis with obliteration of the small peripheral vessels. Focal venous vasculitis can masquerade as branch vein occlusion. I7,20 Syphilis is in the differential diagnosis of intermediate uveitis. I As mentioned earlier, intraocular inflalnmation of the anterior segment in syphilitic disease is often associated with a vitreal reaction. If the vitreal involvement is more prominent than anterior segment inflammation, it will resemble the picture of intermediate uveitis as seen in other entities (e.g., Lyme disease or sarcoidosis). Associated signs that are typically seen in intermediate uveitis due to other entities, like macular edema, peripheral vasculitis, and disk edema, may also be present. A true pars plana exudate usually is not present. Finally, patients can present with a true panuveitis. 9 In Barile and Flynn's series,2 27% of their patients presented with panuveitis, and Tamesis and Foster1 found that almost half of their patients presented with ocular inflammation in both anterior and posterior seglnents. Papillitis,9 vitritis,l, 8,15 serous retinal detachment,8,21 disciform macular detachment,22 subretinal fibrosis,22 and uveal effusion 21 are other described signs of syphilitic posterior segment involvement.

AND PATHOGENESIS Damage and destruction of ocular tissue is secondary to the host inflammatory response directed against invading spirochetes. Reports in the literature of the isolation of spirochetes from eye pathologic specimens are unconlmon. 23-25 However, examination of aqueous humor samples in patients with syphilitic uveitis have revealed treponemes in the eye. 9 In the 1960s, several authors reported on finding treponeme-like forms from aqueous samples obtained by diagnostic paracentesis (a common practice in the United States at that time, and aCOlnmonly prac-

CHAPTER i 5: SYPHILIS

ticed procedure in Europe and other areas of the world today) or during cataract surgery. In some of the studies, the spiral forms could be successfully labeled with anti- T. pallidum globulin. Although there was concern of falsepositive findings from mouth treponemes, which are part of the normal human flora, passive transfer studies of these spiral forms into laboratory animals resulted in seroconversion to a Venereal Disease Research Laboratory (VDRL)- and fluorescent treponemal antibody (FTA)-reactive state, suggestive more of T. pallidum rather than nonpathogenic commensal organisms. 25 , 26 The role of the host immune response in syphilitic infection is still being investigated. One important fact is that long-term immunity against syphilis is not conferred after initial infection: A treated individual may be reinfected on subsequent exposures. The other interesting point is the chronicity of syphilis infection, which can last for a host's entire lifespan. One mechanism proposed to playa role in chronic infections is a switch from a Th1mediated process to that of a Th2-mediated type. Most acute infections are resolved by the Th1 pathway, which eventually leads to cure and long-term immunity. Evidence shows that in leishmaniasis, another cause of chronic infection, organism components preferentially activate Th2lymphocytes, leading to minimization ofTh1 effects and predisposing one to chronic infection. It has also been shown that administration of factors that induce switching from Th2 to Th1 (e.g., interferon gamma) can reverse this effect. Some evidence suggests that syphilis may also work in this manner, hcrt additional studies are necessary to explore this theory further. There is evidence to support the idea that syphilis may induce autoimmune disease in infected individuals. In the course of mapping the genome of T. pallidU1n, researchers identified a coding region that resembles one found in sequences coding for mammalian fibronectins. Animals immunized with such molecules were found to have modified responses when challenged with viable T. pallidum, and also developed classic Arthus reaction when injected intradermally, suggesting that antifibronectin antibodies may playa role in immune complex formation. Indeed, immune complexes have been shown to play an important part in the pathogenesis of certain syphilitic entities in vivo. 27 Solling and colleagues 28 showed that C1q-binding immune complexes are elevated in patients with secondary syphilis but not in those with primary syphilis; not enough data were available to examine latent or tertiary stages. Gamble and colleagues 29 were able to isolate antitreponemal antibodies within the glomerular deposits in a patient with nephrotic syndrome secondary to syphilis. Tourville and associates 30 showed that such glomerular deposits also contain treponemal antigens. It is possible that such antigen-antibody complexes may play a role in ocular inflammation. The complete genome of T. pallidum has been determined, consisting of 1.1 million base pairs containing 1041 open reading frames. 4 The difficulty in culturing T. pallidum in vivo has frustrated scientists' ability to study the pathogenic mechanisms of the microbe. Kn.owledge of the genomic structure will allow investigators to study the organism's protein products, permitting greater understanding of their role as biologic and pathogenic factors. The potential future benefits include a greater un-

derstanding of the virulence factors of the organism, as well as the development of a method of culture, more specific and sensitive diagnostic tests, and a vaccine.

TESTS There is no standard method of culturing T. pallidum, at this time. Diagnosis of syphilis as the causative agent in a patient with uveitis usually relies on serologic tests in association with the clinical picture. There are two groups of serologic tests commonly used: nonspecific tests and specific tests (Table 15-4). Nonspecific tests quantify the amount of serum antibody directed against particular host antigens. These antigens are typically incorporated by the infecting spirochete; the host is then stimulated to produce nonspecific antibodies against these antigens. The main antigen of this type is cardiolipin, which is a phospholipid produced by the liver. The most commonly used nonspecific tests are the rapid plasma reagin (RPR) test, and the VDRL test. These tests quantify the amount of anticardiolipin antibody present in serum. Results are reported as reactive, weakly reactive, borderline, and nonreactive. The sensitivity and specificity depend on the stage of syphilis and status of treatment. Titers generally are high during active infection, like secondary syphilis, but drop when spirochetes are not active, such asin latent syphilis or after completion of successful treatment. Serum titers do not correlate with the disease severity.31, 32 Specific tests quantify the amount of serum antibody directed against treponemal antigens. The most commonly used test today is the fluorescent treponemal antigen absorption (FTA-ABS) test. FTA-ABS tests become positive during secondary stage and remain positive for the patient's lifetime, regardless of treatment status. FTAABS testing is much more sensitive than nonspecific serologic tests during latent stage, the stage in which most uveitic patients will present. Another diagnostic tool is the direct demonstration of spirochetes. Treponemes can be visualized by incubating body fluid containing the infective organisms with fluorescent-tagged antibody and visualizing it under darkfield microscopy.25 One limitation to the test is that it requires obtaining infected body fluid, which is usually only possible in patients with primary syphilis (i.e., from the initial chancre) or secondary syphilis, when an open pustule on the skin is present. Another limitation is that antibodies may cross-react with other species of treponemes, including nonpathogenic cOlnmensal treponelnes harbored in the oral cavity, for example. However, several series have described the use of testing aqueous humor for spirochetes with this technique in patients with clinical evi-

TABLE 15-4. DIAGNOSTIC TESTS FOR SYPHILIS Nonspecific tests: rapid plasma reagin (RPR) , Venereal Disease Re'search Laboratory (VDRL) Specific tests: Fluorescent treponemal antibody absorption test (FTAABS), Microhemagglutination assay for T pallidurn (MHA-TP) T pallidurn immobilization test (TPI) T pallidU1n particle agglutination (TP-PA) Darkfield microscopy Polymerase chain reaction (peR)

m

CHAPTER 15: SYPHILIS

dence or SUSpICIOn of syphilis. Treponemes were recovered from aqueous in many cases, and treatment was associated with disappearance of these organisms. Unfortunately, these studies are small, uncontrolled case series, and no definitive conclusions can safely be made. Polymerase chain reaction (PCR) testing for syphilis is now possible. Several different PCR assays are available, and with the complete mapping of the T. pallidum genome, more will become available. Currently targeted regions include a 366 bp region of the 16S rRNA, and the 5' and 3' flanking regions of the 15-kDa lipoprotein gene (tpp15), which can aid in the differentiation of different subspecies of T. pallidum. In vivo studies of PCR testing for syphilis show that positive specimens may persist even after treatment, owing to the slow elimination of the organisms from the body by macrophages. The DNA of dead organisms injected into rabbits may persist for up to 30 days. However, the clinical usefulness of PCR testing in syphilitic uveitis is still yet to be determined. Theoretically, it would be useful in circumstances when FTA-ABS testing was not reliable. Such circumstances are difficult to imagine but conceivably, would include those patients who concomitantly had a disease associated with false-positive FTA-ABS results (e.g., systemic lupus erythelnatosus), or in the 2% of patients whose FTA-ABS returns as falsely negative during latent or late syphilis. Realistically, PCR will aid most in research studies, because it will help determine whether spirochetes (or their antigens) are present in late lesions in which~'flive treponemes are difficult to harvest (e.g., late skin manifestations), and may help in our understanding of immunity to syphilis.

Perils in Serology Interpretation An understanding of the limitations of serologic testing in syphilis is essential to the investigating physician. Misinterpretation of the tests may lead to unwarranted anxiety by the patient and the patient's sexual partners, and the possibility of overlooking another serious disease process. False-positive results in RPR and VDRL testing have been described in a variety of medical conditions. Transient false-positive results, persisting for no longer than 6 months, have been associated with atypical pneumonia, malaria, and vaccinations. Persistent false-positive RPR and VDRL results are seen in systemic lupus erythematosus, leprosy, and advanced age. Falsely positive VDRL tests have been reported in narcotic addicts. False-positive results have also been described in FTAABS testing. These disorders include systemic lupus erythematosus, rheumatoid arthritis, and biliary cirrhosis. Advanced age has also been associated with false-positive FTA-ABS results. These false-positive results tend to persist for the patients' lifetime, most likely representing antibodies that coincidentally cross-react with antibody against treponemal antigens. Intravenous fluorescein testing does not have any effect on FTA-ABS testing. 33 The microhemagglutination assay for T. pallidum (MHA-TP) was commonly used as a second, confirmatory test in an effort to reduce the likelihood of basing therapy on a falsely positive FTA-ABS; it is no longer commercially available. The T. pallidum particle agglutination test (TPPA) shows 97% agreement with the MHA-TP, and it is

this test and Western blotting (the gold standard) that are now most appropriate for confirming a positive FTA-ABS.

Sensitivity of

Testing

VDRL and FTA-ABS testing are comparable in primary and secondary disease, the sensitivity increasing from 70% and 85% to 99% and 100%, as the anticardiolipin antibodies increase. However, Inost patients diagnosed with ocular syphilis described in the literature fall under the category of latent syphilis. In this population, VDRL testing is falsely negative in 30% of these patients, whereas FTA-ABS testing is falsely negative in only 1% to 2% of these patients. But the false-positive rate can be as high as 10% in patients with AIDS. Examination of the cerebrospinal fluid (CSF) for syphilis is warranted in every case of syphilis found in patients with uveitis. It is necessary in staging, because neurosyphilis has its own associated morbidity and mortality separate from ocular disease. Also, one cannot clinically assess which uveitic patients will also have neurosyphilis. 34 Disk edema is not a reliable indicator of a positive yield from CSF studies; nor is the absence of disk edema an assurance of a normal spinal tap.34 It should be noted, however, that most case reports of syphilitic uveitis patients have found a low prevalence of positive results from CSF analysis among patients tested. 2, 8

Penicillin has been the mainstay of treatment for syphilis since its introduction in the 1940s. There are two regimens used in syphilitic uveitis as reported in the literature. Some authors use the Centers for Disease Control and Prevention (CDC) recommendation for latent syphilis, which consists of intramuscular injections of penicillin once weekly for 3 weeks. Other authors consider ocular syphilis a form of neurosyphilis and use the treatment recommendations for this: intravenous penicillin daily for 10 to 14 days. There is substantial evidence favoring the use of the neurosyphilis regimen for the treatment of syphilitic uveitis, the least of which are the multiple reports in the literature describing treatment failures with intramuscular penicillin. To underscore this belief, in Barile and Flynn's study;2 34% of their patients had already undergone treatment for syphilis before the onset of uveitis, although they do state that the previous treatment was poorly documented, poorly recalled, and appeared incomplete in many cases. T. pallidwn divides only once every 30 hours. 6 Because of this factor, sustained levels of penicillin in the aqueous must be maintained in order to exert its bactericidal effect. It has been shown that a single intramuscular injection of 2.5 million units of penicillin yields adequately bactericidal levels in the aqueous. However, the levels drop below the minimum inhibitory concentration (MIC) to kill T. pallidum in less than 2 hours. It has been shown that the addition of probenecid sustains the penicillin levels in the aqueous, presumably by competing with the transport of penicillin across the ciliary body. Still, this is yet more theoretic support that a regimen of weekly intramuscular injections is inadequate in the treatment of intraocular syphilis, and that intravenous

CHAPTER 15: SYPHILIS

therapy should be considered the standard of care for these patients. The CDC recommendations for the neurosyphilis regimen in the average adult is infusion of intravenous penicillin G 18 to 24 million units per day for 10 to 14 days.35 Patients can then be supplemented with intramuscular benzathine penicillin G at a dose of 2.4 million units weekly for 3 weeks (Table 15-5). There are reports of "relapse" of syphilis in patients who had previously received treatment. Several case reports indicate that many of these relapses probably represent inadequate treatment due to poor patient compliance. 2 Another possibility is the inadequacy of intramuscular penicillin therapy in the treatment of all intraocular syphilis infectionsY Finally,' another explanation is the. possibility of L-forms of the spirochete: Without cell walls, L-fonns would be resistant to the action of penicillin. This last mechanism is only speculative and requires further study. Reinfection is also possible. Penicillin allergy requires alternative medication (see Table 15-5). Traditionally, tetracycline or doxycycline have been the alternative treatments. Doxycycline is given at 200 mg orally once daily, whereas tetracycline is given at 500 mg orally four times daily. The treatment regimen for these medications is administered for 30 days. Macrolides (e.g., clarithromycin) are other alternatives, and some initial reports using ceftriaxone are encouraging, although the treating clinician is reminded of the crossreactivity of cephalosporins and penicillins. 31 , 36 Chloramphenicol has also been reported to lf~ve been used with success. 37 Another approach is penicillin desensitization. Increasing dosages of penicillin are given, orally or intravenously, with careful. monitoring. Chisholm and colleagues reported on 16 successful desensitization procedures performed on pregnant women infected with syphilis.38

SYPHILIS IN PATIENTS WITH IMMUNODEFICIENCY VIRUS INFECTION The incidence of syphilitic uveitis in patients with human immunodeficiency virus (HIV) infection is probably not greater than that in non-HIV-positive population. Some reports find syphilis as an etiology of only 1% of cases of uveitis in patients with HIV, similar to series of non-HIVinfected patients with syphilitic uveitisY This finding is also supported by the fact that ocular syphilis in patients with HIV-l does not seem to be correlated with decreased absolute T4 cell counts. 31 ,32 The natural course of syphilis is altered by HIV infection: It tends to run a Inore severe course and requires longer treatment for adequate cure.34, 39, 40 Manifestations of ocular syphilis in HIV-positive individuals are similar to those in immunocompetent individ-

TABLE 15-5. TREATMENT FOR SYPHILITIC UVEITIS Intravenous penicillin G 18 to 24 million units daily for 10 to 14 days For penicillin-allergic patients:

Tetracycline hydrochloride 500 mg PO QID for 30 days or Doxycycline 100 mg PO BID for 14 days Consider penicillin desensitization in certain individuals

uals, and include iridocyclitis,31 intermediate uveitis,31 panuveitis,40 papillitis,31, 32, 41, 42 optic perineuritis, branch retinal vein occlusion, neuroretinitis, chorioretinitis,37,43 dense vitritis,44 retinitis,31, 32, 41 and serous and rhegmatogenous retinal detachmentY' 32, 37, 42, 45 As in non-HIV patients, iritis is the most common manifestation of ocular syphilis in HIV-positive individuals, accounting for up to 70% of cases. 42 Ocular syphilis may be the presenting sign of HIV infection and neurosyphilis. 32 Coexisting syphilitic uveitis and HIV infection has been reported to masquerade as Crohn's disease. 43 HIV-infected patients have been shown to have relapses of syphilis infection despite the administration of highdose intravenous penicillin therapy.32, 46 It is possible that prolonged treatment is necessary in this group of patients. Deschnese and colleagues recomlnend treating HIV-infected patients with ocular syphilis for a full 14day neurosyphilis course with the supplemental weekly penicillin intramuscular injectionsY Monitoring of successful treatment by serologic testing is not accurate in HIV-infected patients, because they are slower to seroconvert from a positive to a negative RPR status despite treatment. However, a randomized trial showed that these patients were not at higher risk for treatment failure and probably represent another facet of their altered immune response. Additionally, one study showed that at I-year follow-up of HIV-infected individuals after treatment for syphilis, 9% of patients showed reversion to a negative FTA-ABS status. Immunoblotting studies of serum of HIV-infected individuals who are FTA negative reveal positive antibodies reactive against T. pallidum antigens: RPR reactivity in these individuals were overlooked in light of their negative FTA status and history of intravenous (IV) drug abuse. This further supports that HIV infection may alter the response to serologic testing for syphilis to make such testing unreliable in certain individuals.

COMPLICATIONS Complications from syphilitic uveitis are no different from those from other types of uveitis. Cataracts and glaucoma can occur as a result of inflammation or topical steroids. Macular edema and epiretinal membranes are major causes of significant visual loss. Retinal detachInents are usually exudative in nature and resolve with appropriate medical therapy without the need for surgical intervention. However, rhegmatogenous retinal detachments have also been observed and are related to the development of proliferative vitreoretinopathy, leading to retinal traction and the development of a tear. Choroidal neovascular membrane is a rare complication of syphilitic uveitis. Chorioretinitis leads to changes in retinal pigment epithelium and breaks in Bruch's membrane. These breaks may predispose the patient to the development of neovascular membranes. Because cases are so rare, it is unclear whether laser photocoagulation has a poor or favorable effect in the treatment of these membranes. However, medical treatment aimed at eliminating syphilis and controlling intraocular inflammation is warranted, because such treatment has been known to cause remission of neovascular Inembranes in other uveitis entities. Complications can occur secondary to treatment. Un-

CHAPTER 15:

recognized penicillin allergy requires switching to an alternative antibiotic such as doxycycline. Even in the absence of a drug allergy, patients should be monitored for the Jarisch-Herxheimer reaction. This occurs as the result of a hypersensitivity reaction of the host to treponemal antigens, which are released in large numbers as spirochetes are killed during the initial infusions. 48 Patients present with fever, myalgia, headache, and malaise. There may be a concomitant increase in the severity of the ocular manifestationsY' 17 Although nonsteroidal anti-inflammatory drugs may alleviate the systelnic symptoms, increased local steroids and the use of systemic corticosteroids may become necessary to control severe inflamlnation. However, supportive care and observation are usually all that is necessary in the majority of cases.

PROGNOSIS If the condition is recognized early and treated appropriately, the majority of cases of syphilis infection can result in a cure. 1, 2, 8 In untreated cases, approximately one third of patients progress to tertiary syphilis, with potentially ;serious morbidity and mortality if cardiovascular syphilis or neurosyphilis develop. Unfortunately, several reports confirm that ophthalmologists are often guilty of overlooking syphilis as a potential cause of ocular inflammation. I ,2

CONCLUSIONS Syphilis is one of the few treatable causes of uveitis. Its ability to present in a wide variety of uveitic forms is reflective of its status as "the Great Imitator" in its systemic manifestations. Because' of this, it is not suggested by any particular clinical presentation, and requires the appropriate blood testing in all patients with uveitis, or any ocular inflammation of unknown etiology. The ophthalmologist who appropriately screens and treats this disease may not only save patients' vision but may also prevent morbidity and death.

References 1. Tamesis R, Foster CS: Ocular syphilis. Ophthalmology 1990; 97:1281-1287. 2. Barile GR, Flynn H: Syphilis exposure in patients with uveitis. Ophthalmology 1997;104:1605-1609. 3. Margo C, Hamed, L: Ocular syphilis. Surv Ophthalmol 1992;37:203-220. 4. Fraser C, Norris SJ, Weinstock GM, et al: Complete genome sequence of Treponema pallidum, the syphilis spirochete. Science 1998;281:375-388. 5. Greene R: History of Medicine. New York, Institute for Research in History/Haworth Press, 1988. 6. Schlaegel TF, O'Connor GR: Metastatic nonsuppurative uveitis. Int Ophthalmol Clin 1977;17:87-108. 7. Crouch ER, Goldberg MF: Retinal periarteritis secondary to syphilis. Arch Ophthalmol 1975;93:384-387. 8. Deschenes J, Seamone CD, Baines MG: Acquired ocular syphilis: Diagnosis and treatment. Ann Ophthalmol 1992;24:134-138. 9. Belin MW, Baltch AL, Hay PB: Secondary syphilitic uveitis. Am J Ophthalmol 1981;92:210-214. 10. Duke-Elder S. Perkins ES: Diseases of the ureal tract. In: Duke-Elder S, ed: System of Ophthalmology, vol 9. London, Kingston, 1966. 11. Schwartz LK, O'Connor GR: Secondary syphilis with iris papules. Am J Ophthalmol 1980;90:380-384. 12. de Souza EC,Jalkh AE, Trempe CL, et al: Unusual central chorioretinitis as the first manifestation of early secondary syphilis. Am J Ophthalmol 1988;105:271-276. 13. Ouano DP, Brucker AJ, Saran BR: Macular pseudohypopyon from secondary syphilis. AmJ Ophthalmol 1995;119:372-374.

14. Savir H, Kurz 0: Fluorescein angiography in syphilitic retinal vasculitis. Ann Ophthalmology 1976;8:713-716. 15. Stoumbos YD, Klein ML: Syphilitic retinitis. in a patient with acquired immunodeficiency syndrome-related ·complex. Am J Ophthalmol 1987;103:103-104. 16. GassJDM, Braunstein RA, Chenoweth RG: Acute syphilitic posterior placoid Chorioretinitis. Ophthalmology 1990;97:1288-1297. 17. Mendelsohn AD,Jampol LM: Syphilitic retinitis. Retina 1984;4:221224. 18. Regan CDJ, Foster CS: Retinal vascular diseases: Clinical presentation and diagnosis. Int Ophthalmol Clin 1986;26:25-53. 19. Halperin LS, Berger AS, Grand MG: Syphilitic disc edema and periphlebitis. Retina 1990;10:223-225. 20. Lobes LA, FolkJC: Syphilitic phlebitis simulating branch vein occlusion. Ann Ophthalmol 1981;13:825-827. 21. DeLuise VP et al. Syphilitic retinal detachment and uveal effusion. AmJ Ophthalmol 94:757-761, 1982. 22. Saari M: Disciform detachment of the macula. Acta Ophthalmol 1978;56:510-517. 23. Montenegro ENR, Israel CW, Nicol WG, Smith JL: Histopathologic demonstration of spirochetes in the human eye. Am J Ophthalmol 1969;67:335-345. 24. Blodi FC, Hervouet F: Syphilitic Chorioretinitis. Arch Ophthalmol 1968;79:294-296. 25. SmithJL, Israel CW: Treponemes in aqueous humor in late seronegative syphilis. Transactions of the American Academy of Ophthalmology and Otolaryngology 1968;72:63-74. 26. Golden B, Thompson HS: Implications of spiral form in the eye. Surv Ophthalmol 1969;14:179-183. 27. Wozniczko-Orlowska G, Milgrom F: Immune complexes in syphilis sera. J Immunol 1981;127:1048-1051. 28. SoIling J, From E, Mogensen CE: The role of immune complexes in early syphilis and in the Jarisch-Herxheimer reaction. Acta Derm 1982;62:325-329. 29. Gamble CN, ReardanJB: Immunopathogenesis of syphilitic glomerulonephritis. Elution of antitreponem antibody from glomerular immune-complex deposits. N EnglJ Med 1975;202:449-454. 30. Tourville DR, Byrd LH, Kim DU, et al: Treponemal antigen in immunopathogenesis of syphilitic glomerulonephritis. Am J Pathol 1976;82:479. 31. Shalaby IA, Dunn JP, Semba RD, Jabs DA: Syphilitic uveitis in human immunodeficiency virus-infected patients. Arch Ophthalmol 1997;115:469-473. 32. McLeish WM, Pulido JS, Holland S, et al: The ocular manifestations of syphilis in the human immunodeficiency virus type I-infected host. Ophthalmology 1990;97:196-203. 33. Jost BF, Olk RJ, Spirner MH, et al: Effect of intravenous fluorescein on fluorescent treponemal antibody testing. Am J Ophthalmol 1986;102:278-279. 34. Katz DA, Berger JR, Duncan RC: Neurosyphilis. Arch Neurol 1993;50:243-249. 35. Beary CD, Hooton TM, Collier AC, Lukehart SA: Neurologic relapse after benzathine penicillin therapy for secondary syphilis in a patient with HIV infection. N EnglJ Med 1987;316:1587-1589. 36. Dowell ME, et al: Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus. AmJ Med 1992;93:481-487. 37. Passo MS, Rosenbaum JT: Ocular Syphilis in patients with human immunodeficiency virus infection. Am J Ophthalmol 1988;106:1-6. 38. Chisholm CA, Katz VL, McDonald TL, Bowes WA: Penicillin desensitization in the treatment of syphilis during pregnancy. Am J Perinatol 1997;14:553-554. 39. Johns DR, Tierney M, Felsenstein D: Alteration in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus. N EnglJ Med 1987;316:1569-1572. 40. Hodge WG, Seiff SR, Margolis TP: Ocular opportunistic infection incidences among patients who are HIV positive compared to patients who are HIV negative. Ophthalmology 1998;105:895-900. 41. Levy JH, Liss RA, Maguire AM: Neurosyphilis and ocular syphilis in patients with concurrent human immunodeficiency virus infection. Retina 1989;9:175-180. 42. Becerra LI, Ksiazek SM, Savino PJ, et al. Syphilitic uveitis in human immunodeficiency virus-infected and noninfected patients. Ophthalmology 1989;96:1727-1730. 43. Kleiner RC, Najarian L, Levenson J, Kaplan HJ: AIDS complicated by syphilis can mimic uveitis and Crohn's disease. Arch Ophthalmol 1987;105:1486-1487.

CHAPTER ·15: SYPHILIS 44. Kuo IC, Kapusta MA, Rao NA: Vitritis as the primary manifestation of ocular syphilis in patients with HIV infection. Am j Ophthalmol 1998;125:306-31l. 45. Williams jK, Kirsch LS, Russack V, Freeman WR: Rhegmatogenous retinal detachments in HIV-positive patients with ocular syphilis. Ophthalmic Surg Lasers 1996;27:699-705. 46. Gordon SM, Eaton ME, George R, et £11: The response of symptom-

atic neurosyphilis to high-dose intravenous penicillin G in patients with human immunodeficiency virus infection. N Engl j Med 1994;331:1469-1473. 47. Deschenes j, Seamone CD, Baines MG: Acquired ocular syphilis: Diagnosis and treatment. Am Ophthalmol 1992;24:134-138. 48. SoIling j, Solling K, jacobsen KD, et £11: Circulating immune complexes in syphilis. Acta Denn Venereol 1978;58:263-267.

John C. Baer

Definition Lyme borreliosis is a multisystem disorder c~use~ by Borrelia burgdorferi infection and its sequelae. ThIs· spIrochete is transmitted by a tick vector. Diagnosis is based on clinical history and examination with support from laboratory data.

History In 1975, a cluster of children was identified in Old Lyme, Connecticut, with a syndrome Iuimicking juvenile rheumatoid arthritis. 1, 2 Erythema migrans, and neurologic and cardiac manifestations were subsequently recognized as part of the syndrome, which became known as Lyme disease or Lyme borreliosis. 3 Erythema migrans had been recognized in European reports earlier in the century and attributed to bites by Ixodes ricinus ticks. 4 , 5 The epidemiologic studies of Lyme patients also suggested a vector-borne dis~ase t~-ansmit.ted by Ixodes ticks. 6 In 1982, a previously unIdentlfied spIrochete, B. burgdorferi, was isolated from Ixodes ticks 7, s and in patients with Lyme disease,s confirming it as the causative agent. Since the identification of 13. burgdorferi, it has been recognized that there are several distinct genospecies.. The group has become known collectively as B. burgdorfen sensu lato. At least three genospecies cause disease in Europe: B. burgdorferi sensu stricto, B. afzelii, and garinii. 9 , 10 In the United States, only B. burgdorfen sensu stricto has been implicated. Other genospecies, for example, B. valaisiana, B. lusitaniae, and B. Japonica, have been identified, but their role in human disease is not established.9, 11

!3.

Epidemiology

. .

Since its recognition in 1975, Lyme borrehosIs has been reported in North America, Europe, and Asia. There have been isolated reports from Australia, Mrica, and South America, although these are not generally considered to be endemic regions for Lyme borreliosis. In the United States, the Centers for Disease Control and Prevention has received reports of Lyme borreliosis from 48 of the 50 states and from the District of Columbia. However, cases are highly concentrated in the Northeast, Mid-Atlantic and upper Midwest regions. A focal "hot spot" has also been identified in the Pacific Northwest. In 1996, the overall annual incidence in the United States was 6.2 cases per 100,000. 12 Eight states had an incidence that exceeded the national average, and these eight accounted for 91 % of the reported 16,461 cases (Table 16-1). Incidence exceeded 100 cases per 100,000 population in 18 counties and reached 1247.5 cases per 100,000 population in Nantucket County, Massachusetts, the highest county-specific incidence in 1996.I2 . The number of cases reported to the Centers for DIS-

ease Control and Prevention increased annually through 1996, with a moderate decline in 1997. The steadily increasing incidence probably represents a combination of increased tick density in endemic areas and better reporting. I3 Incidence data from Europe is less comprehensive because of variation in reporting practices among countries. Reporting of Lyme borreliosis cases is man~a~or'y only in Slovenia and Scotland. I4 Only neuroborrehosIs IS reportable in Denmark. Estimates of incidence in other European countries depend on published scientific studies, and indirect methods such as tick counts and prevalence of seropositivity in the population. 9 The incidence appears to be higher in Eastern Europe than in Western Europe. In Austria and Slovenia, incidence exceeds 100 cases per 100,000 population per year (Table 16-2), with a peak incidence of 350 per 100,000 in some states of eastern and southern Austria. 9 Focal areas of higher incidence occur in regions of Northern Europe, where overall incidence is low. I5 This usu~lly occurs in areas where there is a larger deer populatIOn to support the tick vector. I4 A similar pattern is seen in the Far East. I6 Persons of all ages are affected by Lyme borreliosis. The incidence is highest in children younger than 159,17 and adults aged 30 to 59 yearsP The incidence of clinical manifestations varies with age 9 with cranial neuropathy more common and chronic disease manifestations less common in children than adults. IS The incidence is somewhat higher in men than women. 9, 12 Although the majority of cases are believed to arise from exposure around domestic residences, occupational and recreational exposures are also important and may help explain the gender difference. Because of. the nature of the vector transmission, the onset of first SIgns and symptoms most often occurs during warmer weather. 19 TABLE 16-1. ANNUAL INCIDENCE OF LYME BORRELIOSIS IN THE UNITED STATES BY STATE IN 1996 12 STATE

Connecticut Rhode Island New York New Jersey Delaware Pennsylvania Maryland Wisconsin Minnesota Massachusetts Maine Vermont New Hampshire 37 states and Washington, DC

ANNUAL INCIDENCE PER 100,000 POPULATION

94.8 53.9 29.2 27.4 23.9 23.3 8.8 7.7 5.4 5.3 4.9 4.4 4 1.4 or less

CHAPTER 16: BORREUOSIS TABLE 16-2. ESTIMATED INCIDENCE OF LYME BORREUOSIS IN EUROPE9 COUNTRY

ANNUAL INCIDENCE PER 100,000 POPULATION

United Kingdom Ireland France Germany Switzerland Czech Republic Bulgaria Sweden (south) Slovenia Austria

0.3 0.6 16.0 25.0 30.4 39.0 55.0 69.0 120.0 130.0

Clinical Characteristics of Systemic Disease LYJ-ne borreliosis is a multisystem disorder whose most prominent manifestations affect the skin, nervous system, musculoskeletal system, and heart. A wide spectrum of eye involvement has been describe? The clinical c?urse has been divided into early, dissemmated, and persIstent (or late) stages (Table 16-3). Patients may not exhibit all stages.

Early Disease

.

Erythema migrans is the characteristic ras~ of early ~IS­ ease. A red macular lesion forms at tl;te sIte of the tIck bite 2 to 28 days after the bite. 20 Beci;"lse of the size of the tick, most patients do not remember the bite. As the lesion enlarges and becomes papular, the paracentral area may clear, forming a "bull's eye" or target shape with the site of the bite at the center (Fig. 16-1). The lesion may itch or be painful but is often asymptomatic. The rate of expansion of erythema migrans lesions is about 1 cm per day to a maximum size of 20 to 30 cm diameter. 2o , 21 Constitutional sYJ-TIptoms including fever, malaise, fatigue, myalgias, and arthralgias often accompany the rash. According to one standard surveillance definition of erythema migrans, a skin lesion must have a delayed onset and expand to a diameter exceeding 5

TABLE 16-3. SYSTEMIC MANIFESTATIONS OF LYME BORREUOSIS EARLY STAGE

Erythema migrans DISSEMINATED STAGE

Erythema chronica migrans Borrelial lymphocytoma Arthritis Meningitis Cranial neuropathy Motor and sensory radiculitis Encephalitis/myelitis PERSISTENT STAGE

Acrodermatitis chronica atrophicans Arthritis Encephalopathy Sensory neuropathy

FIGURE 16-1. Erythema migrans is a target-shaped skin lesion centered around the site of the tick bite. (Courtesy of the Centers for Disease Control and Prevention, Division of Vector-Borne Infectious Diseases.)

cm in an individual known to have been exposed to a potential tick h~bitat in ~he p'revi~us 30. days.22 .These criteria help aVOId confusIOn WIth tIck or Ins.ec~ bite hypersensitivity reactions, which have an onse.t WIth~n hours, are smaller in size, and a're of shorter duratIon. BItes from other ticks and insects, cellulitis, hyperkeratotic disorders, contact dermatitis, tinea, and granuloma annulare may also be confused with erythema migrans. 21 In Missouri, an area with a low incidence of Lyme borreliosis, a study of patients with rashes mimicking erythema migrans failed to identify borrelia in biopsy specimens but showe~ a possible association to tick bite by Amblyomma amencanum. 23 When erythema migrans is positively identified, it is diagnostic of LYJ-TIe borreliosis. However, as many as 20% to 40% of patients never develop a rash. 22 , 24

Disseminated Disease SKIN MANIFESTATIONS

Several weeks after exposure, hematogenous dissemination occurs with potential involvement of the skin, nervous system, joints, heart, and eyes. Secondary erythe~na migrans lesions may occur at sit~s remo~e from the tIC!,bite (known as erythema chronicum migrans). Borrelza IYJ-TIphocytoma (also known as IYJ-TIPhocyton:a benigna cutis) is a bluish red lesion with a predilectIon for the ear lobes of children and the nipple region of adults. 20 This manifestation is more commonly reported in European patients than in the United States. JOINT MANIFESTATIONS

Up to 80% of untreated eI~y~hema n:igran~ pa~~ents .in the United States develop JOInt malufestatIOns.- WhIle joint involvement is less commOI~ in Europe, th~ clinical presentation is similar to that m North Am~I~Ican p~­ tients. 25 The arthritis is typically monoarthntis or 011goarthritis of large joints most commonly involving t!le knee. The process may be chronic, or recurrent, With each episode resolving over days to months. Tendons and

CHAPTER 16: BORREUOSIS

small joints, especially the temporomandibular joint, may be affected. 25 Especially in children, joint manifestations may be the only clinical feature of Lyme borreliosis. 25

TABLE 16-4. BORREUOSIS

OF LYME

EARLY STAGE

Conjunctivitis Episcleritis

NEUROLOGIC MANIFESTATIONS

Neurologic involvement occurs in the disseminated and persistent stages of Lyme borreliosis, and can affect both the central and peripheral nervous systems. In the central nervous system (CNS) , meningeal signs, cranial neuropathy, and radiculitis are accompanied by pleocytic lymphocytosis in the cerebrospinal fluid (CSF) .26, 27 Meningeal involvement may present with headache, nausea, photophobia, and vOllliting. Cranial nerve palsy may be unilateral or bilateral, and most often affects the facial nerve. Both sensory and motor radiculopathy occurs. Neurologic involvement more commonly presents with meningeal signs in the United States, whereas painful radiculitis is more common in Europe. 26 Symptoms of encephalitis such as alterations in mood, behavior, and mental capacity suggest direct brain involvement.

DISSEMINATED STAGE

Cranial neuropathy Papillitis Papilledema Optic atrophy Pupillary abnormalities Anterior, intermediate, and posterior uveitis Neuroretinitis Retinitis Retinal vasculitis Choroiditis Panuveitis PERSISTENT STAGE

Chronic intraocular inflammation Keratitis Episcleritis

CARDIAC MANIFESTATIONS

Cardiac involvement occurs in fewer than 5% of treated patients. 28 The most common manifestation is atrioventricular block of varying degree. 29 Other conduction system defects, arrhythmias, myocarditis, and pericarditis also occur. 29

Persistent Disease

,'l

The skin, nervous system, and 'joints are most often affected in late disease. Acrodermatitis chronica atrophicans is a bluish red lesion usually found on the extremities, predominately in women between 40 and 70 years 01d. 20 Fibrous bands and nodules may form. In its late stages, the lesion becomes atrophic and wrinkled. This lesion is much more commonly reported in European patients than in the United States. Late neurologic involvement manifests as subacute or chronic encephalopathy with subtle memory and cognitive dysfunction, progressive encephalomyelitis with white matter lesions, and peripheral neuropathy.26-28 In late joint disease, the duration of acute attacks of arthritis may become longer, and intermittent arthritis may become chronic.2, 25 Some patients with so-called atypical clinical manifestations of Lyme borreliosis may actually be coinfected with other tick-borne pathogens, for example, tlle parasite Babesia rnicroti or the Ehrlichia species, which causes human granulocytic ehrlichiosis. Coinfection is discussed further in the section titled "Coinfection."

Clinical Characteristics of Ocular Disease As with systemic findings, the ocular findings of Lyme borreliosis differ with the stage of disease (Table 16-4), and patients may not present with clinical manifestations from each stage. Most descriptions of eye findings in the literature consist of case reports and case series. These reports provide excellent insight into the spectrum of eye manifestations, but caution is appropriate given the limitations of Lyme serologic testing and the tendency to overdiagnose Lyme borreliosis. 28 , 30 .

E.arly Disease CONJUNCTIVITIS

Following a tick bite, in the early stages of disease, photophobia and conjunctivitis may accompany the constitutional symptomsY Conjunctivitis is present in approximately 11 % of patients. 1, 32 Because the eye signs and symptoms are generally mild and self-limited, the patient often is not seen by an ophthalmologist. Case reports ili. the ophthalmic literature have described follicular conjunctivitis with positive Lyme serology.31, 33 EPISCLERITIS

Episcleritis may accompany the conjunCtIVItIs and erythema migrans during the local phase or early disseminated phases. 15 It has also been reported during the late, persistent phase of the disease, described later.

Disseminated Disease NEURO-OPHTHALMIC MANIFESTATIONS

In the disseminated phase of the disease, neuro-ophthalmic manifestations accompany the neurologic involvement. Cranial neuropathy and optic nerve involvement are the most common. CRANIAL NEUROPATHY

Seventh cranial nerve palsy (Bell's palsy) is the most common cranial neuropathy.34,35 In one series, 10% of Lyme borreliosis patients had seventh nerve palsies. 36 As many as 25% of new-onset Bell's palsy cases may be attributed to Lyme borreliosis in endemic areas. 36 The palsy is bilateral in up to one-third of patients. 34, 37 Involvement of the sixth cranial nerve may be unilateral or bilateral.34, 38 Third, fourth, and fifth cranial neuropathies also occur, but less frequently.39, 40 Multiple cranial nerves may be affected in the same patient. Cranial neuropathies result from direct infection or inflammation

CHAPTER 16: BORRELIOSIS

fiGURE 16-2. A young woman complaining of bilateral floaters was noted to have bilateral vitritis and papillitis. Visual acuity was 20/20 Lyme serology was positive. The vitritis and papillitis cleared promptly after antibiotic treatment. Convalescent titer confirmed the diagnosis.

of the nerve, or indirectly as a result of meningitis, autoimmune process, or increased intracranial pressure. 34, 38, 39, 41 Cranial neuropathies often resolve without sequelae over weeks to months but may recur even after treatment. 38 ,42 OPTIC NERVE INVOLVEMENT

Optic nerve findings include optic n~~uritis, papilledema, and papillitis. Isolated optic nerve involvement has been reported. 43 Papilledema occurs in association with meningitis and increased intracranial pressure 38,44 and may present as transient visual obscurations. Optic nerve inflammation may result in optic atrophy. 43-47 Papillitis often occurs in association with Lyme uveitis 15 (Fig. 16-2). Optic nerve swelling in patients with positive Lyme serology. has been descriqed as optic neuritis or ischemic optic neuropathy. This has led to speculation about borreliosis as a cause of multiple sclerosis and temporal arteritis. As reviewed elsewhere, these associations have not been confirmed and probably represent overdiagnosis or coincidence. 39

au.

illitis, neurosensory retinitis, choroiditis, or panuveitis l5 , 45 (see Fig. 16-3). Lyme choroiditis, especially if it is long standing, leads to clumping and atrophy of the retinal pigment epithelium, and may be confused with other syndrOlnes. 15, 51 Filling of choriocapillaris is delayed or uneven with areas of choroidal hyperfluorescence and blockage by pigmentary clumping. Retinal vasculitis may affect the disc, posterior pole, or periphery. Fluorescein angiography demonstrates late filling of retinal vessels with perivasculitis or occlusion. ORBITAL INFLAMMATION

One case of orbital inflammation in a child has been reported, with pain, proptosis, and diplopia. 58 Enlargement of the extraocular muscles was confirmed radiographically. Although systemic myositis occurs in Lyme

PUPILLARY INVOLVEMENT

Horner's syndrome has been described early in the clinical course in several patients. 39 ,48 Tonic pupi144 and mydriasis 15 have also been described. INTRAOCULAR INFLAMMATION

Anterior uveitis, intermediate uveitis, neuroretinitis, retinal vasculitis, choroiditis, and panuveitis have all been reported as a result of infection with B. burgdorferi sensu lato. 15 , 45, '19-56 These protean presentations are similar to those described for syphilis, caused by another spirochete, Treponema pallidum. In the author's experience, and that of others,15, 42, 45, 52, 53, 57 intermediate uveitis is one of the most common intraocular presentations (Figs. 16-2 and 16-3). The vitritis is frequently severe (Fig. 16-4). It may be accompanied by a granulomatous anterior chamber reaction, pap-

fiGURE 16-3. Vitreous "snowballs" are present in the inferior vitreous cavity of a patient with Lyme borreliosis. (Courtesy of William W. Culbertson, M.D.)

CHAPTER 16: BORREUOSIS

FIGURE 16-4. Severe vitritis in a patient with Lyme borreliosis and intraocular involvement. (Courtesy of William W. Culbertson, M.D.)

borreliosis, the diagnosis of Lyme borreliosis in this case has been questioned. 27 , 39

Persistent Disease KERATITIS

Keratitis occurs months to years after onset of infection. Patients complain of mild blurting of vision and photophobia. On clinical examination, keratitis presents as a patchy or nebular subepithelial and stromal infiltration, usually bilateralY' 42, 59-52 The infiltrates have indistinct borders, may be peripheral or diffuse, and may involve both superficial and deep stroma. Keratic precipitates may underlie the infiltrates. 31 Neovascularization is minimal or absent. Episcleritis may accompany the keratitis or reappear as an isolated late manifestation. 31 , 52 Because keratitis responds to topical steroids alone, it has been speculated that it is an autoimmune rather than an infectious process.

E.co/ogy In the Northeast, Mid-Atlantic, and Mid-West regions of the United States, Ixodes scapularis (commonly known as the black-footed tick, the deer tick, or the bear tick) is the· vector for Lyme borreliosis. The literature first associated Lyme borreliosis with the vector 1. dam1Tz,ini, a new species of Ixodes tick. Separate species status has since been rejected for this tick, and it is now recognized as a northern variant of 1. scapularis. 53 1. scapularis has a 2-year life cycle. 42 Mter the tick egg hatches in the spring, the larva-stage tick attaches to a passing small mammal for a blood meal. The preferred host is the white-footed mouse, Peromyscus leucopus. Mter the blood meal, the larva is donnant over the winter until it molts into a nymph. The following spring, the nymph stage takes a blood meal for 3 to 4 days. Again, the preferred host is the white-footed mouse, although birds and other mammals including humans may serve as host.

The n)'lnph molts into an adult, and in late SUlnlner or fall, the adult takes a third blood meal. The adult's preferred host is the white-tailed deer. Mter the blood meal, the ticks mate, and the adult female tick drops to the ground to lay her eggs and restart the cycle. During their blood meals, the larval-stage and nymphstage ticks become infected with B. burgdorferi by feeding on an infected mouse. Mter molting to the nymph or adult stage respectively, the infected tick can infect the subsequent host during the next blood meal. Because the nymph population feeds earlier in the season than the following year's larvae, there is a reservoir of infection in the white-footed mouse population to infect the new larvae and perpetuate the cycle. Unlike white-footed mice, white-tailed deer are not competent reservoirs for borrelia infection. An average of 25% of nymphs become infected as larvae. 53 An average of 50% of adults become infected in the larval or nymph stage but before their adult meal. Despite the higher infection rate in adults, most human infection is attributed to a bite by a nymph-stage tick because nymphs are more aggressive feeders, are more numerous than adults, and feed during the warm months, when human encounters are more likely. Nymphs are also smaller in size and are less likely to be noted and removed before transmission of infection (Fig. 16-5). Transmission of borreliosis is less likely early in the blood meal. 54 In the Western United States, 1. pacificus, the Western black-footed tick, has been identified as the vector for Lyme borreliosis. This tick feeds on lizards as its preferred host. Lizards, like white-tailed deer, are incompetent reservoirs of infection. Occasionally, however, 1. pacificus will feed on a secondary host, for example, a rodent or human. There is a reservoir of infection in rodents maintained by a second tick, 1. neotomae. 1. neotomae is host specific and, therefore, not a vector for human infection. 53 However, when 1. pacificus feeds on an infected rodent, then takes a subsequent blood meal from a human, borrelia infection can be transmitted. In Europe, 1. ricinus is the primary tick vector. Other possible tick vectors, 1. hexagonus and 1. uriae, have also been described. 53 Competent reservoir hosts include mice (Apodermus flavicollis and A. sylvaticus) and voles (Clethrionomys glariolus). In Asia, 1. persulcatus and 1. ovatis are the tick vectors. 15

Genospedes Several genospecies of B. burgdorferi sensu lato have been identified. 10 Although each genospecies is clearly capable of causing a broad range of clinical manifestations, individual clinical manifestations of Lyme borreliosis have been associated with particular genospecies. 55 , 55 B. burgdorferi sensu stricto is the genospecies implicated in North American Lyme borreliosis but only in a portion of European disease. Patients with Lyme disease in North America were first identified as a cluster of patients with oligoarthritis,1 and arthritis is more common in American patients with Lyme disease than European patients. 25 It has since been recognized that patients infected with B. burgdorferi sensu stricto are more likely to experience joint symptoms and arthritis.

16: BORRELIOSIS

FIGURE 16-5. Ixodes scapulans ticks are shown above a centimeter ruler. From left, they are an adult female, an adult male, a nymph, and a larva. (Courtesy of the Centers for Disease Control and Prevention, Division of Vector-Borne Infectious Diseases.)

B. aftelii is associated with acrodermatitis chronicum atrophicans, and B. garinii has been associated with increased risk of neurologic symptoms. These two genospecies have been identified as infectious agents in Europe, where acrodermatitis and neurologic symptoms are more commonly recognized than in the United States. It has been postulated that some cases of broad organ system involvement in Europe may represent infection with more than one genospecies, either from multiple tick bites or from a bite by a tick simultaneously infected with more than one genospecies. 67

Host Sensitivity Differences in human host response may also be responsible for some differences in clinical manifestations. In North American patients, chronic arthritis has been associated with HLA-DR4 and HLA-DR2. 68 Patients who are HLA-DR4 positive also have a poorer response to antibiotic treatment. 68 European studies have been contradictory on these associations. 69 , 70, 71 An association has been identified between risk of developing chronic arthritis and increased humoral response to the borrelia outer surface proteins (Osp) .72 However, this association has not been identified for other chronic Lyme manifestations, for example, chronic neuroborreliosis.

Immunopathogenesis The interaction between the spirochete, tick, and human host is complex. During the tick's blood meal, B. burgdorJeri uses the plasminogen and plasminogen activators from the host's blood to enhance dissemination of spirochetes in the tick and to increase the number of spirochetes in the tick's salivary glands. 73 Plasminogen may also enhance the efficiency of spread of organism in the host's skin and tissues. 73 ,74 Tick saliva down-regulates the host immune response and may promote spirochete infection and persistence. The down-regulation by saliva persists throughout the duration of the blood meal. 74 At the time of the blood meal, the presence of the borrelia's outer surface protein A (OspA) is down-regulated, while OspC is up-regulated. Because OspA is highly

immunogenic, this may be a way to evade or adapt to host defenses. 74 The host humoral response to OspA occurs only late in the course of disease possibly after there is an adaptation to host response. 72 , 74 Mter invasion, B. burgdorJeri is capable of attaching to human cell receptors and may use this process to facilitate migration across vascular endothelium. Once it is established in the host, the organism resides predominantly in the extracellular compartment but has been identified intracellularly. It has been postulated that the intracellular location may contribute to protection of the organism from effective treatment with some antibiotics and contribute to persistent disease. 74 Once disseminated infection occurs, the organism is capable of persisting despite an intense inflammatory response by the host. In vitro studies have demonstrated that B. burgdorJeri is a potent stimulator of interleukin1 (IL-l), tumor necrosis factor a (TNF-a), and other inflammatory factors in macrophages and monocytes. 74 , 75 The outer surface protein OspA stimulates production of the cytokines IL-6, IL-8, and other chemokines by endothelial cells and fibroblasts,76, 77 and stimulates the production of the cell adhesion molecules E-selectin, Pselectin, ICAM-l, and VCAM by endothelial cells. 76- 78 Other spirochete components also seem to cause upregulation of adhesion molecules. 79 The up-regulation of the adhesion molecules may result in migration of neutrophils into the perivascular space as part of the pathogenesis of Lyme-associated tissue damage. 8o During the humoral response, both immunoglobulin (IgM) and IgG are produced against multiple borrelia antigens. The start of IgM production and the switch to IgG production occur at different times for different antigens. Animal studies suggest that humoral immunity is an effective protection against infection with B. burgdorJeri if immunity is present before infection or shortly after infection. 74 It has been postulated that pre-existing antibody protection may be effective in part because ingestion of antibody during the blood meal kills spirochetes in the tick gut before host infection. 74 A recombinant lipidated OspA vaccine for B. burgdorJeri sensu stricto recently has been marketed for human use. 81 Animals immunized later after infection tended to

CHAPTER 16: BORREUOSIS

progress to chronic disease. In humans with persistent disease, infection has been demonstrated despite detectable levels of Lyme-specific antibodies. Cell-mediated immunity also appears to playa role in modulating the severity of infection. In mouse models, CD4 + helper cells of the Th1 subset increase the joint inflammation, but Th2 cells appear to be preventive. 82 , 83 In humans, a subset of CD4 + cells that produces the same pattern of lymphokines as murine Th1 cells is selectively activated by B. burgdorferi. 84 Late in the course of Lyme borreliosis, chronic inflammatory manifestations sometimes occur in the absence of active infection. An autoimmune response may account for this in some cases. Molecular mimicry has been proposed as one possible autoimmune mechanism. 85 Patients with neurologic involvement have antiaxonal antibodies in their serum,86 and there are crossreactive epitopes between human axons and borrelia flagella. 87 This factor may contribute to Lyme peripheral neuropathy during the late stage of the disease.

Diagnosis

Clinical Diagnosis The diagnosis of Lyme borreliosis is primarily based on clinical presentation with support from laboratory data. 24, 88, 89 The Centers for Disease Control and Prevention has established a set of diagnostic criteria for disease surveillance. 22 These criteria have been adopted for clinical use 24, 89 and are presented iUjtTable 16-5. Erythema migrans is the best clinical marker for Lyme borreliosis and is present in 60% to 80% of patients. In cases of erythema migrans, serologic testing is not routinely recommended, does not greatly increase the likelihood of a correct diagnosis,89 and may be misleading because of the time lag until seroconversion. Clinical diagnosis in the disseminated and persistent stages of disease is based on the musculoskeletal, neurologic, and cardiovascular manifestations outlined in Table 16-5, with confirmation by laboratory testing. Another diagnostic system proposes assigning point values to signs, symptoms, and laboratory results. Based on the point score, patients are classified as unlikely, possible, or highly likely to have Lyme borreliosis (per Joseph]. Burrascano,Jr, M.D., http://www2.lymenet.org/ domino/ file.nsf/UID / guidelines) .

Laboratory Testing CULTURE

The gold standard for laboratory diagnosis of infection is culture of the organism from a tissue or fluid specimen. Unfortunately, except for skin biopsies, B. burgdorferi is difficult to culture from tissue and bodily fluids. 7l , 89 Culture of a skin punch biopsy from erythema migrans is positive in 60% to 80% of verified cases and may be helpful in atypical cases. 89-91 As already discussed, erythema migrans can be confused with other annular rashes. 21 , 23 A positive culture from a punch biopsy of the leading edge of a skin lesion is diagnostic of Lyme borreliosis, but a negative result does not rule out the diagnosis.

TABLE 16-5. DIAGNOSIS OF LYME BORREUOSIS22, 86, 87 CONFIRMED CASE:

Erythema migrans or At least one late manifestation that is laboratory confirmed LATE MANIFESTATIONS:

Nlusculoskeletal system-Recurrent, brief attacks (weeks or months) of objective joint swelling in one or a few joints, sometimes followed by chronic arthritis in one or a few joints. Manifestations not considered as criteria for diagnosis include chronic progressive arthritis not preceded by brief attacks and chronic symmetrical polyarthritis. Additionally, arthralgia, myalgia, or fibromyalgia syndromes alone are not criteria for musculoskeletal involvement. Nervous system-Any of the following, alone or in combination: lymphocytic meningitis; cranial neuritis; particularly facial palsy (may be bilateral); radiculoneuropathy; or, rarely, encephalomyelitis. Encephalomyelitis must be confirmed by demonstration of antibody production against Borrelia burgd01jeri in the cerebrospinal fluid (CSF), evidenced by a higher titer of antibody in CSF than in serum. Headache, fatigue, paresthesia, or mildly stiff neck alone are not criteria for neurologic involvement. Cardiovascular system-Acute onset of high-grade (second degree or third degree) atrioventricular conduction defects that resolve in days to weeks and are sometimes associated with myocarditis. Palpitations, bradycardia, bundle branch block, or myocarditis alone are not criteria for cardiovascular involvement. LABORATORY CONFIRMATION:

Isolation of B. bwgd01jeri from a clinical specimen or Demonstration of diagnostic immunoglobulin M (IgM) or immunoglobulin G, (IgG) antibodies to B. burgd01jeri in serum or CSF. A two-test approach using a sensitive enzyme immunoassay or immunofluorescence antibody followed by Western blot is recommended. Significant change in IgM or IgG antibody response to B. burgdorferi in paired acute- and convalescent-phase serum samples.

SEROLOGY

Serology, usually by enzyme-linked immunosorbent assay (ELISA), is the most commonly used diagnostic test in the clinical setting. The indirect immunofluorescence assay can also be used, but it requires more expertise in interpretation and is more difficult to automate. Unfortunately, there is great inter-test variability and poor agreement among commercially available test kits. 92 Even among reference laboratories, the accuracy and precision of results has been variable.93 The ELISA method uses a colorimetric measure to assess the binding of immunoglobulin in the serum specimen to Lyme antigen that has been applied to tlle ELISA plate. The result of ELISA testing comes in the form of an optical density. The level at which a measurement is positive has not been standardized for Lyme borreliosis, but it has been recommended that the optical density be at least three standard deviations above the mean reading for negative controls. 89 Optical density readings are taken on progressively diluted aliquots of the serum specimen to determine the highest "titer" at which the specimen is positive for Lyme-specific IgM, for IgG, or for IgM and IgG combined. ELISA results are classified as negative, equivocal, and positive, depending on the titer. Again, recommendations have been made regarding the titers at which results become equivocal and positive, but no universal standard has been adopted. 89 The variation in testing method suggests that the clinician may wish to question the laboratory about the Lyme antigen used, ask

CHAPTER 16: BORREUOSIS

whether IgM and IgG were tested separately or together, and request that titers be reported. There is general agreement that Western blotting should be used to confirm equivocal serologic tests. 89,93-95 Some also advocate confirming all positive tests as well. 89 , 94, 95 If there are cross-reacting antibodies (e.g., other spirochete infections, ehrlichia, rickettsia, HIV) or polyclonal B-cell activation (e.g., Epstein-Barr virus infection or systemic lupus erythematosus), 11 the immunoblot can correctly identify equivocal or false-positive ELISA results as truly negative. It also confirms equivocal and weakly reactive ELISA tests as true positive results. I5 Western blotting has been recommended for both IgM and IgG if the illness has lasted for less than 1 month and for IgG only if the disease has lasted for longer than 1 month. 95 The Western blot technique separates proteins by weight using gel electrophoresis. After blotting the proteins onto nitrocellulose paper, the paper is reacted with a serum specimen, then checked for antigen-antibody complexes. If antibodies specific for borrelia protein antigens are present in the serum, they are detected adhering to the bands of protein on the blot. For Lyme borreliosis, guidelines have been proposed about which pattern of Lyme-specific protein bands must be present to consider the blot positive. 95 These guidelines improve the specificity of Western blotting, but it has been suggested that they may be so restrictive as to decrease sensitivity. 11 False-negative results from serologic tests also occur. Because seroconversion has a lag time of 4 weeks or longer after initial infection, and depending on the particular antigen tested, patients with early infection may have negative serologic results. 96 It has been proposed that a false-negative result may also occur after incomplete antibiotic treatment early in the disease course. The treatment may blunt or delay the antibody response while still permitting persistence of B. burgdorferi infection. Patients with detectable borrelia-specific antibodies present in the form of immune complexes may also be classified as seronegative. 96 A false-negative ELISA test may also result if the lower threshold for equivocal results is set too high and Western blot confinnation is not performed. 15 In general, when rigorously performed serologic testing is negative late in the disease process, alternate diagnoses should be considered. 15 , 21 Seronegative patients with probable Lyme-associated intraocular inflammation have been reported, but the details of the serologic testing method are not given. 55 The sensitivity of serologic testing increases with the length of borrelia infection. In one study of a two-step test protocol (ELISA followed by Western blot), the sensitivity in patients with erythema migrans (57% to 76%) or early neurologic involvement (63% to 75%) was lower than in patients with arthritis (89% to 95%) or late neurologic findings (91 % to 100%) .93 In a combined analysis of two other studies, the sensitivity was 59% for erythema migrans and 95% after several weeks of infection,89 and the specificity was 93% for erythema Inigrans and 81 % in later disease. Sensitivity and specificity in patients with early or late eye findings have not been well defined. The predictive value of a positive or negative test changes with the pretest likelihood of having the disease (e.g., the prevalence of the disease in the population

studied). In Lyme borreliosis, great care Inust be taken in interpreting a positive test in a patient who has a pretest probability of less than 20% of having the disease (e.g., vague symptoms or no history of exposure to an endemic area for Lyme borreliosis). In these patients, a positive result is more likely to represent a false-positive result than a true positive result. 89 ,97-99 For this reason, it has been recommended that LYlne titers should not routinely be included in the screening work-up of uveitis in patients in a nonendemic area for LYlne borreliosis. 97 Likewise, in the cases in which the pretest probability of Lyme borreliosis is high (greater than 80%) based on clinical presentation, positive serologic testing does not add substantially to the already high probability that Lyme is the correct diagnosis. 89 Therefore, it is recommended that patients with typical erythema migrans should not routinely undergo serologic testing. 22 , 24, 89 Serologic testing can also be used to determine Lymespecific antibody levels within infected body compartments. In infected compartments that are sequestered from the systemic circulation (e.g., the CNS, joints, and eye), the antibody level in compartmental fluid may be higher than in the serum. Paired samples of compartmental fluid and serum are measured by ELISA for specific antibody after diluting the specimens to achieve equal total immunoglobulin levels. 89 A higher antibody titer in the compartment compared with the serum is suggestive of local antibody production in the compartment in response to active borrelia infection. An alternative method is to measure the levels of total and specific antibodies in each specimen, then to calculate an antibody-to-total immunoglobulin ratio for the compartment and the serum. A higher ratio in the compartment suggests local antibody production and active infection. HISTOPATHOLOGY

Histopathologic examination using silver stain can identify spirochetes in tissue specimens. While identification of spirochetes in tissue is suggestive, it is not diagnostic for B. burgdorferi sensu lato because other spirochetes Inay have a similar histologic appearance. Connective tissue fibers or artifacts may be misinterpreted as organisms. 28 Similar concerns arise when staining tissue with monoclonal antibodies. Spirochetes have been identified histologically in the vitreous compartment. 47 ,55 POLYMERASE CHAIN REACTION

Polymerase chain reaction (PCR) has been used to amplify both genomic and plasmid B. bwrgdorferi DNA. Because standardized guidelines for PCR use are not yet defined, the procedure is not in routine clinical use. PCR has been applied to skin, urine, serum, and cerebrospinal, synovial, and ocular fluids,I00 with the highest yield from skin specimens.u As in all circumstances with PCR, the specificity of the primers used and the risk of contamination must be considered. 28 The fact that detection of B. burgdorferi DNA may not indicate the presence of viable organisms is also a theoretical consideration. 11, 28 T-cell proliferation assay may be helpful in distinguishing persistent infection from inflammation in patients

CHAPTER 16: BORREUOSIS

with chronic neurologic or joint symptoms. 89, 101 Further confirmation of the test's usefulness is needed.

Because Ixodes ticks are transferred to a host when the host comes in contact with low-growing vegetation, prevention strategies for Lyme borreliosis in humans focus on limiting access to body surfaces by the tick. Tucking or taping the cuff of pant legs, wearing light-colored clothes so that ticks are more visible, use of insect repellent, and careful inspection for and removal of ticks after outdoor activities reduce the risk of tick contact. Even after a tick bite, early removal of the tick reduces the risk of spirochete transmission because a blood meal of several hours duration is required for efficient transmission of spirochetes. 64 A vaccine for LYlne borreliosis has become available. 81 The vaccine is a lipidated recombinant outer surface protein A (OspA) from B. burgdorferi sensu stricto. In a multicenter clinical trial in the United States, the efficacy in preventing asymptomatic seroconversion was 83% after two doses and 100% after three doses. The efficacy in preventing Lyme borreliosis was 50% after two doses and 78 % after three doses. The duration of protection is unknown. Because patients with successfully treated Lyme borreliosis may become reinfected, the duration of vaccine protection is probably limited. 85 The vaccine may act by reducing the number of viable spirochetes inside the tick when antibody is ingested during the blood mea1. 85 In the United States, the vacchae is recommended for those with frequent or prolonged exposure to ticks in areas that are endemic for Lyme borreliosis. 81

Treatment ~-lactam and tetracycline antibiotics are effective against B. burgdorferi sensu lato. As in other spirochetal diseases, 15% of patients may experience a Jarisch-Herxheimer reaction within hours of treatment. 102 Patients may experience constitutional symptoms, fever, tachycardia, vasodilation, and an increased white blood cell count. Prophylactic measures with anti-inflammatory agents should be considered and an infectious disease consultation may be helpful prior to treatment. The usefulness of prophylactic antibiotic treatment for Lyme borreliosis after tick bite but before the onset of symptoms has not been proved. l03 The risk of developing clinical disease after untreated deer tick bite is between 1% and 2 %.18,103 Careful observation for signs and symptoms of LYlne borreliosis before initiation of testing and treatment appears to be safe, because early treatment has a high success rate with low morbidity. 102, 104 This approach also appears to be more cost effectiveYl5 If erythema migrans does develop, it can be treated with oral antibiotics alone. 102 , 104 The current recommendation for adults is 2 to 3 weeks of treatment with doxycycline 100 mg bid, or amoxicillin 500 mg qid (with or without probenecid), or cefuroxilne 500 mg bid. 2l , 28,104 Treatment regimens for children, pregnant women, and those with beta lactam allergy have also been developed. 28 For Lyme arthritis, oral antibiotic therapy with doxycycline, amoxicillin, or cefuroxime for 1 to 2 months is first-line therapy, with a response rate of 80% to 90%.106

Intravenous therapy with ceftriaxone (2 g IV qd in adults) is a more costly alternative. 2l , 106, 107 Intravenous therapy is recommended for neuroborreliosis with CNS involvement and for all but the mildest cardiac manifestations. 2l , 29 A regimen of ceftriaxone 2 g qd or cefotaxime 2 g q8h for 2 to 4 weeks has been recommended. In cases of isolated facial nerve palsy without CNS involvement, oral treatment may be adequate. 21 , 26,28 However, it is important to recognize any subtle CNS involvement, because treatment with oral antibiotics, and especially with amoxicillin and probenecid, may be counterproductive. 28 ,106 Treatment of ocular manifestations is based largely on case reports and case series. The mild conjunctivitis that occurs during the early stages of infection is self-limited and requires no specific ocular therapy. As already described, the accompanying systemic manifestations of early disease should be treated with oral antibiotics. For intraocular involvement, the route and duration of antibiotic treatment has not been well defined. 42 , 45,108 It is probably most appropriate to consider intraocular involvement as a possible manifestation of neuroborreliosis. A detailed neurologic evaluation and a lumbar puncture are recommended. Confirmation of accompanying CNS involvement is an indication for intravenous antibiotic therapy, as in other cases of neuroborreliosis with CNS involvement. In the absence of CNS involvement, oral antibiotic treatment may be curative.42, 45 However, in some cases of intraocular involvement, oral therapy has been reported to suppress the signs and symptoms with relapse occurring when the antibiotic is stopped. 45 If the response to oral therapy is not rapid and complete, intravenous therapy should be considered. l08 Mter systemic antibiotic treatment has been initiated, residual intraocular inflammation may be treated with topical corticosteroids and mydriatics. Lyme keratitis, a late manifestation, is also treated with topical corticosteroids. 59 , 60 The use of systemic corticosteroids has been described as part of the management of Lyme borreliosis. 35 ,45 However, this is controversial because systemic corticosteroid treatment has been associated with an increased risk of antibiotic treatment failure. 45 , 109 The ocular response to systemic antibiotic therapy can be used as a guide to planning further therapy. As in all cases of intermediate and posterior uveitis, resolution of the cells in the vitreous cavity is a gradual process. If there is appropriate response of other ocular signs and symptoms, incomplete resolution of inflamlnatory cells in the vitreous should not be mistakenly regarded· as a treatment failure. 108 As in systemic Lyme borreliosis, treatment failure in cases of intraocular disease should prompt a reconsideration of the diagnosis. 28

Prognosis Natural history studies show that during the early and disseminated stages of Lyme borreliosis, clinical disease is often self-limited even without treatment. Erythema migrans and the early constitutional signs resolve without treatment after several weeks. llo After dissemination, there may be a period of months or years when Lyme borreliosis is clinically silent before sYlnptoms of nervous system, joint, heart, eye, or other organ system involve-

CHAPTER 16: BORREUOSIS

ment becomes apparent. Many untreated patients will not exhibit late manifestations, and of those who do, some may experience spontaneous resolution. 25 , 39, III "When the condition is left untreated, neurologic manifestations often follow an intermittent, relapsing course. 37,38 Arthritis also has a relapsing and remitting course with prolonged remissions in some untreated patients. 2,25 Intraocular inflammation and neuro-ophthalmic manifestations may be intermittent or chronic. 45 , 48, 108 Chronic inflammation is more common during the late phase of disease. Symptoms of chronic arthritis,2,25 chronic neurologic findings (i.e., encephalopathy and sensory neuropathy), and chronic skin involvement (e.g., acrodermatitis chronica atrophicans) may be persistent or even progressive. With early diagnosis, appropriate antibiotic therapy is curative with no long-term sequelae in a majority of cases. Untreated patients who do have long-standing disease manifestations also usually respond to antibiotic therapy.74 However, additional long-term morbidity is associated with later treatment. 112 In a minority of patients, chronic neurologic and joint manifestations persist or reappear despite antibiotic treatmenL This chronic course has been attributed to persistent spirochete infection, immune response to persistent infection, immune response to spirochete antigen in the absence of active infection, and molecular mimicry.85 Ad-· vanced tissue destruction may explain the persistence of symptoms in some patients in the absence of persistent infection or inflammation. 1l3 Despitte prior antibiotic treatment, retreatment can produce temporary or permanent improvement in some chronic neurologic manifestationsYo Cases of intraocular involvement with a chronic or relapsing course have been described. 45 , 108 As in neurologic involvement, additional treatment with intravenous antibiotics should be considered. COMPLICATIONS

The term post-Lyme syndrome has been used to describe a subset of patients with complaints of arthralgias, soft tissue pain, fatigue, memory impairment, difficulty concentrating, confusion, headache, malaise, and depression. These symptoms do not respond to continued antibiotic therapy. Unfortunately, there is a tendency to use the term chronic Lyme disease to refer both to these patients with subjective complaints and to patients with late stage Lyme borreliosis who have objective signs of persistent or recurrent joint inflammation or neurologic dysfunction. Great effort should be made to document any objective evidence to support subjective reports. In particular, the mild progressive encephalopathy of late Lyme borreliosis is easily missed and can be documented by psychometric testing and CSF abnormalities. 1l4 Patients with this late manifestation may respond to further antibiotic treatment, while those with subjective symptoms alone generally do noL 113 , 114 Cases of post-Lyme syndrome can often be attributed to another disease process, even in patients in whom the diagnosis of Lyme borreliosis has previously been confirmed. 30 The differential diagnosis includes a number of syndromes in which subjective symptoms are prominent: fibromyalgia, chronic fatigue syndrome, and de-

pression. As discussed later, coinfection with a second vector-borne disease should also be considered. Fibromyalgia, in particular, has been mistaken for or attributed to Lyme borreliosis. It has been identified soon after rigorously diagnosed borrelia infection, raising the possibility that it may be triggered by the infection. 30, 110 However, fibromyalgia can follow other infectious processes,28 does not respond to antibiotics,28 and is clinically distinct from the rheumatic presentation of Lyme borreliosisYo It should not be regarded as a form of chronic Lyme borreliosis. Other neurologic and psychiatric illnesses should also be considered. Alzheimer's, multiple sclerosis, amyotrophic lateral sclerosis, and demyelinating disease have all been mistakenly attributed to Lyme borreliosis. 28 , 30 In patients with depressed mental function without CNS abnormalities, reactive depression may provide the explanation. 114 Most patients with long-standing B. bUTgdoTferi infection are strongly seropositive. 2l Confirmed seronegativity in a patient who carries the diagnosis of chronic Lyme disease or "post-Lyme syndrome" should prompt a diligent search for an alternate diagnosis. 21

Coinfection Several infectious diseases other than borre1ia are transmitted by Ixodes ticks. These ticks are the vector for the parasite which causes human babesiosis, for EhTlichia which causes human granulocytic ehrlichiosis, and possibly for viruses known to cause encephalitis. 28 Human babesiosis is caused by an intraerythrocytic parasite, B. 1nicmti. B. micmti is endemic in many of the same areas where B. bUTgdoTferi is found. The illness presents with fever, chills, sweats, arthralgias, headache, and fatigue. 85 , 115 Eye findings are rare, but retinal nerve fiber layer infarcts have been reportedY6, 117 A positive blood smear is diagnostic, but false-negative results are frequent. Serology and PCR may assist in the diagnosis. Conventional treatment is with clindamycin and quinine. Without treatment, there may be prolongation of symptoms and persistence of babesia in the blood. 118 Even with treatment, recrudescent disease may occur years later. Simultaneous Lyme borre1iosis and babesiosis has been well documented. 115 , 119 Coinfection may alter the clinical course of LYlue borreliosis. In one study, 11 % of those with clinical Lyme disease were simultaneously infected with babesiaY5 In these patients, fatigue, headache, nausea, sweats, anorexia, chills, emotional lability, conjunctivitis, and splenomegaly were more frequent than in patients who had Lyme disease alone. Patients with coinfection had more signs and symptoms, had longer duration of their symptoms, and spirochetemia persisted longer. Coinfection was characterized by persistent and debilitating fatigue lasting for more than 6 months in 35% of coinfected patients. Human granulocytic ehrlichiosis has been recognized as an emerging vector-borne disease. 12o The organism causing this disorder is similar to EhTlichia equi and E. phagocytophilia, which cause disease in animals, and the three organisms may represent different strains of a single species. 120 The organism has been identified over a broad geographic region in the United States and in Europe,

CHAPTER 16:

and because of the shared Ixodes vector, there is geographic overlap with the endemic areas for babesiosis and Lyme borreliosis. 120 Human granulocytic ehrlichiosis presents as a flulike illness with fever, chills, malaise, headaches, nausea, and vomiting. l2l Leukopenia, thrombocytopenia, and hepatic involvement are typically present on laboratory testing. The condition may be fatal, especially in the elderly. In one retrospective study, two of 41 patients died. 121 Eye findings have not yet been identified in hlllnan. granulocytic ehrlichiosis, but they occasionally occur with other human ehrlichioses,122, 123 and in animals. 124 Diagnosis is made by a positive smear of the buffy coat, but a negative smear does not rule out the diagnosis. 125 Serology and PCR can also be used to assist in the diagnosis. The infection is treated with tetracyclines. Concurrence of Lyme borreliosis and human granulocytic ehrlichiosis has been reported.125-127 Coinfection may alter the clinical presentation of borreliosis and the response to treatment. 28 Because ehrlichiosis may cause immunosuppression, simultaneous infection with Ehrlic1~ia and B. burgdorferi may cause a more refractory or severe presentation of Lyme borreliosis. Even in the absence of coinfection, hlllnan granulocytic ehrlichiosis can cause a false-positive result for Lyme ELISA and immunoblot tests. 127 This may lead to the incorrect diagnosis of atypical Lyme disease. When a patient presents with a new-onset febrile illness following Ixodes tick exposure, associated with constitutional signs and positive LYlne serology, but without erythema migrans, one should consider hu'inan granulocytic ehrlichiosis. 128 If empirical antibiotic therapy is to be given, a tetracycline should be considered instead of a 13-lactam because the tetracycline will cover both infectious agents. 128 Coinfection probably accounts for some cases of postLyme syndrome. Because simultaneous infection with Babesia, Ehrlichia, or other yet-to-be-identified tick-borne diseases may alter the clinical presentation of Lyme borreliosis, patients with Lyme disease who demonstrate atypical symptoms, a severe or prolonged clinical course, or who are refractory to appropriate treatment should be evaluated for other concurrent infectious disease.

Summary Lyme borreliosis is a spirochetal infection commonly affecting the skin, joints, and nervous system. A minority of patients have ocular involvement. A self-limiting conjunctivitis may accompany early infection. With dissemination, neuro-ophthalmic signs and intraocular inflammation occur. Anterior uveitis, intermediate uveitis, neuroretinitis, retinal vasculitis, choroiditis, papillitis, and panuveitis have been described. Keratitis and episcleritis occur during the late stages of disease. The diagnosis is made by careful history and thorough physical examination. Confirmation by laboratory testing is indicated in some cases. Early treatment with appropriate antibiotic therapy is curative. Late sequelae involving the skin, joints, and nervous system can occur.

RELAPSING Definition Relapsing fever is an acute borrelia infection that is characterized clinically by fever, followed by an afebrile pe-

riod, then recurrence of the fever. Several species of borrelia have been implicated. Disease transmission has two vector patterns: louse borne and tick borne.

Epidemiology Louse-borne disease is transmitted by the body louse Pediculus humanus. When the human host scratches the site of infestation, lice infected with Borrelia recurrentis are crushed, and the infected material is rubbed into the abraded skin. The cycle is perpetuated by lice that feed on an infected host, become infected, then transfer to an uninfected host, and are crushed. There does not appear to be an animal reservoir. The distribution of louse-horne disease is worldwide and is more dependent on living conditions than geography. The last large epidemic occurred during and after World War II, when millions of people were infected in the Mediterranean basin, North Mrica, and the Middle East. Because of famine and poor social conditions, endemic patterns of disease have been identified in East Mrica, and in parts of South A1nerica and the Far East. Tick-borne relapsing fever is transmitted by several species of Ornithodoros tick, each of which is associated with a corresponding borrelia species. 129 When all tickvector combinations are considered, the geographic distribution of tick-borne disease includes portions of North and Central America, Southeastern Europe, and portions of Mrica, Asia, and the Middle and Far East. In the United States, Ornithodoros hermsi and Ornithodoros turicata ticks infected with B. hermsii and B. turicatae respectively inhabit the burrows or nests of rodents who serve as asymptomatic hosts for the infection. 130 Each summer and fall, sporadic cases of tick-borne relapsing fever are reported throughout the Western and Southwestern United States, from Texas to the state of Washington. 130 Common-source epidemics occur when humans interrupt the natural infection cycle and become incidental hosts. 95 , 130-133 These epidemics are associated with having stayed in wilderness cabins or caves that harbor the borrows or nests of infected rodents. Symptoms may not develop until the patient has returned to his or her home, which may be outside the endemic area for relapsing fever.

Clinical Characteristics The manifestation for which the disease is named is the recurrent intermittent episodes of fever. Mter an incubation period lasting days to weeks, fever, constitutional symptoms, and photophobia begin. A period of defervescence is followed by an afebrile period of relative wellbeing, then recurrence of the fever. This cycle Inay be repeated many times. Patients with louse-borne disease are generally sicker. In severe cases, cardiac involvement, hepatitis with secondary jaundice, and splenic enlargement Inay occur. Bleeding is common, presenting as petechiae, ecchYlnoses, hematuria, and epistaxis. Infrequently, massive hemorrhage occurs. Meningismus and headache are commonly reported, but CSF abnormalities are not. 134 Intracranial bleeding may cause these symptoms in some patients. Encephalopathy and depressed mental status may occur. Eye involvement has not been· reported. 134

CHAPTER 16: BORRELIOSIS

In tick-borne disease, patients may be unaware of having been exposed because Ornithodoros ticks are night feeders whose bite often goes unnoticed. 130 An eschar may develop at the site of the bite. Mter the incubation period, the first episode of fever occurs. As the fever abates, petechial, macular, or papular rash may present in up to half of patients. In untreated patients, an afebrile period of about 1 week is typically followed by 2 to 4 subsequent recurrences of fever, each less severe than the previous. This pattern is quite variable. Other clinical features include hepatomegaly and splenomegaly. Some species of borrelia causing tick-borne relapsing fever are neurotropic: B. tuncatae in the Southwestern United States, and B. duttonii in Sub-Saharan Mrica. 134 In untreated patients, neurologic manifestations similar to those of Lyme borreliosis may occur after several recurrences of fever. These include radiculopathy, neuropsychiatric changes, and cranial neuritis, especially Bell's palsy.134 Ocular involvement in tick-borne relapsing fever is associated with the neurotrophic borrelia species and, to a lesser extent, with B. hispanica, endemic in Northern Mrica. 134 As with neurologic disease, ocular manifestations present after 3 to 4 febrile episodes. Al1terior uveitis, vitritis, choroiditis, and optic neuropathy have been described.l3'1-137 Ocular involvement occurs in 10% to 15% of patients.

Pathogenesis The pathogenesis of the relapsing cdtlrse of fever is attributed to continuous variation in the borrelia outer surface protein antigens. Fever accompanies the spirochetemia with each new antigenic variant until the organisms are cleared and the cycle repeats itself. 138

Diagnosis During febrile periods, a peripheral blood smear can be examined for spirochetes. The presence of spirochetes is diagnostic for relapsing fever. A thick smear l35 or fluorescence microscopy after staining with acridine orange may increase the sensitivity. 135, 139 Smears are negative when the patient is afebrile. Culture of borrelia from blood is possible but requires special medium and is not widely available clinically.140 Serologic testing for relapsing fever has not been standardized. ELISA has a high degree of cross-reactivity with B. burgdoifen, but Western blot testing for B. burgdoifen is negative. Because Lyme serology testing is widely available clinically, some have suggested that a positive Lyme ELISA and a negative Lyme Western blot could be used as a screening serologic test for relapsing fever until a standardized test is available. This combination of tests could aid in the diagnosis of relapsing fever during an afebrile period or when the peripheral blood smear is negative. In the United States, Western blot testing for at least one tick-borne species, B. hennsii, is available through the Centers for Disease Control and Prevention. In the United States, the endemic areas for tick-borne relapsing fever and LYlne borreliosis are beginning to overlap. This may cause a diagnostic dilemma in patients with neurologic or ocular involvement, because manifestations of the two conditions may be similar.134, 1'11

Oral tetracyclines are the most commonly used treatment for both tick-borne and louse-borne disease. ~-lactam antibiotics are also effective. As in Lyme borreliosis, neurologic disease is treated with intravenous therapy, for example, ceftriaxone. Intraocular involvement should prompt a work-up for evidence of neurologic involvement.

Summary Relapsing fever is an acute borrelial infection that is transmitted by tick and louse vectors. Neurologic and ocular manifestations of tick-borne disease have some similarity to those of Lyme borreliosis.

Acknowledgement The author wishes to thank medical librarians Vicky Spitalniak and Dianne Deck for their assistance in the preparation of this manuscript.

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CHAPTER 16: BORRELIOSIS 80. Sellati TJ, Burns MJ, Ficazzola MA, et al: Borrelia burgd01feri upregu~ lates expression of adhesion molecules on endothelial cells and promotes transendothelial migration of neutrophils in vitro. Infect Immun1995;63:4439-4447. 81. Centers for Disease Control and Prevention: Notice to readers: Availability of Lyme disease vaccine. MMWR 1999;48:35-36, 43. 82. Keane-Myers A, Nickell SP: T cell subset-dependent modulation of immunity to Borrelia burgdorferi in mice. J Immunol 1995; 154:1770-1776. 83. Keane-Myers A, Nickell SP: Role of IL-4 and IFN-gamma in modulation of immunity of Bornlia burgdOlferi in mice. J Immunol 1995;155:2020-2028. 84. Yssel H, Shanafelt MC, Soderberg C, et al: Borrelia burgdorferi activates a T helper type I-like T cell subset in Lyme arthritis. J Exp Med 1991;174:593-601. 85. Evans J: Lyme disease. Curr Opin Rheumatol 1998;10:339-346. 86. Sigal L, Tatum A: Lyme disease patients' serum contains IgM antibodies to Borrelia burgdoiferi that cross-react with neuronal antigens. Neurology 1988;38:1439-1442. 87. Sigal LH, Tatum AH: Lyme disease patients' serum contains IgM antibodies to Borrelia burgdorferi that cross-react with neuronal antigens. Neurology 1988;38:1439-1442. 88. Nightingale SL: Public health advisory: Limitations, uses, and interpretation of assays for supporting clinical diagnosis of Lyme disease. JAMA 1997;278:805. 89. Tugwell P, Dennis DT, Weinstein A, et al: Laboratory evaluation in the diagnosis of Lyme disease. Ann Intern Med 1997;127:11091123. 90. Wormser GP, Forseter G, Cooper D, et al: Use of a novel technique of cutaneous lavage for diagnosis of Lyme disease associated with erythema migrans. JAMA 1992;268:1311-1313. 91. Berger BW, Lesser RL: Lyme disease. Dermatol Clin 1992;10:763775. 92. Quan TJ, Wilmoth BA, Carter LG, Bailey RE: A comparison of some commercially available serodiagnostic kits for- Lyme disease. In: Proceedings of the First National ConfereJJ,.ce on Lyme Disease Testing (Dearborn, Michigan). Washington? DC: Association of State and Territorial Public Health Laboratory Directors, 1991, pp 61-73. 93. Craven RB, Quan TJ, Bailey RE, et al: Improved serodiagnostic testing for Lyme disease: Results of a multicenter serologic evaluation. Emerg Infect Dis 1996;2:136. 94. Johnson BJ, Robbins KE, Bailey RE, et al: Serodiagnosis of Lyme disease: Accuracy of a two-step approach using a flagella-based ELISA and immunoblotting. J Infect Dis 1996;174:346-353. 95. Centers for Disease Control and Prevention: Recommendation for test performance and interpretation fi'om the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR 1995;44:590-591. 96. Schutzer SE, Coyle PK, Dunn jJ, et al: Early and specific antibody response to OspA in Lyme disease. J Clin Invest 1994;94:454-457. 97. Rosenbaum JT: Prevalence of Lyme disease among patients with uveitis; AmJ Ophthalmol 1991;112:462-463. 98. Mikkila H, Seppala I, Leilisalo-Repo M, et al: The significance of serum anti-Borrelia antibodies in the diagnostic work-up of uveitis. Eur J Ophthalmol 1997;7:251-255. 99. Breeveld J, Kuiper H, Spanjaard L, et al: Uveitis and Lyme borreliosis. Br J Ophthalmol 1993;77:480-481. 100. Hilton E, Smith C, Sood S: Ocular Lyme borreliosis diagnosed by polymerase chain reaction on vitreous fluid. Ann Intern Med 1996;1125:424-425. 101. Dressler F, Yoshinari NH, Steere AC: The T-cell proliferative assay in the diagnosis of Lyme disease. Ann Intern Med 1991;115:533539 102. Nadelman RB, Luger SW, Frank E, et al: Comparison of cefuroxime axetil and doxycycline in the treatment of early Lyme disease. Ann Intern Med 1992;117:273-280. 103. Warshafsky S, NowakowskiJ, Nadelman RB, et al: Efficacy ofantibiotic prophylaxis for prevention of Lyme disease. J Gen Intern Med 1996;11:329-333. 104. Dattwyler RJ, Volkman DJ, Conaty SM, et al: Amoxicillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis. Lancet 1990;336:1404-1406. 105. Fix AD, Strickland GT, GrantJ: Tick bites and Lyme disease in an endemic setting: Problematic use of serologic testing and prophylactic antibiotic therapy. JAMA 1998;279:206-210.

106. Steere AC, Levin RE, Molloy PJ, etal: Treatment of Lyme arthritis. Arthritis Rheum 1994;37:878-888. 107. Eckman MH, Steere AC, Kalish RA, et al: Cost effectiveness of oral as compared with intravenous antibiotic therapy for patients with early Lyme disease or Lyme arthritis. N EnglJ Med 1997;337:357363. 108. Suttorp-Schulten MSA, Kuiper H, KijlstTa A, et al: Long-term effects of ceftriaxone treatment on intraocular lyme borreliosis. Am J Ophthalmol 1993;116:571-575. 109. Dattwyler RJ, Halpern jJ, Volkman DJ, et al: Treatment of late Lyme borreliosis-randomised comparison of ceftriaxone and penicillin. Lancet 1988;1:1191-1194. 110. Rahn DW: Natural history of Lyme disease. In: Rahn DW, Evans J (eds): Lyme disease. Philadelphia, American College of Physicians, 1998, p 35. 111. Szer IS, Taylor E, Steere AC: The -long-term course of children with Lyme arthritis. N EnglJ Med 1991;325:159-163. 112. Shadick NA, Phillips CB, Logigian EL, et al: The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study. Ann Intern Med 1994;121:560-567. 113. Logigian EL, Kaplan RF, Steere AC: Chronic neurologic manifestations of Lyme disease. N Engl J Med 1990;323:1438-1444. 114. Kaplan RF, Jones-Woodward L: Lyme encephalopathy: A neuropsychological perspective. Semin Neurol 1997;17:31-37. 115. Krause PJ, Telford SR 3rd, Spielman A, et al: Concurrent Lyme disease and babesiosis: Evidence for increased severity and duration of illness. JAMA 1996;275:1657-1660. 116. Zweifach PH, Shovlin J: Retinal nerve fiber layer infarct in a patient with babesiosis. AmJ Ophthalmol 1991;112:597-598. 117. Ortiz JM, Eagle RC Jr: Ocular findings in human babesiosis (Nantucket fever). AmJ OphthalmoI1982;93:307-311. 118. Krause PJ, Spielman A, Telford SR 3rd, et al: Persistent parasitemia after acute babesiosis. N EnglJ Med 1998;339:160-165. 119. Sweeney Gj, Ghassemi M, Agger WA, et al: Co-infection with Babesia microti and Borrelia burgdorferi in a western Wisconsin resident. Mayo Clin Proc 1998;73:338-341. 120. Walker DH, Barbour AG, Oliver JH, et al. Emerging bacterial zoonotic and vector-borne diseases: Ecological and epidemiological factors. JAMA 1996;275:463-469. 121. BakkenJS, KruethJ, Wilson-Nordskog C, et al: Clinical and laboratory characteristics of human granulocytic ehrlichiosis. JAMA 1996;275: 199-205. 122. Carter N, Miller NR: Fourth nerve palsy caused by Ehrlichia chaf feensis. J Neuroophthalmol 1997;17:47-50. 123. Petersen LR, Sawyer LA, Fishbein DB, et al: An outbreak of ehrlichiosis in members of an Army Reserve unit exposed to ticks. J Infect Dis 1989;159:562-568. 124. Goodhead AD: Uveitis in dogs and cats: Guidelines for the practitioner. J S Mr Vet Assoc 1996;67:12-19. 125. Nadelman RB, Horowitz HW, Hsieh TC, et al: Simultaneous lmman granulocytic ehrlichiosis and Lyme borreliosis. N Engl J Med 1997;337:27-30. 126. Barton LL, Luisiri A, Dawson JE, et al: Simultaneous infection with an Ehrlichia and Borrelia burgdorferi in a child. An.n N Y Acad Sci 1990;590:68-69. 127. Paparone PW, Glenn WB: Lyme disease with concurrent ehrlichiosis. J Am Osteopath Assoc 1994 Jul;94:568-570, 573, 577. 128. Wormser GP, Horowitz HW, Dumler JS, et al: False-positive Lyme disease serology in human granulocytic ehrlichiosis. Lancet 1996;347 (9006) :981-982. 129. Barbour A, Fish D: Biology of Borrelia species. Microbiol Rev 1986;50:381-400. 130. Centers for Disease Control and Prevention: Common source of outbreak of relapsing fever-California. MMWR 1990;39:579-586. 131. Meader CN: Five cases of relapsing fever originating in Colorado, with positive blood findings in two. Colo Med 1915;12:365-369. 132. Thompson RS, Burgdorfer W, Russell R, et al: Outbreak of tickborne relapsing fever in Spokane County, Washington. JAMA 1969;210:1045-1050. 133. Boyer KM, Munford RS, Maupin GO, et al: Tick-borne relapsing fever: An. interstate outbreak originating at Grand Canyon National Park. AmJ EpidemioI1977;105:469-479. 134. Cadavid D, Barbour AG: Neuroborreliosis during relapsing fever: Review of the clinical manifestations, pathology, and treatment of infections in humans and experimental animals. Clin Infect Dis 1998;26:151-164.

CHAPTER 16: BORREUOSIS 135. Horton JM, Blaser MJ: The spectrum of relapsing fever in the Rocky Mountains. Arch Intern Med 1985;145:871-875. 136. Southern PM, SanfordJP: Relapsing fever: A clinical and microbiological review. Medicine 1969;48:129-149. 137. HamiltonJB: Ocular complication in relapsing fever. Br J Ophthalmol 1943;27:68-80. 138. Barbour AG: Antigenic variation of a relapsing fever Borrelia species. Annu Rev Microbiol 1990;44:155-71.

139. Sciotto CG, Lauer BA, White vVL, et al: Detection of Borrelia in acridine orange-stained blood smears by fluorescence microscopy. Arch Pathol Lab Med 1983;107:384-386. 140. Spach DH, Liles WC, Campbell GI, et al: Tick-borne diseases in the United States. N EnglJ MedI993;329:936-947. 141. Rawlings JA. All overview of tick-borne relapsing fever with emphasis on outbreaks in Texas. Tex Med 1995;91:56-59.

Louis J. Chorich

There are currently 11 recognized species of the genus Bartonella. Four are recognized as human pathogens: B. bacilliformis (bartonellosis or Carri6n' s disease), B. quintana (trench fever), B. elizabethae (endocarditis), and B. henselae. Members of the genus Bartonella are classified within the alpha subdivision of the Proteobacteria. They are gram-negative, oxidase-negative, fastidious, and aerobic bacilli. Their growth on blood agar is slow, usually requiring at least 12 to 14 days. B. henselae is the bacterial pathogen associated with the clinical entity commonly known as cat-scratch disease (CSD) . B. henselae (formerly Rochalimaea henselae) is an emerging pathogen that has only recently been positively identified as a cause of neuroretinitis. Our understanding of the numerous clinical manifestations of CSD and their appropriate treatment are evolving.

Human Bartonella infection was first recognized in 1909 by Alberto Barton, who noted infected erythrocytes in patients with bartonellosis (Carri6n's disease).l The first recorded observation of CSD is thought to have been made by Parinaud in 1889 when he ,~ssociated conjunctivitis and enlarged regional lymph nodes with exposure to animals. 2 The condition was termed Parinaud's oculoglandular syndrome. Debre was the first to associate the disease with cats when he encountered a 10-year-old boy with suppurative adenopathy. 2 The boy, who played and slept with cats, was initially thought to have tuberculosis, but the disease remitted spontaneously. The term catscratch fever was coined by Foshay in 1932. 3 Presme and Marchland associated CSD with Parinaud's oculoglandular syndrome in 1950, whereas Sweeny and Drance associated CSD with intraocular inflammation in 1970. 4 Leber first described a case of stellate neuroretinitis characterized by optic disc edema and a macular star. The condition became known as Leber's idiopathic stellate neuroretinitis (LISN). Gass suggested that LISN represents a primary optic neuropathy with macular manifestations. s Gass later hypothesized that B. henselae is a causative agent of LISN,6 but positive identification of its role as the pathogen of CSD and CSD-associated neuroretinitis was later demonstrated by serologic testing, blood and tissue cultures, histopathologic examination, and immunologic testing. 7- 10

CSD occurs in immunocompetent individuals of all ages worldwide and is the leading cause of regional lymphadenopathy in children and young adults. CSD is more common in children and adolescents, possibly because they are more likely to provoke a cat to scratch or bite. There is no known sex or ethnic predilection toward CSD. The prevalence of CSD in the United States isapproximately 22,000 cases per yearY The disease is most preva-

lent in the southern states, California, and Hawaii, which reflects the distribution of cat fleas, B. henselae antibodies, and positive blood cultures in cats. 12 In the San Francisco area, B. henselae was isolated from the blood of 41 % of pet, pound, and stray cats. 13 Pet cats reside in nearly one third of U.S. homes and provide a vast reservoir from which human B. henselae infection may be acquired. 14 The infection is not known to be transmitted from human to human. CSD follows a seasonal pattern, with peaks in the fall and winter months, although cases have been reported at all times of the year. IS, 16 Daniels and MacMurray report that 30% of patients are under 10 years and two thirds are under 30 years of ageY They report a positive history of contact with cats in 92% of cases and a history of associated trauma such as a bite or scratch in 76% of those cases. Although the incidence of ocular involvement in cases of CSD is not known with certainty, studies by Margileth estimate that between 5% and 10% of CSD patients develop conjunctivitis, and 30 of 2006 cases of CSD developed neuroretinitis. IS, 19

CLINICAL B. henselae infection is associated with a wide range of systemic and ocular symptoms and findings. Primary inoculation often results in a systemic infection. The eye is rarely the primary site of inoculation. More cOlnmonly, a scratch or bite occurs on the hands, arms, or neck. Systemic signs and symptoms usually precede ocular manifestations and are of importance in establishing the diagnosis. Three to 10 days after inoculation, a small erythematous papule forms on the skin at the site of inoculation. Seven to 14 days after exposure, conjunctival injection, chemosis, and watery discharge may follow. Follicular conjunctivitis may affect the bulbar and palpebral conjunctiva, and if the conjunctiva is the site of inoculation, a conjunctival granuloma may be present at the inoculation site. Two to 3 weeks after the scratch, regional lymphadenopathy occurs and is often accompanied by myalgias, malaise, fatigue, and low-grade fever. The skin papule may have faded by this time. Most patients experience localized disease with mild systemic symptoms that resolve within several months. The presence of conjunctivitis accompanied by regionallYlnphadenopathy defines the clinical entity known as Parinaud's oculoglandular syndrome. The most common complaint in CSD neuroretinitis is decreased vision. 20 The onset of visual symptoms usually follows the inoculation by approximately 1 month, and it follows the onset of constitutional symptoms by approximately 2 to 3 weeks. 21 The visual acuity usually ranges from 20/25 to 20/200 but may be worse in some cases. The condition is usually unilateral but may be bilateral in both immunocompetent and immunocompromised patients. 22 ,23 When the condition is bilateral, one eye is often affected more than the fellow eye. A relative afferent pupillary defect is usually present. Most patients pre-

CHAPTER i 7: BARTONELLA

flammatory mass in the posterior pole. Cunninghalll and colleagues reported two cases 6f an inflammatory mass of the optic nerve head,24 while Pollock and Kristinsson documented a choroidal inflammatory lesion associated with CSD.28 Occasionally, the inflammatory lesion is highly vascular, resembling the lesions seen in bacillary angiomatosis, a condition characterized by lllultiple vascular skin and mucous membrane lesions associated with B. henselae infection in patients with acquired immunodeficiency syndrome (AIDS) .26,29,30 Fluorescein angiography demonstrates early peripapillary telangiectasis with progressive leakage from the disc and vessels. Formal visual field testing often demonstrates a cecocentral scotoma, a paracentral scotoma, or an enlarged physiologic blind spot.21, 23 Other forms of ocular· inflammation associated with CSD include intermediate uveitis,31 anterior uveitis,23 conFIGURE 17-1. A macular star accompanied by an intraretinal hemorrhage near the optic disc. junctivitis, and orbital abscess. 32 Conjunctivitis is associated with Parinaud's oculoglandular syndrome. The conjunctiva is thought to become involved either by direct sent to the ophthalmologist with the striking clinical fea- inoculation by a cat or by indirect inoculation with con.:. tures of optic disc edema and a macular star. The optic taminated hands. 15 The prognosis is very good, because most patients disc is the primary target of the neuroretinitis. 5 The inflammatory process leads to leakage from the optic disc with CSD neuroretinitis recover excellent visual acuity.6, 26 and retinal microvasculature with accumulation of intra- There may be mild residual color vision abnormalities. retinal lipids in the pattern of a macular star (Fig. 17-1). The average visually evoked potential (VEP) is reduced The macular star may be partial or complete. When a when compared tp an unaffected fellow eye, but the partial star pattern is seen, it is usually present in the electroretinogram (ERG) remains normal. 16 Mild optic nasal macula. In severe cases, lipid exudates can be seen nerve dysfunction is the most common cause of residual well outside the macula and ma~ulopapillary bundle or visual loss. In patients with AIDS, B. henselae is known to cause nasal to the optic disc. 24 The macular star resolves in approximately 8 to 12 weeks (Fig. 17-2). There may be bacillary angiomatosis, a disease characterized by the one or more white areas of inner retinitis or chorioretini- presence of any number of vascular lesions involving one tis, which some authors have found to be more common or more organ systems. Nearly any organ system may be than a macular star. 20 , 25, 26 A neurosensory detachment of affected, either singly or in combination with other organ the macula or inferior retina as well as a few posterior systems. The skin is frequently involved, and the lesions vitreous cells may be noted. 23 , 27 When present, intrareti- may be easily mistaken for Kaposi's sarcoma. 33 One case nal hemorrhages and cotton-wool spots reflect the of bacillary angiomatosis of the conjunctiva has been involvement of the retinal microvasculature. Less com- reported. 30 monly, branch retinal arteriolar occlusion or branch retinal venous occlusion may be associated with an area of In human disease, B. henselae was initially characterized focal retinitis. 20 CSD may occasionally present with a large focal in- by ReIman and colleagues in the tissue of patients with bacillary angiomatosis of AIDS.10 Subsequently, Regnery described B. henselae antibodies in 86% of patients with CSD, compared with 6% of healthy controls. 7 Further histopathologic, serologic, and molecular biologic analyses have confirmed this agent as the cause of both entities. Current evidence would suggest that the predominant mode of transmission of B. henselae is through a cat scratch or bite. Polymerase chain reaction (PCR) assays have detected B. henselae in fleas from infected cats,13 and experimental transmission from cat to cat via the cat flea (Ctenocephalides felis) has been delllonstrated. 34 There are no data to confirm that arthropods play a role in the pathogenesis of human disease, but cat fleas are often not specific with regard to host, biting both cats and humans. It has been proposed that they may act as a vector of transmission of B. henselae from cat to human. 13 Most cases are acquired from cats less than 1 year old. The exact etiology of CSD-associated neuroretinitis is FIGURE 11-2. Partial resolution of the macular star 6 weeks later.

CHAPTER 17: BARTONELLA

not understood. It is unknown whether fundus changes are the direct result of optic nerve or intraocular infection, or both, by Bartonella or if the ocular findings represent a parainfectious inflammatory response. B. henselae has been isolated from a focus of retinitis in a patient with human immunodeficiency virus (HIV) ,35 and B. bacilliformis has been shown to invade vascular endothelium. 36 Western blot analysis is being used as a means to determine the important antigens that trigger the immunologic response of the host. 8, 37 Identification of such antigens may lead to the development of a human vaccine for CSD.

DIAGNOSIS The diagnosis of CSD is currently based on clinical features supported by laboratory testing to detect genetic material from B. henselae or the host's immunologic response to the organism. The earliest tests for CSD took the form of skin tests with antigens prepared from lymph node aspirates of CSD patients. 38 A positive skin test is likely to remain positive for life. 15 The Warthin-Starry silver impregnation stain applied to a lymph node or conjunctival biopsy may demonstrate bacilli in the tissue. The organism can be identified by culture on bloodenriched agar or cocultivation in cell culture, but it may require 12 to 45 days before colonies become apparent. 39 With the development of serologic testing for B. henselae, the diagnosis is no longer made by exclusion. An indirect fluorescent antibody (IFA) test was developed to detect the humoral response to the organi~ and was found to be 88% sensitive and 94% specific. 7 Titers greater than 1:64 are considered positive. Enzyme immunoassay (EIA) and Western blot procedures were later developed, and EIA was shown to have IgG sensitivity of 86% to 95% and specificity of 96% cOlnpared with IFA.8,9 More recently, PCR assays have been employed for diagnostic purposes. ReIman and colleagues developed the first primers for the specific detection of Bartonella DNA.I0 PCR is able to determine the presence of B. henselae in a very small sample of serum or other body fluids by detecting and amplifying a small fragment of the bacterial 16S rRNA gene.

There are no guidelines for the treatlnent of CSD or its ocular complications, because randomized controlled trials have not been performed. Consequently, there is disagreement regarding the efficacy of antibiotic treatment for CSD in the immunocompetent individual. Although B. henselae is sensitive to a number of antibiotics in vitro,40 only aminoglycosides have been shown to have bactericidal activity against the bartonellaeY Many physicians do not treat mild to moderate systemic CSD, but those who do often use a 10- to 14-day course of doxycycline, erythromycin, trimethoprim-sulfamethoxazole, rifampin, or intramuscular gentamicin. 42 ,43 The effect of oral steroids on the course of the disease is unknown. Overall, the response to tl'eatment is usually unimpressive. 43 Golnik and colleagues noted improvement in visual acuity in three patients with intl'aocular inflammation treated with oral ciprofloxacin 500 mg twice daily.23 Two

of the three were treated with oral prednisone 40 mg/ day after beginning ciprofloxacin.They treated another patient with oral doxycycline 250 mg four times daily and also noted prompt improvement in visual acuity with less optic disc edema and fewer vitreous cells. It is noteworthy that one of the patients who responded favorably to ciprofloxacin and another who responded favorably to doxycycline first experienced their initial visual loss while taking cephalexin 250 mg four times daily and dicloxacillin 250 mg four times daily, respectively. Both of these patients began antibiotic treatment earlier in the course of their disease. Because the natural history of Bartonellaassociated neuroretinitis has not been well defined, it is not apparent whether antibiotics hasten visual recovery or the recovery is expected at that point in the natural course of the disease. Other investigators report favorable responses to treatment with oral antibiotics. 16 , 25, 31 The safety of ciprofloxacin in individuals younger than 18 years of age has not been established, and the use of doxycycline in those younger than 9 years of age is contraindicated because of the risk of permanent discoloration of the teeth. 44 One case of bacillary angiomatosis of the conjunctiva was successfully tl"eated with topical gentamicin and systemic erythromycin, which brought about resolution of the lesion in 8 weeks. 30 The prevention of GSD may be possible with the future development of vaccines for both cats and humans. 45 For the time being, common sense would dictate immediate cleansing and disinfection of any cat scratch or bite as well as avoiding contact with stray felines.

DIAGNOSIS Parinaud's oculoglandular syndrome is a clinical entity with numerous other etiologies. Additional causes of conjunctivitis with regional lymphadenopathy include tularemia (Francisella tularensis; necrotizing conjunctivitis with lymphadenopathy), sporotrichosis (Sporotrichum schenckii; ulcerative nodules on eyelids with lymphadenopathy), tuberculosis, syphilis, infectious mononucleosis, coccidioidomycosis, lymphogranuloma venereum, leprosy, and Yersinia. 46 ,47 A number of infectious and inflamlnatory conditions have been identified as causes of neuroretinitis, including tuberculosis, toxoplasmosis, syphilis, Lyme disease, toxocariasis, leptospirosis, mumps, varicella, and herpes simplex. 6 A macular star accompanied by vitritis has been specifically reported in association with toxoplasmosis. 48 Other causes of a macular star include vascular disorders such as acute systemic hypertension,49 increased intracranial pressure, 50 and anterior ischemic optic neuropathy. 6 By inflammatory or ischemic mechanisms, or both, each of these conditions may compromise the microvasculature of the optic disc, resulting in leakage of serum and lipids with subsequent macular star formation.

CONCLUSION When a patient presents with conjunctivitis and a history of feline exposure, or with neuroretinitis, retinitis, chorioretinitis, papillitis, or intermediate uveitis, a detailed history must be taken with attention to the systemic Inanifestations of CSD. Treatment guidelines for CSD-associated

CHAPTER 11: BARTONELLA

neuroretinitis are poorly defined. If antibiotic treatment is considered, oral ciprofloxacin 500 mg twice daily or doxycycline 250 mg four times daily are appropriate choices. The effect of oral steroids on the course of disease is unknown. Our understanding of CSD and its ocular complications has expanded exponentially over the past 10 years. We can hope that current and future research will bring a deeper understanding of the etiology of CSD-associated neuroretinitis, as well as guidelines for treatment.

References 1. Maurin M, Birtles R, Raoult D: Current knowledge of Bartonella species. Eur] Clin Microbiol Infect Dis 1997;16:487-506. 2. ]erris R], Regnery RL: Will the real agent of cat scratch disease please stand up? Arm Rev Microbiol 1996;50:707-725. 3. Hellry M: Leptotllricosis .COI1Jullctivae (Parillaud's COIljllllCtivitis). Trans Pacific Coast Oto-ophthalmol Soc 1952;33:173-196. 4. Sweeny VP, Drance SN: Optic neuritis and comprehensive neuropathy associated with cat scratch disease. Can Med Assoc] 1970; 103:1380-1381. 5. Gass ]D: Diseases of the optic nerve that may simulate macular disease. Trans Am Acad Ophthalmol Otolaryngol 1977;83:766. 6. Dreyer RF, Hopen G, Gass]DM, Smith]L: Leber's idiopathic stellate neuroretinitis. Arch Ophthalmol 1984;102:1140-1145. 7. Regnery R], Olson ]G, Perkins BA, Bibb W: Serological response to Rochalimaea henselae antigen in suspected cat scratch disease. Lancet 1992;339:1443-1445. 8. Litwin CM, Martins TB, Hill HR: Immunologic response to Bartonella henselae as determined by enzyme immunoassay and Western blot analysis. Am] Clin Pathol 1997;108:202-209. 9. Barka NE, Hadfield T, Patnaik M, et al: EIA for detection of Rochalimaea henselae-reactive IgG, IgM, and IgA antibodies in patients with suspected cat scratch disease.] Infeq,pis 1993;167:1503-1504. 10. ReIman DA, Loutit ]S, Schmidt TM, J et al: The agent of bacillary angiomatosis: An approach to the identification of uncultured pathogens. N Engl] Med 1990;323:1573. 11. Jackson LA, Perkins BA, Wenger ]D: Cat scratch disease in the United States: An analysis of three national databases. Am] Public Health 1993;83:1707-1711. 12. Jameson P, Green C, Regnery R, et al: Prevalence of Bartonella henselae antibodies in pet cats throughout regions of North America. ] Infect Dis 1995;172:1145-1149. 13. Koehler ]E, Glasor CA, Tappero]W: Rochalimaea henselae infection: A new zoonosis with the domestic cat as reservoir. ]AMA 1994;271:531-535. 14. Wise ]K, Yang.IT: Veterinary service market for companion animals. Part I: Companion animal ownership and demographics.] Am Vet Med Assoc 1992;201:990-992. 15. Carithers HA: Cat scratch disease: An overview based on a study of 1200 patients. Am] Dis Child 1985;139:1124-1133. 16. Reed ]B, Scales DK, Wong MT, et al: Bartonella henselae neuroretinitis in cat scratch disease. Ophthalmology 1998;105:459-466. 17. Daniels WB, MacMurray FG: Cat scratch disease: Report of one hundred sixty cases.]AMA 1954;154:1247-1251. 18. Margileth AM, Hadfield T: Cat scratch disease: Etiology, pathogenesis, diagnosis, and management. American Society of Clinical Pathologists Teleconference Series, Chicago, IL, April 21, 1994. 19. Margileth AM: Cat scratch disease. In: Aronoff, SC, ed: Advances in Pediatric Infectious Diseases, vol 8. St. Louis, MO, Mosby, 1993, pp 1-21. 20. Solley WA, Martin DF, Newman NJ, et al: Cat scratch disease: Posterior segment manifestations. Ophthalmology 1999;106:15461553. 21. Newson RW, Martin T], Wasilauskas B: Cat-scratch disease diagnosed serologically using an enzyme immunoassay in a patient with neuroretinitis. Arch Ophthalmol 1996;114:493-494. 22. Schlossberg D, Morad Y, Krouse TB, et al: Culture-proved disseminated cat-scratch disease in acquired immunodeficiency syndi-ome. Arch Intern Med 1989;149:1437-1439.

23. Golnik KC, Marotto ME,· Maher MF, et al: Ophthalmic manifestations of Rochalirnaea species. Am] OphthalmoI1994;118:145-151. 24. Cunningham ET, McDonald HR, Schatz H, et al: Inflammatory mass of the optic nerve head associated with systemic Bartonella henselae infection. Arch Ophthalmol 1997;115:1596-1597. 25. Ormerod LD, Skolnick KA, Menosky MM, et al: Retinal and choroidal manifestations of cat-scratch disease. Ophthalmology 1998; 105:1024-1031. 26. Gass ]DM: Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment, 4th ed. St. Louis, MO, Mosby, 1997, pp 604-606. 27. Zacchei AC, Newman N], Sternberg P: Serous retinal detachment of the macula associated with cat-scratch disease. Am] Ophthalmol 1995;120:796-797. 28. Pollock SC, Kristinsson J: Cat-scratch disease manifesting as unifocal helioid choroiditis. Arch Ophthalmol 1998;116:1249-1251. 29. Fish RH, Hogan RN, Nightingale SD, et al: Peripapillary angiomatosis associated with cat-scratch neuroretinitis. Arch Ophthalmol 1992;110:323. 30. Lee WR, Chawla ]C, Reid R: Bacillary angiomatosis of the conjunctiva. Am] Ophthalmol 1994;118:152-157. 31. Soheilian M, Markomichelakis N, Foster CS: Intermediate uveitis and retinal vasculitis as manifestations of cat scratch disease. Am] Ophthalmol 1996;122:582-584. 32. Gaebler]W, Burgett RA, Caldmeyer KS: Subacute orbital abscess in a four-year-old girl with a new kitten. Pediatr Infect Dis] 1998;17:844-846. 33. LeBoit PE, Berger TG, Egbert BM, et al: Epithelioid haemangiomalike vascular proliferation in AIDS: Manifestation of cat scratch disease bacillus infection? Lancet 1988;1 (8592) :960-963. 34. Chomel BB, Kasten RW, Floyd-Hawkins K, et al: Experimental transmission of Bartonella henselae by the cat flea. ] Clin Microbiol 1996;34:1952-1956. 35. Warren K, GolsteiIF E, Hung VS, et al: Use of retinal biopsy to diagnose Bartonella (formerly Rochalinzaea) henselae retinitis in an HIV-infected patient. Arch Ophthalmol 1998;116:937-940. 36. Garcia FU, Wojita], Hoover RL: Interactions between live Bartonella bacillifonnis and endothelial cells.] Infect Dis 1992;165:1138-1141. 37. McGill SL, Regnery RL, Karem KL: Characterization of human immunoglobulin (Ig) isotype and IgG subclass response to Bartonella henselae infection. Infect Immun 1998;66:5916-5920. 38. Moriarity RA: Cat scratch disease. Infect Dis Clin North Am 1987;1:575-590. 39. Maurin M, Birtles R, Raoult D: Current knowledge of Bartonella species. Eur] Clin Microbiol Infect Dis 1997;16:487-506. 40. Lucey D, Dolan Mj, Moss CW, et al: Relapsing illness due to Rochalimaea henselae in immunocompetant hosts: Implication for therapy and new epidemiological associations. Clin Infect Dis 1992;14:683688. 41. Musso D, Drancourt M, Raoult D: Lack of bactericidal effect of antibiotics except aminoglycosides on Bartonella (Rochalimaea) henselae.] Antimicrob Chemother 1995;36:101-108. 42. Margileth AM: Antibiotic therapy for cat-scratch disease: Clinical study of tl1erapeutic outcome in 268 patients and a review of the literature. Pediatr Infect Dis] 1992;11:474-478. 43. Spach DH, Koehler ]E: Bartonella-associated infections. Infect Dis Clin North Am 1998;12:137-155. 44. Physician's Desk Reference, 53rd ed. Montvale, NJ, Medical Economics, 1999, pp 641-646, 2427-2430. 45. Olsen CW: Vaccination of cats against emerging and reemerging zoonotic pathogens. Adv Vet Med 1999;41:333-346. 46. Chandler]W, Sugar], Edelhauser HF: Textbook of Ophthalmology, vol 8. St. Louis, MO, Mosby. 1994, pp 2-26. 47. Chin GN, Hyndiuk RA: Parinaud's Oculoglandular Conjunctivitis. In: Tasman W, Jaeger EA, eds: Duane's Clinical Ophthalmology, vol 4. Philadelphia, Lippincott, 1992, pp 1-6. 48. Burnett A], Shortt SG, Isaac-Renton ], et al: Multiple cases of acquired toxoplasmosis retinitis presenting in an outbreak. Ophthalmology 1998;105:1032-1037. 49. Noble KG. Hypertensive retinopathy simulating Leber idiopathic stellate neuroretinitis. Arch Ophtl1almol 1997;115:1594-1595. 50. Maitland CG, Miller NR: Neuroretinitis. Arch Ophthalmol 1984;102: 1146-1150.

I C. Michael Samson and C. Stephen Foster

Tuberculosis (TB) is an airborne communicable disease caused by Mycobacterium tuberculosis or by one of three other closely related mycobacterial species (M. bovis, M. africanum, and M. microti). The term tuberculosis implies active disease: Only 10% of infected individuals become symptomatic; 90% remain infected for the rest of their lives without manifesting disease. Ocular tuberculosis encompasses any infection by M. tuberculosis in the eye, around the eye, or on its surface. Classically, ocular tuberculosis has been divided into two types: primary and secondary. Primary ocular TB implies that the eye is the initial port of entry; this type includes conjunctival, corneal, and scleral disease. Secondary disease implies that organisms spread to the eye hematogenously; this type includes tuberculous uveitis. These ocular definitions should not be confused with the definitions of primary and secondary systemic tuberculosis, which differentiate between disease from recent infection as opposed to reactivation of old disease.

HISTORY Tuberculosis has caused suffering in humans since ancient times: Egyptian mummies datrd back to 2400 Be show pathologic evidence of tuberculous spondylitis. 1 The disease has been called by many names, including phthisis, consumption, and the "white plague." Robert Koch developed a staining technique that could demonstrate M. tuberculosis, and in 1882, he proved that these bacilli were the cause of the various TB lesions in animal experiments, the same experiments that helped him formulate his now-famous postulates. 2 The first report of a case of tuberculous disease of the eye is attributed to Maitre:Jan, who in 1711 described a case of an iris nodule that led to corneal perforation. 3 The first description of histopathologically proven tuberculosis of the eye was by Von Michel in 1883. 4 Robert Koch developed the use of injections of "old" tuberculosis (heat-killed mycobacteria) as a potential remedy, not as a diagnostic test. Less than two decades later, von Pirquet developed a scratch test; soon after, Mantoux introduced the intradermal tuberculin skin test. It was not until the late 1940s that the purified protein derivative (PPD) test became available. 2 The other diagnostic aid in the fight against TB was the x-ray, first developed by Wilhelm Konrad von Rontgen in 1895. 1 The x-ray provided physicians with a tool by which they could objectively monitor the. progress of TB patients. The most important advance in the history of TB was the discovery of curative antibiotics. In 1943, streptomycin was shown to cure M. tuberculosis infection in animals, with little associated systemic toxicity. The following year, streptomycin was used to successfully cure an infected human patient. Isoniazid, pyrazinamide, and cycloserine therapy followed in the 1950s, and ethambutol and rifampin in the 1960s.

There has been a decline in the prevalence of uveitis cases attributed to TB since the beginning of the 20th century. In Woods' series of uveitis patients reported in 1944,just over halfwere thought to be due to M. tuberculosis, whereas in Schlaegel's series 25 years later, only 0.28% of cases were attributed to the mycobacterium. In 1996, Biswas reported only five cases of micro biologically proven tuberculous uveitis in 1273 patients (0.60%) seen over 2 years at a uveitis referral clinic in India, a country in which TB is endemic. This trend has been attributed to the decline of TB, the discovery of other entities capable of causing granulomatous inflammation, and the diminished emphasis placed on TB by ophthalmologists. s The overall decrease of the incidence of TB in developed countries commenced in the 19th century, attributed to improved living conditions. 6 With the discovery of effective antibiotics, deaths due to TB continued to fall. In the United States, there was an average annual decline of 5.6% of reported cases from the 1940s to 1984. From 1985 to 1993, however, annual TB began to rise, increasing 14% over that short period. This was in part attributed to the acquired inmmunodeficiency syndrome (AIDS) epidemic, but increased immigration from countries where TB is endemic, transmission of TB in congregate settings (health care facilities, correctional facilities, and homeless shelters), and a deterioration of the healthcare infrastructure were also contributing factors. 1 Recently, TB in developed countries seems to be on the decline again, most likely due to the institution of direct observed therapy and the initial benefits from the new protease inhibitors in the human immunodeficiency virus (HIV)-infected population. 7 Worldwide, however, it remains a significant problem, with some estimates as high as one third of the world's population being infected. 9 Even when ocular TB was believed to be a major cause of uveitis, ophthalmologists of the time agreed that eye disease in patients with active systemic TB was uncommon. In 1967, Donahue reported ocular morbidity of only 1.4% in a TB sanatorium. 10 In a recent study, Biswas and Badrinath prospectively examined 1005 consecutive mycobacteria-infected patients in India and likewise found a very small percentage of eye disease: only 14 patients, or 1.39%Y A recent survey of autopsy eyes found only 0.4% of AIDS patients with ocular involvement affected by M. tuberculosis. lla These findings support the contention of past ophthalmologists that the eye is somewhat protected against infection by M. tuberculosis. Known risk factors for TB infection include close contact with infected individuals and HIV infection. In addition, individuals from countries in which TB is endemic are at risk; these countries include Haiti, India, Mexico, the People's Republic of China, the Philippines, and Vietnam. The main difficulty in the accurate collection of authentic cases of ocular TB is that diagnosis is often presumptive 12 ;

CHAPTER 18: TUBERCULOSIS

histopathologic confirmation. from ocular specimens is uncommon. Some ophthalmologists extend diagnostic criteria to include patients presenting with ocular manifestations known to be caused by M. tuberculosis if there is histopathologically confirmed systemic infection. Another extension of the diagnostic criteria includes cases that manifest findings typical of TB that subsequel~tlyrespond to empiric antimycobacterial therapy. Ocular involvement in these cases, in the strictest sense, is still presumptive. Analysis of these cases is helpful in attempting to understand intraocular TB and its manifestations, but one lllUSt keep in mind that cases without histopathologic confirmation may actually represent nontuberculous disease. Uveitis is the most comlllon ocular manifestation of TB. Scleritis may present concomitantly with uveitis. Lid lesions,13 orbital involvement, conjunctival involvement,14, 15 and keratitis are other ocular manifestations and usually do not present in association with uveitis. External disease is presumed to be primary ocular TB, whereas uveitis is thought to occur by hematogenous spread from distant foci of infection. The most common presentation of tuberculous uveitis is of disseminated choroiditis. I 6-1S The discrete lesions may number from five to several hundred. The lesions range from 0.5 to 3.0 mm in diameter, and may vary in size and elevation within the same eye. 1S They are deep, in the choroid; appear yellow, white, or gray; and are fairly well circumscribed. In the vast majority of cases, the lesions present in the posterior pole. Right eyes may be more affected than left eyes. Disc<;edema with nerve fiber layer hemorrhages can also be seen. 1S An associated anterior uveitis may be severe, mild, or absent. Mter uveitis, the next most common clinical presentation is a single tubercle, also termed focal choroiditis. 19 In these cases, a single choroidal mass is the characteristic feature on presentation, although a few adjacent satellite lesions may also be seen. A large tubercle may measure up to 4.0 mm in diameter; however, reports of choroidal masses up to 14 mm in diameter have been reported. 20 The mass. is typically elevated, and may be accompanied by an overlying serous retinal detachment. 19, 21 A macular star may develop. 19, 21 Other posterior manifestations include subretinal abscess, retinal detachment, retinal vasculitis,22 and optic neuritis. Anterior tuberculous uveitis is typically granulomatous with extensive granulomatous keratic precipitates. 22 Iris nodules can also be seen. 22 An accompanying vitritis is not uncommon, and can be so dense as to obscure fundus details. 22 Intraocular pressure may be normal or elevated. 22 Other anterior presentations include an exudative mass in the anterior chamber, and an associated scleritis with spontaneous perforation. 23 TB is typically considered in the differential diagnosis of chronic anterior granulomatous uveitis witl10ut posterior segment involvement. Cases that fit this clinical picture with microbiologic confirmation of mycobacterium infection, however, are rare. A total of 46 cases of intraocular TB confirmed by histopathologic or microbiologic specimens from the eye exists in the literature 23-25 ; only six describe anterior uveitis without posterior involvement. On closer inspection, one of the six cases represented a post-traumatic infection, and in two others, the

posterior segment was not visualized, one of which was eventually shown to have diffuse choroidal involvement on pathologic examination. 26 Uveitis due to M. tuberculosis may present as a panophthalmitis. Similar in presentation to acute onset endophthalmitis, inflammation can be severe and unrelenting; the eye can be lost in a matter of days, even with the initiation of appropriate therapy.24, 27 Sometimes, an epibulbar mass can be seen 27 and can be a sign of spontaneous scleral perforation due to massive caseating necrosis. It would be useful for the ophthalmologist to know if ocular TB is more or less likely to present in patients with signs of active or past systemic TB infection, but review of the literature is not helpful in this regard. Many case reports represent "presumptive ocular tuberculosis." The clinician should keep in mind that histopathologically proven intraocular TB has been shown to occur in patients without systemic signs or symptoms of TB infection other than reactive skin testing: Hence, the absence of clinically evident systemic TB does not rule out the possibility of ocular TB. Although TB may manifest in the eye without these signs, the ophthalmologist should include questions directed toward the possibility of systemic TB infection in the review of systems of patients with uveitis. Most clinicians are familiar with the symptoms and signs of pulmonary TB, but the possibility of extrapulmonary disease, often accompanied by headache, change in mental status, localized back pain, increased abdominal girth, or abdominal pain, must not be ignored. Fever, sweats, and weight loss are present in both pulmonary and extrapulmonary infections, and are often present in systemic tuberculosis.

The chronicity of tuberculosis is the main reason that it has remained one of the most important diseases in the history of humanity, even in modern times. Its ability to remain dormant in its host for years explains how it was able to spread to all the continents. 2s Therefore, it is critical to understand how M. tuberculosis accomplishes this, in order to help guide our therapeutic approach. Most understanding of the pathogenesis of TB comes from study of lesions in the lung. Many pathologic characteristics of these lesions are probably applicable to disease in the eye. In an active lesion, one can classify the different populations of mycobacterial organisms based on their activity.29 The "actively multiplying group" resides extracellularly in an open area of necrosis and represents the majority of organisms within the lesion. The "slowgrowing group" can be found either in closed necrotic lesions or intracellularly within macrophages. Detailed reports of pathologic eye specimens from recent cases of intraocular TB are uncommon. This is in part due to the success and effectiveness of modern treatment of the disease, resulting in less need for enucleation. Furthermore, diagnostic procedures to obtain aqueous or vitreous samples for the purpose of miCl-obiologic and histopathologic examinations are considered risky by most clinicians, who are more likely to start treatment based on presumptive evidence of infection

CHAPTER 18: TUBERCULOSIS

when other clinical noninvasive testing (positive PPD, history of previously treated tuberculosis) is available. Ocular TB pathology reports vary depending on the prevalence of TB; reports from developed countries tend to be from older literature and more recent reports are from countries where TB is endemic. Many of the cases represent panophthalmitis, followed by blind painful eye, requiring enucleation. 27 Typically, the choroid is the site with the most severe involvement, demonstrating multiple tubercles with surrounding necrosis, and extension to the overlying retina. Caseating necrosis is specific but not always present. 20 Lymphocytes, plasma cells, and giant cells accompany the essential epithelioid cells as the major infiltrating inflammatory cells. The iris and ciliary body usually also demonstrate inflammatory cells, granulomas, and caseation necrosis. Occasionally, a cyclitic membrane is present. Corneal findings may range from little involvement to marked thinning and diffuse inflammation with stromal neovascularization. The sclera is usually uninvolved; if affected, it may show a focal area of necrosis or, occasionally, spontaneous perforation. The optic nerve usually shows inflammation and may contain granulomas. Appropriate staining will reveal disseminated acid-fast bacilli.

PATHOGENESIS

that peripheral blood mononuclear cells (PBMCs) in children with active TB had lower IFN-)' production than did PBMCs of children who were PPD reactive but without systemic infection. 30 Furthermore, cytotoxic T lymphocytes able to recognize M. tuberculosis antigens have been isolated from human serum; these cells are capable of recognizing and lysing monocytes acutely infected with M. tuberculosis,31 Another critical protective immune response is the ability to form granulomas. Granuloma formation is also probably dependent on relative concentrations of particular cytokines, with interleukin-l[3 (IL-l[3) and tumor necrosis factor ex (TNF-ex) having been implicated as important factors. If BCG-resistant mice are treated with anti-TNF-ex antibody before challenge with BCG, they fail to form granulomas and they develop lethal BCG infection. Although these studies do not have any direct clinical applications, it is clear that a patient's ability to limit tissue destruction and organism replication might be modifiable with cytokine-directed therapy, therapy already available in clinical practice. The emergence of multidrug-resistant (MDR) TB led to the increased interest in research aimed at discovering the mechanism of antituberculous medications and the mechanisms behind antimicrobial resistance. Various gene mutations can result in different mechanisms of loss of susceptibilities td,drugs, including decreased interaction with drug, impaired conversion of the drug to the active form, and overcoming the antimicrobial therapy by a "superphysiologic" state. Other mutations exist in which resistance is confirmed, but the exact mechanisms are unknown. 32

The reaction of the immune system to M. tuberculosis serves as the model for what is now known as type IV hypersensitivity and is the basis for the mechanism behind tuberculin skin testing. Interestingly, Koch's original use of heat-killed (or "old") tuberculin in patients was intended as a cure for TB. This was based on the wellknown fact of the time that animals injected with large amounts of attenuated mycobacteria became immunized against the disease. Although Koch did not meet with the great success he had hoped for, the idea was reborn as Fluorescein Angiogram the bacille Calmette-Guerin (BCG) vaccination, which Fluorescein angiogram testing may be helpful in cases in used a live, nonvirulent strain of bovine mycobacterium. 2 which a single or prominent choroidal mass is present. As with other infections, the immunopathologic pro- Typically, the choroidal mass exhibits diffuse fluorescence cess of infection with M. tuberculosis is a struggle between in the early arterial phase, which evolves into intense two forces: the bacteria and its virulence factors, and the diffuse hyperfluorescence by the venous phase. Large host's immune response. The fact that only 10% of in- vessels are typically not present within the choroidal lefected individuals eventually develop disease suggests that sion. These findings may aid the clinician in suspecting an adequate immune response can mount an effective TB over other entities such as choroidal melanoma or defense against the organism, and that factors deleteri- metastasis. Careful examination of fluorescein angiogram ously affecting the immune system may allow the disease findings may reveal data that are clearly not consistent to develop. Laboratory studies using murine models and with choroidal melanoma, thus avoiding unnecessary human cell cultures have helped provide a better under- enucleation. 20 standing of the immunology behind TB infection. The ability to replicate within cells, specifically macro- . Tuberculin SI
CHAPTER. 18: TUBER.CUlOSIS

BCG vaccination or infection with nontuberculous mycobacteria. 33 Certain basic facts must be kept in mind when using and interpreting these diagnostic tests. First, tuberculin skin testing is not a diagnostic test for tuberculosis disease: it determines only whether an individual has been infected by mycobacteria, and only 10% of such people are believed to go on to active disease. In patients from areas in which TB is endemic, it not uncommon to have positive tuberculin skin test incidence as high as 35% to 40%, most of whom never get the disease. PPD testing cannot distinguish between past and active disease. 33 Furthermore, it is not completely reliable; patients in whom cellular ilumunity is depressed (e.g., HIV infection) often show nonreactive skin tests. 20 Likewise, the immune response lessens in certain individuals and may require a booster shot 1 to 2 weeks after the initial injection. Finally, not all patients with active tuberculosis respond to tuberculin skin testing: Studies report 10% to 25% of active TB patients as nonresponders. 33 Knowledge of BCG vaccination is also important in the interpretation of a positive PPD. BCG is a vaccine consisting of a live mycobacterium, a species not able to cause disease. BCG vaccination is most comluonly used in developing countries in which TB is endemic.· Its usefulness is controversial. Beliefs vary about the length of time one is positive to BCG. According to the American Thoracic Society (ATS), a single BCG vaccination during the first year of life rarely remains positive. A single BCG vaccination during childho~d or adulthood remains positive for about 5 years. Multiple BCG vaccinations probably result in lifelong reactivity. It has not been confirmed that worsening of the uveitis following PPD testing is a reliable diagnostic sign of a tuberculous etiology. In fact, it has been shown that uveitis may be triggered by PPD testing in the absence of evidence of systemic TB infection and without prior history of uveitis. 34

Isolation of Mycobacteria-Add-Fast Staining and Culture The next step in TB diagnosis is isolation of organisms from systemically infected sites. This process usually consists of sputum testing, but collection of urine, gastric aspirates, or cervical lymph node biopsy are relatively benign procedures. Acid-fast staining and culture are both used to identify the causative organisms. Most ophthalmologists attribute ocular disease to M. tuberculosis if a known ocular manifestation occurs in conjunction with isolation of mycobacteria from other body sites, either concurrently or in the recent past. However, when documented systemic disease occurred in the patient's distant past, it is more difficult to attribute ocular involvement as the only site of reactivation. If such a patient also has a history of having completed adequate treatment for TB, another dilemma arises, the possibility of drug-resistant TB. This poses significant risks for both treating and withholding treatment, and direct diagnostic methods may be required for the ophthalmologist to be comfortable with instituting therapy with potential systemic toxicity. There are two general approaches to diagnosing TB

localized to the eye. The first method is acquiring intraocular fluid. Both anterior chamber taps and pars plana vitrectomy, known methods for diagnosing intraocular infection from other causes (endogenous bacterial and fungal endophthalmitis, for example), have also been used to identify mycobacteria. 2'1 These fluids can be sent for acid-fast staining and culture. Acid-fast staining is rapid but is neither sensitive nor specific. There is some evidence that fluorescence microscopy may be a more sensitive test for visualizing tubercle bacilli. 20 Culture is extremely specific and sensitive and provides information on susceptibility, but is limited by delay in obtaining results. It is the gold standard to which other tests are compared in clinical and laboratory studies.

Isolation of M)'C(JIDalct~erla--NIUll'iI. . RcmlL. Amplification Ocular specimens may also be tested using nucleic acid amplification techniques. This is especially useful in anterior chamber taps, in which the small amount of harvested material is unlikely to yield useful information when analyzed by standard luethods. Two general nucleic acid amplification methods are available: transcriptionmediated alnplification (TMA) , which targets unique lVI. tuberculosis rRNA sequences (specifically, the 16S rRNA) , and polymerase chain reaction (PCR), which targets unique M. tuberculosis DNA sequences. The M. tuberculosis direct test (MTD) is a commercially available assay based on TMA; there are also several commercial assays based on PCR. Each method can furnish a result in less than 7 hours.33, 35 Clinical studies have used both MTD and PCR, with most data obtained from studies of pulmonary disease (i.e., sputum samples). Both methods yield high specificity and sensitivity when used in conjunction with acid-fast bacillus smears. PCR-based methods with a sensitivity as high as 100% have been reported, but some studies show a specificity as low as 70%.33 False-positiveresults are an unfortunate consequence of extremely sensitive tests. 36 Theoretically, MTD carries certain advantages over PCR. MTD might yield fewer false-positive results because RNA degrades easily outside of the reaction tube. In addition, MTD should result in higher sensitivity, because there are. 2000 rRNA copies per mycobacterium versus 10 to 16 copies of DNA targets. 37 However, studies comparing PCR and MTD testing on sputum specimens revealed similar results. 33,37 Other clinical uses of MTD and PCR have included examination of gastric aspirates and tissue samples. 38 Because these tests are new, their exact role in the diagnosis of systemic tuberculosis has not yet ·been defined. 33 Nucleic acid amplification techniques have been .used to diagnose intraocular TB in uveitis cases. 36, 38-40 Five cases were diagnosed by anterior chamber tap, and one case used PCR applied to an ocular pathologic specimen. However, specificity and sensitivity from ocular specimens are not known. Clinical studies lack sufficient numbers, and to our knowledge, laboratory studies have not been performed. It is possible that biologic fluids from different organ sites may require different preparation techniques from those used to prepare sputum samples. For example, use of MTD in cerebrospinal fluid seelued to

CHAPTER 18: TUBERCULOSIS

give better results when a 500-/-Ll sample was used (instead of the 50 /-Ll required from respiratory specilnens) if specimens were pretreated with sodium dodecyl sulfate and amplification time was increased to 3 hours. 33 Similar special preparation techniques may need to be applied to ocular specimens for optimal results. Additionally, it is of concern that among the six patients reported in the literature who had a positive PCR for M. tuberculosis, only one had histologic confirmation of TB infection, which was by cervical lymph node biopsy. Only two of the six patients had other objective signs suggestive of TB infection: one had a history of pulmonary TB, and one other had a strongly positive PPD; the other four had no other clinical data suggesting TB infection. Although others believe that positive rapid diagnostic tests in the absence of positive acid-fast smears or culture may warrant initiation of antituberculous therapy, ophthalmologists are well advised to proceed with caution when using and interpreting these tests until more reliable data come to lightY, 39 The second approach to achieving a diagnosis of M. tuberculosis infection in isolated eye disease is chorioretinal biopsy.17 This procedure entails more risks to the patient. However, it is used in patients in whom the clinical evidence also suggests other infectious causes that may present as a mass (sarcoid, fungal) when different diagnostic entities call for radically different therapies. Nucleic acid amplification techniques used in addition to histologic examination may be useful. The last and most dramatic apP'I"0ach is enucleation. This is usually reserved for patients presenting with a blind painful eye, or with aggressive bilateral panophthalmitis with one eye salvageable and one eye lost. In cytoInegalovirus retinitis, acute retinal necrosis, and endogenous bacterial and fungal· endophthalmitis, enucleation is performed in an attempt to establish a definitive diagnosis to save the remaining eye. Ocular TB is reported to occur bilaterally. and has been known to present as a fulminant panophthalmitis. 26 , 27 The last relevant aspect in the diagnosis of intraocular TB is that of drug susceptibility. The importance of establishing susceptibilities in a time when MDR strains are modifYing Centers for Disease Control and Prevention (CDCP) therapy recommendations may suggest that ophthalmologists take more aggressive steps toward obtaining ocular specimens for culture than has been done in the past. "Presumed" ocular TB may not be an engaging diagnosis for the patient or the physician when it requires numerous medications on a daily basis for a minimum of 6 months. Although standard methods of determining antimicrobial resistance have been successfully used for years, these methods carry the same disadvantage as culture identification of M. tuberculosis: The tests take time, from weeks to months. Increased knowledge of the cell biology and genetics of M. tuberculosis has led to the development of PCR tests capable of detecting genes associated with antimicrobial resistance. Similar techniques have been used to detect point mutations associated with resistance to antituberculous medications. These methods have the advantages of rapid acquisition of the desired information (as little as 24 hours), and increased safety for microbiology technicians by decreasing risk of infection as com-

pared with standard culture techniques. These tests include PCR restriction fragment length polymorphism (RFLP) analysis, PCR single-strand conformation polymorphism (SSCP), universal heteroduplex generator analysis, and DNA oligonucleotide arrays on silica microchips.41

Therapeutic Trial Schlaegel and associates conducted a study examining the effectiveness of antituberculous therapy in uveitis patients without evidence of systemic TB. 42 Their results led to the recommendation that a therapeutic trial of isoniazid at 300 mg daily for 3 weeks be attempted in these patients; a favorable clinical response was considered indicative of a tuberculous etiology of the uveitis, and warranted proceeding to a complete regimen. Randomized doubleblind trials, however, show no difference between isoniazid (INH) and placebo, suggesting that the approach described earlier is probably invalid. Additionally, singledose therapy in a. patient with suspected TB does not meet with current recommendations for prophylaxis in most regions.

It is important for the ophthalmologist to be familiar with current guidelines for TB treatment, even if the treatment specifics are deferred to the internist or other specialist. First, the ophthalmologist can prepare the patient for the difficult regimen that must be followed. Nonadherence to the program can sabotage a condition that could have been cured, and even strict compliance can still lead to loss of vision, owing to the virulence of this organism. Second, these medications have potential toxicities, including eye-related adverse effects; the ophthalmologist has an ethical and medicolegal obligation to monitor for the relevant symptoms of these possibilities on follow-up examinations. Last, TB is an epidemic with evidence suggesting that it continues to cause significant morbidity and mortality worldwide. It will certainly be a condition most physicians will encounter during their career in the 21 st century. The drugs that make up first-line treatment of TB are INH, rifampin, pyrazinamide (PZA) , streptOlnycin, and ethambutol. They are first-line drugs because they are bactericidal (although ethambutol requires a higher starting dose for this to be true). Isoniazid and rifampin each are bactericidal for both actively dividing extracellular and slow-dividing intracellular mycobacteria; used in combination, they are very effective in susceptible populations. 28 PZA is the only other first-line therapy capable of targeting slow-growing intracellular organisms; this probably explains its excellent efficacy in early treatment. 28 Streptomycin and ethambutol are effective mainly against actively dividing organisms. 28 Current CDC recommendations use INH and rifampin combined therapy as the core of treatlnent for a minimum of 6 months. Because of the evolution of MDR strains, PZA has been added to the starting regimen and is used in conjunction with the two main drugs for the first 2 months of treatment. In areas in which prevalence of INH resistance exceeds 4%, streptomycin or ethambutol is added as the fourth drug. The "added" drugs are

CHAPTER 18:

discontinued when susceptibility testing shows that the organisms are susceptible to both INH and rifampin. When resistance to antimicrobial agents is detected, treatment is more complex. Isolated resistance to INH or rifampin requires continuation of the supplemental firstline agents. Discontinuation of the drug to which there is resistance is not routine, because SOlne clinicians believe that there is benefit to continuation if the resistance level is low. When MDR is present (resistance to at least INH and rifampin), authorities recommend treatment with three or four drugs to which the mycobacterium is susceptible and prolongation of therapy.43 Some evidence supports the efficacy of quinolones, and second-line agents, such as cycloserine and para-aminosalicylic acid, have been known to be effective, albeit less so than firstline drugs, and with increased risk of drug toxicityY Consultation with an infectious disease expert or other knowledgeable authority is recommended in cases of MDR TB. Direct observed therapy (DOT) is the process of receiving treatment under the direct supervision of a health-care worker. It plays a critical role in TB therapy because compliance with long-term treatment is essential for cure. First instituted in 1979 as a niethod of targeting patients identified as noncompliant, it has since been promoted to the standard of care in the treatment of tuberculosis. 44 This came as a result not only of the obvious effectiveness in improving patient compliance, but because of the newer problems of emerging MDR strains in the HIV epidemic. Furthermofe, studies demonstrated that degree of noncompliance did not vary with any demographic variables; there are no good methods to reliably predict which patients will adhere to treatment. 44 DOT has generally been enforced in large urban centers. Up to one third of new TB cases in these regions are thought to be contracted by recent transmission and not by reactivation of old disease. 45 Major cities around the United States have each implemented their unique DOT legislation and programs. 44 ,46-49 In New York City in 1993, the Commissioner of Health was given the power to use legal action to ensure treatment of patients infected with TB. A study of the first 2 years of the program showed an incredible 96% rate of treatment completion among patients legally required to undergo treatment; ultimately, new cases decreased by 55% and MDR disease decreased by 87.3% between 1992 and 1997. 50 These recent actions have opened debate about the differences in public opinion concerning the conflict posed by DOT: the rights of the individual versus the benefits to society.7,45 Because of the debate, proponents of legal action must tread lightly in cases in which danger to society is not obvious, and health department policies typically institute detention only when all less restrictive approaches fail to· work. 7 This will generally work against the ophthalmologist, because intraocular TB is often encountered in patients with no concurrent sign of active systemic disease. Convincing a legal authority that it is to the public's benefit to detain a patient with isolated ocular disease would be extremely difficult. However, current legal doctrine also allows detention of a patient to perform diagnostic tests if TB infection is suspected. An ophthalmologist who reveals evidence of potential sys-

temic disease during a review of systelns may be able to justify invoking legal action to ensure diagnosis (or absence of disease), and subsequently ensure compliance to treatment.50 This touchy issue will most likely spur more research to find therapies that work as effectively as the currently available medications without the necessity of long-term treatment.

Many of the complications of tuberculous uveitis are also commonly seen in uveitis from other causes; these include posterior synechiae, retinal detachment, and neovascular glaucoma. Some complications are more specific-subretinal abscesses, for example. There are also a few case reports of spontaneous scleral rupture. Retinal neovascularization can be seen,22, 51 with one report noting a good response to sector ablation with argon laser photocoagulation while the patient was on antimycobacterial treatment. 52 Unfortunately, enucleation or evisceration of a blind and painful eye is not a rare consequence of tuberculous uveitis. 20 , 24, 27, 53 These cases tend to present as uncontrolled panophthalmitis, which can progress unremittingly even when the patient is on antimycobacterial treatment. Complications can occur from the antilnycobacterial therapy itself. Isoniazid toxicity includes neurologic toxicity, which includes peripheral neuritis, insomnia, increased agitation, urinary retention, and seizures. These effects are thought to occur from a relative pyridoxine deficiency and can be minimized with the administration of pyridoxine. INH is also associated with hepatotoxicity, and associated fatalities have been reported. Rifampin has been associated with thrombocytopenia, nephritis, and liver toxicity. Pyrazinamide has also been associated with liver toxicity. Ethambutol has been associated with optic neuritis that can regress with discontinuation of the drug. Streptomycin is associated with eighth nerve toxicity. INH can increase blood levels of phenytoin, and rifampin induces microsomal enzymes and can affect metabolism of microsome-dependent drugs (e.g., warfarin).

HIV disease is a contributing factor in the re-emergence of TB in recent times. Because of impaired cell-mediated immunity in HIV-infected individuals, one would expect to see increased susceptibility and increased severity of TB when compared with TB infection in patients with intact immune systems. This is, in fact, what is observed: patients with AIDS have nearly 500 times the risk of contracting TB than those in the general population. 10 Most reported cases of TB uveitis in HIV-infected individuals occur in the context of chorioretinitis presenting in association with active systemic TB or while on treatment for proven systemic infection 54 - 56 (Table 18-1). Sometimes, choroidal tubercles are noted on routine ophthalmic examination in the absence of ocular complaints. Tuberculous eye lesions undergo resolution paralleling the systemic course. 54,56 One case report described a patient whose autopsy revealed disseminated miliary TB, which had not been suspected clinically.25 Ophthalmologic examination of the patient had revealed two

CHAPTER 18: TUBERCULOSIS TABLE 18-1. CASE REPORTS ON HIV-INFECTED PATIENTS WITH TB UVEITIS

AUTHORS

PATIENT CHARACTERISTIC

EYE

METHOD OF DIAGNOSIS

SYSTEMIC SIGNS OF TB?

Croxatto JO et aI, 198625

32 yo m

OU

Biopsy (postmortem)

Yes

Blodi BA et aI, 198955

34 yo m

OD

Presumed (positive sputum culture)

Yes

Blazques EP et aI, 199454

31 yo m

OD

Yes

28 yo m

OU

35 yo m

OD

19 yo m

OU

Muccioli C et aI, 199656

35 yo w

OU

Recillas-Gispert C et aI, 199740

29 yo w

OS

Presumed (tests positive for systemic) Presumed (tests positive for systemic) Presumed (tests positive for systemic) Presumed (tests positive for systemic) Presumed (AFB-positive sputum) PCR from aqueous specimen

Yes (systemic meningitis) Yes

TYPE OF UVEITIS

Focal chorioretinitis OD; cottonwool spots OU Granulomatous anterior uveitis, disseminated chorioretinitis OD Focal chorioretinitis OD

+

Focal chorioretinitis OU Focal chorioretinitis OD

Yes

Disseminated chorioretinitis OU

Yes

Focal chorioretinitis OD; vitritis OU An.terior uveitis, vitritis, vasculitis OS

Yes

AFB, Acid-fast bacilli; peR, polymerase chain reaction.

choroidal nodules in the right eye, illustrating that routine ophthalmologic examination may aid the internist in formulating a differential diagnosis in an HIV-infected patient with an undiagnosed systemic illness. The treatment of TB in HIV-infected individuals is also problematic. Patients with AIDS often have decreased gastrointestinal absorption, resulting in inadequate serum levels of the antimycobacterial drugs. The CDC recommends extending the duration of TB treatment in HIVinfected individuals.

PROGNOSIS If TB is diagnosed and treated promptly, in most cases, a cure follows. With appropriate monitoring and adherence to current treatment guidelines, medications are safe and well tolerated. Reports in the ophthalmic literature support the fact that current antituberculous medications are extremely effective, and failures in treating ocular disease have been attributed to delayed diagnosis, a rapid and aggressive course, death of the patient to systemic infection, or noncompliance. The most common reason cited for treatment failure among patients with pulmonary TB is nonadherence to the therapeutic regimen. In New York City in 1991, a study showed that 89% of 189 patients failed to complete therapy, and 80% of those brought back failed a second time. 44 Resistance to isoniazid or rifampin in 1991 was 23%, the high number most likely related to the number of patients who stopped treatment before eradicating the organism from their body. It is for this reason DOT is now recommended by the CDC as a routine part of treatment. Failures in DOT cases have led investigators to realize that other aspects of the disease process and therapy are still not well understood. One such aspect is therapeutic drug monitoring (TDM) ,57 the process of adjusting drug doses based on serum concentration. Bioassays demonstrate that bioavailability of the drug can vary greatly among individuals and may account for failures in which compliance is not an issue. 58

Mycobacterium tuberculosis is one of the few causes of uveitis for which we have a definitive, highly effective treatment. Its most common manifestation is disseminated or focal chorioretinitis, which may be associated with vitritis or anterior uveitis. It can occur both in patients with active TB infection and in patients without signs or symptoms of systemic TB. Definitive diagnosis is often difficult; treatment is often instituted if other contributory objective data strongly support the diagnosis. Prognosis is excellent if an appropriate drug regimen is prescribed and patient compliance can be ensured.

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14. 15. 16. 17.

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the face (eyelids) of a child [letter]. Am j Ophthalmol 1996; 121:717-718. CameronjA, NasI' AM, Chavis P: Epibulbar and ocular tuberculosis. Arch Ophthalmol1996;114:770-771. Anhalt EF, Zavell S, Chang G, Byron HM: Conjunctival tuberculosis. Amj Ophthalmol 1960;50:265-269. Grewal A, Kim RY, Cunningham ET: Miliary tuberculosis. Arch Ophthalmol 1998;116:953-954. Barondes Mj, Sponsel WE, Stevens TS, Plot:nik RD: Tuberculous choroiditis diagnosed by chorioretinal endobiopsy. Am J Ophthalmol 1991;112:460-461. Mansour AM, Haymond R: Choroidal tuberculomas. without evidence of extraocular tuberculosis. Graefe's Arch Clin Exp Ophthalmol 1990;228:382-385. Cangemi FE, Freidman AH, josephberg R: Tuberculoma of the choroid. Ophthalmology 1980;87:252-258. Lyon CE, Grimson BS, Pfeiffer RLL, et al: Clinicopathological correlation of a solitary choroidal tuberculoma. Oph thalmol 1985; 92:845-850. Berinstein DM, Gentile RC, McCormick SA, Walsh jB: Primary choroidal tuberculoma. Arch Ophthalmol 1997;115:430-431. Rosen PH, Spalton Dj, Graham EM: Intraocular tuberculosis. Eye 1990;4:486-492. Biswasj, Narain S, Das D, Ganesh SK: Pattern of uveitis in a referral uveitis clinic in India. Int Ophthalmol 1996;20:223-228. Biswasj, Madhavan HN, Gopal L, Badrinath SS: Intraocular tuberculosis. Clinicopathologic study of five case. Retina 1995;15:461468. Croxatto jO, Mestre C, Puente S, Gonzalez G: Nonreactive tuberctllosis in a patient with acquired immune deficiency syndrome [letter]. Amj Ophthalmol 1986;102:659-660. Dvorak-Theobald G: Acute tuberculous endophthalmitis. Amj Ophthalmol 1958;45:403-407. Ni C, Papale lJ, Robinson NL, Wu BF: Uveal tuberculosis. Int Ophthalmol Clin 1982;22:103-124. Stead WW: The origin qnd erratic;, global spread of tuberculosis. Clin Chest 1997;18:65-78. ~ Dutt AK, Stead W: The treatment of tuberculosis. Dis Mon 1997;43:247-271. Swaminathan S, Gong j, Zhang M, et al: Cytokine production in children with tuberculosis infection and disease. Clin Infect Dis 1999;28:1290-1293. Mohaghehhpour N, Gammon D, Kawamura LM, et al: CTL Response to Nlycobacterium tuberculosis: Identification of an immunogenic epitope in the 19-kDa lipoprotein.j Immunol1998;161:24002406. Telenti A: Genetics of drug resistance in tuberculosis. Clin Chest 1997;18:55-64. LoBue PA, Catanzaro A: The diagnosis of tuberculosis. Dis Mon 1997;43:185-219. Burgoyne CF, Verst:raeten TC, Friberg TR: Tuberculin skin-test induced uveitis in the absence of tuberculosis. Graefes Arch Clin Exp Ophthalmol 1991;229:232-236. jonas V, Longiaru M: Detection of Nlycobacteriwn tuberculosis by molecular methods. Clin Lab Med 1997;17:119-128.

36. Kotake S, Kimura K, Yoshikawa K, et al: Polymerase chain reaction for the detection of Nlycobacteriuni tuberculosis in-ocular tuberculosis [letter]. Am j Ophthalmol 1994;117:805-806. 37. Gladwin MT, Plorde lJ, Martin TR: Clinical application of the Nlycobacterium tuberculosis direct test. Chest 1998;114:317-323. 38. Sarvanantahn N, Wiselka M, Bibby K: Intraocular tuberculosis without detectable systemic infection. ArchOphthalmol 1998;116:13861388. 39. Bowyer jD Gormley PO, Seth R, et al: Choroidal tuberculosis diagnosed by polymerase chain reaction. Ophthalmol 1999;106:290294. 40. Recillas-Gispert C, Ortega-Larrocea G, Arellanes-Garcia L, et al: Chorioretinitis secondary to iVIycobacteriwn tuberculosis in acquired immune deficiency syndrome. Retina 1997;17:437-439. 41. Cokerill FR: Conventional and genetic laboratory tests used to guide antimicrobial therapy. Mayo Clin Proc 1998;73:1007-1021. 42. Schlaegel TF jr, Webber jC: Double-blind therapeutic trial of isoniazid in 344 patients with uveitis. Br j Ophthalmol 1969;52:425-427. 43. Bradford WZ, Daley CL: Multiple drug-resistant tuberculosis. Infect Dis Clin North A 1998; 12:157-172. 44. Fl~iwara PI, Larkin C, Frieden TR: Directly observed therapy in New York City. Clin Chest 1997;18:135-148. 45. Campion EW: Liberty and the control of tuberculosis. N Engl ] Med 1999;340:385-386. 46. Chaluk CP, Pope DS: The Baltimore city healtll department program of directly observed therapy for tuberculosis. Clin Chest 1997;18:149-154. 47. Weis SE: Universal directly observed therapy. Clin Chest 1997;18:155-163. Francisco. CUn Chest 48. Schecter GF: Supervised therapy in 1997;18:165-168. 49. Sbarbaro jA: Directly observed therapy. Clin Chest/l~97;8:131-133. 50. Gasner MR, Maw KL, Fledman GE, et al: The use of legal action in New York City to· ensure treatment of tuberculosis. N Engl j Med 1999;340:359-365. 51. Chung YM, Yeh TS, Sheu Sj, Liu jH: Macular subretinal neovascularization in choroidal tuberculosis: Ann Ophtll1amol 1989;21:225229. 52. Gur S, Silverstone BZ, Zylberman R, Berson D: Chorioretinitis and extrapulmonary tuberculosis. Arm Ophthalmol 1987;19:112-115. 53. Darrel RW: Acute tuberculous panophthalmitis. Arch Ophthalmol 1967;78:51-54. 54. Blazques EP, Rodriguez MM, Mendes Ramos MJ: Tuberculous choroiditis and acquired immunodeficiency syndrome. Arm Ophthalmol 1994;26:50-54. 55. Blodi BA,jolmson MW, McLeish WM, GassjD: Presumed choroidal tuberculosis in a human immunodeficiency virus infected host. Am j Ophthalmol 1989;108:605-606. 56. Muccioli C, Belfort R: Presumed ocular and central nervous system tuberculosis in a patient with the acquired immunodeficiency syndrome [letter]. Amj Ophthalmol 1996; 121:217-219. 57. Peloquin CA: Using therapeutic drug monitoring to dose the antimycobacterial drugs. Clin Chest 1997;18:79-87. 58. Heifets L: Mycobacterial laboratory. Clin Chest 1997;18:35-53. 59. Helm Cj, Holland GN: Ocular tuberculosis. Surv Ophthalmol 1993;38:229-256.

M. Reza Dana

Leptospirosis is a zoonotic infection caused by the gramnegative helical spirochete Leptospira interrogans. The infection, which has a worldwide distribution, is most common in warmer climates. The reservoir for leptospirosis is animals, often rodents and cattle, which excrete leptospires in their urine as a result of chronic infection. The disease is usually contracted by humans exposed to contaminated soil or surface water. It is characterized by an acute short phase of 7 to 10 days, followed by an immune phase that may last for many months. Ophthalmic complications of systemic leptospirosis were first reported by Adolf Weil in 1886. 1, 2 Inflammatory ophthalmic disease, which typically occurs several months after the onset of the acute systemic disease, can vary greatly in presentation and severity. However, leptospiral uveitis generally has a favorable prognosis if diagnosed and treated appropriately. Leptospirosis is one of the most common zoonoses in the world. 3 Although the distribution is worldwide, it occurs most frequently in the tropical and subtropical areas of the globe, and in developing nations where contact with infected animals, or water or solI contaminated with their urine, is most likely to occur. 4 ,5 The natural hosts of leptospira are rodents, dogs, pigs, and cattle, which may transmit the disease to humans. 6 Maternal-fetal transmission may occur but is thought to be uncommon. The most common sources of infection include urine of infected animals, and contaminated surface water or mud harboring infectious leptospira from animal excretions. Infection occurs via direct contact with animal blood or urine (e.g., farmers and abattoir workers) or, more commonly, via indirect contact with contaminated water, as may happen with farmers in rice paddies, sewer workers, or swimmers in contaminated waters. 5 , 7 Leptospires usually enter the body through mucous membranes or skin abrasions. 5 Because of these epidemiologic characteristics of disease transmission, the majority of infected patients are young men and boys in the lower socioeconomic strata of the population. Because the disease occurs primarily in less developed areas of the globe, the true incidence remains largely unknown. It is believed, however, that the prevalence of leptospirosis is underreported, even in the United States, where many cases eventually related to leptospirosis are initially misdiagnosed. s, 9 In countries where leptospirosis is endemic, it is often confused with malaria, tuberculosis, viral hepatitis, typhoid, aseptic meningitis, influenza, or other infections, because these diseases themselves are so common in these areas. 10, 11 In the United States, where approximately 100 cases are reported annually to the Centers for Disease Control and Prevention in Atlanta, leptospirosis is most common in Hawaii. 5 This disease is considered an important occupational hazard of taro farming, which involves wading in shallow water.

Nonocular Disease The spectrum of human disease caused by leptospira species is extremely wide, ranging from subclinical infection to a fatal syndrome (Weil's syndrome), characterized by multisystem hemorrhage, renal failure, jaundice, and cardiac shock. 10 Accordingly, mortality can vary greatly from nearly zero to over 30%, depending on multiple variables including the serovar of the infecting organism. 10, 12 Generally, the disease is biphasic.u It begins acutely with the abrupt onset of fever, headache, fatigue, and myalgia. Some patients develop significant abdominal pain and associated nausea and vomiting, or diarrhea. These symptoms herald the onset of the spirochetemic phase of the illness, during which spirochetes can be found in the blood, cerebrospinal fluid, kidneys, and other organs. 13 Although a variety of rashes can accompany other stigmata of the disease, there is no consistent pattern to the rashes. 14 Occurrence of leptospirosis in pregnancy carries a high risk of intrauterine infection and fetal death. 6 The spirochetemic phase can vary from 2 to 3 days of mild disease to 7 to 10 days of severe multisystem symptoms in some patients. The septicemic stage of lep- ' tospirosis is followed by the spirocheturic (or immune) phase of the disease. This occurs as a result of the immune response to the infection; however, the kidneys and ocular compartments can harbor live leptospira for a longer period. 5 ,lO There is often a quiescent period between the two stages of the illness before the immune phase becomes clinically apparent. The subsequent course of the illness depends largely on which of the two clinical syndromes develops: anicteric leptospirosis (90% of cases), or icteric leptospirosis (10 % of cases), according to the degree of hepatic involvement. Many patients with anicteric disease have a mild course characterized by a self-limited condition that can resolve with no serious sequelae. The most important features of the immune stage are meningitis and leptospiruria. Fever is generally not a prominent sign. Other sYJ-TIptoms may develop such as nonmeningitic neurologic manifestations, nerve palsies, myelitis, or uveitis, which can occur many months after the acute stage of the illness. Commonly, patients with anicteric disease seek medical attention without a clear preceding illness. 5 On the other hand, some patients with very mild septicemic disease do not develop any clinical disease during the immune phase of the disease. Unlike the mild course of anicteric leptospirosis, icteric disease, which is characterized by jaundice and azotemia, can lead to a mortality rate of over 10% to 30%. In fact, the illness in some individuals is so severe that it obscures the biphasic nature of the disease. 5 In Weil's sYJ-1.drome, patients may progress rapidly to multisystem failure with a high chance of mortality unless they receive

CHAPTER 19 LEPTOSPIROSIS

early (e.g., in the first 4 days) antimicrobial and supportive treatment (see later) for their illness.

Ocular Disease The incidence of ocular disease in leptospirosis remains unknown. Given that systemic leptospirosis is underdiagnosed9 and leptospiral uveitis often occurs many months after the onset of the systemic disease, there is little doubt that the burden of eye disease due to leptospirosis is underestimated. The earliest and most common sign of ocular leptospirosis is conjunctival hyperemia or hemorrhage,6, 15,16 but this finding does not lead to visual disability. In contrast, the most serious ocular complication of leptospirosis is the development of uveitis. It is estimated that uveitis occurs in 2% to 10% of patients suffering from leptospirosis. 12 This syndrome, which was first described by Wei1,2 has been reported to occur either early, or as late as several years after the onset of the systemic disease. 15 ,16 Two distinct categories of leptospiral uveitis have been described. One form involves patients who develop anterior uveitis with photophobia, blurred vision, and pain. Leptospiral anterior uveitis, which is thought to be largely benign,17, 18 is believed to be the most common fonn of uveitis in leptospirosis by a number of investigators. 1, 15, 17 A second group of patients are those who develop posterior segment involvement including vitritis, choroiditis, papillitis, or panuveitis. 1, 19 In a study of leptospiral and nonleptospiral uveitis in India, Chu ll:Pd colleagues 10 evaluated a number of clinical variables to determine the constellation of findings most suggestive of leptospiral uveitis in an endemic area. These investigators concluded that in comparison to other forms of uveitis, leptospirosis has a higher propensity for posterior uveitis, vasculitis, papillitis, and vitritis. The potential development of posterior findings including vitreal membranes, retinal exudates, and optic neuritis in leptospirosis is well dOCllmented. 1, 19-21 However, it remains unclear whether generalizations regarding disease manifestations in one geographic region can be validly applied to other endemic areas. Disparities in data regarding the ocular presentation of leptospirosis most likely occur because the clinical presentation of infectious disease depends both on the virulence of the infecting organism and on the genotype of the host (which dictates the immune response to the infectious agent). Because of significant variations in both these parameters between different geographic locales, leptospiral uveitis may present very differently from one endemic area to another. Two recent case series have evaluated the ocular manifestations of leptospirosis. Martins and coworkers reported on 21 patients, 20 men and one woman, presenting with acute systemic leptospirosis in Brazil. 16 They reported conjunctival hyperemia among 86%, increased retinal venous caliber among 57%, optic nerve head hyperemia among 57%, subconjunctival hemorrhage among 19%, optic disk edema among 5%, and retinal vasculitis and hemorrhage among 5%. The visual acuity of affected patients ranged from 20/20 to light perception. Interestingly, they did not observe a single case of anterior segment inflammation, underscoring the fact that

uveitis tends to occur in the late immune phase of leptospirosis. In the other recent series, Rathinam and coinvestigators reported on cases of uveitis seen in Madurai, India, after heavy rainfall and unexpected flooding led to an epidemic outbreak of leptospirosis. 4 In 73 consecutive patients with leptospiral uveitis associated with this epidemic, III eyes were examined. As in the group in Brazil, the vast majority (82%) of patients were young men (mean age, 35), and 78% were classified as having "low socioeconomic status," emphasizing the group at highest risk for this zoonosis. Of the 73 patients, 52% had bilateral involvement. Among the III eyes with uveitis, panuveitis was seen in 95%, anterior uveitis alone in 3%, and vitritis alone in 2%. Typical anterior segment findings among these patients included nongranulomatous reaction (92%), posterior synechiae (24%), and hypopyon (13%). Typical posterior segment findings included vitreous inflammation and debris (89%), and intermittent periphlebitis (51 %). Notably, macular edema, epiretinal membrane formation, and intermediate uveitis were distinctly rare complications, occurring in less than 2% to 3% of affected eyes. Interestingly, in spite of the frequency of posterior findings and panuveitis, final visual acuity was 20/20 in 52% of eyes; another 16% showed improvement in acuity following treatment, but not to the level of 20/20. The authors of this study concluded that the prognosis of leptospiral uveitis is generally favorable even when the ocular inflammation is severe and the involvement is posterior. 4

Leptospirosis is a zoonotic infection caused by the gramnegative helical spirochete Leptospira. Spirochetes are grouped together on the basis of their common structural features and motility characteristics. 11 Within the order Spirochaetales are two families: Spirochaetales and Leptospiraceae. Four genera belong to the former, and two to the latter. Of the six genera, three- Treponema, Borrelia, and Leptospira-contain organisms that cause hUlnan disease. The leptospira can be divided into those that are pathogenic (i.e., L. interrogans) and those that are saprophytic (i.e., L. bijlexa).5 The saprophytes can be differentiated from the pathogens by their ability to grow at lower temperatures. Among the pathogenic species L. interrogans are over 200 serovars. Serovars that are closely related because they share common antigenic epitopes are grouped into serogroups. These organisms have a short incubation period, and as early as the first week after infection the host IgM response can be detected. This peaks during the next 2 to 4 weeks and may remain positive for significantly longer. The exact immunopathogenesis of leptospiral uveitis is not completely understood. It has been proposed that uveitis occurs because antileptospiral antibodies are slow to migrate into the anterior chamber but are rapidly cleared, allowing the organism to flourish. 22 It has been speculated that the clinical disease in leptospirosis is both a reflection of bacterial toxins or enzymes released by the infecting organisms that can cause direct tissue injury, 15, 23 and an immune vasculopathy related to activation of complement and deposition of immune com-

CHAPTER 19 LEPTOSPIROSIS

plexes. This microangiopathy can lead to neutrophilluargination to the vascular endothelium-'-thereby allowing tissue injury after transendothelial migration of activated leukocytes. 24

Diagnosis of human leptospiral infection relies on either isolation of the causative organism, or its DNA, from body fluids, or demonstration of a rise in specific serum antibodies. 25 Detection of leptospires in body fluids by darkfield microscopy is limited because of proteinaceous filaments (pseudoleptospires) that can be present. 26 The isolation of leptospira is best done during the early spirochetemic phase of the infection-typically during the first week of infection. During this period, leptospira may be isolated from blood and cerebrospinal fluid (CSF) , although the yield is higher frOlu the bloodY Recovery can be optimized if samples are obtained daily, preferably before antibiotic therapy, although delay in treatment in an attempt to increase diagnostic yield is generally illadvised, as other diagnostic measures may be employed (see later). Usually, only one to two drops of blood are inoculated in medium (bovine serum albumin-Tween 80, semisolid [0.2% agar]), because larger inocula are paradoxically associated with growth inhibition. l l , 27 One method of increasing the yield of the infecting organism is to inject the specimen derived from the patient into hamsters or guinea pigs, and then to isolate th~ leptospires from moribund animals. Isolation media are incubated at 30°C and examined 'weekly. Growth is usually detectable after 2 weeks of incubation, but it may require longer than 6 weeks. Mter the first 1 to 2 weeks of disease, when leptospirosis enters its spirocheturic phase, leptospires may be detected in urine, where they are shed for 1 month or longer. Because the organism has a short half-life in acidic urine, specimens should be cultured as soon as possible-usually within the hour. l l Isolation of leptospira, as has been described, is difficult and very resource intensive. Moreover, because of the time lag between culture and diagnosis, isolation techniques for spirochetal disease are not always useful from an acute patient management standpoint. Over the years, the microscopic agglutination test (MAT) has become the reference test for diagnosis of leptospiral disease. This test, which can detect antibodies to many different serovars, is complex and needs maintenance of stock cultures of different leptospiral serovars; hence, it is best performed in specialized reference laboratories such as those of the World Health Organization or the Centers for Disease Control and Prevention. 4, 10, 25 Generally, serum samples from suspected patients are collected and diluted at 1:50 to 1: 100 and tested against a pool of several dozen pathogenic serovars of L. interrogans. Reactive sera are then subjected to serial twofold dilutions and reacted against each serovar to determine the end-point titer. 4, 10 Because there is cross-reactivity to different seroval'S, standard practice dictates that the serovar reacting at the highest titer is presumed to be the one responsible for the infection. The MAT requires a specialized laboratory and personnel.2 5 For this reason, practical diagnosis of leptospirosis is becoming increasingly based on enzyme-linked immu-

nosorbent assays (ELISA) for leptospiral-specific antibodies. ELISA offers a rapid, sensitive, and specific assay for detecting immunity to leptospiral antigens, and it is less susceptible to subjective interpretation of laboratory personnel than MATY, 25, 2S, 29 ELISA kits are commercially available and have been shown to have a 100% sensitivity when tested to known infected sera. ELISA titers can be positive for sera from patients with Brucella, Epstein-Barr virus, cytomegalovirus, mycoplasma, Q fever, toxoplasma, and several other diseases, but the reactive titers in these cases are almost universally low. Moreover, the persistence of high IgM titers in leptospirosis for as long as 48 months after infection, which has been reported by multiple investigators,25 makes assaying for IgM a sensitive and good initial screen for leptospirosis. High titers can then be confirmed by MAT in a specialized reference laboratory. More recently, polymerase chain reaction (PCR) has been used to amplify leptospiral DNA. 10, 30,31 PCR can be used to detect leptospiral DNA in aqueous humor of individuals with suspected leptospiral uveitis. IS The capacity of PCR to profoundly amplify low copy numbers of DNA theoretically provides for a highly sensitive assay.lO In a recent study in India, 28% of aqueous humor PCRpositive leptospiral uveitis patients did not demonstrate serum antileptospiral antibodies. lo Hence, it remains unknown whether leptospiral uveitis correlates well with serum antibody titers. It has been postulated that because uveitis typically occurs months after the acute illness and seroconversion, systemic antibody levels may not be sensitive indicators of disease. However, because concerns regarding false-positive and false-negative results with PCR persist, it is strongly advisable to use this diagnostic modality primarily in cases when the diagnosis is uncertain and as an adjunct to ELISA and MAT.

The diagnosis of leptospiral disease is primarily based on clinical and laboratory criteria. Because none of the ocular findings are specific or pathognomonic, definitive diagnosis requires laboratory confirmation. However, because timely treatment can have significant extraocular ramifications, it is important to consider and discuss the differential diagnosis. Although leptospiral uveitis may present with profound anterior chamber inflammation and hypopyon, it may be differentiated from HLA-B27-associated uveitis by the high prevalence of bilaterality, vitreal inflalumation, and vasculitis. These features, although possible in seronegative spondyloarthropathies, are uncommon. Moreover, the nonocular clinical presentation in HLA-B27associated disease is very different from that seen in leptospirosis. Leptospiral uveitis may be· differentiated from idiopathic pars planitis by the preponderance of cystoid macular edema in idiopathic pars planitis, and intense anterior chamber inflammation in the former. Occasionally, leptospiral .disease can be confused with Adamantiades-Beh<;et's disease (ABD), especially because ABD can also cause panuveitis, retinitis, and central nervous system stigmata. However, the pattern of vasculitis varies between these entities. ABD patients often have occlusive vasculitis as opposed to the intermittent periphlebitis seen in leptospirosis. Moreover, ABD is associ-

CHAPTER 19

ated with HLA-B5/51, whereas such an association is not present in leptospirosis. Similarly, patients with Eales' disease have peripheral vasculitis and neovascularization, whereas .severe vitritis and panuveitis are uncommon. Finally, because mycobacterial and spirochetal diseases often coexist with a similar epidemiology, it is important to consider ocular tuberculosis (TB) in the differential diagnosis. Patients with the ocular TB are purified-protein-derivative (PPD) positive, and they often have positive chest x-ray findings suggestive of granulomata. Ocular TB is among the great masqueraders, but there is often a choroidal tubercle and the uveitis is typically granulomatous in type, as opposed to the overwhelmingly nongranulomatous disease in leptospiral uveitis. There is some controversy about the treatment of leptospirosis. 32 First, it is important to recognize that results of in vitro susceptibility testing for leptospires cannot be automatically extrapolated to the clinical setting. l l In vitro susceptibility studies suggest that pathogenic leptospiral serovars are susceptible to all of the commonly used antibiotics except chloramphenicol. However, whereas the minimal inhibitory concentration (MIC) for penicillin G is generally low, penicillin appears to have inadequate leptospiricidal activity in vivo. 33 Hence, although penicillin G is highly effective against some spirochetes (e.g., treponemes), it should not be assumed that it is the drug of choice for leptospirosis. At present, doxycycline at the adult dose of 10Q, mg twice daily for 10 to 14 days is the standard antimiclobial treatment,34,35 although many alternatives including cephalosporins may be used instead. 36 , 37 A critical facet of systemic treatment is that it should be instituted, whenever possible, during the first 4 days of illness to shorten the duration and decrease the severity of the disease. Significant controversy exists concerning the effectiveness of antimicrobial therapy later in the course of the disease. 4, 11 Most authors believe that treatment late in the course of the disease is of limited value. However, because others have argued that pathogenic leptospira can survive and multiply in the blood and anterior chamber for a long time,38 we agree with the recommendations of Rathinam and colleagues,4 who propose systemic antibiotic treatment for eye disease even months after onset of the acute systemic illness. In addition to instituting appropriate systemic antimicrobial treatment, the care of the patient with leptospiral uveitis involves judicious use of local (topical and. periocular depot injections) corticosteroids to suppress ocular inflammation. Anticholinergic mydriatics can relax the iris sphincter and provide some relief to patients with ocular pain. Moreover, anticholinergics can help with the resolution of anterior uveitis by promoting restoration of the blood-ocular barrier. Most uveitic cases are brought under rapid control with adoption of these standard antiinflammatory measures. There is no place for immunosuppressive chemotherapy in the care of patients with leptospiral disease.

PROGNOSIS Most of the available data suggest that the visual prognosis of leptospiral uveitis is quite favorable. 4, 16 Attention

to fundamentals of good ophthalmologic care of uveitis patients, namely suppression of oCLllar inflammation and treatment of comorbidities such as ocular hypertension and macular edema, is imperative. Because leptospirosis is an infectious disease, it is important (particularly in the acute phase) to institute proper systemic antibacterial treatment before intensive anti-inflammatory strategies are employed, as the latter can suppress innate and acquired immune responses to pathogenic leptospira. The most critical prognosticator for the patient with leptospirosis is the severity of the systemic illness as detailed in the preceding sections. Patients with multisystem disease (Weil syndrome) and impending renal failure need life-saving dialysis,16 and those with hemorrhagic disease need intensive intravenous fluids to prevent cardiac shock. Often, with appropriate and timely treatment, even the most severe cases of leptospiral infection can be successfully treated with little to no functional deficits.

CONCLUSIONS Leptospirosis is a common zoonosis, particularly among patients from low socioeconomic strata of developing nations. Leptospiral uveitis can have a wide range of presentations during both the acute and chronic phases of the illness. Most patients have a favorable visual prognosis with appropriate therapy, even when the ocular involvement is extensive and severe. Timely diagnosis of leptospirosis is critical not only for maximizing visual potential but also for appropriate systemic monitoring and treatment of extraocular involvement in this potentially fatal condition. Ultimately, effective public health and sanitation measures in endemic areas are imperative for optimal protection of farmers and other laborers against exposure to infecting leptospira.

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19 LEPTOSPIROSIS phytic leptospires. 1. Growth at low temperatures. J Bacteriol 1967;94:27. 12. Johnson RC: Isolation techniques for spirochetes and their sensitivity to antibiotics in vitro and in vivo. Rev Infect Dis 1989;II(S) :S1505. 13.. Feigin RD, Anderson DC: Human leptospirosis. Crit Rev Clin Lab Sci 1975;5:413. 14. Schmid GP, Steere AC, Kornblatt AN, et al: Newly recognized species ("Leptospira inadai" serovar lyme) isolated from human skin. J Clin Microbiol 1986;24:484. 15. Farr RW: Leptospirosis. Clin Infect Dis 1995;21:1. 16. Martins MG, Matos KTF, da Silva MV, de Abreu MT: Ocular manifestations in the acute phase of leptospirosis. Ocul Immunol Inflamm 1998;6:75. 17. Barkay S, Garzozi H: Leptospirosis and uveitis. Ann Ophthalmol 1984;16:164. 18. Merien R, Perolat P, Mancel E, et al: Detection of Leptospira DNA by polymerase chain reaction in aqueous humor of a patient with unilateral uveitis. J Infect Dis 1993;168:1335. 19. Levin N, Ngyuyen-Khoa JL, Charpentier D, et al: Panuveitis with papillitis in leptospirosis. Am J Ophthalmol 1994;117:118. 20. Whitcup SM, Raizman MB: Spirochetal infections and the eye. In: Albert DM,Jakobiec AF, eds: Principles and Practice of Ophthalmology, vol 5. Philadelphia, W.B. Saunders, 1994, p 3089. 21. Woods AC: Granulomatous uveitis. In: Endogenous Inflammations of the Uveal Tract. Baltimore, Williams and Wilkins, 1961, p 76. 22. Austoni M, Moro F: L'uveite quale manifestazione della sindrome oculoinflammatoria della leptospirosi, con particolare riguarelo ad una forma di ciclite sierosa silente in pazienti clinicalmente guariti. G Mal Infett Parassit 1952;4:339; summary in Exerpta Med [sect 12} OpthalmoI1954;8:353. 23. Watt, G: Leptospirosis. In: Strickland GT, ed: Hunter's Tropical Medicine. Philadelphia, W.B. Saunders, 1991, p 317. 24. Dobrina A, Nardon E, Vecile E, et al: Leptospira icterohenwrrhagiae and Leptospire peptidoglycans induce endothelial cell adhesiveness for polymorphonuclear leukocytes. Infect Immun 1995;63:2995. 25. Winslow WE, Merry DJ, Pirc ML, Dhine P: Evaluation of a commercial enzyme-linked immunosorbent assay for detection of immuno-

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34. 35. 36. 37.

38.

globulin M antibody in diagnosis of human leptospiral infection. J Clin Microbiol 1997;35:1938. Faine S, Alder B: Leptospirosis. In: Hartwig N, ed: Clinical Microbiology Update Program, no 24. Department of Microbiology; Monash University, Melbourne, Victoria, Australia, 1984, pp 7-19. Johnson RC: Leptospirosis. In: StriCKland GT, ed: Hunter's Tropical and Geographic Medicine. Philadelphia, W.B. Saunders, 1990, p 889. Cinco M, Balanzin D, Banfi E: Evaluation of an immunoenzymatic test (ELISA) for the diagnosis of leptospirosis in Italy. Eur J Epidemiol 1992;8:677. da Silva MV, Camargo ED, Vaz AJ, Batista L: Immunodiagnosis of human leptospirosis using saliva. Trans R Soc Trop Med Hyg. 1992;86:560. Bal AE, Gravekamp C, Hartskeerl RA, et al: Detection of leptospires in urine by PCR for early diagnosis of leptospirosis. J Clin Microbiol 1994;32:1894. Brown PD, Gravekamp C, Carrington DG, et al: Evaluation of the polymerase chain reaction for early diagnosis of leptospirosis. J Med Microbiol 1995;43:110. Stoenner HG: Treatment and control of leptospirosis. In: Johnson RC, ed: The Biology of Parasitic Spirochetes. New York, Academic Press, 1976, p 375. Cook AR, Thompson RE: The effects of oleandomycin, erythromycin, carbomycin, and penicillin G on Leptospira icterohaemorrhagiae in vitro and in experimental animals. Antibiot Chemother 1957;7:425. McClain JBL, Ballou WR, Harrison SM,. Steinweg DL: Doxycycline therapy for leptospirosis. Ann Intern Med 1984;100:696. Takafl~i ET, Kirkpatrick]W, Miller RN, et al: An efficacy trial of doxycycline chemoprophylaxis against leptospirosis. N Engl J Med 1984;310:497. Alexander AD, Rule PL: Penicillins, cephalosporins, and tetracyclines in treatment of hamsters with fatal leptospirosis. Antiinicrob Agents Chemother 1986;30:835. Oie S, Hironaga K, Koshiro A, et al: In vitro susceptibilities of five Leptospira strains to 16 antimicrobial agents. Arltimicrob Agents Chemother 1983;24:905. Gollop JH, Katz AR, Rudov RC, Sasaki DM: Rat bite leptospirosis. WestJ Med 1993;159:76.

Albert T. Vitale

Brucellosis is a zoonotic disorder caused by infection with Brucella spp. and remains a major source of disease in domesticated animals and in humans in many parts of the world. Its clinical manifestations in humans include a broad spectrum of multisystemic and ocular findings, with uveitis being the most common ophthalmic presentation. Diagnosis requires a high degree of suspicion within the appropriate clinical context and may be confirmed by serologic testing and by isolation and culture of the causative organism. Timely recognition of this disease is highly desirable, because therapy with specific antimicrobial agents may be curative.

HISTORY Following the capture of Malta from the French in 1799, many British soldiers were afflicted by a febrile illness known as Maltafever; a disease that had been prevalent in the Mediterranean region for centuries. 1 Its etiology was elucidated by the army surgeon, Sir David Bruce, who recovered the organism (which he called Micrococcus melitensis) from the spleens of 19 fatal cases in 1887, and for whom the disease is named. 2 Other names for this malady have included undulant fever, melitensis fever, Mediterranean fever, and Bang's disease following the isolation of a similar organism (Brucella abortus) from cows in Denmark in 1897. 1 Ocular brucellosis was first recognized in domestic animals by Fabyan in 1912,3 whereas that in humans was initially reported by Lemaire,'l who in 1924 described bilateral optic neuritis complicating a case of brucellar meningitis. Since that time, numerous case series and individual reports of ophthalmic brucellosis involving multiple ocular structures, especially the uvea, have appeared in the literature. 5-15

Brucellosis is caused by small aerobic, nonmotile, nonspore-forming, gram-negative coccobacilli, of which seven species with multiple biotypes have been identified: Brucella melitensis (three biovars), B. abortus (seven biovars), B. suis (five biovars), B. neotomae, B. ovis, B. canis, and most recently, a type affecting marine mammals, tentatively named B. maris.16, 17 Each species may have one or more hosts; the principal host or hosts of B. melitensis are sheep, goats, camels, and some cattle, while that of B. abortus is cattle, B. suis is swine, B. neotomae is the rat, B. ovis is sheep, and B. canis is the dog. B. abortus is the most widespread form among animals, whereas in humans, B. abortus, B. suis, B. canis, and B. melitensis may produce disease, with B. melitensis being the most pathogenic and clinically apparent.

Brucellosis is distributed worldwide, infecting an estimated one-half million individuals annually, and remains

a significant economic problem with respect to disease among domesticated animals and livestockP Although mandatory pasteurization of dairy products and veterinary control measures (livestock slaughter, quarantine, and vaccination) have dramatically reduced the incidence of human brucellosis to less than 0.5 cases per 100,000 population in the United States,lS it remains prevalent in the developing world, especially in the Mediterranean basin, the Arab Gulf countries, India, and in certain regions of Central and South America. Since 1980, fewer than 200 cases have been reported annually in the United States, with more than half of these being frOlTI four states (Texas, California, Virginia, and Florida). In Saudi Arabia, where the disease is endemic, the prevalence of brucellosis has been estimated to range between 8.8% and 38%.19-21 In domesticated animals, Brucella spp. infection manifests as a chronic genitourinary tract infection, eventuating in abortions, retained placentas, epididymitis, and chronic interstitial mastitis. 17, 22 Erythritol, a growth factor for Brucella, has been,demonstrated in the seminal vesicles and placentas of sheep, goats, swine, and cattle but not in human tissuesP' 22, 23 Recently, the ery gene has been reported to have undergone a 7.2-kbp deletion in the B. abortus strain, possibly explaining this strain's erythritol sensitivity, and its attenuation. 16, 24 Human disease may follow consumption of contaminated meat, unpasteurized milk or cheese, or through occupational contact with infected animals and their products. 16, 25 Transmission may occur directly through abraded skin or mucous membranes, byaerosolization,26 and even from cosmetics prepared from bovine placental extracts. 27 High-risk groups include abattoir workers, meat inspectors, animal handlers, veterinarians, laboratory workers handling the organism,27-30 and travelers to endemic areas,31 Although human-to-human transmission has been reported through tissue transplantation or sexual contact, such incidences are exceedingly rare. 32 Brucellosis in children comprises 3% to 10% of all reported cases and is often a mild and self-limited process. 33 However, the diagnosis must be considered in any child residing in an endemic area who presents with a febrile illness and a history of animal exposure. 34

AND IMMUNOLOGY Over the past decade, substantial progress has been made in the characterization of the molecular genetics of Brucella, as is superbly reviewed by Corbel. 16 Brucella is classified as a monospecific genus, with all its members demonstrating greater than 95% homology in DNA-pairing studies,35 with the average molecular complexity of the genome being 2.37 X 109 daltons and the molar G+ C being 58% to 59%.36 Natural plasmids have not been detected in Brucella, with the genome being comprised of two chromosomes (2.1 and 1.5 mbp respectively), which

«

CHAPTER 20:

encode all essential metabolic and replicative functions. 37 ,38 Ribosomal RNA sequencing has identified a phylogenetic relationship to Agrobacterium, Phyllobacterium, Ochrobacteriwn, Rhizobium, and the Bartonella group.39-'i2 The susceptibility and magnitude of infection with Brucella are dependent on multiple factors, including the route and size of the inoculum, the nutritional and immune status of the host, and the species itself, with B. melitensis and B. suis being the most virulent in humans, followed by B. abortus and B. canisP' 25 The principal determinant of both the antibody response and of virulence is the cell wall lipopolysaccharide (LPS) complex, which contains two major surface antigens (A and M) .16, 17 The structure of the LPS of smooth-phase strains (S-LPS) is essentially the same as that of nonsmooth strains (RLPS), except for minor differences in the a-specific side chains, with the specificity of the R-LPS being conferred largely by the core polysaccharide. 16 Virulence and resistance to intracellular killing by polymorphonuclear leukocytes (PMNs) appear to be associated with S-LPS strains. 25 Having invaded the body through the portal of entry (skin, mucous membranes, lungs, or gastrointestinal tract), brucellae are phagocytized by PMNs and macrophages. These microorganisms are capable of surviving within phagocytic cells for prolonged periods of time, having evolved a number of mechanisms to evade intracellular killing. Survival within PMNs appears to involve a potent superoxide dismutase system. 43 The production of adenine and guanine monophosphate, which inhibit phagolysozome fusion, degranul'ation of peroxidase-positive granules in PMNs, and thus the myeloperoxidaseH 20 2-halide antibacterial system, is thought to prOlTIote intracellular survival,44 and may be responsible for the greater virulence of B. melitensis. 45 Organisms capable of evading killing by PMNs migrate to regional lymph notes, the systemic circulation, and the organs of the reticuloendothelial system (RES), most notably the spleen, where they may survive and multiply within monocytes and macrophages. Survival within macrophages is promoted by the production of specific stressinduced proteins. 16,46 Macrophage activation is associated with intracellular killing of the organism and the release of endotoxin from the bacterial cell wall, the latter being at least partially responsible for some of the signs and symptoms of acute brucellosis. 17, 47, 48 Both humoral and cell-mediated immune responses arise in response to brucellosis infection and to immunization with live-attenuated vaccines. Antibodies to Brucella are detectable within 1 to 2 weeks following exposure. 25 IgM rises first and begins to decline within 3 months from the onset of the infection. The switch to the IgG isotype occurs by the second week and may remain elevated for at least a year in untreated patients. 49 IgG levels are undetectable or fall to very low levels within 6 months in adequately treated individuals. IgA antibodies are detectable weeks after the appearance of IgG. 17 Reinfection or disease recrudescence may be heralded by elevated IgG and possibly IgM anti-Brucella antibody titers. 49 A recent study suggests, however, that IgG and not IgM antibody levels become elevated in relapsing brucellosis.50 Undoubtedly, specific antibodies opsonize Brucellae, promoting uptake by phagocytic cells and reducing the num-

bel' of organisms in the liver and spleen, and to playa role in resistance. 51- 53 However, the elimination of intracellular microorganisms requires the activation of macrophages and the development of Th1-type cell-mediated immunity.25 Studies in experimental animals have demonstrated the presence of lymphokines and cytokines (IL-1, IL-2, IFN-l', TNF-a) 7 to 10 days following infection, produced by specifically sensitized T lymphocytes, which activate macrophages and enhance the elimination of intracellular bacteria. l7 , 25, 54, 55 Coincident with the development of cellular immunity, granulomata may form in the liver and spleen, together with dermal hypersensitivity to various Brucella antigensP' 25 Clinical manifestations of acute brucellosis are thought to be the direct consequence of infection with the microoi-ganism itself; however, immune complex-mediated disease has been describedp,56 In addition, autoantibodies (rheumatoid factor and antinuclear antibodies) have been reported in patients with active disease, suggesting a putative pathogenetic role. 57 The pathogenesis of ocular disease, which may manifest during either the acute or chronic phase of systemic brucellosis, is largely unknown. Because systemic infection is necessary for the production of disease, it is quite conceivable that some of the ocular manifestations are due to direct bacterial invasion, at least during the acute phase of disease. With respect to the pathogenesis of uveitis, which may evolve well after adequate systemic therapy for the acute disease, a combination of synergistic mechanisms, including initial direct invasion of the microorganism with subsequent hypersensitivity to bacterial products or the development of autoimmunity, are likely to be operative.

Systemic Disease Systemic brucellosis may involve any organ system in the body with protean nonspecific signs and symptoms, the nature and severity of which are related to the immune status of the host, the presence or absence of underlying disease, and the species and strain of the offending organism. More severe disease and subsequent complications involving multiple organ systems are more often associated with infection by B. melitensis, and, to a lesser extent, B. suis, than that with B. abortus or B. canis. 58 Clinically, brucellosis may be divided into subclinical disease, acute or subacute illness, localized disease and complications, relapsing infection, and chronic disease.

Subclinical Disease The incubation period for brucellosis is variable, ranging from 1 week to several months, with symptoms generally appearing within 2 to 3 weeks of inoculation. 17,25 Subclinical disease is most often diagnosed serologically among high-risk individuals (e.g., veterinarians, abattoir workers) and manifests as a mild fiulike illness, usually without sequela. Subclinical cases are common among children from endemic areas and are thought to outnumber clinically apparent brucellosis by 12:1. 33

CHAPTER 20: BRUCEllOSIS

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In approximately 50% of patients, acute brucellosis may present as an acute, toxic illness arising over a period of days (especially with B. melitensis infection), whereas in the remainder, the onset is insidious. Acute disease is characterized by multiple somatic complaints, of which fever, drenching sweats, chills, and weakness are present in over 90% of cases. 59- 61 Fever, which occurs in all patients at some point during the illness, tends to peak in the afternoon, whereas an undulating or intermittent pattern, once thought to be characteristic of the disease, is distinctly unusual. 10, 60, 61 Other common symptoms include malaise, headache, anorexia, weight loss, luyalgias, arthralgias, and back pain. Mild lymphadenopathy, involving predominantly the cervical and inguinal chains, together with splenomegaly, may occur in up to 21 % and 30% of patients, respectively.60

Localized Disease and Complications Almost any organ or organ system may become involved with, and develop complications arising from, Brucella infection, particularly those containing elements of the reticuloendothelial system. In such instances, the disease is said to be localized, more commonly involving bone, central nervous system (CNS) , heart, lungs, hepatobiliary system, testes, and skin. Localized disease may arise with either acute or chronic infection. Osteoarticular involvement is most frequent, occurring in approximately 40% of cases in someseries. 62 Sacroiliitis, arthritis involving the knee and
ever, caseating granulomata and calcifications resembling renal tuberculosis have been reported. 69 It is well established that brucellosis may produce abortions in animals. Whether infection with Brucella per se increases the risk of abortion in humans, as compared with that of other bacteremic infections occurring dming pregnancy, has not been properly evaluated in case-controlled studies. 17, 25 Frank CNS involvement is rare, occurring in less than 2% of cases, with acute or chronic meningitis being the most common manifestation. 70 , 71 On the other hand, depression and mental fatigue are commonly observed among patients with brucellosis. 25 Examination of the cerebrospinal fluid (CSF) usually reveals a lymphocytic pleocytosis with an elevated protein and a reduced glucose level. 71 Except in cases of acute meningitis, the organism is rarely cultured from the CSF; however, Brucella-specific antibodies are usually present in the CSF, providing specific confirmation for the diagnosis of neu1'0 brucellosis. 17, 71 The most common cause of death among patients with brucellosis is endocarditis, occurring in less than 2% of cases. 72 Treatment usually involves both the administration of systemic antibiotics and surgical replacement of the involved (usually the aortic) valve73; however, successful conservative treatment of Brucella endocarditis, with antibiotics alone, has been described. 74 Cutaneous manifestations of brucellosis are often transient and nonspecific, occurring in approximately 5% of patients. 6o Erythema nodosum, papules, a variety of rashes (eczematous, rubeliform, scarlatinoform) , petechiae, purpura, and cutaneous granulomatous vasculitis have all been reported. 17

Relapsing Infection Relapsing disease occurs in up to 10% of patients with brucellosis,33 usually within weeks to months after the completion of antibiotic therapy.25 The cause of disease relapse is thought. to relate to the intracellular location of the organism and its ability to evade phagocytosis, particularly when sequestered in a localized site requiring surgical drainage, together with an inadequate or abbreviated course of antibiotic therapy. Although antibioticresistant strains have been isolated,75 they are not thought to be responsible for the vast majority of relapses.

Chronic Disease Chronic brucellosis, by definition, is disease that persists for more than 1 year. Many of these patients manifest objective signs of infection and are found, on thorough examination, to have actually relapsing disease due to inadequate antibiotic treatment or to sequestered localized infection. 76 A subset of these patients with no objective signs of infection complain of fatigue, malaise, and depression, benefitting little from retreatment with antibiotics. The question of whether these patients may suffer from a form of psychoneurosis, or whether their delayed convalescence, despite adequate treatment, may be a variant of the chronic fatigue syndrOlue, is a matter for further study.77

CHAPTER 20: BRUCELLOSIS

An increased incidence of brucellosis has been observed in patients with Hodgkin's disease and other lymphomas. 33 In contrast, human immunodeficiency virus (HIV) infection did not seem to increase the incidence of brucellosis in one series of 12 HIV-infected patients diagnosed with brucellosis. 78 Conversely, the evolution of HIV did not appear to be influenced by the presence of brucellosis The clinical presentation, diagnosis, response to therapy, and outcome were similar to those observed in non-HIV-infected patients.

Vaccine-Related Disease In recent years, cases of brucellosis among veterinarians accidentally inoculated with vaccines derived from strains with attenuated virulence for immunization of animals (B. abortus strain 19 and B. melitensis strain Rev-I) have been reported. 79 ,80 Percutaneous needle sticks, conjunctival splashes, or ingestion are the common modes of exposure. Veterinarians previously exposed to Brucella are at less risk of acquiring the disease by virtue of pre-existing antibodies but frequently develop severe inflammation at the site of the inoculation. The absence of pre-existing antibodies to Brucella and exposure through the conjunctival route (larger inoculum size) are associated with a greater risk of acquiring the disease. In general, vaccineassociated disease is milder than the natural disease.

Ocular Manifestations Eye disease in systemic brucello~s is uncommon but may involve a wide variety of ocular structures. Although 20% of patients reported by Spink had visual symptoms, only 2% manifested ocular findings. 60 Of 100 consecutive cases of systemic brucellosis seen in Saudi Arabia, the prevalence of ophthalmic disease was found to be 3%.81 The array of ocular disease includes (Table 20-1) nummular keratitis, corneal ulceration, scleritis, granulomatous or nongranulomatous iridocyclitis, vitritis, panuveitis, endophthalmitis, multifocal choroiditis, retinitis, retinal vasculitis, cystoid macular edema (CME), retinal detachment, papilledema, retrobulbar optic neuritis, chiasmal arachnoiditis, and optic atrophy.5-15, 81, 82 Uveitis is thought to be the most common ocular manifestation of brucellosis,1,5, 12, 13, 81, 82 developing in one or both eyes, usually during the acute phase of systemic infection. However, it may persist as chronic, smoldering, recurrent intraocular inflammation, either after initial TABLE 20-1. OPHTHALMIC FINDINGS IN BRUCELLOSIS Nummular keratitis Corneal ulcer Scleritis Diffuse Nodular Uveitis Iridocyclitis Granulomatous Nongranulomatous VitI-itis Panuveitis

Endophthalmitis Multifocal choroiditis Retinitis Retinal vasculitis Cystoid macular edema Retinal detachment Optic nerve involvement Papilledema Retrobulbar optic neuritis Arachnoiditis of the chiasm Optic atrophy

treatment with systemic antibiotics 82 or in cases in which the diagnosis was not suspected. 13 Anterior uveitis may be either granulomatous or nongranulomatous, ranging in severity from mild inflammation with typical "mutton-fat" keratic precipitates to severe inflammation with the development of hypopyon, metastatic endophthalmitis, and phthisis bulbi. 1, 11 Chronic iridocyclitis may produce thickening of the iris with the formation of Koeppe's nodules, posterior synechiae, lenticular opacities, and secondary glaucoma. Multifocal choroiditis, either in a geographic pattern 12 or associated with circumscribed nodular exudates with little surrounding retinal edema or inflammation, 1 is thought to be characteristic of posterior segment disease. Well-circumscribed choroidal lesions in the retinal periphery have also been recently described. 82 Although the choroidal exudates usually resolve, leaving hyperpigmented scars in their wake, they may recur. 1 Vitritis of varying degrees is quite common. Cystoid macular edema, retinal vasculitis,12, 81 and retinal detachment9 may also complicate brucellar uveitis. Optic nerve involvement, usually as a direct extension of leptomeningeal infection, may manifest as papilledema, retrobulbar optic neuritis, optic atrophy, or arachnoiditis of the chiasm, with accompanying enlargement of the blind spots, bilateral visual field constriction, and in some cases, profound visual 10ss.8, 14 In the series reported by Puig-Solanes and coworkers,8 44 of 413 (10.7%) patients were observed to have optic nerve involvement, whereas only eight had uveitis. Uncommon ocular manifestations of brucellosis include nummular subepithelial corneal infiltrates or ulcers with accompanying iritis, as reported by Woods 6 among five patients with serologic or allergic evidence of Brucella exposure. Conjunctivitis and scleritis, of either the diffuse or nodular variety, have also been described. 12

DIAGNOSIS The diagnosis of both systemic and ocular brucellosis cannot be made on clinical grounds alone, because most patients present with nonspecific signs and symptoms shared by many other infectious diseases. However, a history of fever, chills, arthralgias and night sweats, together with that of occupational exposure, travel to endemic areas, or the ingestion of unpasteurized milk or dairy products, raises brucellosis as a diagnostic possibility. The definitive diagnosis of brucellosis relies on the isolation and culture of the organism from the blood, bone marrow, or other tissues, including the ocular fluids. Routine laboratory tests are generally uninformative, except that there may be a mild leukocytopenia, or abnormal liver function tests. A presumptive diagnosis is suggested by elevated or rising titers of specific anti-Brucella antibodies. Overall, blood cultures are positive in 10% to 30% of cases of acute brucellosis,33 with a much higher yield on blood and bone marrow specimens (70% and 90%, respectively) in patients infected with B. melitensisP Among individuals with meningitis, the CSF is culture positive in 45% of cases. 33 Isolation of the organism in subacute cases of B. melitensis and chronic infection with all other species is typically unrewarding. Because the organisms are slow growing, cultures should be main-

CHAPTER 20: BRUCELLOSIS

tained for between 4 and 6 weeks. A commonly employed method uses the Casteiieda system; however, radiometric detection systems and lysis concentration have shortened the incubation time to a matter of days.83 Although brucellae have not been cultured or demonstrated histopathologically from the cornea in patients with keratitis, B. melitensis biotype 3 was successfully cultured in a 17-yearold patient found to have Brucella-induced endophthalmitis. l l In another patient with uveitis, the organism was isolated from a paravertebral abscess. 13 A variety of serologic techniques have been applied in the presumptive diagnosis of brucellosis, the most common of which is the serum agglutination test (SAT). This test, which uses an antigen prepared from B. abortus strain 119, detects antibodies against B. abortus, B. melitensis, and B. suis but not B. canis. 25 Infection with B. canis requires specific B. canis agglutination tests or an enzyme-linked immunosorbent assay (ELISA), which uses an antigen prepared from the outer membrane proteins of B. melitensis. 84 The SAT, which measures the total quantity of agglutinating antibody (i.e., both IgG and IgM) , is considered significant with titers in excess of 1:160 in patients with acute or recently acquired infection. However, these titers may persist for more than 1 year, even after appropriate antibiotic therapy, obfuscating the differentiation between relapsing and chronic disease. The quantity of specific IgG antibody may be determined by the addition of 0.05 M 2-mercaptoethanol (2-ME) to the SAT, which inactivates IgM antibodies. 85 Although no single value is uniformly diagnostic, a 2-ME Brucej,la titer of 1:160 or greater is indicative of ongoing infection, whereas a titer of less than 1:160 argues against chronic disease if it is obtained a year or more following the onset of the illness.85, 86 In cases of ocular brucellosis, calculation of the Witmer coefficient of ocular and systemic antibodies may be diagnostically valuable. 87 Akduman and colleagues 15 reported a case of brucellar uveitis that presented 3 monthsfollowing systemic antibiotic therapy in which the agglutination titer in the vitreous specimen (1:640) far exceeded that of the aqueous humor (1:40) and the serum (1:20). A false-negative SAT may occur due to the presence of blocking antibodies in the patient's serum. 25 This effect may be obviated by diluting the serum beyond 1:320 and repeating the SAT in patients with initially negative results yet clinically suspected of having brucellosis. In addition, the Brucella SAT may cross-react with antibodies in patients infected with Francisella tularensis, Yersinia enterocolitica, or Vibrio cholerae. 17 Among the newer available serologic tests, the ELISA appears to be the most sensitive. In a prospective study of 400 cases of brucellosis in Kuwait, ELISA readily detected Brucella-~pecific immunoglobulins IgG, IgM, and IgA in the CSF and allowed the differentiation, based on serum immunoglobulin profiles, of patients with chronic (elevated IgG and IgA) from acute (elevated IgM alone or IgG, IgM, or IgA) disease. lO More experience with ELISA is necessary before it replaces the SAT, because the SAT remains the serologic "gold standard." Polymerase chain reaction (peR), using random or

TABLE 20-2. DIFFERENTIAL DIAGNOSIS OF OCULAR BRUCELLOSIS Infectious Tuberculosis Syphilis Lyme disease Outer retinal toxoplasmosis Diffuse unilateral subacute neuroretinitis (DUSN) Septic choroiditis Viral retinitis (cytomegalovirus, herpes simplex, herpes zoster) Presumed ocular histoplasmosis syndrome (POHS) Noninfectious Sarcoidosis Multifocal choroiditis and panuveitis (MCP) Subretinal fibrosis and uveitis (SFU) Vogt-Koyanagi-Harada syndrome (VKH) Birdshot retinochoroidopathy (BSRC) Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) Multiple evanescent white dot syndrome (MEWDS) Punctate inner choroidopathy (PIC) Syn1pathetic ophthalmia Masquerade syndrome (large-cell lymphoma) Collagen vascular disease HLA-B27-associated iridocyclitis

selected oligonucleotide primers, is a prOlllising diagnostic technique. 88 ,89 Likewise, Western blotting against selected cytoplasmic proteins may prove to be a useful screening modality for the differentiation between acute and subclinical infection. 16, 90 Finally, although dermal hypersensitivity reactions are common among patients with brucellosis, skin testing is neither standardized nor employed for diagnostic purposes. 25 The differential diagnosis of ocular brucellosis is broad and requires the systematic exclusion of other infectious and noninfectious causes of uveitis, especially those producing multifocal choroiditis (Table 20-2). Among the infectious entities to be considered, the most important are tuberculosis and syphilis, because their antimicrobial therapy is specific and different from that of brucellosis. Other infectious diseases would include Lyme disease, outer retinal toxoplasmosis, diffuse unilateral subacute neuroretinitis (DUSN), septic choroiditis, viral retinitis (cytomegalovirus, herpes simplex, herpes zoster), and presumed ocular histoplasmosis syndrome (POHS). Among the noninfectious uveitides simulating brucellar multifocal choroiditis, sarcoidosis is the lllOSt important differential, followed by those entities listed in Table 20-2. Because some patients with ocular brucellosis may present with iridocyclitis, with or without posterior uveitis, together with the not infrequent occurrence of osteoarticular involvement, HLA-B27-associated ocular inflammatory disease, as well as that associated with collagen vascular diseases, should be considered in the differential diagnosis. Effective antibiotic therapy for brucellosis requires good intracellular penetration because the organisms are facultative intracellular pathogens, a prolonged course to prevent relapse, and bactericidal drugs for the treatment of endocarditis and CNS disease. Moreover, monotherapy

20:

with agents such as tetracycline, streptomycin, rifampin, or trimethoprim-sulfamethoxazole (TMP-SMZ) result in an unacceptably high (10% to 40%) rate of relapse. 59, 91 Although it is generally agreed that combination therapy is indicated, there is no consensus as to which regimen is optimal for the treatment of systemic brucellosis. The combination of tetracycline 2g/ day orally for 6 weeks plus streptomycin 1 g/day intramuscularly for 3 weeks has been widely employed for the treatment of acute brucellosis in the absence of endocarditis or CNS involvement and is associated with a less than 5% relapse rate. 25 ,92 Doxycycline has replaced tetracycline owing to its longer half-life and the need for less frequent dosing. Gentamicin, although equally effective and less toxic than streptomycin, has been used as a second agent, but both drugs require parenteral administration. 93 The regimen currently recommended by the World Health Organization is doxycycline 200 mg/day orally plus rifampin 600 to 900 mg/day orally for a 6-week period. 54 Rifampin has excellent intracellular penetration, crosses the blood-brain barrier well, and is the drug of choice for pregnant women. 54 Similar efficacy has been demonstrated in studies comparing the doxycycline-rifampin and the doxycycline-streptomycin regimens, although the latter may be more effective for the treatment of complications such as spondylitis. 94 ,95 Whereas monotherapy with TMP-SMZ is associated with an unacceptably high rate of relapse in adults,91 it may be used as an alternative to rifampin during pregnancy and is the preferred d~ug for the treatment of children younger than 6 years of age with acute brucellosis for whom tetracyclines are contraindicated. 25 The drug is administered four times daily orally for 6 weeks, with some experts advocating the concomitant use of gentamicin for the first 5 days to prevent relapse. 96 As with other drugs that demonstrate good in vitro activity against Brucella, the fluoroquinolones, specifically ofloxacin, were associated with high relapse rates when used alone. However, the combination of ofloxacin 400 mg plus rifampin 600 mg daily compared favorably with the doxycycline (200 mg)-rifampin (600-mg) regimen when administered for 6 weeks. 97 The treatment of endocarditis and CNS complications arising from systemic brucellosis infection is similar to that described for acute disease, except that longer courses of therapy are recommended, usually between 6 and 9 months. 25 In addition to prolonged antibiotic therapy, endocarditis frequently requires cardiac surgery to replace the infected valve. 72 , 73 Brucellar meningitis has responded to triple therapy with doxycycline, rifampin, and TMP-SMZ.71 However, some authorities have suggested that a combination of rifampin and a third-generation cephalosporin, such as ceftriaxone or ceftizoxime, be employed in these patients, because both drugs achieve good CSF levels. 98 , 99 Therapy for uveitis associated with brucellosis mandates adequate initial treatment of the underlying infectious disease, as outlined earlier. As with treatment of CNS complications, there is a rationale for the use of rifampin and a third-generation cephalosporin for eyes with uveitis in which intraocular pathogens are demonstrated, because these agents also achieve good intraocu-

lar drug levels. However, many cases of brucellar uveitis may appear after adequate initial antibiotic therapy, supporting the notion that, at least in some cases, the ocular manifestations are due to a noninfectious imillune response. Treatment in such cases would then consist of nonspecific anti-inflammatory therapy with topical or systemic steroids, titrated to the degree and location of the intraocular inflammation, provided the systemic disease has been adequately controlled with antibiotic therapy.

PROGNOSIS With the prompt institution of appropriate antimicrobial therapy, most cases of acute brucellosis are curable. Prolonged antibiotic therapy reduces the risk of localized and chronic disease. Most patients develop immunity to reinfection following the initial infection with Brucella. 33 Endocarditis associated with severe congestive heart failure is the leading cause of mortality, occurring in less than 2% of patients. 72 Similarly, the visual prognosis with ocular disease depends on timely diagnosis and treatment. Tabbara and AlKassini reported a case of a young woman with chronic, recurrent uveitis in which the diagnosis of ocular brucellosis was missed for a period of 9 years. 13 With appropriate antibiotic therapy, the patient's symptoms improved dramatically, with a reduction of the intraocular inflammation and a marked improvement in visual acuity. Secondary complications arising from inappropriately treated chronic, smoldering intraocular inflammation (cataract, glaucoma, cystic macula, optic neuropathy and vitreous condensation with fibrosis and tractional retinal detachment) may produce irreversible damage to ocular structures critical for good vision. Patients with optic nerve involvement8, 14 or choroiditis involving the fovea may experience profound visual loss.

The elimination of brucellosis among domesticated animals and livestock is the principal means for the prevention of human disease. Surveillance and eradication programs for the identification and elimination of infected animals and the use of B. abortus strain 119 vaccine in cattle and B. melitensis strain Rev-1 vaccine in sheep and goats has virtually eliminated the disease in these animals in the United States. 18, 25 The implementation, execution, and funding of such programs in the developing world remains problematic. Nevertheless, pasteurizing or heating milk to 60°C for 10 minutes kills Brucella in dairy products. 81 Both live attenuated vaccines 100 and a variety of killed Brucella fractions 101 have been used to immunize humans at high risk of contracting the disease; however, these strategies are not without the risk of producing disease itself or are of heretofore unproven benefit. Hence, universal precautions should be exercised by individuals at high risk for contracting the disease, and travelers to endemic regions should be educated as to the potential avenues of exposure.

Although brucellosis among animals and humans is uncommon in developed countries, it remains a significant

20: BRUCELLOSIS

economic and public health problem in many parts of the developing world, especially where it is endemic. A heightened degree of clinical suspicion in patients with an exposure history, together with supporting serologic testing, isolation, and culture of the organism, are essential to making the diagnosis. Early institution of specific multiagent antimicrobial therapy may be curative, reduce morbidity, and is an essential first step in the treatlnent of associated ocular disease. Uveitis is the most common ophthalmic manifestation, although virtually any ocular structure may be involved. The precise pathogenesis of intraocular inflammation is unknown but may involve direct invasion of the microorganism, a noninfectious immune response, or both. As with systemic infection, prompt recognition and timely treatment of intraocular inflammation is vital for the preservation of vision.

33.

References

34.

1. Duke-Elder S, Perkins ES: Disease of the uveal tract. In: DukeElder S, ed: System of Ophthalmology, vol 9. London, Kimpton, 1966, pp 236-242. 2. Bruce D: Note on the discovery of microorganism in Malta fever. Practitioner 1887;39:161-170. 3. Fabyan M: A contIibution to the pathogenesis of B. abortus, Bang.II. J Med Res 1912;21:441-487. 4. Lemaire MG:Meningite a melitocoques alterations importantes du liquide cephalo-rachidien. Bulletins et Memoires de la Societe Medecin de l'H6pital de Paris 1924;48:1636-1652. 5. Green J: Ocular manifestations in brucellosis (undulant fever). Arch Ophthalmol 1939;21:51-67. 6. Woods AC: Nummular keratitis and ocular brucellosis. Arch Ophthalmol 1946;35;490-508. 7. Foggit Iill: Ocular disease due to bru~llosis.Br J Ophthalmol 1953;38:273. 8. Puig-Solanes M, Heatley J, Arenas F, et al: Ocular complications in brucellosis. Am J Ophthalmol 1953;36:675-689. 9. Rolando I, Carbone A, Hal'O D, et al: Retinal detachment in chronic brucellosis. Am J Ophtl1almol 1985;99:733-734. 10. Lulu AR, Arah GF, Khateeb MI, et al: Human brucellosis in Kuwait: A prospective study of 400 cases. QJ Med 1988;66:39-54. 11. Al-Faran MF: Brucella melitensis endogenous endophthalmitis. Ophthalmologica 1990;201:19-22. 12. Tabbara KF: Brucellosis and nonsyphilitic treponemal uveitis. Int Ophthalmol Clin 1990;30:294-296. 13. Tabbara KF, Al-Kassini H: Ocular brucellosis. Br J Ophthalmol 1990;74:249-250. 14. Abd Elrazak M: Brucella optic neuritis. Arch Intern Med 1991;151:776-778. 15. Akduman L, Or M, Hasenreisoglu B, et al: A case of ocular brucellosis: Importance of ocular specimen. Acta Ophthalmol 1993;71;130-132. 16. Corbel MJ: Brucellosis: An overview. Emerg Infect Dis 1997;3:213221. 17. Mikolich DJ, Boyce JM: Brucella species. In: Mandell GL, Douglas RG, Bennett JE, eds: Principles and Practices of Infectious Diseases, 3rd ed. New York, Churchill Livingstone, 1990, pp 17351742. 18. Centers for Disease ContI-ol: Disease Information, Division of Bacterial and Mycotic Diseases. Brucellosis. Atlanta, Centers for Disease ContI-ol, December, 1999. 19. Talukder MA, Moaz A, Al-Admawy 0, et al: Brucellosis: Experiences in Saudi Arabia. Dev BioI Stand 1984;56:597-599. 20. Arrighi HM: Brucellosis surveillance in Saudi Arabia's Eastern Province. Ann Saudi Med 1986;6(Suppl 5):5-10. 21. Talukder MA, Abomelha MS, Higham RH: Brucellosis in a farming community in Saudi Arabia. Dev BioI Stand 1984;56:593-595. 22. Evans LS, Tessler HH: Brucellosis. In: Gold DH, Weingeist TA, eds: The Eye in Systemic Disease. Philadelphia, Lippincott, 1990, pp 159-161. 23. Al-Kaff AS: Ocular brucellosis. Int Ophthalmol Clin 1995;35:139145. 24. Sangari FJ, Garda-Lobo JM, Aguero J: The Brucella abortus vaccine

25. 26. 27. 28. 29. 30. 31. 32.

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48. 49.

50. 51.

52.

strain B19 carries a deletion in the erythritol catabolic genes. FEMS Microbiol Lett 1994;121:337-342. Young EJ: An overview of human brucellosis. Clin Infect Dis 1995;21:283-290. Kaufmann AF: Airborne spread of brucellosis. Ann N Y Acad Sci 1980;353:105-114. Grave W, Sturm AW: Brucellosis associated witll a beauty parlour. Lancet 1983;1:1326-1327. Al-Aska AK: Laboratory acquired brucellosis. J Hosp Infec 1989;14:69-71. Kiel FW: Brucellosis among hospital employees in Saudi Arabia. Infect Control Hosp Epidemiol 1993;14:268-272. Mazuelos-Martin E: Outbreak of Brucella melitensis among microbiology laboratory workers. J Clin Microbiol 1994;32:2035-2036. Steffen R: Antacids-a risk factor in travelers' brucellosis. Scand J Infect Dis 1977;9:311-312. Mantur BG, Mangalgi SS, Mulimani B: Brucella melitensis-a sexually tI-ansmissible agent. Lancet 1996;347:1763. Salata RA: Brucellosis. In: Wyngarden JB, Smith LH, Bennett JC, eds: Cecil Textbook of Medicine, ed. 19, vol. II. Philadelphia, WB Saunders, 1992, pp 1727-1729. Benjamin B: Childhood brucellosis in Soutllwestern Saudi Arabia: A 5-year experience. J Trop PediatI- 1992;38:167-172. Verger JM, Grimont F, Grimont PAD, et al: Brucella, a monospecific genus as shown by deoxyribonucleic acid hybridization. Int J Syst Bacteriol 1985;35:292-295. De Ley J, Mannheim W, Segers P, et al: Ribosomal ribonucleic acid cistron similarities and taxonomic neighbourhood of Brucella and CDC Group Vd. IntJ Syst Bacteriol 1987;37:35-42. Michaux S, Paillisson J, Carles-Nurit MJ, et al: Presence of two independent chromosomes in the Brucella melitensis 16 M genome. J Bacteriol 1993;175:701-705. Jumas-Bitlak E, Maugard C, Michaux-Charachon S, et al: Study of the organization of the genomes of Escherichia coli, Brucella melitensis, and Argobacterium twneJaciens by insertion of a unique restriction site. Microbiology 1995;141:2425-2432. Cieslak TJ, Robb ML, Drabick q, et al: Catheter-associated sepsis caused by Onchrobactrum anthropi: A report of a case and review of related non-fermentative bacteria. Clin Infect Dis 1992;14:902-907. Da Costa M, Guillou j-P, Garin-Bastuji B, et al: Specificity of six gene sequences for the detection of the genus Brucella by DNA amplification. J Appl Bacteriol 1996;81:267-275. Minnick MF, Stiegler GL: Nucleotide sequence and comparison of the 5S ribosomal genes of Rochalimaea henselae, R. quintana, and Brucella abortus. Nucleic Acids Res 1993;21:2518. Relman DA, Lepp PW, Sadler KN, et al: Phylogenetic relationships among the agent of bacillary angiomatosis, Bartonella bacillifonnis, and other alpha-proteobacteria. Mol Microbiol 1992;6:1801-1807. Bricker BJ, Tabatabai LB, Jurge BA, et al: Cloning, expression and occurrence of the Brucella Cu-Zn dismutase. Infect Immun 1990;58:2933-2939. Canning PC, Roth JA, Deyoe BL: Release of 5 ' -guanosine monophosphate and adenine by Brucella abortus and their role in the intracellular survival of the bacteria. J Infect Dis 1986;154:464-470. Young EJ, Borchert M, Kretzer FL, et al: Phagocytosis and killing of Brucella by human polymorphonuclear leukocytes. J Infect Dis 1985;151:682-690. Lin J, Ficht TA: Protein synthesis in Brucella abortus induced during macrophage infection. Infect Immun 1995;63:1409-1414. AbernatllY RS, Spink WW: Studies with Brucella endotoxin in 1111mans: The significance and susceptibility to endotoxin in the pathogenesis of brucellosis. J Clin Invest 1958;37:219-231. Spink WW: Host-parasite relationship in brucellosis. Lancet 1964;2:161-164. White RG: Immunoglobulin profiles of the chronic antibody response: Discussion in relation to Brucella infection. Postgrad Med J 1998;54:595-601. Pellicer J, Ariza J, Fox A: Specific antibodies detected during relapse of human brucellosis. J Infect Dis 1998;157:918-924. Guerra H, Deter AL, Williams RP: Infection at the subcellular level. II. Distribution and fate of intI-avenously ir~jected Brucellae within phagocytic cells of guinea pigs. Infect Immun 1973;8:694699. Sulitzeanu D: Mechanism of immunity against Brucella. Nature 1965;205:1086-1 088.

CHAPTER 20: BRUCELLOSIS 53. Plommet M, Plommet AM: Immune serum-mediated effects of brucellosis evolution in mice. Infect Immun 1983;41:97-105. 54. Joint FAO/WHO Expert Committee on Brucellosis: Geneva, World Health Organization, 1986. 55; Meyer ME: Brucellosis. In: Samter M, ed: Immunological Diseases. Boston, Little Brown, 1978, pp 651-659. 56. Hodinka L, Gomor B, Meretey K: HLA-B27-associated spondylarthritis in chronic brucellosis. Lancet 1978;1:499. 57. Gotuzzo E, Bocanegra ]S, Alacron GS, et al: Humoral immune abnormalities in human brucellosis. Allergol Immunopathol (Madr) 1985;13:417-424. 58. Braude AI: Studies in the pathology and pathogenesis of experimental brucellosis I. A comparison of the pathogenicity of Brucella abortus, Brucella melitensis, and Brucella suis for guinea pigs. ] Infect Dis 1951;89:76-82. 59. Buchanan TM, Faber LC, Feldman RA: Brucellosis in the United States, 1960-1972. An abattoir-associated disease. Part I, clinical features and therapy. Medicine 1974;53:403-413. 60. Spink WW: The Nature of Brucellosis. Minneapolis, University of Minnesota Press, 1956. 61. Dalrymple-Champneyes W: Brucella Infection and Undulant Fever in Man. London, Oxford University Press, 1960. 62. Mousa ARM, Muhtaseb SA, Almudallal DS, et al: Osteoarticular complications of brucellosis: A study of 169 cases. Rev Infect Dis 1987;9:531-543. 63. Ariza], PlTIol M, Valverde], et al: Brucellar sacroiliitis: Findings in 63 episodes and current relevance. Clin Infect Dis 1993;16:761765. 64. Ariza], Gudiol F, Valverde], et al: Brucellar spondylitis: A detailed analysis based on current findings. Rev Infect Dis 1985;7:656-664. 65. Young EJ: Brucella melitensis hepatitis: The absence of granulomas. Ann Intern Med 1979;91:414-415. 66. Spink WW, Hoffbauer FW, Walker WW, et al: Histopathology of the liver in human brucellosis.] Lab Clin Med 1949;34:40-58. 67. Williams RK, Crossley K: Acute and chronic hepatic involvement of brucellosis. Gastroenterology 1982;83:455-458. al: Pulmonary brucellosis. Q] 68. Lubani MM, Lulu AR, Araj GF, Med 1989;71:319-324. 69. Kelalis PP, Greene LF, Weed LA: Brucellosis of the urogenital tract. A mimic of tuberculosis. ] Urol 1962;88:347-353. 70. Bouza E, Garda de la Torre M, Parras E, et al: Brucellar meningitis. Rev Infect Dis 1987;9:810-822. 71. McLean DR, Russell N, Khan MY: Neurobrucellosis: Clinical and therapeutic features. Clin Infect Dis 1992;15:582-590. 72. Al-Harthi SS: The morbidity and mortality pattern of Brucella endocarditis. Int] Cardiol 1989;25:321-324. 73. Jacobs F, Abramowicz D, Vereerstiaeten P, et al: Brucella endocarditis: The role of combined medical and surgical treatment. Rev Infect Dis 1990;12:740-744. 74. Cohen N, Golik A, Alon I, et al: Conservative treatment for Brucella endocarditis. Clin Cardiol 1997;20:291-294. 75. de Raotlin de la Roy YM, Grignon B, Grollier G, et al: Rifampicin resistance in a strain of Brucella melitensis after treatment with doxycycline and rifampicin [letter].] Antimicrob Chemother 1986;18:648-649. 76. Spink WW: What is chronic brucellosis? Ann Intern Med 1951;35:358-374. 77. Cluff LE: Medical aspects of delayed convalescence. Rev Infect Dis 1991;13(Suppll):SI38-S140. 78. Moreno S, Ariza], Espinosa D, et al: Brucellosis in patients infected witll the human immunodeficiency virus. Eur] Clin MicrobioI Infect Dis 1998;17:319-326. 79. Spink WN, Thompson H: Human brucellosis caused by Brucella abortus strain 19.]AMA 1953;153:1162-1165.

et

80. Blasco ]M, Diaz R: Brucella 'melitensis Rev-l vaccine as a cause of human brucellosis [letter]. Lancet 1993;342:805. 81. TabbaraKF: Brucellosis. In: Pepose ]S, Holland GN, Wilhelmus KR, eds: Ocular Infection and Immunity. St. Louis, Mosby-Year Book, 1996, pp 1249-1251. 82. Walker ], Sharma OP, Rao NA: Brucellosis and uveitis. Am ] Ophthalmol 1992;114:374-375. 83. Kolman S, Maayan MC, Gotesman G, et al: Comparison of the Bactec and lysis concentration methods for recovering Brucella species from clinical specimens. Eur] Clin Microbiol Infect Dis 1991;10:647-648. 84. Hunter SB, Bibb WF, Shah CN, et al: Enzyme-linked immunosorbent assay witll outer membrane proteins of Brucella melitensis to measure immune response to Brucella species. ] Clin Microbiol 1986;24:566-572. 85. Young EJ: Serologic diagnosis of human brucellosis: Analysis of 214 cases by agglutination tests and review of tlle literature. Rev Infect Dis 1991;13:359-372. 86. Buchanan TM, Faber LC: 2 Mercaptoethanol Brucella agglutination test: Usefulness for predicting recovery from brucellosis. ] Clin Microbiol 1980;11 :691-693. 87. Renoux GM, Larmande A, Poletti]A: Le diagnostic biologique de la brucellose ocularies. Arch Ophthalmol 1977;37:767-770. 88. Matar FM, Khreissir IA, Abdonoor AM: Rapid laboratory confirmation of human brucellosis by PCR analysis of a target sequence on the 31-kilodalton Brucella antigen DNA. ] Chn Microbiol 1996;34:477-478. 89. Herman L, De Ridder H: Identification of Brucella spp by using the polymerase chain reaction. Appl Environ Microbiol 1992;58:2099-2101. 90. Goldbaum FA, Leoni], Walach]C, et al: Characterisation of an 18 kilodalton Brucella cytoplasmic protein which appears to be a serological marker of active infection of bOtll human and bovine brucellosis.] Clin Microbiol 1993;31:2141-2145. 91. Ariza], Gudiol F, Pallares R, et al: Comparative trial of co-trimoxazole versus tetracycline-streptomycin in treating human brucellosis. ] Infect Dis 1985;152:1358-1359. 92. Elberg SS: A Guide to the Diagnosis, Treatment and Prevention of Human Brucellosis, WHO Document VPH/81.31. Geneva, World Health Organization, 1981. 93. Rubenstein E, Lang R, Shasha B, et al: In vitro susceptibility of Bnlcella melitensis to antibiotics. Antimicrob Agents Chemother 1991;35:1925-1927. 94. Ariza], Gudiol F, Pallares R, et al: Comparative trial of rifampindoxycycline versus tetracycline-streptomycin in the therapy of human brucellosis. Antimicrob Agents Chemother 1985;28:548-551. 95. Ariza], Gudiol F, Pallares R, et al: Treatment of human brucellosis with doxycycline plus rifampin or doxycycline plus streptomycin: a randomized, double-blind study. Ann Intern Med 1992;117:25-30. 96. Hall WH: Modern chemotherapy in brucellosis in humans. Rev Infect Dis 1990;12:1060-1069. 97. Akova M, Uzun 0, Akalin N, et al: Quinolones in treatment of human brucellosis: A comparative trial of ofloxacin-rifampin versus doxycycline-rifampin. Antimicrob Agents Chemother 1993; 37:1831-1834. 98. Young ES: Human brucellosis. Rev Infect Dis 1983;5:821-842. 99. Palenque E, Otero ]R, Noriega AR: In vitro susceptibility of Brucella melitensis to new cephalosporins crossing the blood-brain barrier. Antimicrob Agents Chemother 1986;29:182-183. 100. Vershilova PA: The use of live vaccine for vaccination of human beings against brucellosis in the USSR. Bull World Health Organ 1961;24:85-89. 101. Roux J: Les vaccinations dans les brucelloses humaines et animales. Bull Inst Pasteur 1972;70:145-202.

Roxanne Chan and C. Stephen Foster

'Whipple's disease is a rare chronic bacterial infection with multiorgan manifestations. Primary involvement is of the gastrointestinal tract and its lymphatic drainage. 1, 2 Other common sites of disease include the lungs, heart, central nervous system (CNS) , kidneys, and eyes. Whipple's disease is often difficult to diagnose and treat, especially when there is eye involvement, which was first reported by Jones and Paulley in 1949. 3 The fatality rate is high if the disease is left untreated by antibiotics; therethe bacterial infection must be recognized so that timely management is initiated. Three important developments concerning Whipple's disease occurred in the last 15 years: A probable pathognomonic disorder was described and named oculomasticatory myorrhythmia (OMM)4; polymerase chain reaction (PCR) analysis confirmed the bacterial nature of Whipple's disease with greater sensitivity and specificity than either light microscopy (LM) or electron microscopy (EM); and the emergence of acquired immunodeficiency syndrome (AIDS) in the mid 1980s, with its concomitant opportunistic infections, introduced a challenging differential diagnosis and has heretofore unknown effects on the disease process and mechanism of Whipple's disease. This chapter will review Whipp~e's disease, including a discussion of the aforementioned new developments.

Whipple's disease is defined on the basis of clinical features and LM, EM, or PCR of biopsy specimen findings. The presence of periodic acid-Schiff (PAS)-positive macrophages on LM of the small intestine, or the presence of characteristic bacilli on EM, or a diagnostic amplified DNA sequence on PCR in affected tissues is required to confirm clinical suspicions.

Perhaps Allchin and Hebb described the first Whipple's disease case in 18955; however, if so, they apparently did not realize their patient had a new disease. 6 George Hoyt Whipple described in 1907 a patient "characterized by a gradual loss of weight and strength, stools consisting chiefly of neutral fat and fatty acids, indefinite abdominal signs, and a peculiar multiple arthritis," and he is given credit today for his recognition of this as a new disease. 1 The first case of ocular Whipple's disease (OWD) was reported by Jones and Paulley in 1949. 3

EPIDEMIOLOGY Since Whipple's description, there were 617 more systemic cases reported up to 1986. The prevalence and death rate are unknown because of the low incidence rate of 18 to 30 systemic cases per year per 100,000 people. OWD is even more unusual, occurring in 19 of 696 patients with systemic Whipple's disease. 6 Although both the systemic and the ocular forms of Whipple's disease are rare, they are well described. Whip-

pIe's disease usually affects middle-aged Caucasian men in the United States and continental Europe. There may possibly be an increased incidence in farmers. 7 The peak age for systemic disease is 40 to 49 years, with a range from 3 months to 81 years. 2 Eighty-eight percent of patients are in their fifth decade. s, 9 This disease is not familial but may be associated with HLA-B27. Eye manifestations are present in the 76 cases we have collected between 1907 and 1999 (Table 21-1). These, including four new cases of ours, are consistent with the well-known but unexplained middle-aged white male predOluinance (Table 21-2). Patient age and sex are presented in Table 21-3. There are more patients older than 49 years among those with uveitis only (50%) than among those with neurophthalmologic manifestations (33.3%). In this review, 76.3% of patients were male and 22.4% female. The most common age group, 40 to 49 years (38.2%), is consistent with that reported for systemic Whipple's disease. The age range in our four patients is 26 to 69 years.

ETIOLOGY Direct transmission from one person to another has not been established, nor has the reproducibility of the disease in laboratory animals, either as origin or vector. 10 The mechanism of dissemination is also unclear. Robert Koch's postulates have not been satisfied because the bacterium causing Whipple's disease has not been culttued. Therefore, the presumed bacterial etiology of Whipple's disease has been studied with methods such as LM and EM. The Whipple '5 bacterium was characterized in 1991 by its 16S rRNAY Mter PCR showed that the Whipple's disease bacterium was not closely related to any known genus, the name Tropheryma whippelii was proposed. 12 This name describes an actinomycete (a high guanine-pIus-cytosine [G+ C], Gram-positive bacillus) most closely related to the nocardioform Rhodobacter equi. 13 If T. whipjlelii is a soil bacterium like its phylogenetic neighbors, then an explanation for the large proportion of farmers with Whipple's disease may be possible if its place in normal human flora can safely be excluded. 7 Although seemingly more common in patients who are farmers or who are otherwise exposed to dirt, as in Case 1, inciting factors or vectors are still unknown. 6 Light microscopy of intestinal mucosa reveals PAS positive and diastase-resistant bacilli within foamy macrophages. There are three pathologic lesions described in the eye. 14 LM of brain or spinal cord shows multifocal nodules of inflammation, which have a predilection for the gray matter of the hypothalamus, cingulate gyrus, basal ganglia, insular cortex, and cerebellum. Subependymal nodules found in periventricular and periaqueductal areas that resemble tumors may be difficult for antibiotics to penetrate. 15

CHAPTER 21: OCULAR WHIPPLE'S DISEASE

TABLE 21-1. OPHTHALMIC WHIPPLE'S DISEASE CASES IN THE LITERATURE GROUP I Central (CNS)

0

G

A

PRE-1984 Jones & Paulley (1949)54 Tracey & Brolsma (1950)54 Hendrix et al. (1950)54

0

G

A

Smith et al. (1965)54 Switz et al. (1969)"4 Feurle et al. (1976)54

Ritama & Haapanen (1953)54 Kruke & Stochdorph (1962)54

1 1 1 0 1 1 1 1

0 PM 1 0 0 0 0 0 1 1 1

1 PM NS 0 1 1 0 1 0 1 0

0 0 1

1 NS 1

0 0 0

0

0

Knox et al. (1995)14 Riskind (new)

GROUP 3 Peripheral (Eye)

0

G

A

0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 1 1 1 1 1 1 0

1 1 1 1 1 1 1 1 1 1 1

Dybkaer (1965) 54 Knox et al. (1968)54 Vazquez Rodriguez et al. (1972)54 Leland & Chambers (1978)5"1 Selsky et al. (1984)97

Knox et al. (1976)54 Font (1978)/Finelli (1977)/Johnson (1979)54 Canoso et al. (1978)54 Schliep et al. (1979)54 Gartner (1980)54 Schmitt et al. (1981)/Clancy (1975)H.96

Lampert et al. (1962)54 Enziger & Helwig (1963)"4 Badenoch et al. (1963) 54 Stoupal et al. (1969)54 Henry et al. (1974)54 Knox et al. (1976) a 54 Knox et al. (1976) b 5'1 Knox et al. (1976) C54 Masson et al. (1976)54 Silbert et al. (1976)54 Feurle et al. (1976) a54 Feurle et al. (1976) b 54 Finelli et al. (1977)54.94 DeJonghe, et al. (1979)/ vanBogaert (1963) 54 Fernandez Pascual et al. (1979)54 Welck.er et al. (1981) a54 Welck.er et al. (1981) b 5'1 Malamud and Harrington55 Romanul (1977)61 Halperin (1982)95 PosT-1984 Schwartz et al. (1986) a 4 Schwartz et al. (1986) b 4 Robson (1990)'10 Amarenco (1991) 1:; Adler (1989) 28 Grotta (1987)29 Adams (1987)42 Tison (1992)30 Hausser (1988)31 Simpson (1995)43 Jankovic (1986)/Nath (1987)4'1·47 Brown (1990)45 Fleming et al. (1988)48 Louis (1997) /Lynch (1997) a 32 . 49 Louis (1997) /Lynch (1997) b 32 . 49 Louis (1997) /Lynch (1997) C 32 . Rajput (1997)33 Verhagen (1997) 34 Cooper et al. (1994)19 Wroe et al. (1991)46

GROUP 2 Central & Peripheral

Durant (1984) a 98 Durant (1984) b 98 Avila (1984) a5"' Avila (1984) b 5"

1 0

0 0

PM 1

Rickman et al. (1995) 12 Wechsler et al. (1995) ,;,35 Hollerbach et al. (1995) *36 Schrenk et al. (1994)37 Disdier (1991) 41 Playford (1992) 18 Foster (new) Foster (new) Yannuzzi (new) Williams (1998)38 Nishimura (1998)39

LF 0 0 0 0

1 1 1 0

0 1 1 1

TOTAL

45

11

19

o = no significant improvement, 1 = significant improvement, NS = not specified, LF = lost follow-up, PM = postmortem, 0 = oculomasticatory myorhythmia (OMM),G gastrointestinal symptoms, A = antibiotics, a = Case a, b = Case b, c = Case c. *Classified by abstract only.

CHAPTER 21: OCULAR WHIPPLE'S DISEASE 21-2. WHIPPLE'S DISEASE WITH OCULAR INFLAMMATION CASE

AGE (YR)/ SEX

PRESENTING SIGNS AND SYMPTOMS

53/F

Floaters, decreased vision

3

341M 69/M

Decreased vision Floaters

4

44/F

Progressive memory loss, onset of diplopia and ataxia, oligomenorrhea

2

PRINCIPAL METHOD OF DIAGNOSIS

OCULAR MANIFESTATIONS

Keratic precipitates, multiple 200 to 400 j-lm white choroidal lesions, macular edema, vitreous strands Papillitis, multifocal chorioretinitis Circumferential inflammatory debris accumulation and diffuse vitreous infiltrate, epiretinal membrane, cottonwool spot, macular edema Filamentary keratitis

PCR (vitreous)

PAS-positive (duodenum) PAS-positive (jejunum)

PAS-positive (hypothalamus), classical neurophthalmologic findings

peR, polymerase chain reaction; PAS, periodic acid-Schiff.

Electronic microscopy reveals characteristic "bacillary bodies" with a trilaminar outer cell membrane. 16 The immunopathology of Whipple's disease is still unclear. An altered host response is proposed to explain the predisposition of certain individuals for direct bacterial invasion or proliferation. Evidence of direct damage is seen in the· identification of rod-shaped bacteria in the retina. 17 Therefore, protection from, or ability to eliminate, infection in these individuals may be impaired. Immune system defects may be cell mediated (decreased T-cell function) or humoral (decreased immunoglobulin A response), or there may be m~crophage defects (difficulties phagocytosing intracellular gram-positive bacteria), leading to altered cytokine profile (gamma interferon, interleukin 12, CD11b, and decreased CD4/CD8 ratio). On the other hand, hypersensitivity phenomena (erythema nodosum, arthralgias, fever, and contact dermatitis), supported by identified circulating rhamnosebinding antibodies against organisms and the presence of circulating immune complexes, are also possible. 1s Patients with cell-mediated deficiencies may be predisposed to relapse. These include those treated with methotrexate (MTX) 19 and corticosteroids,20 or those who are immunocompromised, such as by AIDS21 and leukopenia. 20 As in AIDS patients, there are signs of impaired cellular immunity with decreased T-helper cells (decreased CD4/CD8 ratio) during active Whipple's disease. 7,22 There is one PCR-confirmed AIDS patient with

Whipple's disease. 21 This 56-year-old man is the first reported confirmed case, with the same deletion of cytosine at position 1160 of Whipple's-specific DNA sequence as another patient. 23 Although the clinical symptoms of patients with AIDS and Whipple's disease are very similar, the PAS-positive macrophages on LM were not as prominent and did not resemble the sickle-form particle-containing cells characteristic of Whipple's disease, and so the case had to be diagnosed with PCR. The coexistence of AIDS and Whipple's disease may be coincidental, or T. whippelii may have acted as an opportunistic pathogen. Prior to the use of PCR in 1992, there was confusion because of the LM resemblance of Whipple's disease to opportunistic infections such as those caused by the Mycobacterium avium-intracellulare complex (MAC) and R. equis. 24 , 25 Whipple's disease has coexisted with opportunistic diseases. 23 , 26, 27

NICAl Extraocular Whipple's disease is a chronic, relapsing, multiorgan disease. Extraintestinal signs and symptoms, which may be minimal, as in Case 1 (Table 21-2, Figs. 21-1 and 21-2), include, most commonly, arthralgias, often months to years before diagnosis. Fever, weight loss, pericarditis, and pleural effusions (Case 2 and see Table 21-2) also occur. The patient shown in Case 3 (see Table 21-2; Figs. 21-3 to 21-5) had had one episode of abdominal pain.

TABLE 21-3. AGE AND SEX DISTRIBUTION GROUP:

Male Female Not specified Total

<40 years 40-49 years >49 years Not specified Total Male range Female range

36 8 1 45

2

3

7 4 0

15 5 0 20

11

TOTAL

TOTAL %

58 17 1 76

76.3 22.4 1.3 100

M

F

M

F

M

F

Total

Total %

7 18

2 2 4 0 8

1 3 3 0 7 32-65 26-44

2 2 0 0 4

4 4 7 0 15 34-69 33-59

2 0 3 0 5

18 29 28 1 76 32-69 26-69

23.7 38.2 36.8 1.3 100

11

1 37 31-65 28-69

Patients older than 49 years (Group 1: 15/45

33.3%; Group 3: 10/20 = 50%).

21: OCULAR WHIPPLE'S DISEASE

bp 600

250 'lOa 150

100

50 25

FIGURE 21-1. Case #1: Multiple faint, white choroidal lesions. (See color insert.)

FIGURE 21-3. Case #3: Vitreous strands. (See color insert.)

FIGURE 21-2. Case #1: Agarose gel showing band specific for Tropheryma whippelli. (See color insert.)

FIGURE 21-4. Case #3: Diffuse, fluffy, white infiltrate. (See color insert.)

FIGURE 21-5. Case #3: Cotton-wool spot in superior macula. (See color insert.)

CHAPTER 21: OCULAR WHIPPLE'S

IW'U;;:U:H=\.;:JlI;;

TABLE 21-4. PRESENTING SYMPTOMS IN 32 CASES PUBLISHED AFTER 1984 GROUP:

I (REf)

Gastrointestinal

10, 24, 26

Arthralgiaslarthritis"

9(2), 12, 13, 15, 16,22(2),24, 25,26 11, 14, 17, 18, 20, 22, 27

Central nervous system ocular

NUMBER

2 (REf)

3

Case 4

NUMBER

Case 4,32

2

°

°

One case did not specify presenting symptoms. 21 "Migratory polyarthralgias are most specific."' 9(2),16,22,2'1,25,:Hi, 37, C",e 2

The most common presenting manifestations of Whipple's disease are gastrointestinal (weight loss, malabsorption, abdominal pain) and polyarthalgias (migratory, nondeforming, and seronegative) (Table 21-4) .4,12,19,28-39 Others presented with gastrointestinal tract, CNS, and ocular symptoms. 14, 15, 18, 19, 32, 33, 35, 38-45 Late terminal-phase gastrointestinal disease may include fever, weight loss, diarrhea, and steatorrhea. 31 , 33, 34, 37, 40, 41, 43, 4'1, 47-'19 Arthralgias usually appear about 1 year before the malabsorption syndrome, especially if there is also fever or persistent lymphadenopathy. Sarcoid-like disturbances, which may include symptoms and signs such as migratory nondeforming arthralgias, abdominal pain, increased skin pigmentation, lymphadenopathy, chronic nonp¥oductive cough, pleural effusion, mediastinal widening' from adenopathy, and chest pain from pleurisy can also occur. Extraintestinal involvement includes primarily the CNS, heart, and sometimes the lungs, but the involvement of these sites plus the eyes is unusual. CNS manifestations, in order of descending frequency, are dementia, supranuclear ophthalmoplegia, myoclonus, and hypothalamic signs such as insomnia, hyperphagia, and polydipsia. 50

Ocular Ocular inflammation caused by Whipple's disease often occurs late in the course of disease, leading to vision impairment (Table 21-5). Concomitant gastrointestinal, neurologic, or other systemic manifestations are possible, but ocular findings may be solely CNS or intraocular. 51, 52 Common primary intraocular involveluent of this group includes keratitis, in.flamluatory vitreous opacities (vitritis), vitreous hemorrhage, retinal hemorrhage, retinitis, choroiditis, chorioretinitis, optic atrophy, papilledema, and cotton-wool spotS. 12 Also reported are retrobulbar neuritis, glaucoma, bilateral central scotomas,

NUMBER

35, 38, 39, Case 3 4, 35, 36, 37, Case 1, Case 2,40,41

11

7

3 (REf)

40, 41

TOTAL

4

8

25

8

19

59.4

°

9

28.1

2

6.3

2

chemosis, fibrovascular pannus, epiphora, and superficial punctate keratitis. Iris nodules and greasy keratic precipitates, like those of sarcoidosis, have also been reported. Cases 1 to 3 in our series had abdominal manifestations prior to visual change with or without floaters, indicative of posterior uveitis. These findings may be superimposed upon the neurologic findings of ophthalmoplegia, supranuclear gaze palsy, nystagmus, myoclonus, and ptosis.

Neurophthalmo/ogy Central nervous system involvement is diagnosed by clinical presentation in, about 10% of all patients with Whipple's disease. 53 Some authors believe that as many as 43% to 100% of patients have CNS colonization with T. whippelii without neurologic signs. The CNS is a repository for bacteria that cause CNS relapse, the most common, often late, and devastating complication of Whipple's disease. 5 , 48 Probably all patients have CNS involvement; however, all are not clinically obvious. 15 Generally, there is concomitant gastrointestinal involvement. Neurophthalmologic disease usually causes ophthalmoplegia (primarily supranuclear, with occasional progression to total, without response to head or caloric stimulation), gaze palsy, and/or nystagmus. Myoclonus may be independent or associated with cranial musculature, eyes, jaws, and face involvement. Headaches, ptosis, seizures, and ataxia also occur. Another neurophthalmologic manifestation is oculomasticatory myorhythmia (OMM), named since the last own review54 when researchers collected two cases of what was then probably a newly described disorder. 4 Perhaps Knox's case is the first documented OMM case. 55 OMM consists of pendular vergent oscillations (PVOs) or smooth vergent nystagmus associated with tongue and mandibular myoclonus, not be confused with oculopalatal myoclonus. These patients generally have gaze paralysis, hypersomnia, and arthralgias without early magnetic resonance imaging (MRI) or gastrointestinal findings. The fundamental characteristics of OMM are high ampli-

TABLE 21-5. OCULAR INFLAMMATION COMPARED TO CNS CASES GROUP:

Before 1984 Mter 1984 Total

25 20 45

%

2

%

58.1 60.1

9 2

20.9 6.1

11

%

3

%

TOTAL

9

20.9 33.3

43 33 76

11 20

CHAPTER 21: OCULAR WHIPPLE'S DISEASE

tude (5° to 25°), low frequency (0.5 to 1.6 Hz), smooth continuous oscillations in the z-axis without palatal movement. The oscillations in OMM are unrelated to those in Palinaud's syndrome, and unrelated to saccadic effort, visual stimuli, or sleep. There is no palatal myoclonus, nor olivary pseudohypertrophy, one of the hallmarks of oculopalatal myoclonus. The case described by DeJonghe and coworkers 56 resembles spinal segmental myoclonus but seems to be of brain stem origin instead. The remaining differential diagnoses are the other disorders with pendular nystagmus. The lesion(s) responsible for these abnormal movements have not been found. 4, 28 The suggestion of cerebral atrophy has been made because a prominent feature is dementia, which, along with myoclonus, may be attributed to diffuse cerebral cortical disease, but this does not explain the more specific lesion of a supranuclear palsy. 14, 57 Since Schwartz's first observations, 14 additional OMM cases have been described (see Table 21_1).4,9,14,28-32,43, 44,54,56 CNS and intraocular involvement can also occur together.

ing, is required in extraintestinal sites whenever diagnosis has not been established on the basis of gastrointestinal pathology. Yardley and Hendrix first confirmed the LM findings by EM in 1961. 16 The "bacillary bodies" have a characteristic trilaminar outer cell membrane on EM. Delicate intracellular and extracellular rodlike bacillary structures detected with both silver and PAS staining were confirmed with EM. Although late diagnosis may be made with the pathognomonic neurologic findings of OMM, a potential tool for definitive diagnosis is now possible with PCR,13 which allows identification of early or difficult-to-diagnose systemic disease because of its greater sensitivity. This technique may simplify diagnosis of nonintestinal specimens and show the disease to be more common than suspected. 50 It is unfortunate that there is no single diagnostic test for Whipple's disease. Pitfalls abound in the available methods. PAS also stains gastric lipophages, colonic muciphages, brain, and lymph node macrophages, and it does not stain' macrophages in granulomas. 16 Laboratory findings may include increased white blood cells and mononuclear cells in the vitreous. Brain biopsy, when there is DIAGNOSIS Whipple's disease is typically difficult to diagnose because high suspicion of CNS disease, is possible, but lesions are of its diverse clinical signs and symptoms, especially in frequently inaccessible and high false negatives may occur patients with minimal or no gastrointestinal manifesta- because of the focal nature of the lesions. 42 , 57, 62, 63 MRl tions. In 1907, Whipple used Levaditi silver stain to reveal may show high signal intensity42 but may not be able to rod--shaped organisms. 1 Hendrix diagnosed 23 cases via detect focal lesions. 64 Computed tomography scans usuclinical descriptions in 1950. 59 Analysis of tissue samples ally do not show abnormalities. 65 Diagnosis is often late because the nonspecific preby LM, EM, and/ or PCR is required to confirm clinical suspicions because T. whippelii has not been cultured58 senting signs and symptoms and the extensive differential diagnosis delay the initiation of investigation. Most biop(Table 21-6). McManus developed the PAS stain in 1946. In 1949, sies are performed later in the clinical course. A survey Black-Shaffer was the first to show PAS-positive inclusions of presenting signs and symptoms published after 1984 within the lamina propria of the small intestine and reveals that 59.4% of patients first exhibit arthralgias or lymph nodes of patients with Whipple's disease. 6o These arthritis (migratory polyarthralgia is most specific, 27%) inclusions were also diastase resistant; they corresponded and only 6.3% demonstrated ocular findings (see Table to foamy macrophages, which contained fragmented bac- 21-4) . One of 4 new and 2 of 72 published own cases were teria and large numbers of phagocytosed intact bacteria. 7 Hendrix then confirmed 4 of his 23 clinically described diagnosed by PCR on vitreous samples and subsequently cases by LM in 1950. 59 Jejunal biopsy (Case 3, see Table treated successfully with antibiotics without devastating 21-2), the gastrointestinal diagnostic procedure of CNS sequelae. 12 ,38 Case 1 is the third reported case in choice, reveals clubbed villi and a lamina propria infil- which PCR was used to detect the T. whippelii 16sRNA in trated with PAS-positive bacteria both within and outside a vitreous sample. This patient responded to the prompt of foamy macrophages. However, patchy or submucosal institution of appropriate antibiotic therapy. disease (Case 2) may result in negative biopsies. We found PAS-positive "foamy" macrophages in both the duode- laboratory Technique num and vitreous aspirates in Case 2, in the jejunum in Probably the most sensitive indicator of persistent organCase 3, and in the hypothalamus in Case 4. isms is PCR when used on vitreous samples. This method Electron microscopy or PCR, in addition to PAS stain- requires rigorous and well-controlled experimental proce-

TABLE 21-6. DIAGNOSIS OF WHIPPLE'S DISEASE DIAGNOSTIC METHOD

FIRST DESCRIBED FOR WD

YEARS

Clinical Light microscopy

G, H. Whipple: first case report Non-PAS staining Black-Shaffer60 : PAS + in lamina propria of small intestine and lymph nodes pathognomonic Yardley and Hendrix (16): bacillary bodies Rickman 61

1907-1949 1949 to present

Electron microscopy Polymerase chain reaction PAS, periodic acid-Schiff.

1961 to present 1992 to present

CHAPTER 21: OCULAR WHIPPLE'S DISEASE

dures to ensure validity of results. 7 Rickman described a 57-year-old woman in whom a mononuclear cell infiltrate composed of foamy macrophages was found in vitreous samples.12, 61 Oligonucleotide primers were used to amplify a universally conserved 1321-base sequence to identify the bacillus. 12 The PCR technique was used to detect the 16S ribosomal RNA (rRNA) gene from T. whippelii isolated from the vitreous of Case 1 reported from the Ocular Immunology & Uveitis Service of the Massachusetts Eye and Ear Infirmary. Briefly, DNA in 300 microliters (f-LI) of undiluted vitreous from our Case 1 was extracted in an equal volume of phenol! chlorofonn/isoamyl alcohol (25:24:1), mixed vigorously for 30 sec, and then microcentrifuged for 15 sec at 13,000 rpm (room temperature). The top aqueous phase and organic interface (about 250 /-11) containing DNA was removed to a new Eppendorf tube. Twenty-five microliters of 3M sodium acetate, pH 5.2, was added, followed by the addition of 825 /-11 icecold 100% ethanol. Mter mixing, the sample was stored at - 70°C overnight. It was then centrifuged for 5 min at 13,000 rpm at room temperature. The pellet was dried and resuspended in 20 /-11 TE buffer (10 mM Tris-HCI and 1 mMEDTA, pH 8.0) at room temperature and stored at - 20°C for PCR analysis. The T. whippelii 16S rRNA primer, W4RB (5' CGG GAT CCT GTG AGT CCC CGC CAT TAC GC) was obtained from Ransom Hill Bioscience (Ramona, CA) and used to amplify a 154-base-pair (bp) int~rnal portion of the T. whippelii 16S rRNA gene. PCR was performed with the DNA mixture in a 20 /-11 reaction volume containing 20 mM Tris-HCI (pH 8.3), 50 mM KCI, 1.5 mM MgCI 2, 100 /-1M each dNTP, 2 mg/ ml bovine serum albumin, specific 5' and 3' primers, and 0.2 units (5 units/ /-11) of Taq DNA polYJ-nerase (Boehringer Mannheim, IN). The optimal concentration for each primer set (4 /-11 sense and antisense) was as follows: positive control, negative control, T. whippelii, varicella zoster (VZV) , herpes simplex (HSV) , cytomegalovirus (CMV) , Borrelia burgdorferi (Lyme) disease, toxoplasmosis, and Mycobacterium tuberculosis (TB) (5 pmol/ /-11 each). Thirty-five cycles were used for all samples. Amplification was performed in a thennocycler model 9600 Perkin Elmer Cetus (Norwalk, CT) programmed for denaturation at 94°C for 10 seconds, annealing at 55°C for 1 min, and extension at 72°C for 7 min. PCR products were electrophoretically fractionated on a 1.5% agarose gel, stained with ethidium bromide, visualized by ultraviolet light, and photodocumented using Polaroid photography. The observed PCR products corresponded to their expected molecular weights (HSV = 327 bp, VZV = 203 bp, CMV = 361 bp, TB = 240 bp, Toxoplasma = 193 bp, LYJ-TIe = 248 bp, and T. whippelii = 154 bp).

DI

DIAGNOSIS

Whipple's disease is a great milnic that bears similarities to gastrointestinal, neurologic, and other diseases that affect multiple organs and have protean manifestations. Patients with uveitis may have a choroiditis-like picture, similar to that of presumed ocular histoplasmosis, multifocal choroiditis and panuveitis, sarcoidosis, malig-

nancy (i.e., primary intraocular lymphoma), MAC, amyloidosis, tuberculosis, and/ or retinal vasculitis (as in collagen vascular diseases, or LYJ-TIe disease). Patients with histoplasmosis usually have maculopathy, peripapillary pigment changes, and a clear vitreous. Mycobacterium avium-intmcellulare complex is a systemic opportunistic infection that often involves imlnunocompromised patients; the organism is acid fast, easily cultured, and causes 50- to 100-/-1m choroidal lesions without visual changes. 21 Immunologic defects predispose AIDS patients to entities such as MAC, which also have PASpositive granular macrophages. However, since they are also acid fast, they are unlike those found in VVhipple's disease. Concomitant MAC and Whipple's disease has been reported by several authors. 3, 24, 25 Other illnesses resembling Whipple's disease, but not necessarily AIDS related, include M. pamtuberculosis and R. equi. 13 The deep yellow choroidal granulomas of sarcoidosis may look like those of histoplasmosis, but vitreal inflammatory cells are typically present in sarcoid uveitis. Patients with Whipple's disease may have iris nodules and greasy keratic precipitates like those found in sarcoidosis. 66-69 These clinical resemblances may be the result of antigenic and structural similarities. 70, 71 Adamantiades-Beh<;et's disease is a multisystemic disorder that presents with not only recurrent aphthous and genital ulcerations, but also eye involvement similar to OWD. Eye disease may be rapidly progressive and is usually present at the onset of the disease. Patients with Adamantiades-Beh<;et's disease may have iritis, posterior uveitis, retinal vascular occlusions, and optic neuritis. Rarely, the hallmark hypopyon uveitis is seen. CNS manifestations, more common in northern Europe and the United States, include benign intracranial hypertension, a multiple sclerosis-like picture, pYJ-~amidal involvement, and psychiatric disturbances. Other systemic manifestations are nondeforming arthritis, mucosal ulcerations of the gut,. skin problems, and thrombosis or vasculitis. The patients in Cases 1 to 3 had a nonspecific uveitis similar to that of the reported cases, whereas the patient in Case 4 developed filamentary keratitis.

Medical Whipple's disease was invariably fatal prior to the discovery of the bacterial etiology and subsequent availability and use of antibiotics. 72 Before 1957, the diagnosis of Whipple's disease had the same significance as end-stage AIDS does today. Steroids and adrenocorticotropic hormone (ACTH), employed for treatment in the mid 1950s, achieved clinical remissions of short duration. 73 Radiation therapy was apparently not successful. Mter the first accidental and successful antibiotic treatment for Whipple's disease with chloramphenicol, other antibiotics, such as tetracycline (Case 1 initially, and Case 2), penicillin, and streptomycin have been employed.7'1 Nevertheless, steroids remained a controversial adjunct to antibiotics 16, 73, 75 until Davis 20 compared steroids and antibiotics in 15 patients (on steroids, 2 of 7 died, 5 of 7 did poorly; on antibiotics, 8 of 8 did well). Since then, many antibiotics were used, with some prompt responses.

CHAPTER 21: OCULAR WHIPPLE'S DISEASE

Tetracycline is most commonly used, with a 43% relapse rate. 72 Successfully treated cases include both mono- and multidrug systemic regimens such as 1.2 million units procaine penicillin and 1 g streptomycin for 10 to 14 days followed by PO tetracycline for 10 to 12 months9 or intravenous (IV) chloramphenicol for 10 days then paraaminosalicylic acid and INH.76 Chloramphenicol,74 IV and PO penicillin,77 PO ampicillin,78 trimethoprim-sulfamethoxazole (TMP-SMX) ,52,79,80 and rarely salicylazosulfapyridine,9 chlortetracycline,9 and doxycyline 81 have all been used. All patients may have CNS involvement,51 but probably only 10% to 20% present clinically.82 Treatluent after CNS relapse is generally not successful except to halt progression. 57 Antibiotic effectiveness is unclear for intraocular and CNS Whipple's disease, even though antibiotic therapy achieves good results with gastrointestinal involvement. The blood-brain and blood-retina barriers are challenges for drug penetration. Neurologic relapse even after systemic improvement is still the most common and most serious complication. 83 Of the 672 patients reviewed by Dobbins, 179 died of Whipple's disease, with 68 deaths since 1961 and 16 deaths between 1980 and 1986. 6 Based on empirical observations, Ryser and Keinath suggested the current drug of choice, TMP-SMX (Bactrim, Septra) (Cases 1, 3, and 4) for improved CNS penetration. 72 ,84 Optimal duration of antibiotic therapy has yet to be determined, but 1 year of double-stl'ength TMP-SMX (960 ~g) twice a day after 2 weeks of IV therapy is the current empirically recommended tl-eatment. 72 , 83 Various combinations of initial IV therapy have been proposed: (1) ceftriaxone 2 g twice daily and streptomycin 1 g daily for 2 weeks, (2) TMPSMX 960 mg twice daily for 1 to 2 weeks, or (3) penicillin 1.2 million units and streptomycin 1 g daily for 10 to 14 days.72,83 Drugs that penetrate the blood-brain barrier and blood-retina barrier are TMP-SMX, IV penicillin, chloramphenicol, IV ceftriaxone, and PO cefixime, but these are still inadequate. TMP-SMX remains the recommended first-line therapy.72, 84 The signs most amenable to treatment may be gaze palsies and nystagmus. Although they may eradicate Whipple's disease from the gut, PO tetracycline and PO penicillin are no longer recommended as monotherapies because neither penetrates uninflamed meninges. 72 The CNS becomes a reservoir of bacteria for future relapse if the CNS concentration is not high enough. Tetracycline predisposes to CNS relapse in otherwise asymptomatic patients55 , 75, 84 and in those with residual nonprogressive neurologic problems. 55 , 77, 86 PO penicillin has similar problems, with CNS relapse despite good systemic response. 28 Relapse is as high as 43%, compared to 23% for other monotherapies. 72 Chloramphenicol and TMP-SMX may be successfuF2 and some recommend it for all cases of Whipple's disease. 84 Mter treatment with systemic antibiotics is begun, fever dissipates in the first few days and the patient experiences rapid clinical improvement. Upper gastrointestinal series show improvement after 4 months and return to normal after 12 months,85 supporting the recommended I-year

systemic antibiotic plan. However, there is still a need for improved or alternative therapies, especially for TMPSMX-intolerant,12 granulocytopenic,42 or resistant patients. Ceftriaxone resolved some of the neurologic sequelae in one patient. 28 Another patient relapsed while on TMP-SMX and MTX and was treated successfully with cefixilue. 19 Perfloxacine, a quinolone that crosses the blood-brain barrier readily, has produced luoderate neurologic improvement. Others suggest prophylactic treatment of patients with supranuclear palsies and uveitis. 87 However, if relapse still occurs, accessory regimens such as IV chloraluphenicol and IV penicillin or ampicillin for 2 to 4 weeks may be needed. 77 , 81,86 Treating all patients with IV penicillin and streptomycin followed by PO TMP-SMX,88 erythromycin,28 or PO cotrimoxazole for 1 year 82 has also been suggested. 72 Even with antibiotic treatment, the bacillary bodies remain in macrophages causing little or no cellular injury for up to a year. 7 Although antibiotics are effective, no one antibiotic is wholly curative and there is often relapse (especially CNS) , even with TMP-SMX. Studies of drug treatment in OWD that need to be done include comparison of antibiotic effectiveness and toxicity for systeluic and intraocular disease, trial of the new fluoroquinolones (e.g., ciprofloxacin), 89-91 experimental drug delivery methods such as liposomes,92 and whether the best treatments for CNS ocular disease and intraocular Whipple's disease are the same.

Surgical Therapeutic vitrectomy is performed if there are marked vitreous opacities. The vitreous aspirate can be diagnostic.

Since George Hoyt Whipple's 1907 case report, advances in basic science, immunology, and molecular genetics and their clinical applications have provided a better understanding of the pathogenetic role of bacteria in Whipple's disease and have led to improved methods of diagnosis and treatment. Although this broader understanding of human pathobiology has been forged, the process by which T. whippelii induces disease is still not fully understood. High clinical suspicion should be maintained for Whipple's disease in patients with uveitis or classical neurophthalmologic findings. PCR may be used on tissue samples, including vitreous, from patients with uveitis and suspected ophthalmic Whipple's disease for earlier definitive diagnosis, when the disease may be more amenable to antibiotic treatment than later. The reports in the literature of patients with ophthalmic manifestations of Whipple's disease suggest that current antibiotics are not always effective once late manifestations occur. Recognition of migratory polyarthralgias, the most comluon and specific presenting manifestation, will also facilitate an earlier diagnosis.

References 1, Whipple GH: A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues, Johns Hopkins Hasp Bull 1907;18:382-391.

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29. 30.

31.

32.

33. 34.

35. 36.

37. 38.

39.

40. 41. 42. 43.

44. 45.

46.

47. 48.

49. 50. 51. 52.

53. 54.

55.

56. 57.

pIe's disease: Treatment with ceftriaxone. Ann Intern Med 1990;112:467-469. Grotta JC, Petigrew LC, Schmidt WA, et al: Oculomasticatory myorhythmia. A1m Neurol 1987;22:395-396. Tison F, Louvet-Giendaj C, Henry P, et al: Permanent bruxism as a manifestation of the oculo-facial syndrome related to systemic Whipple's disease. Mov Disord 1992;7:82-85. Hausser-Hauw C, Roullet E, Robert R, Marteau R: Oculo-facialskeletal myorhythmia as a cerebral complication of systemic Whipple's disease. Mov Disord 1988;3:179-184. Louis ED, Lynch T, Kaufmann P, et al: Diagnostic guidelines in central nervous system Whipple's disease. Ann NeuroI1996;40:561568. Rajput AH, McHattie JD: Ophthalmoplegia and leg myorhythmia in Whipple's disease: Report of a case. Mov Disord 1997;12:111-114. Verhagen WI, Huygen PL, DalmanJE, Schuurmans MM: Whipple's disease and the central nervous system. A case report and a review of the literature. Clin Neurol Neurosurg 1996;98:299-304. Wechsler B, Fior R, Reux I, et al: Uveitis: Late complications of undiagnosed Whipple's disease. Rev Med Interne 1995;16:687-690. Hollerbach S, Holstege A, Muscholl M, et al: Masked course of Whipple's disease with uveitis, infection, endocardial involvement and abdominal lymphomas-case report and review of the literature. Z Gastroenterol 1995;33:362-367. Schrenk M, Metz K, Heiligenhaus A, et al: Ocular involvement in Whipple's disease. Klin Monatsbl Augenheilkd 1994;204:538-541. Williams JG, Edward DP, Tessler HH, et al: Ocular manifestations of Whipple's disease: An atypical presentation. Arch Ophthalmol 1998;116:1232-1234. Nishimura JK, Cook BE, Pach JM: Whipple's disease presenting as posterior uveitis without prominent gastrointestinal symptoms. Am J Ophthalmol 1998;126:130-132. Robson DK, FarajBB, Hamal PB, Ironside JW: Whipple's disease with cerebral involvement. Postgrad Med J 1990;66:724-726. Disdier P, Harle J-R, Morris-Vidal D, et al: Chemosis associated with Whipple's disease. Am J Ophthalmol 1991;112:217-219. Adams M, Rhyner PA, Day J, et al: Whipple's disease confined to the central nervous system. Ann Neurol 1987;21:104-108. Simpson· DA, Wishnow R, Gargulinski RB, Pawlak AM: Oculofacialskeletal myorhythmia in central nervous system Whipple's disease: Additional case and review of the literature. Mov Disord 1995;10:195-200. Jankovic J, Pardo R: Segmental myoclonus: Clinical and pharmacologic study. Arch Neurol 1986;43:1025-1031. Brown AP, Lane JC, Murayama S, Vollmer DG: Whipple's disease presenting with isolated neurological symptoms. J Neurosurg 1990;73:623-627. Wroe SJ, Pires M, Harding B, Shorvon S: Whipple's disease confined to the CNS presenting with multiple intracerebral mass lesions. J Neurol Neurosurg Psychiatry 1991;54:989-992. Nath A, Jankovic J, Pettigrew LC: Movement disorders and AIDS. Neurology 1987;37:37-41. Fleming JL, Wiesner RH, Shorter RG: Whipple's disease: Clinical, biochemical, and histopathologic features and assessment of treatment in 29 patients. Mayo Clin Proc 1988;63:539-551. Lynch T, Fahn S: Oculofacial-skeletal myorhythmia in Whipple's disease. Mov Disord 1997;12:625-626. Dobbins WO III. The diagnosis of Whipple's disease. N EnglJ Med 1995;332:390-392. PowersJM, Rawe SE: A neuropathologic study of Whipple's disease. Acta Neuropathol 1979;48:223-226. Sieracki JC, Fine G, Horn RC Jr, et al: Central nervous system involvement in Whipple's disease. J Neuropathol Exp Neurol 1960;19:70-75. Schliep G, Muller W, Schaefer HE, et al: Morbus Whipple. Fortschr Neurol Psychiatr 1979;47:167-208. Avila MP, Jalkh AE, Feldman E, et al: Manifestations of Whipple's disease in the posterior segment of the eye. A1-ch Ophthalmol 1984;102:384-390. Knox DL, Bayless TM, Pittman FE: Neurologic disease in patients with treated Whipple's disease. Medicine (Baltimore) 1976;55:467476. DeJonghe P, Martin lJ, Budka H, Ceuterick C: Cerebral manifestations of disease. Acta Neurol Belg 1979;79:305-313. Pollock S, Lewis PD, Kendall B: Whipple's disease confined to the nervous system. J Neurol Neurosurg Psychiatry 1981;44:1104-1109.

CHAPTER 21: OCULAR WHIPPLE'S DISEASE 58. Fredricks DM, ReIman DA: Cultivation of Whipple's bacillus: The irony and the ecstasy. Lancet 1997;350:1262-1263. 59. HendrixJP, Black-Schaffer B, Withers RW, et al: Whipple's intestinal lipodystrophy: Report of four cases and discussion of possible pathogenic factors. Arch Intern Med 1950;85:91-131. 60. Black-Shaffer B: Tinctoral demonstration of glycoprotein in Whipple's disease. Proc Soc Exp BioI Med 1949;72:225-227. 61. Rickman LS, Freeman WR, Green WR, et al: Brief report: Uveitis caused by Tropheryma whippelii. N Engl J Med 1995;332:363-366. 62. Romanul FCA, Radvaqy J, Rosales RK: Whipple's disease confined to the brain: A case studied clinically and pathologically. J Neurol Neurosurg Psychiatry 1977;40:901-909. 63. Feurle GE, Yolk B, Waldherr R: Cerebral Whipple's disease and negative jejunal histology. N Engl J Med 1979;300:907-908. 64. Robson DK, Faraj BB, Hamal PB, Ironside JW: Whipple's disease with cerebral involvement. Postgrad MedJ 1990;66:724-726. 65. Grossman RI, Davis KR, Halperin J: Cranial computed tomography in Whipple's disease. J Comput Assist Tomogr 1981;5:246-248. 66. Cho C, Linscheer WG, Hirschkorn MA, Ashutosh K: Sarcoid-like granulomas as an early manifestation of Whipple's disease. Gastroenterology 1984;87:941-947. 67. Mansbach CM 2d, Whelburne JD, Steven RD, Dobbins WO 3d: Lymph-node bacilliform bodies resembling those of Whipple's disease in a patient without intestinal involvement. Ann Intern Med 1978;89:64-66. 68. Southern JP, Moscicki RA, Magro C, et al: Lymphedema, lymphocytic myocarditis, and sarcoid-like granulomatosis. Manifestations of Whipple's disease. JAMA 1989;261:1467-1470. 69. Spapen HD, Segers 0, De Wit N, et al: Electron microscopic detection of Whipple's bacillus in sarcoid-like periodic acid-Schiff-negative granulomas. Dig Dis Sci 1989;34:640-643. 70. Relman DA: The identification of uncultured microbial pathogens. J Infect Dis 1993;168:1-8. 71. Rook GA, Stanford JL: Slow bacterial infections or autoimmunity? Immunol Today 1992;13:160-164. 72. Keinath RD, Merrell DE, Vlietstra R, Dobbins WO: Antibiotic treatment and relapse in Whipple's disease. G2Istroenterology 1985; 88:1867-1873. 73. Bayless TM: Whipple's disease: Newer concepts· of therapy. Adv Intern Med 1970;16:171-189. 74. PaUlley JW:. A case of Whipple's disease (intestinal lipodystrophy). Gastroenterology 1952;22:128-133. 75. Thompson P, Ledingham JM, Howard AJ, Brown CL: Meningitis in Whipple's disease. Br MedJ 1978;2:14-15. 7&. Maxwell JD, Ferguson A, McKay AM, et al: Lymphocytes in WhippIe's disease: Lancet .1968; 1:887-889.

77. Schmitt BP, Richardson H, Smith E, et al: Encephalopathy complicates Whipple's disease: Failure to respond to antibiotics. Ann Intern Med 1981;94:51-52. 78. Hawkins CF, Farr M, Morris CJ, et al: Detection by electron microscope of rod-shaped organisms in synovial membrane from a patient with the arthritis of Whipple's disease. Ann Rheum Dis 1976;35:502-509. 79. Elsborg L, Gravgaard E, Jacobsen NO: Treatment of Whipple's disease with sulphamethoxazole-trimethoprim. Acta Med Scand 1975;204:423-427. 80. Tauris P, MoesnerJ: Whipple's disease-clinical and histopathological changes during treatment with sulphamethoxazole-trimethoprim. Acta Med Scand 1978;204:423-427. 81. Feurle GE, Dorken B, Schopf E, Lenhard V: HLA-B27 and defects in the T-cell system in Whipple's disease. Eur J Clin Invest 1979;9:385-389. 82. Dobbins WO 3rd: Whipple's disease. Mayo Clin Proc 1988;63:623624. 83. Schnider PJ, Reisinger EC, Berger T, et al: Treatment guidelines in central nervous system Whipple's disease [letter]. Ann Neuro11997; 41:561-562. 84. Ryser RJ, Locksley RM, Eng SC, et al: Reversal of dementia associated with Whipple's disease by trimethoprim-sulfamethoxazole, drugs that penetrate the blood-brain barrier. Gastroenterology 1984;86:745-752. 85. Phillips RL, Carlson HS: The roentgenographic and clinical findings in Whipple's disease. A review of 8 patients. Am J Roentgenol 1975;124:268-273. 86. Feldman M, Hendler RS, Morrison EB: Acute meningoencephalitis after withdrawal of antibiotics in Whipple's disease. Ann Intern Med 1980;93:709-711. 87. Finelli PF, McEntree ~, Lessell S, et a1: Whipple's disease with predominantly neuroophthalmic manifestations. Ann Neurol 1977;1:247-252. 88. Alba D, Molina F, VazquezlJ: Neurologic manifestations of Whipple disease. An Med Interna 1995;12:508-512. 89. EI Baba FZ, Trousdale MD, Gauderman ~, et al: Intravitreal penetration of oral ciprofloxacin in humans. Ophthalmology 1992; 99:483-486. 90. Cokingtin CD, Hyndiuk RA: Insights from experimental data on ciprofloxacin in the treatment of bacterial keratitis and ocular infections. AmJ OphthalmoI1991;1l2(suppl):25S-28S. 91. Serdarevic ON: Role of the fluoroquinolones in ophthalmology. Int Ophthalmol Clin 1993;33:163-178. 92. Niesman MR: The use of liposomes as drug carriers in ophthalmology. Crit Rev Ther Drug Carrier Syst 1992;9:1-38.

Richard Bazin

Tick-Borne Diseases Rickettsial agents are first characterized by the fact that most of them are transmitted by tick bites. Tick-borne diseases in the United States are caused by disparate types of microbes, including spirochetes (Borrelia burgdorferi, the agent of Lyme disease, and other Borrelia species, agents of tick-borne relapsing fever), pleomorphic bacteria (Francisella tularensis, the agent of tularemia), rickettsia (Rickettsia rickettsii, the agent of Rocky Mountain spotted fever [RMSF], and Ehrlichia chaffeensis, the agent of ehrlichiosis), viruses (Coltivirus species, agents of Colorado tick fever), and protozoa (Babesia species, agents of babesiosis). There is also a toxin that causes tick paralysis. 1 Ticks are obligate blood-sucking members of the class Arachnida, a group of arthropods also including scorpions, spiders, and mites. Ticks are grouped into three different families, two of which, the Ixodidae and the Argasidae, are known to infest humans by transmitting microbes through bites. The Ixodidae (hard ticks) are characterized by a hard dorsal sclerotized shield, the scutum. The life cycle of most hard ticks takes 2 years for completion and includes the egg, larva, immature nympllf, and mature adult. At each stage after the egg, a blood meal is required for morphogenesis. While it is feeding, the hard tick may stay attached to the host for hours to days, and evidence of a bite should be looked for when a tick-borne disease is suspected. Hard ticks are responsible for transmitting Lyme disease, tularemia, RMSF, ehrlichiosis, Colorado tick fever, babesiosis, and tick paralysis. 1 The Argasidae (soft ticks) lack the scutum and can be identified by their leathery integument. Their life cycle may go through several nymphal stages, and they may take many blood meals lasting less than 30 minutes at each stage. They can survive m~my years without feeding. Soft ticks are known for transmitting relapsing fever 1 but not rickettsiosis.

Microbiologic Characteristics Rickettsiae are obligate intracellular organisms. They can survive in nature through a cycle involving mammalian reservoirs and insect vectors. Usually, humans are only incidental hosts, with the tick transmitting the disease during feeding. Humans do not seem to be useful in propagating rickettsiae in nature. 2 Many rickettsial agents share the life of their insect vectors in a commensal fashion. On the other hand, Rickettsia prowazekii (louseborne typhus) will kill its vector in 1 to 3 weeks. Three organisms (R. rickettsii [RMSF], Rickettsia tsutsugamushi [scrub typhus], and Rickettsia akari [rickettsialpox]) are transmitted transovarially to their vector's eggs. When the infected larval, nymph, or adult form of the arthropod feeds on small mammals or livestock, it infects them with the bacteria, creating zoonotic reservoirs capable of reinfecting naive ticks that will feed on their blood. 2

Rickettsiae are fastidious gram-negative bacteria. They are small pleomorphic coccobacilli measuring 0.3 /-Lm in diameter for the coccal form, and 0.3 by 1.0 to 2.0 /-Lm in the bacillary form. 3 The cell wall possesses the ultrastructural appearance of a gram-negative bacterium and contains lipopolysaccharide (LPS). However, rickettsiae are difficult to stain with the Gram stain. Giemsa, Gimenez, or acridine orange stains might be Inore suitable to visualize these bacteria. 2 , 4 Rickettsia species include two Inajor, antigenically defined groups: the spotted fever and the typhus group, and a third group that includes other more disparate bacteria types. The first two groups are closely related genetically but differ in their surface-exposed proteins and LPS. Their outer membrane proteins contain crossreactive antigens and surface-exposed epitopes that are species specific. 3 Cell wall LPS is also responsible for the cross-reactivity of rickettsiae with Legionella and Proteus vulgaris, which is the basis of the Weil-Felix agglutination test. 4 In this rather insensitive and nonspecific test, iInmune serum from . infected patients has been shown to cause agglutination of the OX-19 and OX-2 strains of P. vulgaris. 3 Usually, gram-negative bacterial endotoxins are related to the LPS in their cell walls. Interestingly, Coxiella burnetii (Q fever) LPS is rather nontoxic compared to the LPS from other gram-negative bacteria, since even at doses over 80 /-1g per embryo, toxic reactions are not detected. In comparison, Salmonella typhimurium LPS is toxic in nanogram amounts. 4 Spores and plasmids have been described in C. burnetii. Spores may account for the fact that this bacterium, as opposed to other rickettsiae, can survive outside the intracellular environment for months. It is also resistant to relative dehydration and chemical disinfection. Fortunately, Lysol 1 % and 5 % hydrogen peroxide can destroy it. Three different plasmids have been described for C. burnetii, and there seems to be a correlation between the plasmid content and the virulence of the bacteria. 4 Rickettsiae contain both RNA and DNA, possess synthetic and energy-producing enzymes, and multiply by binary fission. They are able to synthesize adenosine triphosphate (ATP) via the metabolism of glutamate. R. prowazekii (epidemic typhus) has a sophisticated transport mechanism exchanging ATP from the host's cytosol for its own energy-depleted ADP. Many rickettsiae also have different transport mechanisms to obtain vital substances like amino acids from their host. The most extreme example of adaptation is C. burnetii, which can survive and proliferate in the harsh, inhospitable environment of phagolysosomes. 3 Because of all these adaptations and independent metabolic activities, it is believed that rickettsiae are not degenerate forms of bacteria but rather a successfully evolved form of intracellular microorganisms. Since rickettsiae are obligate intracellular organisms, they cannot be grown on agar plates or in broth. Eukaryotic cells are necessary for their growth (cell culture,

CHAPTER 22: RICKETTSIAL DISEASES

embryonated eggs, susceptible animals) ,3 but because of non-negligible hazards for laboratory workers,especially with C. burnetii, which resists desiccation and many disinfectants and requires only 10 viable organisms to cause infection in humans, such cultures are often not desirable. s

Classification Rickettsial diseases are classified into three major categories: the spotted fever group, the typhus group, and the other diseases group (e.g., those caused by Ehrlichia and Coxiella) (Table 22-1). The genus Bartonella (B. quintana [trench fever], B. henselae [cat scratch disease], B. bacilliformis [Oroya fever] ), formerly known as Rochalimaea and once thought to be closely related to rickettsiae, is now, after recent phylogenetic analyses, considered to be more closely related to the Brucella and Agrobacterium genera. 3 , 6

HISTORY In the past, humanity has been plagued by disastrous epidemics because of poor sanitary conditions, during famines, or after major armed conflicts. Malaria, yellow fever, cholera, bubonic plague, and epidemic and murine typhus, to name a few, claimed millions of lives during these epidemics. Although typhus, as we see it today, has a low death rate even if left untreated, it used to be a highly fatal disease in its epidemic form, the spread of the disease being promoted by poor hygiene ann overcrowded condi-

tions. Napoleon's Russian campaign in the early 1800s is famous for the terrible toll typhus took. 7 One sergeant in Napoleon's army related how he could not get to sleep because he was covered by lice. Despite the fact that he tried to get rid of them by burning his clothes, lice would continuously come back for 2 months. Many soldiers swarmed with lice developed spotted fever (typhus) after they were bitten. When they returned home, they caused epidemics in many major cities in Europe. s Famous typhus epidemics took place in Philadelphia in 1837, and there were epidemics of typhoid, scarlet fever, and yellow fever in Philadelphia, New York, Boston, New Orleans, Baltimore, Memphis, and Washington D.C. in the aftermath of the civil war in the mid 1860s. 9 During and immediately after World War I, 30 million persons suffered epidemic typhus. Three million deaths resulted. 2 The microbial agent responsible for RMSF was identified by Howard Taylor Ricketts 10- 12 in the early 1900s; the disease was originally described in the late 19th century following outbreaks in the Bitter Root and Snake Valleys of Montana and Idaho. Not only did Ricketts identify the etiologic agent that bears his name, but he also characterized its vector and route of transmission, as well as the protective role of immune serum, which was a remarkable task at that time. 13 In 1919, Wolbach identified the rickettsial pathogen within endothelial cells. 14 In 1935, Derrick, a medical officer of health in Queensland, Australia, conducted a query about an outbreak of febrile illness affecting 20 of the 800 employees of a Brisbane meat works. He coined the term Q (for

TABLE 22-1. RICKETTSIA CLASSIFICATION DISEASE SPOTTED FEVER GROUP Rocky Mountain spotted fever Mediterranean spotted fever (boutonneuse fever) African tick-bite fever Queensland tick typhus Siberian tick typhus

ORGANISM

GEOGRAPHIC DISTRIBUTION

RESERVOIR

TRANSMISSION TO HUMAN

Rickettsia rickettsii

United States

Ticks

Tick bite

Rickettsia conorii

Mediterranean basin, Africa, India

Ticks

Tick bite

Rickettsia ajricae Rickettsia australis Rickettsia sibinca

Africa Australia Russia, China, Mongolia, Pakistan Japan North America, Europe, Korea

Cattle Ticks Ticks

Tick bite Tick bite Tick bite

Unknown Mites

Arthropod bite Mite bite

Africa, United States, Asia Worldwide

Humans, flying squirrels Fleas, rats

Louse feces

Rickettsia tsutsugamushi

Asia, Australia, South Pacific

Trombiculid mite

Larva (chigger) of trombiculid mite

Coxiella burnetii

Worldwide

Ticks, ungulates

Ehrlichia sennetsu EhTlichia chaffeensis

Japan Europe, Africa, North America North America

Unknown Tick?, dog?

Aerosol from infected birth products Unknown Tick bite

Deer?, tick?

Tick bite

Oriental spotted fever Rickettsialpox

Rickettsia japonica Rickettsia akan

TYPHUS GROUP Epidemic typhus

Rickettsia prowazekii

Murine typhus (endemic typhus) Scrub typhus

OTHER DISEASES Q Fever Sennetsu fever Human monocytic ehrlichiosis Human granulocytic ehrlichiosis

Rickettsia t)phi

Ehrlichia species

Flea feces

CHAPTER 22: RICKETTSIAL DISEASES

query) fever to name this new disease. Burnet and Freeman demonstrated later that Q fever was indeed caused rickettsial bacteria. 4 Canine ehrlichiosis was first described in 1935, and until 1987, when the first human case (monocytic ehrlichiosis from E. chajjeensis) was described,15 it was mainly considered a veterinary disease. In 1994, human granulocytic ehrlichiosis was described in a small outbreak of a tick-fever disease in Minnesota and Wisconsin related to a different species of Ehrlichia. 16

Rickettsioses are zoonoses. Most of them are transmitted to humans by the bite of contaminated arthropods (tick, mite, flea, louse, chigger). Hence, their geographic distrihution is closely related to that of their insect vectors, which is, most of the time, also the reservoir host (see Table 22-1). Q fever is the exception; it is distributed worldwide and is transmitted to humans by aerosol from contaminated products (especially during parturition) of cattle, sheep, goats, and also cats. It is more likely to occur in rural areas or among abattoir workers. 3 Although Lyme disease is the leading vector-borne disease in the United States, with an incidence of 9600 reported cases in 1992, RMSF is the most frequently reported rickettsial disease, with an annual incidence of about 600 to 1200 reported cases. l Its causative agent, R. rickettsii, is inoculated through the skin by the bite of Dermacentor andersoni, the wood dck. 13 Ironically, in the United States, the prevalence of RMSF between 1981 and 1991 was higher in the southern Atlantic states and in the west-south-central region than in the Rocky Mountain states. The local prevalence in highly endemic areas such as North Carolina could be as high as 14.59 per 100,000 inhabitants. 4 In a survey of 262 confirmed or highly probable cases of RMSF between 1977 and 1980 from six states where it was endemic, 99% of the cases were diagnosed between April 1 and September 30. The incidence of RMSF was highest among children, with a median age of 15 years. Males accounted for 55% and whites for 85% of the cases. Clinical complications ranging from psychiatric problems to organ failure occurred in 9% of the cases. The death rate was 4%.17 Rickettsialpox is caused by R. akari, which is transmitted among mice by mouse ectoparasites and to humans by bloodsucking mites. It was first described in 1946 following an outbreak originating in a mouse- and miteinfested apartment house in New York. The disease produced blister-like rashes resembling those of chickenpox, hence the name rickettsialpox. Since 1946, about 800 cases have been reported. More than half occurred in the 3 years following the initial episode. IS, 19 Other rickettsial spotted fevers are mostly encountered in continents other than North America. Rarely do we have the opportunity to see the active diseases unless they are brought back by travelers returning from specific endemic areas. Most of those diseases resemble RMSF in their epidemiology and mode of transmission, except for Mrican tick-bite fever (Rickettsia africae) , with cattle as the natural reservoir for the bacteria (see Table 22-1).20

Epidemic or louse-borne typhus is caused by R. prowazekii. The natural reservoir for the bacteria is an infected human. The cycle begins when a louse feeds on a rickettsemic human. The bacteria infect the louse aliluentary tract, and within 1 week, abundant rickettsial organisms are found in its feces. When the infected louse is allowed to infest another person, rickettsial bacteria can be transmitted to the victim. When the louse takes a blood meal, it defecates. The irritation causes the person to scratch, and the louse feces then infect the bite wound. Inoculation through mucous membranes by contaminated louse feces is also possible. The louse dies within 3 weeks of the rickettsial infection, which is not passed to its offspring. A person suffering from the recrudescent form of epidemic typhus, the Brill-Zinsser disease, can, indeed, transmit the bacteria to infesting lice. The southern flying squirrel distributed over most of the eastern states of the United States could also be a reservoir for R. prowazekii. The bacteria is probably transmitted among these rodents by squirrel lice and/or fleas. 21 Louse-borne typhus is usually found in areas of crowded population with poor hygiene conditions, as occur during wars or natural disasters, especially in winter months. The disease is then responsible for an elevated number of casualties. Although similar conditions are found in some developing countries, the death rate is lower because of the availability of even minimal medical facilities. A survey of 3759 cases in Ethiopia in 1984 reported 3.8% fatalities. 22 Murine typhus is caused by Rickettsia typhi, which is found worldwide in warm-climate countries near ports and where rat populations are high and flea vectors are available. Other associations have also been reported with opossums and cat fleas. The flea vector is infected by transovarian transmission from its mother or by bloodfeeding on a rickettsemic animal. Humans acquire the infection via flea feces by scratching a pn.ll~itic flea-bite wound or by direct contamination of the conjunctiva or the respiratory tract. The widespread use of insecticides has considerably lowered the incidence of murine typhus in developed countries. Fatality rates are between 1 % and 4%.3,23

R. tsutsugamushi is the organism causing scrub typhus, a zoonosis found in the Far East. It gets its name from the secondary vegetation in transitional terrain between forest and clearings where the vector lives. The rickettsia is transmitted to humans by the bite of infected larvalstage trombiculid mites (chiggers). That mites are probably the major reservoir for the bacteria has been deduced from its transovarial transmission, and from the facts that most chiggers feed only once and that they spend their whole life within several meters of where they hatch. Mortality rates of 0% to 30% have been reported. 24 Q fever, caused by C. burnetii, is found worldwide; its principal animal reservoirs are cattle, sheep, goats, ticks, and cats. The natural cycle of transmission probably involves ticks or arthropods infecting domestic ungulates or small mammals, but not humans. Infected animals remain asymptomatic until parturition, when the heavily infected placenta contaminates the environment. Air samples can be positive for up to 2 weeks after parturition, and viable organisms can be found in the soil for up to

CHAPTER 22: RICKETTSIAL DISEASES

150 days. Humans get the disease through lung infection after they have inhaled contaminated aerosols. Q fever is mostly an occupational disease affecting farmers, abattoir workers, and veterinarians. Contamination can also result from exposure to infected milk or parturient cats or when skinning wild rabbits, as well as from contact with contaminated manure, straw, or dust. Laboratory personnel are also at risk. 25, 26 Human monocytic and human granulocytic ehrlichioses are caused by E. chaffeensis and by other Ehrlichia species, respectively. Since they have been described only recently, not much is known about their epidemiology. Exposures are mostly during the early summer months and in rural areas. Reservoirs for the bacteria are suspected to be rodents or dogs because of their ability to remain persistently infected. 3, 27 Although the disease can be quite severe, the death rate fortunately seems low. There were no deaths in a recent report on 18 patients with human granulocytic ehrlichiosis. 28 Interestingly, a prospective study demonstrated that under conditions of intense tick exposure, there could be a high rate of seroconversion for rickettsiae without clinical evidence of the disease. 29

PATHOPHYSIOLOGY, IMMUNOLOGY, PATHOLOGY, AND PATHOGENESIS Rickettsial organisms can invade their human victims in three ways. They can directly access the blood stream from a portal of entry in the skin, following the bite of an infected tick, arthropod, mite, G'T chigger. The spotted fever disease group, the ehrlichioses, and scrub typhus are transmitted this way. Second, the organism can contaminate a person who scratches the bite, contaminating the wound with infected louse feces. This is how epidemic and murine typhus are spread to humans. Finally, Q fever is transmitted to the respiratory system of the victim when he inhales aerosols from contaminated products of an infected animal. The microorganisms proliferate in the lung macrophages and finally gain access to the blood stream, where they can spread to distant organs. For most of the organisms of the spotted fever and typhus groups, the target cells are the endothelial cells of the blood vessels and their vascular smooth muscle cells. After they have been phagocytized and have entered the cells, the organisms leave the phagosomes and proliferate intracellularly. Severe damage to the small arteries, veins, and capillaries of many organs results in disseminated vasculitis. The possible mechanisms for cellular damage include activation of rickettsial phospholipase or protease, or free-radical peroxidation of host cell membranes. Rickettsial LPS toxin is relatively nontoxic and does not seem to be involved in tissue injury. 2, 3 Because of multifocal areas of endothelial injury, there is loss of intravascular fluid into the interstitial space, with resulting edema, low blood volume, reduced perfusion to the organs, and, eventually, damaged blood vessels and altered function of tissues and organs (e.g., hemorrhagic rash, encephalitis, pneumonitis, and hepatitis). Attempted plugging of tlle injured vessels results in platelet consumption and relative secondary thrombocytopenia.

Cutaneous necrosis caused by obliteration of infected blood vessels at the site of the tick bite is responsible for the eschar, or tache noire, described for many of the rickettsioses. 3 The membrane LPS of the spotted fever group of rickettsiae is strongly immunogenic, with known crossreactivity with other members of the group as well as with Proteus and Legionella species. Unfortunately, antibodies directed against rickettsial LPS do not afford much protection against infection in the animal model. T lymphocytes, interferon-')' (IFN-')'), and tumor necrosis factor-ex (TNF-ex) seem to play important roles in immune defense against rickettsiosis. 2 The target cells for C. burnetii are macrophages of the lungs, then of liver, bone marrow, spleen, heart valves, and other organs. The organisms are phagocytized, but they have the rare ability to proliferate inside the harsh environment of the host cells' phagolysosomes. The LPS of C. burnetii is also relatively nonendotoxic. T-lymphocyte-mediated granuloma formation seems to be one of the important immune defense mechanisms against this disease. 3 Liver and bone marrow biopsies and autopsy material disclose a characteristic granuloma for Q fever infection: It has a clear central space surrounded by inflammatory cells and a fibrin ring (doughnut lesion) .25 The target cells for the genus Ehrlichia bacteria are cells of the hematopoietic and lymphoreticular systems. The organisms make characteristic clusters, called morulae, within membrane-bound cytoplasmic vacuoles of monocytes and macrophages (human monocytic ehrlichiosis) or neutrophils (human granulocytic ehrlichiosis). Findings in bone marrow biopsies may include granulomas, myeloid hyperplasia, and megakaryocytosis. Although endothelial injury and thrombosis have not been described, perivasculitis with lymphohistiocytic infiltrates of the brain, kidneys, heart, and lungs is commonly seen. Defense mechanisms against Eh:rlichia species might include opsonization of macrophages and INF-')'stimulated macrophage killing. 3 ,27

General A rickettsial disease should be suspected when, during spring or summer, a patient presents with the classic triad of high fever, headache, and rash. A history of outdoor activities, occupational exposure, or tick attachment is frequent. Some of the distinctive clinical characteristics of the rickettsioses are summarized in Table 22-2.

Systemic The initial clinical presentation of most of the diseases in the spotted fever group includes high fever, myalgia, and headaches. A tache noire develops at the site of the arthropod bite. Gastrointestinal involvement with nausea, vomiting, and abdominal tenderness is frequent. Neurologic signs ranging from small focal deficits to major neuropsychiatric disturbances have been reported. The maculopapular rash may be present at the time of presentation or in the following days. In RMSF, it typically starts around the wrists and ankles and eventually spreads to the trunk. Involvement of the palms and soles is consid-

22: RICKETTSIAL DISEASES 22-2. CLINICAL CHARACTERISTICS OF RICKETTSIOSES

DISEASE

ORGANISM (INCUBATION PERIOD, DAYS)

RASH DISTRIBUTION

TACHE NOIRE-ESCHAR

OTHER FEATURES

Extremities to trunk (palms & soles) Trunk, extremities

No

Neuropsychiatric symptoms

Yes

africae (within

Weak or absent

Multiple

australis sibirica akan· (9-14)

Trunk, extremities Trunk, extremities Vesicular: trunk, extremities

Yes Yes Yes

Trunk + axilla to extremities Trunk to extremities Trunk to extremities

No No Yes

SPOTTED FEVER GROUP

Rocky Mountain spotted fever Mediterranean spotted fever Mrican tick-bite fever Queensland tick typhus Siberian tick typhus Rickettsialpox

Rickettsia rickettsii (2-14) Rickettsia conorii Rickettsia 7) Rickettsia Richettsia Richettsia

Lymphadenopathy, lymphangitis

Lymphadenopathy

TYPHUS GROUP

Epidemic typhus

Rickettsia pmwazehii (7)

Murine typhus Scrub typhus

Richettsia typhi (7-14) Richettsia tsutsugamushi (6-18)

Brill-Zinsser disease = recurrent form Lymphadenopathy

OTHER DISEASES

Q fever

Coxiella burnetii (14-39)

Rare

No

Sennetsu fever Human monocytic ehrlichiosis Human granulocytic ehrlichiosis

Ehrlichia sennetsu (14) Ehrlichia chaffeensis (7)

Very rare Maculopapular

No No

Ehrlichia species (1-14)

Rare

No

ered characteristic. In other spotted fever rickettsioses, the rash instead starts over the trunk and later spreads centrifugally to the extremities. Skin necrosis or gangrene secondary to vasculitic complications has been reported in 4 % of cases. 3, '1 In rickettsialpox, the initial lesion that develops at the site of a mite bite is papulovesicular. It evolves to form an eschar with local lymphadenopathy. High fever begins abruptly about 1 week later, and a few days afterward red macules, papules, and papulovesicles resembling chickenpox develop.19 In Mrican tick-bite fever, multiple taches noires with lymphadenopathy and lymphangitis have been described. 2o The initial clinical presentation for the typhus group of rickettsioses is similar to that of the spotted fever group, with high fever, myalgia, and rash. In epidemic typhus, lung and potentially severe neurologic involvement have been reported. A recurrent form of the disorder, the Brill-Zinsser disease, may develop years after the initial infection, following stress or decreased immunity.3, 21 In murine typhus, neurologic symptoms are found in up to 45% of the patients and may include confusion, seizures,· and ataxia. 23 Patients affected by Q fever also present with high fever, headache, malaise, and myalgia, but a rash is not found. Pneumonia is present in up to 90% of patients; it is characterized by patchy infiltrates on chest radiographs. Hepatitis with minimal elevation. of the transaminase enzymes is found in 85% of patients. Jaundice is uncommon. Endocarditis is a rare but serious complication of

Pneumonia, chronic endocarditis Lymphadenopathy Lymphadenopathy

Q fever because it can be lethal. When endocarditis devel-

ops, there is usually concomitant hepatic involvement. 25 ,26 Patients with ehrlichiosis present with fever, myalgia, or arthralgia. Less than 50% develop a maculopapular rash; this is seen more frequently in children. A finding of abnormal liver enzymes is common. Rare complications include respiratory and renal insufficiency, neurologic abnormalities, and gastrointestinal hemorrhage. 27 , 28

Ocular Involvement Ocular involvement in rickettsioses is not reported frequently. Since it can be mild, it is probably overlooked much of the time. I am not aware of a prospective study that has systematically addressed this issue. Contamination of the conjunctiva by a spurt of tick blood has been implicated as the apparent portal of entry for R. rickettsii systemic infection. 13 Conjunctivitis was reported in 30% of the cases in a retrospective study including 262 patients suffering from confirmed or highly probable RMSF between 1977 and 1980 in the United States,17 Conjunctival petechiae and subconjunctival hemorrhages have also been described.30 Rare descriptions of keratitis or corneal ulcerations are found in the literature. 3o A well-documented case of Mediterranean spotted fever keratitis was reported in 1992. The authors believed that the corneal infection was probably secondary to contamination from the tears during systemic rickettsiosis in a 69-year-old man with chronic alcoholism. The lesion consisted of an alneboid type of ulceration similar to herpetic epithelial keratitis.

CHAPTER 22: RICKETTSIAL DISEASES

Corneal scrapings were posItIVe for R. richettsii antigens with direct immunofluorescence studies and negative to herpes simplex immunologic and cytopathic tests. It responded readily to the use of topical tetracycline ointmentY Mild to moderate nongranulomatous anterior uveitis has been described with rickettsioses. 32 It usually resolves with topical corticosteroids and mydriatic treatment, or when the infectious disease subsides after appropriate systemic antibiotic treatment. An iris nodule, similar to the typhus nodule reported at autopsy of the central nervous system following typhus rickettsioses, was reported by Duffey and Hammer in 1987. 33 A case of endogenous endophthalmitis caused by Richettsia conorii and apparently proved by serologic and vitreous direct and indirect immunofluorescen-ce was reported by Mendivil and Cuarto in 1998. 34 A 50-year-old man presented with a leg tick-bite eschar, fever, arthromyalgia, and fatigue of 6-day duration. He developed unilateral loss of vision with relative afferent pupillary defect and hypopyon. Vitreous cultures remained negative, but the ocular condition cleared after intravitreal chloramphenicol injection and systemic doxycycline. Since the physiopathologic basis for rickettsial infectious diseases is vasculitic, most of the ocular inflammatory lesions involve the retinal or optic nerve vasculature. They can include optic nerve head edema; intraretinal hemorrhages; cotton-wool spots; dilated, tortuous retinal veins; vasculitis; and retinal vessel 'occlusion. 35- 37 Fluorescein angiography of the retina of a 9-year-old girl with RMSF demonstrated focal areas of capillary nonperfusion with cotton-wool spots and perivascular staining in the infarcted areas. Late-phase photographs showed hyperfluorescence of the optic disk. 35 There are reports of multiple small retinal white spots or small retinal infiltrates during rickettsioses. Moderate vitreous inflammation can be found, and white retinal infiltrates are seen localized in the neurosensory retina (Fig. 22-1). A blocking effect is produced by these lesions on fluorescein angiography The lesions usually resolve without clinical and angiographic scarring in a few weeks

FIGURE 22-1. Retinal involvement in Rickettsioses. Note the periarteritis, the macular star exudate, and the retinal infiltrates. (Courtesy of C. Stephen Foster, M.D.) (See color insert.)

following appropriate systemic antibiotic treatment. 37- 39 These multiple white dots might be similar to those seen in multiple evanescent white dot syndrome (MEWDS), an acute, multifocal, self-limiting disease affecting young adults after a flulike syndrome. 3s

There are no rapid laboratory tests for rickettsioses. The best early diagnostic tool is the physician's high index of suspicion in the presence of high fever, general malaise, headache, and a rash in a patient living in or traveling back from a· region endemic for rickettsioses. Occupational contact with infected birth products of farm animals should also be inquired about. A complete and careful physical exam is essential. The physician should first look for the presence of the insect vector (louse, flea, or tick). The hard ticks can stay attached for days on their victims and can be overlooked if located on the back or in the axillary or inguinal region. Rash can be very subtle. Tick bites that later develop tache noire should be searched for. The diagnosis of rickettsioses is confirmed when positive serologic tests are found in a patient with a compatible clinical presentation. Positive serologic criteria usually include either initial high antibody titer or a fourfold rise of the titer in the convalescent serum. Serologic tests may include complement-fixing antibody, enzyme immunoassay, indirect fluorescent antibody, indirect hemagglutination, and latex agglutination. 3 The relatively nonspecific and insensitive Weil-Felix test has become obsoleteP Case confirmation with serology might take 2 to 3 weeks. Furthermore, early antibiotic treatment tends to blunt and delay the antibody response to the bacteria. IS Another interesting test has been described in Europe for the diagnosis of rickettsioses. Endothelial cells are isolated from blood samples with the use of immunomagnetic beads coated with endothelial cell-specific IgG1 monoclonal antibodies. The presence of rickettsiae can then be determined using either specific immunofluorescent staining or amplification by polymerase chain reaction. 20 Direct fluorescent antibody testing on paraffin-eInbedded biopsy specimens from eschars or papulovesicles has been reported in rickettsialpox. 19 When ehrlichiosis is suspected, a search should be made for morulae in blood buffy-coat smears stained with Wright'S stain. The test is positive in up to 80% of cases as early as the day of initial presentation. 2s , 40 Because rickettsiae are both fastidious and hazardous organisms, many microbiology laboratories are reluctant to undertake their isolation and identification. 3 Nonspecific laboratory changes during rickettsemia may include anemia, leukocytosis, leukopenia, thrombocytopenia, hyponatremia, hypoalbuminemia, liver function abnonnalities, renal function impairment, coagulation disturbances, and cerebrospinal fluid abnormalities with leukocytosis and hypoglycorrhachia. 13 , 25, 41

Prevention is the best approach for rickettsial diseases. Good sanitary habits and special attention to tick bites in endemic areas are recommended. An attached tick is

CHAPTER 22: RICKETTSIAL DISEASES

best removed with a pair of forceps, trying to keep the arthropod intact. The wound should then be cleansed. 4 Except for epidemic typhus (R. prowazekii) and possibly soon for Q fever (c. burnetii) , human vaccine is not currently available for the rickettsioses. Vaccination is recommended for individuals who are at high risk of becoming infected: scientific investigators, laboratory personnel, people working or traveling in endemic areas, and medical personnel providing care where typhus is found.4, 18, 21, 23, 24, 26, 27 Anterior uveitis can be treated with topical steroids and mydriatic drops. Retinal lesions usually respond to systemic antibiotic treatment. . Rickettsemia is best treated with oral tetracyclInes (25-50 mg/kg/day) or chloramphenicol (50-75 mg/kg/ day) in four divided doses. Doxycycline (100 mg every 12 h) is also very effective, and quinolones (ciprofloxacin [1.5 g/day], and ofloxacin) have been recently described as valuable alternatives. The drugs can be administered orally or intravenously. Because of the effect of tetracyclines on developing bones and teeth, chloralnphenicol or quinolones are preferred in pregnant women and in young children. 4, 18, 21,23, 24 Chloramphenicol is not effective in ehrlichiosis, where tetracycline or doxycycline is the treatment of choice. Rifampin was shown to have in vitro ehrlichicidal properties but its clinical effectiveness has not been evaluated. 27 The treatment of choice for acute Q fever is also tetracycline. Chloramphenicol and quinolones may also be used. Although generally q~ite effective in treating any form of atypical pneumonia, erythromycin might be relatively ineffective for the most severe cases of Q fever pneumonia, unless rifampin (300 mg by mouth twice daily) is added. 25 ,26 There is usually a consensus about using a combination of antibiotics for many months to treat Q fever endocarditis, a chronic, potentially lethal form of C. burnetii infection. The therapeutic regimen might include doxycycline with trimethoprim-sulfamethoxazole or rifampin, doxycycline with fluoroquinolones, or doxycycline with chloroquine or amantadine for months to 2 years. Antibody titers should be monitored regularly. Successful therapy is usually accOlnpanied by normalization of the erythrocyte sedimentation rate, the anemia, and the hyperglobulinemia. Valve replacement may be necessary.26

COMPLICATIONS When appropriate therapy is initiated prOlnptly, most patients recover rapidly and without complications from rickettsioses. Many are fortunate to recover without systemic treatment. Unfortunately, however, rickettsial agents have the potential to cause important systemic complications, including death. The possible systemic complications for rickettsial disease include hemolytic anemia, coagulopathies, focal neurologic deficits, seizures, severe psychiatric disturbances and coma, hepatitis, skin necrosis, renal insufficiency, chronic endocarditis, and osteomyelitis. Fortunately, unless the disease has caused irreversible damage from obstructed blood vessels, most rickettsial ocular lesions resolve without residual visual impairment. This is especially so if systemic antibiotics are used.

The sooner the clinical diagnosis of rickettsial infection is made and appropriate treatment is begun, the better the prognosis. Where medical facilities are easily obtainable, the mortality rate for RMSF is less than 4%, but it can reach 20% to 25% if treatment is delayed or inappropriate. 3 Better overall sanitary conditions also favorably affect the prognosis of the epidemic forms of rickettsioses such as murine or epidemic typhus. In the aftermath of war or natural disasters, the casualties among people living in overcrowded areas with· poor hygiene can reach the thousands, whereas with better sanitary conditions, even in developing countries where medical facilities are limited, the fatality rate is about 4%.22

CONCLUSIONS Rickettsial diseases are characterized by the triad of high fever, headache and general malaise, and skin rash. Occupational hazard (abattoir workers or contact with contaminated birth products of farm animals), living in or traveling back from an endemic area for rickettsioses, or a history of tick bites is usually found when interviewing the patient. The early diagnosis relies entirely on a high index of suspicion and keen clinical acumen, and the sooner the appropriate antibiotic regimen is initiated, the better the prognosis. Although following a tick bite, there is a significant percentage of seroconversion without clinical disease and of spontaneous remission without treatment, rickettsioses are severe, potentially lethal diseases and should be treated accordingly. There is hope that with better sanitary conditions including the control of rat reservoirs and of flea or lice vectors the incidence of the epidemic forms of rickettsioses (murine and epidemic typhus) could be lowered in the areas where it is now endemic. Finally, the development of new, more rapid diagnostic tools needs to be encouraged. In the search for specific rickettsial antigens, the use of immunomagnetic beads to isolate endothelial cells from blood samples 20 may become a gold standard in early detection of the disease. If this test is proved to be reliable, it should improve the prognosis for rickettsioses.

References 1. Spach DH, Liles WC, Campbell GL, et al: Tick-borne diseases in the United States. N EnglJ Med 1993;329:936-947. 2. Saah AJ: Rickettsiosis: Introduction. In: Mandell GL, Douglas JE, and Bennett R, eds: Principles and Practice of Infectious Diseases. New York, Churchill Livingstone, 1995, pp 1719-1720. 3. Walker DB: Rickettsiae. In: Baron A, ed: Medical Microbiology. Galveston, TX, The University of Texas Medical Branch at Galveston, 1996, pp 487-501.. .. 4. Walker DH, Raoult D: Rickettsia rickettsii and other spotted fever group rickettsiae (Rocky Mountain spotted fever and other spotted fevers). In: Mandell GL, Douglas JE, and Bennett R, eds: Principles and Practice of Infectious Diseases. New York, Churchill Livingstone, 1995, pp 1721-1727. 5. CDC and NIH: Rickettsial agents. In: Biosafety in Microbiological and Biomedical Laboratories. 1993. Washington, DC, Centers for Disease Control and Prevention and the National Institutes of Health. 6. Slater NL, Welch DF: Rochalimaea species (recently renamed Bartonella). In: Mandell GL, Douglas JE, and Bennett R, eds: Principles

CHAPTER 22: RICKETTSIAL DISEASES

7. 8. 9.

10.

11.

12. 13.

14. 15.

16.

17.

18.

19. 20. 21.

22. 23.

24.

and Practice of Infectious Diseases. New York, Churchill Livingstone, 1995, pp 1741-1747. Pfeiffer CJ: The Art and Practice of Western Medicine in the Early Nineteenth Century. Jefferson, NC, McFarland, 1985. Major RH: Disease and Destiny. Logan Clendening. Lawrence, K5, University of Kansas Press, 1958. American epidemics. Ohio Network of American History and Research Center. www.infinet.com/~dzimmerm/ohionet.html. Ricketts HT: A summary of investigations of the nature and means of transmission of Rocky Mountain spotted fever. Trans Chicago Pathol Soc 1906;7:73-82. Ricketts HT: The study of Rocky Mountain spotted fever (tick fever?) by means of animal inoculations. A preliminary communication. JAMA 1906;47:33-36. Ricketts HT: Some aspects of Rocky Mountain spotted fever as shown by recent investigations. Med Record 1909;76:843-855. Kirk JL, Fine DP, Sexton DJ, Muchmore HG: Rocky Mountain spotted fever. A clinical review based on 48 confirmed cases. Medicine 1990;69:35-45. Wolbach SB: Studies on Rocky Mo:untain spotted fever. J Med Res 1919;41:2-197. Maeda K, Markowitz N, Hawley RC, et al: Human infection with Ehrlichia canis, a leucocytic rickettsia. N Engl J Med 1987;316:853856. Chen SM, DumlerJS, BakkenJS, et al: Identification ofa granulocytotropic Ehrlichia species as the etiologic agent of human disease. J Clin Microbiol 1994;32:589-595. Helmick CG, Bernard KW, D'Angelo LJ: Rocky Mountain spotted fever: Clinical, laboratory, and epidemiological features of 262 cases. J Infect Dis 1984;150:480-488. Saah AJ: Rickettsia ahari (rickettsialpox). In: Mandell GL, Douglas JE, and Bennett R, eds: Principles and Practice of Infectious Diseases. New York, Churchill Livingstone, 1995, p 1727. Kass EM, Szaniawski WK, Levy H, et al: Rickettsialpox in a New York City hospital, 1980 to 1989. N Engl J Med 1994;331:1612-161 7. Brouqui P, Harle JR, Delmont J, et '9.1: African tick-bite fever. An imported spotless rickettsiosis. Arch Intern Med 1997;157:119-124. Saah AJ: Richettsia pmwazekii (epidemic or louse-borne typhus). In: Mandell GL, DouglasJE, and Bennett R, eds: Principles and Practice of Infectious Diseases. New York, Churchill Livingstone, 1995, pp 1735-1737. World Health Organization: Louse-borne typhus: 1983-1984. Weekly Epidemiol Rec 1984;57:45-46. Dumler JS, Walker DH: Murine typhus. In: Mandell GL, Douglas JE, and Bennett R, eds: Principles and Practice of Infectious Diseases. New York, Churchill Livingstone, 1995, pp 1737-1739. Saah AJ: Richettsia tsutsugamuchi (scrub typhus). In Mandell GL,

25. 26. 27.

28.

29.

30. 31. 32. 33. 34. 35. 36.

37. 38.

39. 40.

41.

DouglasJE, and Bennett R, eds: Principles and Practice ofInfectious Diseases. New York, Churchill Livingstone, 1995, pp 1740-1741. Sawyer LA, Fishbein DB, McDade J: Q fever: Current concepts. Rev Infect Dis 1987;9:935-946. Marrie TJ: Coxiella burnetii (Q fever). In: Mandell GL, Douglas]E, and Bennett R, eds: Principles and Practice of Infectious Diseases. New York, Churchill Livingstone, 1995, pp 1727-1735. Walker DH, Dumler JS: EhTlichia chaffeensis (human ehrlichiosis) and other ehrlichiae. In: Mandell GL, Douglas JE, and Bennett R, eds: Principles and Practice of Infectious Diseases. New York, Churchill Livingstone, 1995, pp 1747-1752. Aguero-Rosenfeld ME, Horowitz HW, Wormser GP, et al: Human granulocytic ehrlichiosis: A case series from a medical center in New York State. Ann Intern Med 1996;125:904-908. Sanchez JL, Chandler WH, Fishbein DB, et al: A cluster of tickborne infections: Association with military training and asymptomatic infections due to Richettsia richettsii. Trans R Soc Trop Med Hyg 1992;86:321-325. Fran\=ois J: Rickettsiae in ophthalmology. Ophtalmologica 1968; 156:459-472. Alio J, Ruiz-Beltran R, Herrera I, et al: Rickettsial keratitis in a case of Mediterranean spotted fever. Eur J Ophtllalmol 1992;2:41-43. Cherubini TD, Spaeth GL: Anterior nongranulomatous uveitis associated with Rocky Mountain spotted fever. First report of a case. Arch Ophtllalmol 1969;81:363-365. Duffey RJ, Hammer ME: The ocular manifestations of Rocky Mountain spotted fever. Ann Ophthalmol 1987;19:301-303. Mendivil A, Cuarto V: Endogenous endophthalmitis caused by Richettsia conorii. Acta Ophthalmol Scand 1998;76:121-122. Smitll TW, Burton TC: The retinal manifestations of Rocky Mountain spotted fever. Am J Ophthalmol 1977;84:259-262. Sulewski ME, Green WR: Ocular histopathologic features of a presumed case of Rocky Mountain spotted fever. Retina 1986;6:125130. Hudson HL, Thach AB, Lopez PF: Retinal manifestations of acute murine typhus. Int Ophthalmol 1997;21:121-126. Lu TM, Kuo BI, Chung YM, Liu CY: Murine typhus presenting with multiple white dots in tlle retina. Scand J Infect Dis 1997;29:632633. Lukas JR, Egger S, Parschalk B, Stur M: Bilateral small retinal infiltrates during rickettsial infection. Br J Ophthalmol 1998;82: 1217-1218. Bakken 1S, Krueth J, Wilson-Nordskog C, et al: Clinical and laboratory characteristics of human granulocytic ehrlichiosis. JAMA 1996;275:199-205. Dumler JS, Taylor JP, Walker DH: Clinical and laboratory features of murine typhus in South Texas, 1980 through 1987. JAMA 1991;266:1365-1370.

Elisabeth M. Messmer

Leprosy (Hansen's disease) is a chronic granulomatous infectious disease caused by Mycobacterium leprae. It mainly involves skin, peripheral nerves, mucous membranes, and ocular structures. According to the World Health Organization (WHO), a "case of leprosy" is defined as a person having one or more of the following features, and who has yet to complete a full course of treatment: 1 Hypopigmented or reddish skin lesion(s) with definite loss of sensation Involvement of the peripheral nerves, as demonstrated by definite thickening with loss of sensation Skin-smear positive for acid-fast bacilli Unfortunately, the WHO considers as "leprosy patients" only those who are untreated or on active treatment. This may be misleading in treated cases of leprosy with ongoing eye disease or leprosy-related visual disability. Depending on the resistance to infection, leprosy may present as tuberculoid (TT) , borderline (TB, BB, BL), or lepromatous (LL) leprosy on a continuous disease spectrum. 2,3 Leprosy patients may be classified as having multibacillary or paucibacillary ,~eprosy according to the degree of skin-smear positivity.4, 5 Because services for processing skin smears are not always available and their reliability is often doubtful, patients are increasingly being classified on clinical grounds. The assumption is that the protective immunity is inversely correlated with the number of skin lesions. The WHO therefore proposes the following classification, which has an important impact on therapeutic decisions: Paucibacillary single-lesion leprosy (one skin lesion) " Paucibacillary leprosy (two to five skin lesions) " Multibacillary leprosy (more than five skin lesions) 1 According to the U.S. Department of Health and Human Services, Centers for Disease Control, leprosy belongs to the group of "Notifiable Diseases."6

HISTORY References to leprosy can be found in the ancient Indian literature (Sushruta Samhita, 600 BC), described as kushtha (kushnati = to gnaw or sashtha = bad, evil) and in the ancient Chinese medical literature as Da Feng (circa 400 BC).7, 8 It is generally doubted that leprosy is menti011.ed in the Bible as tsara'ath, because there is no description of associated nerve damage. 7 In the Western world, no identifiable clinical descriptions of leprosy are known prior to the third century BC, when the lepromatous type came to be known to the physicians of Alexandria under the name elephantiasis. What Hippocrates and other ancient scholars called lepra was an ill-defined and nonspecific eruption of the skin. 7 Wars and crusades caused an epidemic spread of leprosy, which peaked in Europe between the 10th and 14th

centuries AD. Contradicting the traditional view that leprosy was overdiagnosed in the Middle Ages, approximately 80% of the skeletal remains of persons buried in medieval leprosaria reveal the bone changes of leprosy. 9 Central and South America were probably free frOlTI leprosy before the Spaniards and Portuguese introduced it in the 16th century and thereafter. Similarly, leprosy was probably unknown in North America until introduced by successive waves of western European immigrants and slaves from Mrica. 7 Probably the most important scientific event in the history of leprosy took place in 1873 in Bergen, Norway, where Hansen observed rod-shaped bodies in unstained fluid from skin lesions of leprosy patients. He announced them as the cause of the disease in 1874. 10 As early as 1873, Bull and Hansen l l drew attention to leprous eye complications, which may present in up to 100% of patients with longstanding disease. In more recent years, important breakthroughs in leprosy management and research were reported: the introduction of sulphones for chemotherapy (1943),12 the recognition of selective growth of M. leprae in cool parts of the body (1956),13 the development of the mouse footpad model (1960),1'1 the identification of the nine-banded armadillo as an experimental model of leprosy (1971),15 the purification of antigens of M. leprae (1980),16 and the establishment of genomic libraries of M. leprae (1985) .17,18

Considerable progress has been made in the fight against leprosy during the past 10 to 15 years, following the introduction of multidrug therapy (MDT) regimens. Current estimates indicate that there are about 1.15 million cases of leprosy in the world, compared with 10 to 12 million cases in the mid 1980s. 1 During the past 12 years, the number of registered cases in the world has fallen by about 85% in almost all countries and regions where leprosy is endemic. 1 The highest prevalence of leprosy is in central Mrica, the Middle East, and Southeast Asia, including India and Indonesia. 19 Although leprosy is regarded primarily as a tropical disease, 122 new cases were reported in the United States in 1997. The number of reported cases in the United States peaked in 1985 with 361 newly diagnosed leprosy patients, but it has remained stable since 1988. 6 Imported rather than indigenous cases are responsible for the growing incidence of leprosy in the United States, reflecting the increase in numbers of refugees and immigrants, as well as increased world travel and work abroad by American citizens. 2o Indigenous areas continue to exist in Hawaii, Texas, and California. 6, 20, 21 Although humans are considered the major host and reservoir of M. leprae, other animals, including the armadillo, chimpanzee, and mangabey monkey, have also been incriminated as reservoirs of infection. 1 The epidemiologic significance of these findings is unknown, but is

CHAPTER 23: OCULAR likely to be very limited. 1 There is no evidence to suggest an association between HIV infection and leprosy.22 However, previous infection with tuberculosis has been implicated in the resistance to leprosy, and protection against leprosy by bacillus Calmette-Guerin (BCG) vaccination was demonstrated in five large field trials conducted in India, Malawi, Myanmar, Papua New Guinea, and Uganda. The protective effect, however, varied from 20% to 80%. The addition of killed M. leprae did not ilnprove the protection afforded by BCG vaccination alone in either of the trials. 1 The risk of becoming infected with M. leprae remains a controversial issue. A view still prevalent is that subjects become infected only after close and prolonged contact with an infectious patient. However, Godal and colleagues reported that an immune response to M. leprae, indicated by a reactive lymphocyte transformation assay, is present in 50% of contacts of tuberculoid or treated lepromatous patients and in more than 50% of individuals with occupational contact of leprosy for more than 1 year. 23 It seems that -leprosy is more highly infectious than indicated by the prevalence of the disease, and that subclinical infections are common but are eliminated by an appropriate cellular immune response. 1, 23, 24 Airborne spread from the infected upper respiratory tract and discharges from ulcerative skin lesions are considered the major routes of transmission of viable leprosy bacilli. Leprous infection from mother to child may occur by transplacental transmission 25 and infected breast milk. Insects have been incriminated as carriers of M. leprae, but the epidemiology of leprosy is not consistent with a primarily vector-borne transmission. Insect bites may favor the penetration of M. leprae deposited on the skin. 7,26 Factors that influence susceptibility to leprosy infection include age (bimodal age distribution, with the first peak iiI childhood and a plateau between 30 and 60 years), male sex, and low socioeconomic background. 7, 21 Not only may genetic factors influence the pathogenesis of leprosy as seen in identical twins,7 but genetic markers such as human leukocytic antigens (HLA) may also control the type of leprosy that develops.24, 27 There is striking geographic variation in the prevalence of the lepromatous form of leprosy, from below 5% in Burkina Faso to over 60% in Malaysia. Lucio leprosy, a distinct form of lepromatous leprosy, appears to be confined to Latin America. 21 There are few, if any, true incidence data to predict ocular involvement in leprosy. Depending on the investigator, prevalence of ocular leprosy ranges from 0.8% to 100%.28 Many investigators believe that ocular involvement would develop in all leprosy patients with longstandin-g, untreated disease. 29-32

qy

Approximately 2 million people currently have disabilities related to leprosy. Blindness due to leprosy was seen in3.2% of the patients, whereas 7.1 % of leprosy patients had severe visual impairment (visual acuity less than 20/ 200) in a study of 4772 leprosy patients reported by ffytche. 33 The three major causes of visual disability and blindness in leprosy patients are corneal involvement, uveal disease, and cataract formation. 34 Excess mortality with a 4.8-fold risk of death associated with blindness was reported in leprosy patients. 35

Systemic Findings Leprosy ranges from single, selfhealing, symptomless macules to relentless progressive disease. Anesthetic skin lesions, enlarged peripheral nerves, and acid-fast bacilli in skin smears are the main systemic findings in leprosy. The signs and symptoms of the disease result from three interrelated processes: (l) the growth and disselnination of M. leprae, (2) the host immune response, and (3) damage to nerves. 21 Typically, the earliest sign of leprosy is a macule that is slightly hypoesthetic and erythematous or hypopigmented (indeterminate leprosy). Skin lesions of lepromatous (LL) leprosy vary from poorly defined macules to papules, nodules, plaques, or diffuse infiltrations. They tend to be numerous and symmetrically distributed. Sensory disturbances develop later in the course of the disease and are not as distinct as in tuberculoid -leprosy. In tuberculoid (TT) leprosy, early macular lesions are sharply defined and hypopigmented or erythematous, with distinct sensory impairment. Typically, there is a single, well-defined lesion, or only a few, which are asymmetrically distributed. Borderline (BT, BB, BL) leprosy spans the spectrum between TT and LL. Damage to peripheral nerves is often pronounced. 21 The clinical course of leprosy is often exacerbated by acute episodes called leprosy reactions. These reactions fall into two groups: (l) type I reactions, with increased cell-mediated immunity (reversal reactions) or decreased cell-mediated immunity (downgrading reactions), and (2) type II reactions (erythema nodosum leprosum [ENL]), with decreased cell-mediated and altered humoral immunity with deposition of immune complexes in the lesions. 21 , 36 In both type I reactions, skin lesions become erythematous and edematous, and acute neuritis is common. In ENL, leprosy patients typically develop tender subcutaneous nodules, fever, lymphadenopathy, arthralgias, and vasculitis. Type I and type II reactions carry an increased risk for ocular complications. 21 , 37-39

Ocular Lesions Ocular involvement in leprosy varies depending on Inany factors, including the form of leprosy, the duration of the disease, and the previous systemic and local treatment. Ocular lesions may occur by four mechanisms: (1) spread of leprous lesions from adjacent skin or nasal mucosa, (2) neuritis with infranuclear facial nerve palsy or trigeminal nerve involvement and subsequent corneal damage, (3) direct intraocular infection with M. leprae, and (4) allergic reaction to M. leprae antigen. Lepromatous leprosy tends to be associated with more severe intraocular involvement, whereas patients with tuberculoid leprosy typically present with early involvement of the motor and sensory nerves with resulting corneal problems. 40

Lids, Cornea,

Conjunctiva

Brow hair loss and loss of lashes (madarosis) are perhaps the most common manifestations of leprosy.4o It does not have any functional relevance, but it represents a stigma for the patient. Lagophthalmos caused by seventh nerve paralysis, often accompanied by ectropion, occurs in

CHAPTERD: OCULAR LEPROSY about 20% of leprosy patients independent of the type of diseaseY Lagophthalmos is mostly bilateral and a late complication in multibacillary cases, whereas it occurs unilaterally and early in the course of the disease in paucibacillary patients, often associated with leprosy reactions. 42 Lagophthalmos resulted in corneal disease (exposure keratitis, ulcer, or opacity) in 87% of afflicted leprosy patients in a recent study in ChinaY Trigeminal nerve involvement, causing corneal hypesthesia, frequently accompanies facial nerve palsy in leprosy, and the effect of this combination is catastrophic, with a high risk for sightthreatening corneal complications. 44,45 Furthermore, leprosy causes denervation of the lacrimal gland and infiltration of the meibomian glands of the lids, resulting in tear film abnormalities that contribute to corneal morbidity.46,47 Focally enlarged corneal nerves, resembling beads on a string, are pathognomonic of leprosy. Frequently, patients with leprosy exhibit an asymptomatic, avascular, punctate keratitis in the superior quadrant of the cornea caused by direct bacterial invasion. Less frequently, an interstitial keratitis may develop. Classic leprous pannus with microlepromata within the network of newly formed blood vessels occurs late in the course of the disease. Frank corneal lepromas are a rare manifestation of leprosy. Pterygium formation associated with lepromatous granuloma of the conjunctiva has been reported to occur in leprosy patients. 48

Sclera Nodular episcleritis and scleritis usually consist of a focal leproma and an inflammatory response. Diffuse episcleritis and scleritis may also occur as an immunologically driven disease with immune complex deposition without direct bacillary invasion. It is typically observed during leprosy reactions and is often associated with keratitis or iridocyclitis. Chronic or recurrent scleritis may lead to scleral necrosis, scleral "melt," and staphyloma formation. 49

lary reactions 54, 55 with· denervation hypersensitivity to adrenergic agents,5(), 56 and reduced accomodation57 with early presbyopia.58 Iris involvement can be divided into four main groups: acute iridocyclitis, chronic iridocyclitis, miliary iris lepromas, and nodular iris lepromas. ACUTE, DIFFUSE, PLASTIC IRIDOCYCLITIS

Acute nongranulomatous iridocyclitis is a COlnmon, often bilakral, accompaniment of the type II (ENL) reaction. Its clinical presentation does not differ from other fonns of acute nonleprous iritis. The course of the disease is often fulminant, with a sudden painful onset, conjunctival hyperemia, keratic precipitates, aqueous cells, and flare, often with hypopyon formation, posterior synechiae, and secondary glaucoma. 5() Spontaneous hyphema may also occur as a result of the fragility of the iris vasculature.'l0 CHRONIC IRIDOCYCLITIS

The more common chronic iridocyclitis is less dramatic but potentially blinding. It is a low-grade, granulomatous or nongranulomatous iridocyclitis common in lepromatous leprosy but also seen in the tuberculoid form. It is characterized by a lack of sYlnptoms and overt signs, although slit-lamp examination may show aqueous cells and flare with fine or mutton-fat keratic precipitates scattered all over the corneal endothelium5() (Fig. 23-1). However, its chropic course eventually leads to severe iris atrophy and polycoria. Iris adhesions slowly progress to seclude and occlude the pupil. Small, nonreacting pupils, caused by the involvement of sympathetic iris nerves, exaggerate the visual impairment created by developing lens changes and corneal opacities. 5() MILIARY IRIS LEPROMAS (IRIS PEARLS)

Iris, Ciliary Body

Equally asymptomatic is the development of miliary iris lepromas (iris pearls) in the early stages of the disease. These small, glistening, white lesions are pathognomonic for leprosy (Fig. 23-2) and have been shown to represent aggregates of tightly packed living and dead bacilli lying within mononuclear cells (foam or lepra cells). Iris pearls usually develop within a year or two of the COlnmencement of iritis, with little accompanying inflammation or

Uveal tract involvement is primarily seen in lepromatous leprosy, and its incidence is directly proportional to disease duration. In a recent worldwide study on the ocular complications of leprosy in 4772 patients, iris involvement occurred in at least one eye in 7.2% of patients, with variation between centers ranging from 0.5% to 23.8%.34 Iridocyclitis and sequelae were responsible for blindness in at least 5.4% of eyes. 34 Lepromatous iridocyclitis may be (1) caused by direct invasion of M. leprae into ocular structures, hematogenously or by way of ciliary nerves, (2) neuroparalytic, the result of an early involvement of iris sympathetic nerves,5() or (3) a uveal hypersensitivity to M. leprae antigen in association with a leprosy reaction. 4(), 5(), 51 M. leprae has been isolated from the iris of normal-appearing eyes,52 and it has been suggested that the iris is a site in which M. leprae might survive long after skin smears have become negative. 53 Early subtle signs of iris and ciliary body involvement are autonomic dysfunction, including diminished pupil-

FIGURE 23-1. Lepromatous uveitis with corneal edema, retrocorneal fibrovascular membrane formation, mutton-fat keratic precipitates, 3 + anterior chamber inflammation, and secluded pupil. (See color insert.)

CHAPTER 23: OCULAR lEPROSY especially when associated with an erythematous facial skin lesion. 73 Type II reactions (ENL) may develop in multibacillary patients with longstanding untreated disease, but up to 50% of patients develop ENL within the first year of antileprosy treatment. 74 BL and LL leprosy patients are, in particular, at risk of acute iridocyclitis and (epi-) scleritis during treatment and early follow-up. However, once an eye has had acute iridocyclitis, it seems lTIOre prone to recurrent uveitis, without generalized signs of type II reaction.

Ocular Complications

Ocular Hypotony and Glaucoma FIGURE 23-2. Iris granuloma formation (so-called iris pearls) in lepromatous uveitis. (From Messmer EM, Raizman MB, Foster CS: Lepromatous uveitis diagnosed by iris biopsy. Graefes Arch Clin Exp Ophthalmol 1998;236:717"':719. Copyright © 1998 Springer-Verlag.) (See color insert.)

foreign body reaction. 59, 60 Iris pearls are situated mainly at the pupil margin around the collarette, resembling a necklace 59 or the beads of a rosary. 61 Pearls may also develop deep in the iris stroma and occasionally at the iris periphery. Typically, iris pearls slowly increase in size and tend to aggregate. 50 ,62 They may become pedunculated and eventually drop off into the anterior chamber, where they are well. tolerated and p~oduce no inflammatory reaction. They are a transient phenomenon and are rarely responsible for any visual impairment. NODULAR IRIS LEPROMAS

Bacterial invasion of the iris may also give rise to the formation of a nodular leproma. Nodular iris lepromas are yellow, globular, polymorphic masses that occur less commonly than iris pearls. They may occur in clinically uninflamed eyes. 63 Rarely, they disrupt the iris architecture and interfere with vision. 50

Decreased intraocular pressures are typically found in the majority of patients with leprous iridocyclitis. 75- 77 Chronic uveitis is thought to affect the secretory epithelium of the ciliary body and prevent its proper functioning. Moreover, low intraocular pressures might be related to abnormalities in the autonomic innervation of the anterior segment of the eye, with large postural changes in intraocular pressure seen in these patients. 78 Interestingly, low intraocular pressures were also observed in household contacts of patients with leprosy, suggesting that these persons suffered from a subclinical infection with early autonomic nervous system or early ciliary body involvement. 79 Profound ocular hypotension may eventually lead to a phthisical eye. 80 Glaucoma is considered to be an uncommon, but often unrecognized and untreated, complication of leprosy, with a reported average prevalence of 3.9%81 to 12%.82,83 At the GWL Hansen's Disease Centre, Carville, LA, however, 20.5% of leprosy patients are followed as glaucoma patients or as glaucoma suspects. 84 Secondary open angle glaucoma with a history of chronic uveitis and chronic angle closure after intraocular inflammation are the most prominent types, but primary open angle glaucoma and acute angle closure glaucoma caused by iris bombe also occur. 82

Posterior Segment Lesions Uveitis in leprosy usually involves the iris and ciliary body, but it spares the choroid because of the organism's predilection for cooler parts of the body.64, 65 Rarely, leprosy "pearls" have been described in the anterior choroid 66-68 or as retinal pearls situated near the posterior pole of the eye, thus affecting vision. 66-68 Choroidal involvement described in the literature includes proliferation of retinal pigment epithelium (RPE) ,69 hypopigmented patches in the fundus,7° peripheral '10nspecific choroiditis,69 and disseminated choroiditis,71 as well as "colloid degeneration" in the area of the macula. 72 However, these chorioretinal manifestations are thought to be nonspecific and the result of reaction to the .sensitized uveal tract. 72

Ocular Changes During leprosy Reactions The great majority of type I reactions occur either before treatment or during the first 6 months of treatment, especially in borderline-tuberculoid (BT) patieilts. Lagophthalmos often develops as a result of a type I reaction,

Primary or secondary cataract formation was responsible for nearly half of the blindness in a recent study exalTIining ocular complications of leprosy.34 Direct invasion of the lens by M. leprae has never been demonstrated, and many authors deny the existence of a true leprosy cata'ract. A possible cause for cataract formation in leprosy patients was suggested by Prabhakaran, who noted that the reaction of M. leprae with dopa produces high local concentrations of quinones, which are known to be cataractogenic.85 Cataract may be secondary to anterior segment damage, particularly iridocyclitis,50, 72, 86 but in most regions where leprosy is endemic, cataract is the most common cause of blindness in the general community, and its association with leprosy is often coincidenta1. 8o However, multibacillary leprosy patients completing multidrug therapy have a high prevalence of cataract, and social stigmata of the disease often exclude these patients from receiving surgery.87

23: OCULAR LEPROSY

Eyes of armadillos and immunocompetent mice infected with leprosy showed early infiltration of the anterior angle region, ciliary body, iris root, and limbal area with lymphocytes, plasma cells, and macrophages. 88 , 89 In virtually all ocular tissues except the lens, retina, optic nerve, and aqueous and vitreous humor, M. leprae could be isolated in the armadillo, whereas only immune-deficient mice showed considerable numbers of M. leprae in the iris and ciliary body.88, 89 A mangabey monkey, infected with leprosy 46 months earlier, showed early ocular involvement of the cornea with a subepithelial limbal infiltrate, the location of acid-fast bacilli in limbal nerves and blood vessels, and markedly damaged keratocytes by electron microscopy.90 Tissue reactions in humans vary from the intense delayed-type hypersensitivity granulomas of tuberculoid leprosy, to diffuse lymphohistiocytic dermal infiltrates with large vacuolated macrophages (lepra or foam cells) in lepromatous leprosy.21 Histopathologic studies of human eyes have mainly been limited to those with extensive advanced leprosy. Conjunctival biopsies performed in leprosy patients revealed decreased goblet cells, evidence of chronic inflammation,47 and, rarely, M. leprae. 91 Iris specimens obtained during cataract surgery disclosed chronic inflammatory reactions of patients with clinically quiet eyes. Moreover, smooth muscle disruption and destruction, a cause of the miotic pupil in leprosy, was demonstrated. M. leprae was found· in the iris tissue of patients whose skin smears we'e negative and who had completed dapsone or multidrug therapy.92,93 Lepra cells containing globi composed of closely packed M. leprae, coalesce to form clinically visible miliary iris lepromata (iris pearls) .60 In enucleated eyes following intractable uveitis or painful phthisis in patients with untreated leprosy, granulomatous infiltration of the peripheral iris and cornea with lepra cells, lymphocytes, and plasma cells was ~ observed. Large numbers of M. leprae were present, within lepra cells and extracellularly. Strands of inflalllmatory cells extended from the ciliary process through the vitreous, with acid-fast bacilli in some of the cell clumps. Several retinal vessels revealed an intense perivascular infiltrate, predominately composed of lymphocytes. 94, 95 Sometimes small granulomas may be seen in the retina associated with local destruction of the RPE.95

PATHOGENESIS AND IMMUNOLOGY The great variety of clinically established leprosy is mainly the result of the ability of the individual to mount a cellmediated immune response adequate to localize, and possibly to lyse and evacuate, M. leprae. There is a continuous spectrum from the almost completely refractory to the almost completely susceptible patient, from the paucibacillary to the multibacillary form of the disease.

M. leprae M. leprae is an obligate intracellular bacterium measuring 0.5 by 3.0 to 8.0 /-Lm. Mycolic acids in the cell wall are probably responsible for the acid-fastness. In tissues, viable organisms stain solidly with the Fite-Faraco acid-fast stain. M. leprae has probably the longest generation time

(11 to 13 days) of any known bacterium pathogenic for humans; it has resisted all attempts at in vitro cultivation. 21 M. leprae is known to invade and multiply in the cooler regions of the body, and that property seems to be the main reason for the selective involvement of the anterior segment of the eye. 96 The invading organism may show minimal strain variations, but the response of the patient varies within the widest possible limits.

Immunology In tuberculoid leprosy, cellular immunity is intact, as indicated by tubercle formation, intact delayed cutaneous hypersensitivity, well-developed paracortical areas in lymph nodes, and lymphocyte transformation in the presence of M. leprae in vitro. Antibodies to M. leprae antigen can be detected in the sera of less than 10% of patients with tuberculoid leprosy.97 In lepromatous leprosy, cellular immunity is decreased, with diffuse leproma formation, poorly developed paracortical areas in lymph nodes, negative lymphocyte transformation assay, depression of delayed-type hypersensitivity reaction, and slow rejection of skin grafts.7, 97,98 The humoral immune system is intact, with high titers of antibody to M. leprae antigen in most lepromatous patients. Moreover, many autoantibodies including cryoglobulins, rheumatoid factor, thyroglobulin antibodies, antinuclear antibodies, antismooth llluscle antibodies, antineural antibodies, and myelin basic protein antibodies are produced.51, 99-101 Antibodies do not seem to have any protective or useful role in leprosy. On the contrary, antigen-antibody complexes are involved in the pathogenesis of type II leprosy reactions. Cytokines appear to play an important role in the modulation of the immune response, with interferon gamma (IFN-')'), tumor necrosis factor alpha (TNF-a), interleukin (IL)-2, and IL-6 conferring protective immunity to M. leprae.102-104 Serum IL-l f3 levels may have a prognostic value for the susceptibility of leprosy patients to the development of reactions. 105 Leprosy patients may move their position on the clinical and immunologic spectrum toward the lepromatous pole if untreated, or toward the tuberculoid pole if treated. This observation indicates that the presence of M. leprae itself specifically depresses cellular immunity.106 Reversal upgrading reactions represent abrupt increases in cell-mediated immunity. Increases in available mycobacterial antigen (e.g., after starting antileprosy treatment) trigger a type IV immune reaction. The pathogenesis of type II reactions (ENL) includes a typical immune complex disease (type III Arthus immune reaction) accompanied by decreases in the number and function of suppressor T cells and an increase in IL-2 production.36, 107 In acute lepromatous uveitis during a type II leprosy reaction, suppressor T cells were reduced during the acute attack and returned to normal after inflammation had subsided. 51 Unchecked T-helper cell activity may result in an overproduction of serum autoantibodies, raised serum immunoglobulins, and animmune-conlplex-mediated inflammation. In support of this notion, vasculitis or perivasculitis has been observed in iris specimens of patients with inactive lepromatous uveitisY Additionally, immunogenetic factors probably playa

CHAPTER 23: OCULAR LEPROSY

role in the development of uveitis in leprosy patients. In the Japanese population, HLA-DR2 contributes to the susceptibility to uveitis in leprosy.los

DIAGNOSIS The diagnosis of leprosy is based mainly on clinical signs and symptoms including skin manifestations and nerve involvement. 1 Sites of predilection for peripheral nerve damage are, in order of decreasing frequency, the ulnar nerve, the posterior tibial nerve, and the external popliteal nerve. 7 The diagnosis is confirmed by demonstration of the typical acid- and alcohol-fast organisms in material obtained by the slit-smear method from the skin or nasal mucosa. Sometimes, confirmation of the diagnosis must rest on a histologic examination of involved skin, nerve, or ocular tissue. 7 , 62, 63, 91,109 However, the quality of skin smears and of microscopy in countries endemic for leprosy is often insufficient. l Nevertheless, despite the great variety of clinical presentations, most leprosy patients can be diagnosed on the clinical findings, given an adequate familiarity with the disease. The lepromin reaction is still used as an indicator of the ability of the host to mount a cell-mediated immune response to M. leprae. However, its usefulness in diagnosis and classification and as a marker of protective imlTIunity is very limited. The WHO recommended that the use of lepromin should be restricted to research purposes. 1 In cases of ocular leprosy, meticulous history taking and a high index of suspicion on the part of the physician are the key factors to obtaining a cor'rect diagnosis. M. leprae may be isolated from conjunctival tissue,91 scleral nodules,63 aqueous humor,63, 109 and iris tissue. 62 (Fig. 233).

DIAGNOSIS The conditions with which leprosy may be confused are varied. Skin lesions may be modified by factors like pigmentation, nutrition, insulation, and hyperkeratosis. The differential diagnosis for macular skin lesions includes

birthmarks, vitiligo, leukoderma, mycotic lesions, nutritional dyschromias, granuloma multiforme, seborrheic dermatitis, and erythema multiforme. Raised skin lesions may be confused with conditions such as psoriasis, dermatitis, lichen planus, lupus vulgaris, lupus erythematosus, and cutaneous sarcoidosis. Nodular skin lesions resemble lesions in histoplasmosis, Kaposi's sarcomatosis, or von Recklinghausen's neurofibromatosis. Peripheral nerve lesions are, of course, not confined to leprosy, but the combination of peripheral nerve damage with enlargement, hardness, and tenderness of these nerves at sites of predilection is practically diagnostic. 7 Acute lepromatous iridocyclitis in and of itself is not distinct from, and may be confused with, any other acute nonleprous uveitis. The differential diagnosis of chronic granulomatous iritis includes uveitis associated with sarcoidosis, tuberculosis, Lyme disease, syphilis, toxoplasmosis, herpes simplex, and varicella-zoster infection. Iris pearls in chronic iridocyclitis are readily distinguished from Gilbert-Koeppe nodules in that they arise deep in the stroma of the iris, and they become superficial or migratory only after many months to years. Whereas iris pearls are opaque, dense, creamy-yellow, and firm, Gilbert-Koeppe nodules are grayish, semitranslucent, and soft in appearance.60

TREATMENT

Systemic Disease Dapsone has been the standard treatment for leprosy, but drug resistance in M. leprae was reported in 1964 for dapsone llo and in 1976 for rifampicin lll (both have been used with success as monotherapy for leprosy). To prevent drug resistance resulting from the selection of resistant mutants present in multibacillary leprosy, the WHO recommended MDT regimens in 1982.11 2 For multibacillary cases, the standard MDT regimen includes rifampicin (600 mg once monthly), dapsone (100 mg/d) , and clofazimine (300 mg once monthly and 50 mg/ d) for 24 months. Paucibacillary leprosy should be treated with rifampicin (600 mg once monthly) and dapsone (l00 mg/d) for 6 months. However, potent new drugs, such as ofloxacin, minocycline, and clarithromycin, offer the potential to increase the effectiveness and possibly ~o shorten the duration of antileprosy chemotherapy. For single-lesion paucibacillary leprosy, a single-dose drug regimen (called ROM) consisting of rifampicin (600 mg), ofloxacin (400 mg), and minocycline (100 mg) is recommended. l

Dapsone

FIGURE 23-3. Iris biopsy in patient with lepromatous uveitis disclosed abundant Wade-Fite-positive intra-cellular and extracellular organisms consistent with Mycobacterium lepme (Wate-Fite stain,X 330). (From Messmer EM, Raizman MB, Foster CS: Lepromatous uveitis diagnosed by iris biopsy. Graefes Arch Clin Exp Ophthalmol1998;236:717-719, Copyright © 1998 Springer-Verlag.) (See color insert.)

The antimicrobial effect of dapsone is the result of its inhibition of folic acid production, which results in the suppression of DNA and RNA synthesis. Dapsone is inexpensive and relatively nontoxic in the doses used, although mild hemolytic anemia is common and occasional cases of delayed hypersensitivity reactions and agranulocytosis have been reported. When given at a dosage of 100 mg/d, dapsone is weakly bactericidal against M. leprae. In combination with clofazimine, it killed more than 99.9% of viable M. leprae in nude mice after 12 weeks.11 3

CHAPTER 23: OCULAR LEPROSY

Rifampicin Rifampicin is by far the most effective antileprosy drug. It inhibits bacterial RNA polymerase and suppresses chain formation in RNA synthesis. Given at a monthly dose of 600 mg, it is highly bactericidal against M. leprae. Rifampicin is relatively nontoxic, although occasional cases of renal failure, thrombocytopenia, influenza-like syndrOlne, and hepatitis have been reported. 1

60 mg (up to 1 mg/kg). Mild type II reactions can be managed with analgesic or antipyretic drugs. Thalidomide (100 mg three times a day) is also effective for the treatment of severe ENL,74, 129 Clofazimine (300 mg/ d) may be given in type II reactions while withdrawing steroids. 1, 129 Cyclosporin A can induce remissions in types I and II leprosy reactions. 130 , 131

Management of Ocular Complications Clofazimine The active ingredient of clofazimine is a substituted iminophenazine dye. The precise Inode of action is not completely understood. In the standard MDT regimen, clofazimine is given 300 mg once monthly, plus 50 mg/ d. Clofazimine is virtually nontoxic. Pigmentation of the skin is common, but it clears completely after treatment is discontinued. 1 Polychromatic corneal and conjunctival crystals were observed after therapy with clofazimine, but they resolved within several weeks of discontinuation of the drug,u4

OfloxacinlSparfloxacinlPefloxacin Several fluoroquinolones have been reported to be effective in the treatment of leprosy,u5-119 The optimal dosage for ofloxacin seems to be 400 mg/d,u7 Although a single dose of ofloxacin displayed a modest bactericidal effect against M. leprae, 22 doses killed 99.9% of the viable M. leprae in patients with lepromatous leprosy. Side effects include gastrointestinal and central nervous system complaints, including insomnia, h'eadaches, dizziness, and hallucinations. 1 Multidrug resistance to dapsone, rifampicin, and ofloxacin in M. leprae has been reported. 120

Mter the introduction of dapsone treatment in leprosy, a reduction in the occurrence and progression of eye lesions132-134 and a decline in the prevalence of blindness in leprosy was reported. 135 The ocular status remained normal or unaltered in leprosy patients treated with MDT regimens. Lesions such as (epi-) scleritis, iritis, and lepromas subsided on MDT. New complications were usually minor and were related to reactions and the duration of disease. 136 Therefore, the mainstay in the management of ocular complications in leprosy is the continuation of systemic treatment to halt progression of infiltration and thus limit ocular damage. Lid deformities must be repaired promptly, especially if facial and trigeminal nerve palsy coexist, to protect the cornea. In lagophthalmos of recent onset associated with a leprosy reaction, systemic steroid treatlnent is effective. 137 Management of iridocyclitis includes topical corticosteroids, mydriatics, and, in severe cases, the addition of subconjunctival/peribulbar or oral steroids. Oral clofazimine (l00 mg three times a day) is a useful adjuvant in the treatment of leprous uveitis, as are topical and oral nonsteroidal anti-inflammatory agents. 138 Secondary glaucoma must be tl"eated appropriately.

Minocycline Minocycline, a member of the tetracyclines, has significant bactericidal activity against M. leprae. The standard dose of 100 mg/d has been shown to be effective clinically when administered to patients with lepromatous leprosy.121-123 Side effects include discoloration of teeth in children, occasional pigmentation of the skin, gastrointestinal symptoms, and central nervous complaints. It should not be given to children or during pregnancy. 1

Clarithromycin Clarithroinycin is a member of the macrolide antibiotics family and displays significant bactericidal activity against M. leprae in mice 124 and in humans. 125 In patients with lepromatous leprosy, daily administration of 500 mg/d killed 99% of viable M. leprae within 28 days. Side effects are mainly gastrointestinal complaints.

Immunotherapy The rationale for immunotherapy is to boost cell-lnediated immunity. Relatively small, unblinded trials showed encouraging results. 126, 127 But in the absence of any longterm follow-up, and because of an apparent increase in type I reactions, immunotherapy should not be recommended for routine clinical practice. 1, 128

Management of Reactions The drug of choice for type I reactions and severe type II reactions (ENL) is prednisolone at a dosage of 40 to

CONCLUSIONS As a result of ignorance and the social stigma that still exists throughout the world, many leprosy patients are without therapy until late in the course of the disease. Ocular leprosy, however, is the archetypal preventable disease, and simple treatment at an early stage will usually avoid major irreversible damage later. The recognition and treatment of chronic iridocyclitis represents one of the greatest challenges in. the care of leprosy patients. Unfortunately, patients are dismissed from leprosy control programs and are considered "cures" by the WHO after completing MDT regimens. However, 21.3% of patients showed potentially sight-threatening lesions after being discharged from care,80 and the eyes of patients with lepromatous leprosy may harbor living organisms or antigen long after the skin is bacteriologically negative. Completion of systemic leprosy therapy should not be regarded as a guarantee that the eyes are safe, and regular ophthalmologic examinations should be continued long after the patient has been classified as "cured."80

References 1. WHO: WHO Expert Committee on Leprosy: Seventh report. WHO Tech Rep Ser 874. Geneva, 1998. 2. Ridley DS, Jopling WH: Classification of leprosy according to iInmunity. A five-group system. Int J Lepr 1966;34:255-273. 3. Leiker DL: Classification of leprosy. Lepr Rev 1966;37:7-15. 4. WHO Study Group: Chemotherapy of leprosy for control programmes. \mO Tech Rep Ser 675. Geneva, 1982.

CHAPTER 23: OCULAR LEPROSY 5. Flageul B: Quelle place reste-t-il a la classification de Ridley et Jopling en 1997? (Editorial). Acta Lepr 1997;10:187. 6. Summary of notifiable diseases, United States, 1997. MMWR Morb Mortal Wkly Rep 1998;46:3-87. 7. Brown.e SG: Leprosy. In: Acta Clinica, 3rd ed. Basle, Switzerland, Ciba-Geigy Ltd, 1984, pp 12-14. 8. Thangaraj RH, Yawalkar SJ: Leprosy for medical practitioners and paramedical workers. Basle, Switzerland, Ciba-Geigy Ltd, 1986. 9. Ell SR: Plague and leprosy in the Middle Ages: A paradoxical crossimmunity? Int] Lepr 1987;55:345-350. 10. Harboe M: Armauer Hansen: The man and his work. Int] Lepr 1973;41:417-424. 11. Bull OB, Hansen GA: The Leprous Diseases of the Eye (Reprinted). London, Lewis, 1873. 12. Faget GH, Pogge RC, Johansen FA, et al: The Promin treatment ofleprosy: A progress report. Pub1 Health Rep 1943;58:1729-1741. 13. Binford CH: Comprehensive program for inoculation of human leprosy into laboratory animals. Publ Health Rep 1956;71:955-956. 14. Shepard CC: The experimental disease that follows the injection of human leprosy bacilli into footpads of mice. ] Exp Med 1960;112:445-454. 15. Storrs EE: The nine-banded armadillo: A model for leprosy and other biomedical research. Int] Lepr 1971;39:703-714. 16. Brennan P], Barrow WW: Evidence for species-specific lipid antigens in Mycobacterium leprae. Int] Lepr 1980;48:382-387. 17. Clark-Curtiss]E,]acobs WR, Docherty MA, et al: Molecular analysis of DNA and construction of genomic libraries of Mycobacterium leprae.] Bacteriol 1985;161:1093-1102. 18. Young RA, Mehra V, Sweetser D, et al: Genes for the major protein antigens of Mycobacterium leprae. Nature 1985;316:450-452. 19. Noordeen SK: A look at world leprosy. Lepr Rev 1990;62:72-86. 20. Neill MA, Hightower AW, Broome CV: Leprosy in the United States, 1971-1981.] Infect Dis 1985;152:1064-1069. 21. Meyers WM, Marty AM: Current concepts in the pathogenesis of leprosy. Drugs 1991;41:832-856. 22. Lucas S: Human immunodeficiency vili\,llS and leprosy (Editorial). Lepr Rev 1993;64:97-103. . 23. Godal T, Negassi K: Subclinical infection in leprosy. Br Med ] 1973;3:557-559. 24. Dethlefs R: Editorial: Leprosy. Aust N Z] Ophthalmol 1989;17: 211-213. 25. Duncan ME, Melsom R, Pearson ]M, et al: A clinical and immunological study of four babies of mothers with lepromatous leprosy, two of whom developed leprosy in infancy. Int] Lepr Other Mycobact Dis 1983;51:7-17. 26. Geater ]G: The fly as potential vector in the transmission of leprosy. Lepr Rev 1975;46:279-286. 27. Vries de RRP, Eden van W, Rood van lJ: HLA-linked control of leprosy type. Int] Lepr 1984;52S:693. 28. Renard G, Dhenny P, Harter P, et al: Les atteintes du globe oculaire au cours de la lepre. Arch Ophtal (Paris) 1963;23:249252. 29. Choyce DP: Discussions on ocular leprosy. Trans R Soc Trop Med Hyg 1970;64:43-45. 30. Hobbs HE: The blinding lesions of leprosy. Lepr Rev 1971;42:131137. 31. Kirwan EW: The ocular complications of common tropical diseases. Trop Dis Bull 1956;53:693-695. 32. Harley RD: Ocular leprosy in Panama. Am] Ophthalmol.1946; 29:295-316. 33. ffytche TJ: The prevalence of disabling ocular complications of leprosy: A global study. Indian] Lepr 1998;70:49-59. 34. Courtright P: The epidemiology of ocular complications of leprosy. Indian] Lepr 1998;70:33'--37. 35. Courtright P, Kim SH, Lee HS, Lewallen S: Excess mortality associated with blindness in leprosy patients in Korea. Lepr Rev 1997;68:326-330. 36. Modlin RL, Mehra V, Jordan R, et al: In situ and in vitro characterization of the cellular immune response in erythema nodosum leprosum.] Immunol 1986;136:883-886. 37. Shorey P, Krishnan MM, Dhawan S, Garg BR: Ocular changes in reactions in leprosy. Lepr Rev 1989;60:102-108. 38. Hogeweg M, Faber WR: Progression of eye lesions in leprosy: Ten year follow-up study in the Netherlands. Int] Lepr Other Mycobact Dis 1991;59:392-397.

39. Rajan MA: Longitudinal follow-up of eyes in leprosy. Indian] Lepr 1998;70:109-114. 40. Schwab IR: Ocular leprosy. Infect Dis Clin North Am 1992;6:953961. 41. Daniel E: Lagophthalmos in leprosy. Indian] Lepr 1998;70:39-47. 42. Yan LB, Chang GC, Li WZ, et al: Analysis of 2114 cases of lagophthalmos in leprosy. China Lepr] 1993;9:6-8. 43. Courtright P, Lewallen S, Le HY, et al: Lagophthalmos in a multibacillary population under multidrug therapy in the People's Republic of China. Lepr Rev 1995;66:214-219. 44. Karacorlu MA, Cakmer T, Saylan T: Corneal sensitivity and correlations between decreased sensitivity and anterior segment pathology in ocular leprosy. Br] Ophthalmol 1991;75:117-119. 45. Hieselaar LC, Hogeweg M, Vries de CL: Corneal sensitivity in patients with leprosy and in controls. Br ] Ophthalmol 1995;79:993-995. 46. Hodges E], Ostler HB, Courtright P, Gelber RH: Keratoconjunctivitis sicca in leprosy. Lepr Rev 1987;58:413-417. 47. Lamba PA, Rohatgi], Bose S: Factors influencing corneal involvement in leprosy. Int] Lepr 1987;55:667-671. 48. Daniel E, Thompson K, Ebenezer G], et al: Pterygium in lepromatous leprosy. Int] Lepr 1996;64:428-432. 49. Poon A, MacLean H, McKelvie P: Recurrent scleritis in lepromatous leprosy. Aust N Z] Ophthalmol 1998;26:51-55. 50. ffytche TF, Role of iris changes as a cause of blindness in lepromatous leprosy. Br] Ophthalmol 1981;65:231-239. 51. Murray PI, Kerr Muir MG, Rahi AHS: Immunopathogenesis of acute lepromatous uveitis: A case report. Lepr Rev 1986;57:163168. 52. Fuchs A: Ophthalmologisches und Medizinisches aus den Tropen. Klin Monatsbl Augenheilkd 1935;94:244-249. 53. ffytche TF: Editorial: Importance of early diagnosis in ocular leprosy. Br] OphthalmolI989;73:939. 54. Karacorlu M, Surel Z, Cakiner T, et al: Pupil cycle time and early autonomic involvement in ocular leprosy. Br] Ophthalmol 1991;75:45-48. 55. Daniel E, Rao PSS: Pupil cycle time in leprosy patients without clinically apparent ocular pathology. Int] Lepr 1995;63:529-534. 56. Swift TR, Bauschard FD: Pupillary reactions in lepromatous leprosy. Int] Lepr 1972;40:142-148. 57. Lewallen S, Courtright P, Lee HS: Ocular autonomic dysfunction and intraocular pressure in leprosy. Br] Ophthalmol 1989;73:946949. 58. Johnstone PAS, George AD, Meyers WA: Ocular lesions in leprosy. Ann Ophthalmol 1991;23:297-303. 59. Barros de M: A clinical study of leprous iritis. Int] Lepr 1940;8:353-360. 60. Allen ]H: The pathology of ocular leprosy. II: Miliary lepromas of iris. Am] OphthalmoI1966;61:987-992. 61. Ebenezer R: Symposium on uveitis. Iritis in leprosy. Proc All-India Ophthalmol Soc 1963;19:183-188. 62. Messmer EM, Raizman MB, Foster CS: Lepromatous uveitis diagnosed by iris biopsy. Graefes Arch Clin Exp Ophthalmol 1998;236:717-719. 63. Michelson]B, Roth AM, Waling GO: Lepromatous iridocyclitis diagnosed by anterior chamber paracentesis. Am ] Ophthalmol 1979;88:674-679. 64. Allen ]H, Brand M: Ocular leprosy. In: Locatcher-Khorazo D, Seegal BC, eds: Microbiology of the Eye, St. Louis, Mosby, 1972, pp 131-154. 65. Drutz D], Chen TS, Lu WH: The continuous bacteriemia of lepromatous leprosy. N Engl] Med 1972;287:159-164. 66. Moneiro LG, Campos WR, Orefice F, Grossi MAF: Study of ocular changes in leprosy patients. Indian] Lepr 1998;70:197-202. 67. Somerset E], Sen NR: Leprosy lesions of the fundus oculi. Br] Ophthalmol 1956;40:167-172. 68. Elliot DC: A report of leprosy lesions of the fundus. Int] Lepr 1948;16:347-348. 69. Ticho V, Ben Sira 1. Ocular leprosy in Malawi. Br] Ophthalmol 1970;54:107-112. 70. Chatteljee S, Chaudhury S: Hypopigmented patches in fundus in leprosy. Lepr Rev 1964;35:88-90. 71. Duke-Elder, Leigh AG: Leprosy. In: Duke Elder S, ed: System of Ophthalmology. London, Henry Kimpton, 1965, pp 844-852. 72. Weerekoon L: Ocular leprosy in West Malaysia: Search for a posterior segment lesion. Br] Ophthalmol 1972;56:106-113.

CHAPTER 23: OCULAR LEPROSY 73. Hogeweg MK, lUran KU, Suneetha S: The significance of facial patches and type I reaction for the development of facial nerve damage in leprosy. A retrospective study among 1226 paucibacillary leprosy patients. Lepr Rev 1991;62:143-149. 74; Meyerson MS: Erythema nosodum leprosum. Int J Dermatol 1996;35:389-392. 75. Brandt F, MalIa OK, Anten JGF: Influence of untreated chronic plastic iridocyclitis on intraocular pressure in leprous patients. Br J Ophthalmol 1981;65:240-242. 76. Karacorlu MA, Cakiner T, Saylan T: Influence of untreated chronic plastic iridocyclitis on intraocular pressure in leprosy patients. Br J Ophthalmol 1991;75:120-122. 77. Slem G: Clinical studies of ocular leprosy. Am J Ophthalmol 1971;71:431-434. 78. Lewallen S, Hussein N, Courtright P, et al: Intraocular pressure and iris denervation in Hansen's disease. IntJ Lepr 1990;58:39-43. 79. Hussein N, Chiang T, Ehsan Q, Hussain R: Intraocular pressure decrease in household contacts of patients with Hansen's disease and endemic control subjects. Am J Ophthalmol 1992;114:479483. 80. ffytche TF. Residual sight-threatening lesions in leprosy patients completing multidrug therapy and sulphone therapy. Lepr Rev 1991;62:35-43. 81. Spaide R, Nattis R, Lipka A, D'Amico R: Ocular findings in leprosy in the United States. AmJ Ophthalmol 1985;100:411-416. 82. Walton RC, Ball SF, Joffrion VC: Glaucoma in Hansen's disease. Br J Ophthalmol 1991;75:270-272. 83. Shields JA, Waring GO 3d, Monte LG: Ocular findings in leprosy. AmJ Ophthalmol 1974;77:880-890. 84. Joffrion VC: Eye lesions in leprosy-Glaucoma and tension. Lepr Rev 1989;60:328. 85. Prabhakaran K: Cataract in leprosy: A biochemical approach. Lepr Rev 1971;42:11-13. 86. Brandt F, Kampik A, MalIa OK, et al: Blindness from cataract formation in leprosy. Dev Ophthalmol 1983;7:1-12. 87. ffytche TF: The continuing challe~ge of ocular leprosy. Br J Ophthalmol 1991;75:123-124. '1 88. Hobbs HE, Hannan DJ, Rees RjW, McDougall AC: Ocular histopathology in animals experimentally infected with Mycobacterium leprae and M. lepraemurium. BrJ OphthalmoI1978;62:516-524. 89. Brandt F, Zhou HM, Shi ZR, et al: The pathology of the eye in armadillos experimentally infected with Mycobacterium leprae. Lepr Rev 1990;61:112-131. 90. Malaty R, Meyers WM, Walsh GP, et al: Histopathological changes in the eyes of mangabey monkeys with lepromatous leprosy. Int J Lepr 1988;56:443-448. 91. Campos WE, Orefice F, Sucena MA, Rodrigues CAP: Conjunctival biopsy in patients with leprosy. IndianJ Lepr 1998;70:291-294. 92. Brandt F, Zhou HM, Shi ZR, et al: Histopathological findings in the iris of dapsone treated leprosy patients. Br J Ophthalmol 1990;74:14-18. 93. Daniel E, Ebenezer GJ, Job CK: Pathology of iris in leprosy. Br J Ophthalmol 1997;81:490-492. 94. Robertson I, WeinerJM, Finkelstein E: Untreated Hansen's disease of the eye: A clinicopathological report. Aust J Ophthalmol 1984;12:335-339. 95. Hui-Min Z, Zhen-Rong S, Job CK: Unusual histological lesions in the eye of a leprosy patient. IntJ Lepr 1987;55:507-509. 96. Job CK, Ebenezer GJ, Thompson K, Daniel E: Pathology of eye in leprosy. Indian J Lepr 1998;70:79-91. 97. Bryceson A, Pfaltzgraff RE: Leprosy, 2nd ed. Edinburgh, 1979. 98. Turk JL, Waters MFR: Cell-mediated immunity in patients with leprosy. Lancet 1969;2:243-246. 99. Shwe T: Clinical significance of autoimmune antibodies in leprosy. Trans R Soc Trop Med Hyg 1972;66:749-753. 100. ParkJY, Cho SN, YounJK, et al: Detection of antibodies to human nerve antigens in sera from leprosy patients by ELISA. Clin Exp Immunol 1992;87:368-372. 101. Corsico B, Croce MY, Mukheljee R, Segal-Eiras A: Identification of myelin basic proteins in circulating immune complexes associated with lepromatous leprosy. Clin Immunol Immunopathol 1994;71:38-43. 102. Champsi JH, Bermudez LE, Young LS: The role of cytokines in mycobacterial infection. Biotherapy 1994;7:187-193. 103. Sugita Y, Miyamoto M, Koseki M, et al: Suppression of tumour

necrosis factor-a expression in leprosy skin lesions during treatment for leprosy. BrJ DermatoI1997;136:393-397. 104. Barnes PF, Chatteljee D, Brennan PJ, et al: Tumor necrosis factor production in patients with leprosy. Infect Immun 1992;60:14411446. 105. Moubasher AEA, Kamel NA, Zedan H, Raheem DEA: Cytokines in leprosy, II. Effect of treatment on serum cytokines in leprosy. Int J Dermatol 1998;37:741-746. 106. Mohagheghpour N, Gelber RR, Engleman EG: T-cell defect in lepromatous leprosy is reversible in vitro in the absence of exogenous growth factors. J Immunol 1986;138:570-574. 107. Mshana RN: Hypothesis: Erythema nodosum leprosum is precipitated by an imbalance of T lymphocytes. Lepr Rev 1982;53:1-7. 108. Joko S, Nugama J, Fl~ino Y, et al: Nippon-Ganka-Gakkai-Zasshi 1995;99:1181-1185. 109. Campos WR, Orefice F, Sucena MA, Rodrigues CAF: Bilateral iridocyclitis caused by Mycobacterium leprae diagnosed through paracentesis. IndianJ Lepr 1998;70:27-31. 1l0. PettitJHS, Rees RJW: Sulphone resistance in leprosy. Lancet 1964;1:673-674. 111. Jacobson RR, Hastings RC: Rifampicin-resistant leprosy. Lancet 1976;2:1304-1305. 112. WHO: Chemotherapy of leprosy for control programmes. Report of a WHO Study Group. Tech Rep Ser 675, WHO, Genf, 1982. 113. Ji B, Perani EG, Petinom C, Grosset JH: Bactericidal activities of combinations of new drugs against Nlycobacterium leprae in nude mice. Antimicro Agents Chemother 1996;40:393-399. 114. Font RL, Sobol W, Matoba A: Polychromatic corneal and conjunctival crystals secondary to Clofazimine therapy in a leper. Ophthalmology 1989;96:311-315. 115. Saito H, Tomioka H, Nagashima K: In vitro and in vivo activities of ofloxacin against Mycobacterium leprae infection induced in mice. Int J Lepr OtheJ;' Mycobact Dis 1986;54:560-562. 116. Ji B, Perani EG, Petinom C, Grosset JH: Bactericidal activities of single or multiple doses of various combinations of new antileprosy drugs and/or rifampin against M. lepme in mice. Int J Lepr 1992;60:556-561. 117. Ji B, Perani EG, Petinom C, et al: Clinical trial of ofloxacin alone and in combination with dapsone plus clofazimine for treatment of lepromatous leprosy. Antimicrob Agents Chemother 1994;38:662-667. 118. Mochizuki Y, Oishi M, Nishiyama C, Iida T: Active leprosy treated effectively with ofloxacin. Intern Med 1996;35:749-751. 119. Chan GP, Garcia-Ignacio BY, Chavez VE, et al: Clinical trial of sparfloxacin for lepromatous leprosy. Antimicrob Agents Chemother 1994;38:61-65. 120. Cambau E, Perani E, Guillemin I, et al: Multidrug-resistance to dapsone, rifampicin, and ofloxacin in Mycobacterium leprae. Lancet 1997;349:103-104. 121. Ji B, Jamet P, Perani E, et al: Powerful bactericidal activities of clarithromycin and minocycline against Nlycobacterium leprae in lepromatous leprosy. J Infect Dis 1993;168:188-190. 122. Gelber RH, Fukuda K, Byrd S, et al: A clinical trial of minocycline in lepromatous leprosy. Br Med J 1992;304:91-92. 123. Ji B, Jamet P, Perani EG, et al: Bactericidal activit.y of single dose of clarithromycin plus minocycline, with or without ofloxacin, against Mycobacterium leprae in patients. Antimicrob Agents Chemother 1996;40:2137-2141. 124. Ji B, Perani EG, Grosset JH: Effectiveness of clarithromycin and minocycline alone and in combination against experimental Nlycobacterium leprae infection in mice. Antimicrob Agents Chemother 1991;35:579-581. 125. Gelber RH: Successful treatment of a lepromatous patient with clarithromycin. IntJ Lepr Other Mycobact Dis 1995;63:113-115. 126. Majumder V, Mukeljee A, Hajra SK, et al: Immunotherapy of faradvanced lepromatous leprosy patients with low-dose Convit vaccine along with multidrug therapy (Calcutta trial). Int J Lepr 1996;64:26-36. 127. Talwar GP, Zaheer SA, Mukherjee R, et al: Immunotherapeutic effects of a vaccine based on a saprophytic cultivable mycobacterium, Mycobacterium Win multibacillary leprosy patients. Vaccine 1990;8:121-129. 128. Whitty C: Editorial: Mycobacterium W immunotherapy in leprosy. Lepr Rev 1998;69:222-224. 129. Jakeman P, Smith WCS: Thalidomide in leprosy reactions. Lancet 1994;343:432-433.

23: 130. Uyemura K, Dixon FP, Wong L, et al: Effect of cyclosporine A in erythema nodosum leprosum.] Immunol 1986;137:3620-3623. 131. Miller RA, Shen JY, Rea TH, Harnish ]P: Treatment of chronic erythema nodosum leprosum with cyclosporine A produces clinical and immunohistologic remission. Int] Lepr 1987;55:441-449. 132. Amendola F: Ocular and otolaryngological leprosy before and since sulfone therapy. Int] Lepr 1955;23:280-283. 133. Brandt F, Kist P, Wos]: Augenbefunde bei Lepra. Ergebnisse einer Studie im Green-Pastures-Leprosy Hospital Pokhara/Nepal. KEn Monatsbl Augenheilkd 1981;178:55-58.

134. Ticho U, Sira IB: Ocular leprosy in Malawi. Clinical and therapeutic survey of 8,325 leprosy patients. Br] OphthalmoI1970;54:107112. 135. Emiru VP: Ocular leprosy in Uganda. Br ] Ophthalmol 1970;54:740-743. 136. Rajan MA: Eye in multi-drug therapy. Indian] Lepr 1990;62:33-38. 137. Thompson K, Daniel E: Management of ocular problems in leprosy. Indian] Lepr 1998;70:295-315. 138. Brand ME: Care of eye in Hansen's disease, 3rd ed. Gillis W Long Hansen's Disease Centre, Carville, LA, 1993.

Arnd Heiligenhaus, Horst Helbig, and Melanie Fiedler

Virology The term "herpes" stems from the Greek word "herpein," which means "to spread." Herpesviruses are widely disseminated in nature and can be found in nearly all animal species. About 100 different herpesviruses have been described so far, and eight of them are found in humans: herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella zoster virus (VZV), human cytomegalovirus (CMV) , Epstein-Barr virus (EBV), and human herpesviruses 6, 7, and 8 (HHV-6, HHV-7, HHV-8).1-3

The members of the family herpesviridae share a characteristic architecture. The core contains linear doublestranded DNA and is surrounded by the icosahedral capsid consisting of 162 capsomeres, the tegument, an amorphous material, and the envelope. The envelope is derived from the core membrane of the infected cells and consists of lipids with inserted viral glycoprotein spikes. The lipid content of the envelope is responsible for the sensitivity of herpesviruses to lipid solvents aI¥! detergents. 3,4 Specific receptors of the glycoproteins of the viral envelope that recognize complementary receptors on the host target cell membrane and bind to them (adsorption) are a prerequisite for the viral infection. The envelope of the herpesvirus and the cell membrane fuse, and the nucleocapsid of the virus then penetrates into the cell. The viral proteins are typically produced in a cascade. First, the immediate early proteins are produced, then the early proteins, followed by the late proteins. 5 In the

FIGURE 24-1. Detection of a ClVLV immediate early antigen in CMV-infected fibroblasts 36 hours after inoculation by an enzyme immunoassay.

diagnosis of CMV infections, using cell culture to detect an immediate early antigen and of early antigen, the pp65 antigen in peripheral blood mononuclear cells (PBMCs) has become an important method (Figs. 24-1 and 24-2). All herpesviruses share certain biologic properties. They all have a large number of enzymes that are involved in nucleic acid metabolism, DNA synthesis, and possibly the procession of proteins. The synthesis of DNA and the assembly of the capsid take place in the nucleus. The production of infectious virus particles in the cytoplasm leads to the destruction of the infected cell. All known herpesviruses establish latent or clinically silent infection in their natural hosts. 3 The status of latency is restricted to a small range of susceptible cells that vary among the different members of the herpesvirus family. During latency, the herpesvirus genomes form closed circular molecules, and only a small number of viral proteins is expressed, with no mature virus produced.:rhere is evidence that selected regulatory genes are active and may maintain latency, but neither the mechanisms to keep the status of latency nor the factors that cause reactivation to mature viral assembly and replication are completely understood so far. Mter reactivation from latency, infectious viruses are transported to peripheral tissues, for example, by axonal transport. It depends on the immune response of the host as to whether reactivation takes a symptomatic or asymptomatic course. 3 ,6 The family of herpesviridae can be divided into three subfamilies according to differences in host range, reproduction rate, and cell tropism. HSV-1, HSV-2, VZV, and

24: HERPESVIRUSES

FIGURE 24-2. Detection of a CMV early antigen (pp65) in peripheral blood mononuclear cells of a patient by an enzyme immunoassay.

HHV-8 belong to the subfamily of alpha herpesviruses; CMV and probably HHV-6 and HHV-7 to the beta herpesviruses; and EBV is in the family of gamma herpesviruses. 3 Table 24-1 summarizes the clinical characteristics of herpesviruses that are infectious for humans. The two types of herpes simplex viruses described are HSV-1 and HSV-2. HSV-1 and HSV-2 are transmitted during close personal contact. HSV-1 q,luses labial infections (e.g., via transmission from mother to child), and HSV-2 is normally transmitted via sexual contact. The primary infection with HSV-1 is mostly asymptomatic but may occur as gingivostomatitis or, less commonly, as conjunctivitis or keratitis. In most cases, infections with HSV-2 are acquired after infections with HSV-1 and can therefore be regarded as reinfections. This infection by HSV-2 remains

asymptomatic in most cases because of the partial specific immune response already present. In contrast to this, primary infections with HSV-2 without previous contact with HSV-1 may cause apparent local and systemic symptoms. The primary infection with HSV typically involves the mucosa. The virus replicates intracellularly and infects other cells in the mucosa per continuitatem. Lymphogenous-hematogenous spread is rarely found. The virus penetrates in the nerve ends in the mucosa and is transported retrograde via the axon into sensory ganglia. Mter a period of productive infection, replication decreases and a persistent and latent infection is established. A wide range of factors, for example, exposure to ultraviolet (UV) light, fever, and stress, can cause a new period of

TABLE 24-1. SOME IMPORTANT CHARACTERISTICS Of HERPESVIRUSES THAT ARE INfECTIOUS IN HUMANS* HERPESVIRUS

SUBFAMILY·

SITE OF LATENCY

PRIMARY INFECTION

Gingivostomatitis, keratoconjunctivitis, skin infection, genital disease, encephalitis Genital disease, gingivostomatitis, encephalitis, neonatal infection Varicella Mononucleosis, hepatitis, neonatal infection

Human herpesvirus 1

HSV-l

Sensory ganglia

Human herpesvirus 2

HSV-2

Sensory ganglia

Human herpesvirus 3 Human herpesvirus 4

VZV CMV

Human herpesvirus 5

EBV

Human herpesvirus 6

HHV-6

Sensory ganglia Lymphoreticular cells, probably kidney and other tissues Oropharyngeal epithelial sites, B-lynlphocytes, lymphoid tissues Peripheral blood leukocytes?

Human herpesvirus 7 Human herpesvirus 8

HHV-7 HHV-8

*This table includes only a partial listing.

SYMPTOMATIC REACTIVATION

Herpes labialis, keratoconjunctivitis, skin infection, encephalitis Genital disease, skin infection

Zoster Pneumonia, retinitis, colitis

Mononucleosis, hepatitis

Cofactor for "post-transplant" lymphomas

Exanthem subitum, lymphadenopathy No clear evidence for disease Associated with Kaposi's sarcoma

Post-tranplant complications, dimensions not clear so far

CHAPTER 24: HERPESVIRUSES

viral replication, a reactivation. This new period of viral replication can be asymptomatic or cause symptoms (e.g., orolabial lesions or the various ocular manifestations). VZV causes two distinct diseases. Varicella, or chickenpox, is seen in primary infection. It is usually a mild, self-limited infection in children. Zoster occurs after reactivation of the persistent latent VZV infection in sensory ganglia. Typical clinical pictures of intraocular inflammation induced by alpha herpesviruses include endotheliitis, trabeculitis, iridocyclitis, acute retinal necrosis (ARN), and variants of necrotizing herpes retinopathy.7 The clinical pictures of the various forms of intraocular inflammation caused by alpha herpesviruses share many simil.arities, so in individual cases, it is often not possible to differentiate HSV from VZv. Nevertheless, the case history and clinical signs can sometimes point to the causative virus. In a few patients, HSV-1 forms typical blister-like skin eruptions,S,9 or zoster dermatitis may be present. lO , 11

History Iritis and glaucoma secondary to herpesvirus infections of the anterior uvea were characterized in the late 1970s. 12,13 The clinical picture of ARN was first described by Urayama and coworkers in 1971. 14 The disease has been characterized by a combination of peripheral, confluent, necrotizing retinitis, retinal arteritis, and intraocular inflammation. The pathogenetic connection with the herpesviruses was proved by Culbertson and associates in 1982,15

Epidemiology Iritis frequently occurs concomitantly with HSV keratitis but may also develop without it. Previously, it has been shown that iritis presents in up to 40% of the patients with acute herpes zoster ophthalmicus. 16 Necrotizing retinitis from HSV or VZV is a rare disease. The susceptibility for development of herpes retinitis is probably influenced by genetic factors, but HLA associations have differed greatly between the populations studiedP' IS The individual immune status seems to be of special importance. The disease is more common in patients with an impairment of the cellular immune responses, for example, in the elderly population or in patients under immunosuppressive therapy, with acquired immunodeficiency syndrOlue (AlDS) , or malignancies. 11, 19-21 ARN shows a two-peak age distribution, with the first peak at 20 years of age and the second at about 50 years of age. HSV infections manifest themselves in early adulthood and are presumably responsible for the first peak. Zoster dermatitis most likely attacks the older population, which may explain the second peak.22 HSV or VZV retinitis may be seen in certain clinical settings. Congenital varicella zoster retinitis may be observed in the first or second trimester of pregnancy in connection with chickenpox or zoster dermatitis. Retinitis has also been seen in association with chickenpox in adulthood or after the manifestation of HSV encephalitis. 23- 25 Although it has been suggested that the diagnosis of ARN should only be used in otherwise healthy patients, this syndrome has also been described in iinmunocompromised patients. 2o , 26 In comparison to retinitis from

CMV and toxoplasmosis, retinitis from HSV or VZV in AlDS patients is rare.

Clinical Characteristics Iridocyclitis Iritis or trabeculitis may appear with and without corneal HSV lesions. It has been pointed out that iritis in an eye with a known history of herpetic keratitis should be considered herpetic until proved otherwise by the clinical findings or by laboratory testing. 27 Patients suffer from redness, photophobia, pain, and visual impairment. Involvement of the anterior uvea is characterized by typical clinical findings, including ciliary flush, fine or mutton fat keratic precipitates and various degrees of cellular reaction in the anterior chamber. Iritis commonly occurs concurrently with HSV stromal keratitis or endotheliitis. The anterior chamber reaction in these patients is often minimal. Generally, herpesvirus iritis may be focal or diffuse. In focal iritis, iris hyperemia and posterior synechiae are circumscribed and typically leave defects of the pigment epithelium. The diffuse form of HSV iritis is much more common. It is characterized by circumferential iris edema, severe cell and flare reaction in the aqueous humor, and is frequently complicated by fulminant fibrin deposition, hypopyon, complete synechiae formation, or secondary glaucoma. Iris masses have been seen that were masquerading as an iris luelanoma. 2S , 29· The inflammation may involve the trabecular meshwork endothelium, which has been termed "trabeculitis." Clinically, trabeculitis is characterized by a sudden increase of the intraocular pressure and is associated with decompensation of the corneal endothelium. 12 , 30 The glaucomatous episodes may be temporary, but in some individuals, glaucomatous damage of the optic nerve follows. Iridocyclitis is the commonest finding from zoster ophthalmicus and usually presents within the first week of acute disease, but exacerbations have also been seen months after acute herpes zoster. The diagnosis of VZV uveitis may be particularly difficult in cases without a previous zoster dermatitis ("sine herpete"). The course of the iridocyclitis may be luild with few anterior chamber cells and flare, or severe with pain, blurred vision, ciliary hyperemia, miosis, keratic precipitates, and iris hyperemia. Fibrinous exudation into the anterior chamber may be followed by synechia formation. Additional typical findings are iris sector atrophy and sphincter darnage. Hypopyon, hyphema, hypotony, and, very rarely, phthisis bulbi have occurred. 16 A series of patients "vith acute fulminant granulomatous iridocyclitis without known skin eruptions has been reported, in which it was emphasized that herpes zoster sine herpete should be suspected as a potential diagnosis in certain clinical conditionsY Glaucoma has been noted in 10% of the patients.

Acute Retinal Necrosis The most frequent complaints include irritation, slight pain, reddening of the eye, photophobia, tearing, blurring in the facial field, and various grades of visual impairment. ARN begins with sharply demarcated retinal necrosis in the periphery, which rapidly spreads. This is accompanied by occluding vasculitis and severe inflammation in the anterior chamber and vitreous body.7,32

CHAPTER 24: HERPESVIRUSES

ARN begins with an anterior uveitis. The patient's symptoms may be minimal, and examination of the anterior segment may only reveal fine or speckled keratic precipitates. 33, 34 The retinal lesions tend to be round, polymorphous, and yellowish white, and are located at the level of the retinal pigment epithelium or the deep layers of the retina. 35 These lesions are described as retinal exudate, retinitis, white or yellowish white retinal infiltrates, or as a white, swollen retina. They are mostly found between the middle periphery and the ora serrata, the borders of which have a scalloped appearance. 36 Retinal vasculitis and optic nerve head swelling may develop simultaneously.32 Over the ensuing 3 to 21 days, the retinal necrosis spreads quickly peripherally, posteriorly, and circumferentially.7 It may involve several quadrants, to the vascular arcades, or may involve the whole retinal circumference. The macula itself is often spared. The affected retinal area is homogeneously white and thickened, and the posterior border is sharply demarcated (Fig. 24-3). Sometimes the lesions inside a quadrant show a triangular form, the point of which points to the optic nerve. Vascular sheathing and attenuation of retinal arterioles develop. The sheathing of the venules is clearly less pronounced. Often, all of the vessels between the optic nerve and the periphery are affected; in other cases, only segments are conspicuously involved. Frequently, vascular nonperfusion can be found, particularly in the periphery, which may result in retinal neovascularization. Simultaneously, dense vitritis develops. Furt~her progression is mostly characterized by the development of multiple, small or perivascular intraretinal hemorrhages in the affected area. Only in exceptional cases do larger subretinal or epiretinal hemorrhages arise. The regression of ARN begins at the outer peripheral edge, in particular next to the venules, whereby the affected area takes on a Swiss cheese-like pattern. 33 It ends in retinal atrophy. The white retinal coloration recedes, followed by a salt-and-pepper pigmentation with a sharp line of demarcation between the normal and affected retina (Fig. 24-4). Simultaneously, the cellular infiltration

FIGURE 24-4. Regression of acute retinal necrosis with "Swiss cheeselike pattern" and retinal atrophy. (See color insert.)

of the vitreous body usually progresses considerably. Membranes develop, with posterior vitreous detachment, and frequently, proliferative vitreoretinopathy develops.33 In untreated patients, the inflammation usually heals in 6 to 12 weeks. 33 A distinctive course 9f necrotizing herpetic retinopathy in patients with advanced AIDS has been described and is called "progressive outer retinal necrosis syndrome" (PORN). Deep retinal infiltration with a multifocal distribution and involvement of the macula are frequently present initially. Inflammatory spots spread very rapidly to confluence, leaving large areas of necrosis in their wake. The outer retinal layers are principally involved, with little involvement of the retinal vessels, giving the characteristic cracked mud appearance of the fundus. On the other hand, there is a conspicuous discrepancy from the rest of the accompanying inflammation. When low CD4 cell counts are present, the retinal necrosis is accompanied only by a slight vitritis, minimal vasculitis and neuritis (15% to 20%), and minimal inflammation of the anterior chamber. 37 , 38 Varicella zoster virus retrobulbar optic neuritis preceding retinitis has been described in patients with AIDS.39

Retinopathies

FIGURE 24-3. Clinical appearance of acute retinal necrosis with vitritis, yellowish white retinal infiltrates, and vasculitis. (See color insert.)

Twenty-five percent of the children affected from congenital varicella zoster infections show cataracts, and in 37%, pigmented, mostly unilateral chorioretinal scarring can be found. The spectrum of changes also includes optic disc atrophy and microphthalmos, often in combination with generalized malformation. 40-42 The retinal changes in chickenpox-associated retinitis commonly develop when the skin lesions are healing. 43 ,44 Most of those affected are immunocompromised. 45 In addition to focal retinitis, mild retinal vasculitis and vitritis are observed, and occasionally also choroiditis and exudative retinal detachments. The inflammation typically resolves within a few weeks without consequences. 43 ,44 Only in a few individual cases is ARN observed. 45 In congenital HSV infections in the first 01.[' second

CHAPTER 24: HERPESVIRUSES

trimester, salt-and-pepper pigmentation or circumscribed retinal scarring can be observed, and rarely also optic disc atrophy, vitritis, and microphthalmus. Generalized malformation is often found. The course of neonatal HSV retinitis, which in most cases is acquired in the birth canal (HSV-2), varies considerably. The disease can become manifest in a third of the infected infants and mostly develops 4 to 12 days after birth. Mter conjunctivitis and keratitis, retinitis is the third most common form of ocular involvement. Retinitis is often observed in connection with HSV encephalitis, herpes skin lesions, and keratitis. Often, only a sharply demarcated retinal area is affected, and 28 % of the cases later show chorioretinal scarring and changes in the retinal pigment epithelium. Rarely, a fulminant course has been described, which resulted in complete retinal necrosis, retinal detachment, and optic disc atrophy in both eyes. Recurrences later in life have been noted. 46-54 The necrotizing retinitis associated with HSV encephalitis manifests itself in both eyes with rapid progression to complete retinal detachment. 25 , 55, 56

Pathogenesis

Iridocyclitis and Trabeculitis The etiology of these forms of HSV disease are not well established. Intact virus particles have been isolated from the aqueous humor, but there is significant evidence for an important role of immune reactions. 12 ,57 Histopathologically, the iris stroma is pr~marily infiltrated with lymphocytic cells. HSV has been isolated from aqueous aspirates in eyes with endotheliitis and trabeculitis. 12 It has been suggested that the HSV infection of the trabecular meshwork cells leaves swelling and obstruction of the trabecular meshwork by inflammatory debris, and eventually scars develop. Because herpes simplex virus has also been detected in the aqueous humor from patients with Posner-Schlossman syndrome, it has been speculated that it may playa role in the origin of this disease. 58 Furthermore, polymerase chain reaction (PCR) evidence suggests that HSV DNA is present in the corneal specimens from patients with iridocorneal endothelial syndrome, which implies that this entity has an HSV origin. 59 The histologic reports on VZV uveitis have disclosed perineuritis and perivasculitis with a chronic inflammatory cell infiltration mainly consisting of plasma cells and lymphocytes. Chronic uveitis from VZV is believed to represent an immune response against persistent inactivated viral antigens in the eye or continuing low-grade viral replication. 6o , 61 There is evidence that occlusive vasculitis plays an important role in zoster uveitis, and that focal or sectorial iris atrophy is a result of the ischemic necrosis. 62 Ocular hypotony may occur from necrosis of the ciliary body. It has been speculated that the trabecular meshwork may be clogged with inflammatory cell debris.

Acute Retinal Necrosis The acute stage of ARN is characterized by necrotizing retinitis of all retinal layers. The retinal vessels in the diseased area show fibrinoid necrosis of the vessel wall and vascular occlusion. The retinal pigment epithelium

shows focal necrosis and is occasionally separated from Bruch's membrane. The necrotic retinal cells reach the overlying vitreous body, where inflammatory cells surround it. The necrotic retina is sharply demarcated adjacent to the intact retina. Histologically, there are intranuclear inclusions present at these junctional areas; and by electron microscopy, virus particles can be detected in the retinal cells. 25 , 56, 63 The bordering choroid shows severe choroiditis with vascular occlusions. At the same time, optic nerve neuritis and papillitis arise. Inflammatory cells infiltrate the aqueous humor and the anterior chamber angle. The iris and ciliary body show nongranulomatous and granulomatous cell infiltration and perivasculitis. 15 , 62, 64 In the healing phase, the process leads to complete disintegration of the retina and optic nerve with reactive metaplasia of the retinal pigment epithelium. 48 ,65 The histopathologic picture of necrotizing retinitis in patients with advanced AIDS (PORN) has a few peculiarities. Initially, there is multifocal retinal necrosis of the outer or all retinal layers. Only minimal intraocular inflammatory signs are found, which include vasculitis and optic neuritis. In a recent study performed on a transscleral eye wall biopsy in a patient with AIDS and PORN, intranuclear inclusion bodies have also been detected in the choroidal cells. 66 There is experimental evidence that ARN is caused by alpha herpesviruses (VZV and HSV). Herpesvirus can be demonstrated in the retinal lesions and vitreous body in retinitis patients by culture methods, histology or electron microscopy, immunohistochemistry, and PCR methods.8, 15, 27, 38, 6'1, 67 The etiology of ARN remains elusive. Mter a primary infection or reactivation of the herpesviruses from latency, virus replication follows. From animal experiments 68 it is known that viruses migrate through the parasympathetic fibers of the oculomotor nerve that serves the iris and ciliary bodies in the central nervous system (CNS) from the infected eye. The viral replication within the CNS is fairly well limited to the nucleus of the visual system and the suprachiasmatic area of the hypothalamus. Viruses migrate from the brain to the retina via retrograde axonal transport through the optic nerve, along the endocrine-optic path between the retina and the suprachiasmatic nucleus of the hypothalamus. 69 From this site, the viral invasion can spread out to the contralateral regions, which may explain the involvement of the fellow eye in patients with bilateral acute retinal necrosis (BARN). Along the optic nerve, the viruses can reach the ganglion cells of the retina. 7o The retinal pathology represents viral-induced cytopathology.71, 72 However, the accompanying immune reactions are responsible for the further inflammatory process that finally results in the development of retinal necrosis. 71 ,73 Local as well as systemic factors come into effect. 73 It has been shown that the retinal HSV infection is under the control of T lymphocytes,74 and a contribution of T lymphocytes to the pathogenesis of ARN has been suggested. 75 The severe vascular occlusions lead to ischemia of the retina and choroid, and promote the development of necrosis. The massive breakdown of the blood-retinal barrier, with the resulting increase in pro-

CHAPTER 24: HERPESVIRUSES

tein content of the vitreous, is associated with a proliferativeand chemoactive effect on the pigment epithelium and the fibroblasts, which, in turn, promotes the development of proliferative vitreoretinopathy (PVR). The widespread retinal necrosis produces multiple posteriorly located retinal holes; and this, together with the development of vitreous traction and PVR, results in the frequent occurrence of retinal detachment.

lesions. 77 Despite its high sensitivity, even the PCR method yielded positive results in only 30% of the patients with anterior uveitis in a recent study.78 Although some authors have previously shown that herpesviruses can be isolated from aqueous humor obtained from patients with HSV iritis, trabeculitis, and secondary glaucoma,12 others have concluded that viral growth is rarely detected in culture and that this method is not particularly useful for the diagnosis.

Diagnosis

Iridocyclitis and Trabeculitis The medical history is sometimes positive for episodes of HSV keratitis. Even in the absence of such a history or corneal scarring, however, one may find that the corneal sensation is depressed relative to the unaffected cornea. The diagnosis is based on the typical clinical appearance, including the pattern of keratic precipitates, mild flare and cells in the anterior chamber, focal or diffuse iris hyperemia, fulminant inflammatory episodes with high intraocular pressures and (especially) foci of iris atrophy (Fig. 24-5). Endotheliitis may be present in a white eye. Profound redness of the eye, markedly elevated intraocular pressure, corneal haziness from endothelial decompensation, and keratic precipitates are typical for trabeculitis. 30 In herpes zoster ophthalmicus, fluorescein angiography discloses that the iris vessels at the sites of atrophy are occluded. This is in contrast to the findings in HSV disease that typically has intact iris(~circulation in the atrophic areas. 76 Aqueous humor aspirates may be analyzed for antibodies directed against HSV or VZV by the enzyme-linked immunosorbent assay (ELISA) method. Detecting viral DNA in the aqueous humor using PCR technology may be very useful in cases of zoster "sine herpete" or in cases without the typical HSV corneal

Acute Retinal Necrosis and Other Retinopathies ARN and variants of necrotizing herpetic retinopathy in general are diagnosed on the basis of the characteristic clinical picture and the course of the infection. 7 The diagnosis can be substantiated by the clinical signs of a systemic herpes infection. In atypical cases, various laboratory investigations are extremely helpful (see later).

Fluorescein Angiography The fluorescence angiographic findings in the acute stage of ARN include dye leakage from the retinal venules, arterioles, and capillaries. Often, leakage is observed from the optic disc. In the affected peripheral retinal areas, vascular occlusions arise, primarily of the retinal arterioles and capillaries. Retinal neovascularization may be seen. In addition, spotted choroidal ischemia is conspicous. 32 Typical fluorescein angiographic findings in the healing stage of ARN are characterized by atrophy of the retinal pigment epithelium, destruction of the choriocapillaris, and retinal nonperfusion.

Laboratory Investigations In patients with an atypical clinical presentation, and with rapid progression of the retinal inflammation, laboratory tests on aspirates from the aqueous humor and vitreous body can be useful. Negative test results do not rule out the disease complex, however. In doubtful cases, a chorioretinal biopsy may be indicated. 79 The detection of herpesvirus by culture methods is regarded as proof of a viral genesis of the retinitis,8 although the large time interval until the results are available is a distinct disadvantage. Another argument against these test methods is that the cultures were occasionally negative, even when a large number of viruses could be demonstrated by electron microscopy8; but it is technically simple, as is immunofluorescence staining with virus-specific antibodies 8, 80 or in situ hybridization. 65 In the initial stages, immunofluorescence, culture methods, and electron microscopy can be recommended. 81 The PCR technique also permits detection of virus particles even in minimal amounts in the aqueous humor or vitreous fluid.38, 82-84 In a recent study, PCR analysis from intraocular fluid has been able to detect the inciting virus in all patients with ARN.85 In the later stages, determination of intraocularly produced antibodies can be helpful,85,89a whereas antibody titers 80

FIGURE 24-5. Iris atrophy in a patient with HSV. (See color insert.)

or the immune complexes in the serum often remain negative and the specific antibodies in the cerebrospinal fluid can only occasionally be demonstrated. 24, 46

CHAPTER 24: HERPESVIRUSES

CMV retinitis mostly affects immunocompromised patients, especially those with AlDS. In the classic case, granular, hemorrhagic retinal lesions arise with centrifugal spread, yellowish white perivascular infiltration, and retinal edema, with or without vascular sheathing. In the healing stage, atrophy of the retina and pigment epithelium develops with fibrosis of the affected retina. Behc,;:et's disease is a systemic disease characterized by typical oral and genital aphthous ulcers, hypopyon, panuveitis, arthritis, cutaneous lesions, CNS involvement, and necrotizing angiitis. The course is typified by periods of acute exacerbation and remission, with occlusive retinal vasculitis and typical retinal infiltrates and hemorrhages. Bacterial, mycotic, or parasitic endophthalmitis can be ruled out in most cases by the medical history and clinical signs. Intravenous drug abuse, a history of trauma, abdominal operations, or immunosuppression should bring to mind an infectious etiology. In toxoplasmic retinochoroiditis, lesions are typically white and focal, with overlying vitreous inflammatory infiltration. The old chorioretinal scars are demarcated' from the area of recurrent disease. Intraocular lymphoma can manifest as subretinal material with retinal elevations and can mimic intermediate uveitis. The course is not as rapid as in ARN. In doubtful cases, intraocular lymphoma can be ruled out with cytologic investigations from cells in the vitreous body and lack of focal intracranial lesions. Sarcoidosis is characterized by intr;?-vitreous, preretinal, il1.traretinal and uveal granulomata, and periphlebitis and the typical signs of systemic disease. Periphlebitis or (less often) periarteritis, tubercles and tuberculomata, and a positive PPD are typical for tuberculosis.

Treatment Iridocyclitis and Trabeculitis Topical antiviral therapy has little or no effect on the course of disease. In a recently published controlled clinical trial, oral acyclovir proved to be therapeutically useful. However, there is still disagreement on whether or not oral acyclovir actually has a preventive effect on ophthalmic complications after zoster ophthalmicus. 90 The inflammation usually responds promptly to topical corticosteroids. However, the dosages and length' of corticosteroid treatment differ considerably, and must be evaluated on an individual basis according to the inflammatory activity. Steroids must be tapered gradually when inflammation is under control. Some patients must be continued on topical low-dose or low-potency corticosteroid medication. Cycloplegics should be given to all patients. Long-term acyclovir prophylaxis may be important to prevent additional episodes. 91 Elevated intraocular pressure is an indication for the use of antiglaucomatous medication. In eyes with progressive glaucomatous damage of the optic disc, trabeculectomies with or without mitomycin C, seton placement, or cyclophotocoagulation may be warranted.

Acute Retinal Necrosis Antiviral agents The major treatment of alpha herpesvirus retinitis consists of antiviral agents; acyclovir is the most commonly

used drug; it is very effective against HSV and VZv. In 2 days after the beginning of therapy, the existing lesions from ARN start to regress and formation of further lesions is hindered. 92 Treatment with acyclovir reduces infection of the fellow eye from 70% to 13% in the first year. 93 Nevertheless, the density of the vitreous usually increases, because this represents a secondary inflammatory reaction to the retinal necrosis and not a cytopathologic viral effect. Although retinitis generally responds well to acyclovir in otherwise healthy patients, in patients with AlDS, there is mostly no positive change in the course, and the visual prognosis is not improved. 38 Because absorption from the gastrointestinal tract is only 10% to 20%, the initial application should be intravenous. The dosage is 15 mg/kg body weight in three doses for 7 to 21 days.92 Then 2 to 4 g daily is recommended for a further 4 to 6 weeks. 94 The effectiveness of intravitreal acyclovir or ganciclovir (DHPG) injections, which have been given in individual cases with ARN or PORN,95,96 is undefined. In patients with AlDS or other immunodeficiencies with retinal necrosis, DHPG, foscarnet, bromovinyldeoxyuridine, or sorivudine appeared to be more effective than acyclovir. 34 , 37, 79, 97, 98 Long-term maintenance doses of acyclovir are used in AlDS patients to avoid later recur-. rences,37, 99 but when the medication is changed, recurrences may occur: 7, 100, 101 Because prolonged acyclovir treatment increases the chance that the virus will become resistant, therapy may be switched to foscarnet or vidarabine. Retinitis associated with multiple viruses may indicate modifications in the therapy.

Anti-Inflammatory Therapy Whereas the application of antiviral drugs is undisputed in alpha herpesvirus retinitis, treatment with systemic corticosteroids is controversial. The fact that the immune reaction plays a central role in the evolution of retinal necrosis and vitreous infiltration speaks in favor of the use of corticosteroids. High-dose prednisone not· only suppresses the intraocular inflammation but also helps resolve the vitreous infiltration and opacity.33, 92 However, because virus replication can be promoted through corticosteroids, steroids should only be applied in combination with antiviral drugs and only after the beginning of antiviral therapy.6'1 Medication maybe initiated at 1 to 2 mg/kg. In contrast, the topical application of steroids to eliminate inflammation in the anterior chamber is uniformly recommended. Although in animal experiments an improvelnent in herpetic necrotizing chorioretinitis has been observed with immunoglobulins,102 the clinical effect of this approach is not clear. Despite its high price, perhaps immunoglobulin should be used in cases with rapid progression. The occlusive vasculopathy and vasculitis associated with herpetic retinitis do not respond sufficiently to therapy. The effect of anticoagulants, aspirin, and corticosteroids is unclear. 64 Photocoagulation has been advocated for the treatment of retinal neovascularization. In individual patients with optic neuropathy, corticosteroids or anticoagulants were administered, but their influence on the course of the disease is not clear. In selected cases with

CHAPTER 24: HERPESVIRUSES

profound enlargement of the optic nerve, optic nerve sheath decompression has been performed. l03

Retinal Detachment in Acute Retinal Necrosis Retinal Detachment Surgery. Late retinal detachment is a serious and frequent complication of ARN, occurring in more than 75% of untreated cases within 6 to 12 weeks from the onset ofretinitis. 104-10S The combination oflarge, multiple, and posteriorly localized retinal tears typical for necrotizing herpetic retinitis, with severe vitreous infiltration, and the association with proliferative vitreoretinopathy make pars plana vitrectomy the operative method most often selected to treat retinal detachment in these cases. 22 , 104 Use of long-term internal tamponades, e.g., silicon oil, often allows good anatomic results,Sl, 92, 105, 106 although several surgical procedures are frequently necessary. Nevertheless, less than half of the eyes operated upon have a postoperative visual acuity of 20/200 or better. Sl, 106 Detachment Prophylaxis. Because photocoagulation creates firm chorioretinal adhesions at the areas that could develop tears, it has been suggested as an effective prophylaxis against retinal detachment in alpha herpesvirus retinitis. A series of uncontrolled clinical studies indicates that it may be possible to reduce the rate of retinal detachments by prophylactic photocoagulation. l07 , lOS However, we must also consider that the good success rate in these studies might also be based on the milder form of retinitis or on simultaneous treatment with acyclovir and steroids. In another study, 93% of the AIDS patients with severe necrotizing retinitis developed retinal detachment despite laser photocoagulation. 37 In general, laser photocoagulation should be applied early before the increasing infiltration of the vitreous makes it impossible to perform the procedure. Whether or not early vitrectomy actually reduces the rate of retinal detachments is unclear. Surgical removal of the vitreous scaffold and of the infiltrating inflammatory material may inhibit the development of tractional retinal detachment. Indeed, vitrectomy has been effective in several cases in preventing the development of retinal detachment with good visual results. 94 ,95

Complications During the course of iridocyclitis, a wide range of complications may develop, including iris atrophy, posterior synechiae, secondary glaucoma, <;ataract formation, hypotony and phthisis bulbi. The most common typical complication resulting from endotheliitis or trabeculitis is secondary glaucoma. In up to 75% of the patients with ARN, retinal detachment develops.33, 92,105 Typically, the detachment does not arise during the active inflammatory phase, but during the retinal atrophy process, that is, with an interval of 1 to several months after the onset of symptoms. The retinal detachments develop from retinal tears that have typical patterns and localization. The retinal tears are usually centrally localized at the border between the affected and healthy retina or in the necrotic, disintegrated retina. The tears commonly are very large, grouped, and localized in different quandrants. l05 Vitreous body traction

and proliferative vitreoretinopathy are further complicating factors. Generally, the risk of a later retinal detachment rises with the extension of the necrosis, formation of retinal tears, and the severity of the proliferative vitreoretinopathy.l09 Occlusion of the large vessels in the clinical context of arterial occlusion or venous thrombosis may be observed. Often, compromised vascular perfusion of the retina and choroidal circulation may serve to decrease vision. In the acute inflammatory phase, exudative retinal detachments occasionally arise. 32 Progressive optic neuropathy, both primary and secondary to global retinal necrosis, may result in optic atrophy. It has been speculated that inflammation and ischemia of the optic nerve may be the primary causes for optic atrophy that finally occurs in some patients. 15 , 103

Prognosis Visual prognosis is largely dependent on the presence of retinal detachment, vascular occlusion, and optic ne"Llritisyo-1l2 If the condition is left untreated, in about 35% of the cases, the disease attacks the fellow eye as well; hence, the acronym BARN. Mter an interval of 5 days to 30 years, the second eye can be affected. 9, 24, 33, 113-115 Initial reports demonstrated that more than 60% of patients with ARN had a final visual acuity of 20/50 or worse. 32 , 33 When treated with antiviral drugs and steroids, however, 30% to 60% of patients did not suffer such severe visual loss.92, 116 Similarly, early reports regarding retinal reattachment surgery in ARN demonstrated a 63% successful reattachment rate, with 56% of these eyes seeing 20/200 or better. l04 Five years later, the same group of investigators reported a 95% reattachment rate using more sophisticated vitreoretinal techniques; however, only 40% of these anatomically reattached eyes saw better than 20/ 200Y7 The prognosis of alpha herpesvirus retinitis in AIDS patients is very poor. In 90% of these patients, the disease is bilateral (BARN). Various complications develop rapidly, and 70% of the diseased eyes become blind within 4 weeks. 37 The rate of rhegmatogenous retinal detachment is even higher than in the remaining healthy individuals,sl probably because in AIDS patients, the retinitis responds poorly to antiviral drug therapy and there is a tendency toward recurrence. Sl , 100 Mixed infections of necrotizing retinitis with CMV retinitis and toxoplasmosis chorioretinitis have also been reported.

EPSTEIN-BARR VIRUS

Definition EBV belongs to the group of gamma herpesvirusesY·s It contains a double-strand DNA and is surrounded by a complex capsid and envelope. Morphologically, EBV cannot be distinguished from the other herpesviruses.

Epidemiology EBV is widespread. About 90% of the population are seroconverted by the time they reach their thirties. Transmission occurs primarily via the saliva, but it can also happen through blood transfusions. The fact that 15% to 25% of all seropositive healthy individuals shed the virus

24: HERPESVIRUSES

in their saliva is regarded as the luain reason for its broad distribution. The primary infection with a clinical picture of infectious mononucleosis mostly affects the age group of 14 to 18 year 0ldsY9 EBV is also reported to have a pathogenic role in the development of nasopharyngeal carcinoma and Burkitt's lymphoma. In addition, associations have been found between mononucleosis that has run its course and the later appearance of Sjogren's syndrome. 12o

Clinical Characteristics Ocular involvement in EBV infections occurs mostly in primary infections in the context of infectious luononucleosis. Intraocular inflammation may develop several months after the onset of acute infectious mononLtcleosis. The· ocular manifestation of EBV infection encompasses a wide range of anterior segment or neurophthalmic features. Follicular conjunctivitis is seen most often. 121 Also, stromal keratitis and episcleritis can appear. Severe bilateral iritis and iridocyclitis have been seen in other patients. 122 Almost all structures of the posterior ocular segments can be affected. Macular edema, retinal hemorrhages, and punctate outer retinitis 123 or multifocal choroiditis have been seen. 12 4-126 Secondary subretinal neovascularization and progressive subretinal fibrosis and uveitis syndrome 127 may occur. In individual cases, disc edema or optic neuritis has been described as the main finding, which completely regressed with restitution. 128 In the retinal pigment epithelium, ~ne scars and pigmentary changes may remain. The retii1.al vessels are generally unaffected. In the context of severe panuveitis, dense vitritis has been noted. 89 ,129

Pathogenesis EBV shows B-cell tropism. Healing occurs from neutralizing antibodies and the T-cell response, but the pathogenetic role of EBV in intraocular inflammation is undefined. There is no biopsy-proven evidence that the replicating virus is a direct cause of the posterior uveitis.

Diagnosis Depending on the time after transmlsslOn, antibodies directed against EBV-specific capsid antigens can prove EBV disease. The antibodies directed against nuclear antigen (EBNA) are positive after 6 to 8 weeks; antibodies against "diffuse/restricted antigens" (EA-D/R) can be detected after 3 to 4 weeks. 130 A similar variety of clinical changes in the posterior segment of the eye can be caused by sarcoidosis, tuberculosis, or syphilis. The clinical appearance of retinal and choroidal infiltrations can be confused with the acute phase of toxoplasmosis, histoplasmosis, or idiopathic white-dot syndromes.

Therapy Because the ocular disease is mostly self-limited, no treatment is indicated. Occasionally, the iritis necessitates the topical application of corticosteroids and cycloplegic drops, and occasionally, a systemic course of corticosteroids may be indicated. 89

The prognosis concerning VlSlOn may be poor· in cases with chorioretinitis and panuveitis complicated by subretinal neovascularization or cystoid macular edema. Recalcitrant, chronic, smoldering focal or diffuse chorioretinitis is occasionally complicated by the developluent of secondary cataract formation.

CYTOMEGALOVIRUS Definition CMV belongs to the group of herpesviruses. It is a ubiquitous pathogen in the general population but rarely causes clinically apparent disease in an immunocompetent individual. In immunosuppressed patients, CMV can be pathogenic and cause gastrointestinal, CNS, and pulmonary disease. The most common manifestation, however, is CMV retinitis, which is the most frequent cause of blindness in patients with AIDS.

History

"Cytomegalia" was described in 1921 by Goodpasture 131 as the histopathologic finding of large mononuclear inclusions in various organs of a child. The virus responsible for this disease was visualized by electron microscopy,132 isolated, and grown in culture 133 in the 1950s. CMV eye disease was described in a newborn child in 1947 134 and in an adult under chemotherapy in 1964. 135 In the pre-AIDS era, CMV retinitis was a rare disease that was found in adults under medical immunosuppression. 35 In the 1980s with the AIDS pandemic, CMV retinitis became the most common form of posterior uveitis in urban populations. 136 With the introduction of highly active antiretroviral therapy (HAART) in AIDS patients, the incidence of CMV retinitis has declined significantly.137, 138

Epidemiology In about half of a normal population, antibodies against CMV can be detected. In homosexual men, nearly 100% are infected. 139 In the vast majority, CMV infection in immunocompetent hosts does not produce symptomatic disease. Only a small percentage may develop infectious mononucleosis-like symptoms. 140 Primary infection of pregnant WOluen with CMV is the most common cause for intrauterine infection in Western countries. Fortunately, only about 10% of the babies have neonatal disease. 141 There is a 20% mortality rate associated with congenital CMV disease, 90% of the affected survivors develop CNS disease,142 and in 15% of the babies, retinitis is found. 141 The mode of transmission probably requires close contact with body fluids containing the virus. Sexual contact may be an important source of infection in homosexual luen. CMV reaches the eye via infected cells in the blood stream, and the risk for retinitis in immunosuppressed patients can be assessed by the CMV DNA burden in the blood. 143 Owing to systemic viremia, bilateral retinitis and an association of retinitis with extraocular CMV disease are commonly found. In patients with AIDS, CMV is one of the most common144, 145 and most expensive 146 opportunistic infections

CHAPTER 24: HERPESVIRUSES

and is the major cause of blindness. 147 Although the definition of the Centers for Disease Control andPrevention in Atlanta includes CMV retinitis as one of the diseases that defines the diagnosis of AIDS, it is rarely the first manifestation of AIDS and usually presents in an advanced disease stage. 148 The risk for developing CMV retinitis strongly depends on the immune status of the patient, which can be assessed by the number of CD4+ cells in the blood. Almost all cases of CMV retinitis occur in patients with a CD4+ count below 50 cells/mm 3 and only rarely with a CD4+ count of more than 100 cells/ mm 3 • 149 , 150 Altogether, CMV retinitis occurs in developed countries in about 20% of AIDS patients. 136 , 151, 152 In Mrican AIDS patients, CMV retinitis is rare. 153 With the introduction of HAART, the picture is changing. The incidence of opportunistic infections including CMV retinitis in patients with AIDS dropped by more than 80% from 1994 to 1997. 138 CMV retinitis however is not going to disappear. Failure of anti-HIV ~herapy t~ improve the immune status sufficiently, CMV retinitis in patients not receiving antiretroviral therapy, and the development of HIV drug resistance are all still challenging problems.

FIGURE 24-7. Clinical appearance of CMV retinitis: frosted branch angiitis. (See color insert.)

Early CMV retinitis begins with a small, white retinal infiltrate. At this stage, it may be difficult to differentiate from a cotton-wool spot that is commonly present in HIV-related microvasculopathy. Large and atypical cottonClinical Characteristics CMV retinitis commonly begins in the peripheral retina. wool spots in patients with AIDS should therefore be Symptoms of the early disease may therefore be minimal regarded as suspect. Two distinct types of clinical appearor initially even absent. Blurring and floaters may be ances may be seen that represent the ends of a continuexperienced, as well as unspecific visual disturbances. ous spectrum with intermediate forms commonly ocSymptomatic scotomas are usually n@ticed only if more curring. The first form is characterized by fluffy, dense, central parts of the retina are involved. In patients at risk white confluent opacifications of the retina with no with CD4+ cells below 50 cells/mm 3 or if other organs, atrophic zone in the center of the lesion (Fig. 24-6). This have CMV disease, ophthalmologic screening with dilated type commonly has multiple retinal hemorrhages, with pupils every 3 to 4 months is recommended. 149 It should perivascular location and perivasculitis and is more combe noted, however, that CMV retinitis may occur in pa- monly found closer to the posterior pole, with an arcuate tients under HAART who have CD4 counts of more than distribution following the nerve fiber layer. In selected 100 cells/mm 3 •154 Patients should be educated to pay patients, perivasculitis may be predominant, with a cliniattention to the symptoms and seek ophthalmologic care cal picture resembling "frosted branch angiitis" (Fig. after the onset of visual disturbances. In selected moti- 24-7) .1.55 The second form has more granular, less vated patients, entoptic perimetry can be helpful as a opaque-appearing lesions and shows a central atrophic zone, fewer hemorrhages, and less vascular sheathing screening test for CMV retinitis. 150 (Fig. 24-8).

fiGURE 24-6. Clinical appearance of CMV retinitis: fluffy, dense, white confluent retinal infiltrations, multiple retinal hemorrhages, and perivasculitis. (See color insert.)

FIGURE 24-8. Clinical appearance of CMV retinitis: granular, less" opaque lesions. (See color insert.)

CHAPTER 24: HERPESVIRUSES

In both forms, there are no sharply defined edges. of the involved retina. The affected area commonly has irregular borders and is surrounded by satellite infiltrates. The optic disc can be infiltrated as retinitis progresses toward the posterior pole. Primary involvement of the optic disc is less common. There is mostly a low-grade vitritis. Only a mild anterior chamber inflammatory reaction may be present. Fulminant courses with rapid progression rarely occur. Progression of the retinal infiltration without therapy usually is slow, at about 0.2 mm per week, leading to complete destruction of the entire retina in about 3 to 6 months. 156 The clinical course is probably dependent on the immune status of the patient. Complete necrosis of the involved retina develops and atrophic zones with stippling of the underlying retinal pigment epithelium are usually left behind in the center of the lesion as the active lesions resolve. Only the active edges are edematous and opaque. With anti-CMV treatment, the active lesions also become atrophic and the infiltration at the edges becomes less opaque. Remaining opacities do not necessarily represent active inflammation. If they do not progress, they can be caused by fibrosis or necrotic debris that has not cleared. Progression under maintenance therapy is mostly slow and with only mild opacification of the edges of the lesion. Serial photographs are much more sensitive than funduscopy or fundus drawings for the detection of relapsing CMV retinitis. Monthly follow-up of inactive lesions is recommended. Rarely, CMV infections of the retina may present as ARN in immunocompetent157 and immunocompromised patients. 158 CMV has been detected in selected cases of conjunctivitis, iridocyclitis or keratitis, but a causal relationship for CMV with ocular diseases other than retinitis is probably very rare.

Pathophysiology, Immunology, Pathology, and Pathogenesis Mter primary infection, CMV is disseminated by the blood stream, and replication can be found in multiple organ tissues, in polymorphonuclear leukocytes, monocytes, and T lymphocytes. Despite the fact that primary CMV infection is a systemic infection, healthy individuals commonly are without apparent symptoms. This suggests that the CMV-specific immune response must be protective. Both the humoral and cellular immune response, especially the T-cell response, contribute to this observation. 159 Mter primary infection, CMV remains in its host, establishing a latent infection typical for all herpesviruses. The viruses persist in latency in a large variety of tissues, in lymphoreticular cells, and in the secretory glands. 3 In patients with AIDS, CMV infection is one of the most important opportunistic infections. Ninety percent of these patients develop CMV infections,16o generally representing reactivation from latency. In most cases, the retina is infected via hematogenous spread during an episode of systemic CMV replication. An infection via the optic nerve by extension from the CNS or CMV papillitis is less common. There is experimental evidence that an impaired antiviral T-cell response is of particular importance for the development of the

retinitis. 161 , 162 The microangiopathy caused by HIV infection of capillary endothelial cells probably facilitates the passage of CMV-infected cells from the blood stream to the retina. The higher incidence of CMV retinitis in patients with AIDS in comparison to other patients under immunosuppression may be facilitated by this endothelial tropism. 163 Histopathologic examinations have revealed that CMV infects all layers of the retina, including the pigmented epithelium, but without choroidal involvement. It has been demonstrated that HIV accelerates the CMV replication in coinfected retinal cells. Nerve fiber infarcts, retinal hemorrhages, opacifications, and perivascular sheathing can be found. 164

Diagnosis The diagnosis of CMV retinitis is usually based on clinical criteria with the typical ophthalmoscopic picture in an immunosuppressed individual. Serum antibodies can be detected in the majority of the normal population and do not have significant diagnostic value. Elevated or rising CMV DNA blood levels appear to be associated with the development of CMV organ disease 165 and may be helpful in selected cases. Additional diagnostic tools usually require tests on intraocular fluid or tissue. Antibody levels from vitreous and aqueous humor compared with the serum levels (using the GoldmannWitmer coefficient) can support the diagnosis in difficult cases,166 but polyclonal stimulation and reduced antibody formation in immunosuppressed individuals may render interpretation of the results difficult. Virus culture and PCR from ocular tissue or fluid can directly demonstrate the presence of viral DNA,167 but because CMV can persist in the tissue without causing disease, these laboratory tests are helpful only together with the clinical picture. Especially in the differentiation of active and inactive disease, the clinical findings are vastly more important than laboratory tests. The differential diagnosis of early CMV retinitis must include mainly cotton-wool spots. In more advanced cases, retinitis caused by herpes siluplex or varicella zoster virus (ARN and PORN), syphilitic retinitis, toxoplasmic retinochoroiditis, fungal infections, and intraocular lymphomas are the most important diseases that have to be differentiated from CMV retinitis. 168

Treatment The treatment of patients with CMV retinitis is complex and demanding, and requires close collaboration between the ophthalmologist and the treating physician. The drugs used have considerable side effects and interactions. In most cases, therapy is inconvenient (IV or intraocular). The therapeutic plan must be individualized depending on the immune status, concomitant medications, individual tolerance, and the patient's personal preferences concerning the effectiveness and risks of the treatment, as well as restrictions and impact they might have on the quality of life. Anti-CMV drugs are, in general, virostatic and cannot completely eliminate the viral DNA from the retinal cells. Therefore, if immunosuppression persists and anti-CMV treatment is stopped, progression of the disease is inevita-

CHAPTER 24: HERPESVIRUSES

ble if the follow-up is long enough. Without therapy, progression of CMV occurs within 2 to 3 weeks. 145 Lifelong maintenance therapy is therefore required. Even under maintenance therapy, relapses occur after several months, probably because resistant strains of the virus develop or the immune function of the patient declines. With the introduction of potent antiretroviral therapy (HAART) , however, this concept of life-long maintenance therapy is challenged.

Improving the Immune Status In patients under medical immunosuppression, discontinuation or reduction of the dose of the chemotherapy may be sufficient to restore immunocompetence and effectively stop CMV retinitis. 169 In AIDS patients, ilnproving the immune status has only recently been made possible with the introduction of HAART, a regimen that combines two reverse transcriptase inhibitors and one antiprotease medication. This drug combination reduces HIV-1 replication, increases CD4 + cell counts (immune reconstruction), and decreases levels of activation markers.l7° As a result, this therapy has changed the present evolution of AIDS.137 It improves the function of the immune system and increases survival. l7l Early introduction of potent antiretroviral therapy is now recommended for patients with HIV infections. 172 With this treatment, a dramatic decline in the incidence of opportunistic infections, including CMV retinitis, has been observed. 138 HAART is not only beneficial for prevention but also for treating patients who are already 'Buffering from CMV retinitis. In selected patients, regression of CMV retinitis associated with protease-inhibitor treatment has been observed without additional specific anti-CMV Inedications.173-175 However, it is difficult to predict whether the immune system will recover sufficiently to control CMV retinitis without additional anti-CMV treatment and if it does, when this will occur. For immediate, effective treatment and to preserve as much of the retina as possible, especially in patients with sight-threatening retinitis involving the posterior pole, anti-CMV treatment is still mandatory. Patients presenting with CMV retinitis who have not previously received antiretroviral therapy commonly have limited access to medical care, and this fact also (or poor compliance) must be taken into consideration in the therapeutic plan. For patients with inactive CMV retinitis, life-long antiCMV therapy was necessary before HAART. If CD4 increases after HAART, a beneficial effect on CMV recurrences has been observed. 176 Most patients with quiescent CMV retinitis after HAART· have demonstrated strong CMV-specific CD4 + lymphocyte responses, indicating that the loss of CMV-specific CD4 + lymphocyte responses in individuals infected with HIV-1 who have active CMV disease may be restored. 177 In selected patients with immune reconstitution after initiation of HAART, with elevated CD4 + counts above 100 cells/ f-Ll, prolonged relapse-free intervals during the reconstitution period before CD4+ counts rise above 100 cells/f-Ll, and completely inactive retinitis, anti-CMV therapy can be discontinued at least temporarily. Reduced risks of drug toxicity and drug-resistant organisms are potential benefits. Patients who are able to stop daily IV maintenance therapy

definitely experience an improved quality of life. However, close observation for evidence of recurrent retinitis is indicated. Longer follow-up of these patients is needed to determine how long such therapy may be interrupted and when anti-CMV therapy has to be reinstituted.178-18o Some patients respond to antiretroviral therapy with an increase to 500 cells/ f-Ll, but retinitis still showed reactivation, indicating that immunologic deficits to specific pathogens may persist despite an overall ilnprovement in the immune system, and that the CD4 cell count is not an absolutely reliable indicator. 181

Systemic Anti-Cytomegalovirus Virostatic Treatment DHPG, foscarnet, and cidofovir are the most commonly used drugs in the treatment of CMV retinitis. Active CMV disease is treated with an induction therapy of 2 to 3 weeks' duration, followed by maintenance therapy.182 In the preprotease inhibitor era, maintenance therapy did not absolutely prevent the occurrence of retinitis, but the time until a relapse occurred increased considerably. In patients receiving maintenance therapy, survival is also longer, probably because CMV had a direct impact on mortality.183 First relapses of retinitis can be treated with a reinduction with the same drug. A shortening of the intervals between subsequent relapses is commonly ob-:served. In cases of repeated relapses and disease refractory to therapy, the drug should be changed or local application chosen. DHPG was the first effective anti-CMV drug introduced in 1984. 184 The main side effect of DHPG is neutropenia and thrombopenia, but neutrophil counts can be elevated by concomitantly using granulocyte colony-stimulating factor (G-CSF). 185 Induction therapy requires IV infusions twice daily, followed by maintenance therapy with daily IV infusion. Alternatively, DHPG maintenance therapy can be administered orally, but the bioavailability of the orally administered drug is poor and the patient has to swallow 12 to 24 pills daily, and at least in lower dosages, the effectiveness appears less than with IV application. 186 Foscarnet is the least convenient anti-CMV therapy because it requires 2-hour IV infusion and concomitant hydration twice daily during the induction phase. Its main side effect is nephrotoxicity. Intravenous DHPG or foscarnet are equivalent in controlling CMV retinitis. 187 Foscarnet, however, is associated with a slightly reduced mortality compared with DHPG, possibly owing to its inherent antiretroviral activity, but patients may not tolerate foscarnet as well as DHPG.188 In relapsed CMV retinitis with poor therapeutic effect of one drug, a combination of DHPG and foscarnet may be synergistic. 189 Intravenous DHPG or foscarnet is an inconvenient and costly treatment. Both require an indwelling central venous catheter, which carries a risk of a sepsis in about two cases per 1000 catheter days.19o Cidofovir has a prolonged antiviral activity and can be administered· IV weekly during the induction phase and biweekly thereafter. Therefore, it, does not require an indwelling central venous catheter. It is, however, nephrotoxic, and concomitant use of probenecid and hydration is necessary. Ocular side effects are anterior uveitis and hypotony.191-193 DHPG and cidofovir have a synergistic

CHAPTER 24: HERPESVIRUSES

effect in inhibiting CMV replication. Combination therapy with intravenous cidofovir and oral DHPG (a regimen that does not require indwelling central venous catheter access) might enhance clinical efficacy.194

Anti-Cytomegalovirus Virostatic In patients who cannot tolerate high-dose IV therapy, local intraocular application of anti-CMV medication is an alternative approach, but this does not prevent extraocular CMV disease and contralateral eye disease. Therefore, local therapy should be combined with systelnic therapy (e.g., oral DHPG) whenever possible. 195 Intravitreal injections of DHPG196 or foscarnet1 97 can be performed two to three times weekly for the induction phase and weekly for maintenance. Intravitreous injections of cidofovir are effective if repeated in 5- to 6-week intervals, but uveitis and hypotony are serious complications. 198 The DHPG intraocular implant is a sustained-release device that provides consistently high intraocular levels of the drug and appears to be the drug of choice in immediately sight-threatening retinitis cases involving the posterior pole because the implant has clinically the most rapid therapeutic effect (Fig. 24-9) .182 This therapeutic approach requires a surgical intervention with the risk of complications such as vitreous hemorrhage, endophthalmitis, and retinal detachment. 114 Progression of the retinitis occurs with the implant after 221 days versus 71 days with intravenous DHPG. ThuS', the sustained-release DHPG implant is more effective than intravenous DHPG.199 Depletion of the drug occurs after 5 to 8 months, and the device has to be replaced. In patients with recurrent CMV retinitis treated with the DHPG implant, concomitant antiretroviral therapy improves the outcome. 200 With increased patient survival and the potential for CMV retinitis to be controlled by effective antiretroviral therapy, the indications for the DHPG intraocular implant are changing. 201 Fomivirsen provides a new and interesting therapeutic concept. It is an antisense oligonucleotide that specifically

inhibits the replication of human CMV by binding to complementary sequences of messenger RNA of the vi.. rus. For treatment of CMV retinitis, it has to be injected intravitreally.202,203

Complications Loss of vision in patients with CMV retinitis is due to either involvement of the macula or optic disc or retinal detachment. With the introduction of effective antiviral treatment, the incidence of progression of retinitis and macular involvement decreases, but retinal detachment may develop with active as well as inactive CMV retinitis in 20% to 30% of eyes within 6 months. Vitreous traction on the atrophic retina can cause multiple, large, and commonly posteriorly located retinal holes. Risk factors for retinal detachment in CMV retinitis are involvement of large areas of the peripheral retina and active retinitis. 204 Bilateral detachment is common. 81 Laser treatment may delay but not prevent progression of rhegmatogen.:. ous retinal detachment in CMV retinitis. 181 , 205 Scleral buckling is only effective in cases with peripheral holes. The best treatment available for most cases of CMV retinitis and retinal detachment is probably vitrectomy with silicone oil tamponade. 20o , 206, 207 This procedure has a high success rate but generates important side effects, such as a hyperopia of about 6 diopters in phakic eyes. The inevitable development of lens opacifications in silicone-filled eyes becomes a growing problem with the increasing life expectancy of these patients. A new clinical syndrome has been observed after introduction of HAART in patients with CMV retinitis. With the recovery of the immune system, the intraocular immune response to the virus creates an inflammatory response in a previously quiet eye with inactive CMV retinitis. Enhanced inflammatory activity has also been observed in other organs after treatment with protease inhibitors. 208 So-called immune recoveryvitritis develops in more than 50% of patients with inactive CMV retinitis who responded to HAART with an increase of CD4 cell counts of more than 60 cells/mm3.209 This inflammation may be accompanied by papillitis, cystoid macular edema,210 or vitreomacular traction syndrome. 211 Therapy with oral or sub-Tenon's injections of corticosteroids may influence this condition positively.

Prognosis

FIGURE 24-9. Slit-lamp appearance of a sustained-release ganciclovir implant.

The prognosis for VISIon and survival in patients with CMV retinitis is mutually dependent. The longer the life expectancy, the more demanding the task for the ophthalmologist to preserve vision for longer time periods. With improved antiretroviral therapy, the mortality rate in patients with AIDS dropped by 80% from 1995 to 1998. 212 The mean survival after the diagnosis of CMV retinitis was 224 days in patients who took no further antiretroviral therapy, and 914 days in those who took a protease inhibitor. In the early 1990s, central vision could be preserved with systemic anti-CMV drugs in the majority of CMV retinitis patients for a limited time period, but about 10% of the patients had a vision of less than 20/ 40 in the better eye after 6 months. 187 Median time to loss of vision below 20/200 in the better eye was 21 months. 213 Since that time, new antiretroviral and anti-

CHAPTER 24: HERPESVIRUSES

CMV treatme'nt modalities have been introduced. Retinal detachment can be repaired more successfully with silicone oil.2 14 However, the fruition of this progress in positively changing the epidemiology of blindness in patients with AIDS still needs to be evaluated. The situation for patients with CMV retinitis and AIDS has dramatically changed within a very short time. In the early 1980s, it was an untreatable blinding disease in patients with a life expectancy limited to several months. In the late 1990s, several effective therapeutic modalities are available to prevent and treat CMV retinitis; but in many cases, current treatment options are still unsatisfactory, and further progress awaits the development of new pharmacologic and surgical strategies for the treatment and prevention of disease.

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CHAPTER 24: HERPESVIRUSES 158. Akpek EK, Kent C,]akobiec F, et al: Bilateral acute retinal necrosis caused by cytomegalovirus in an immunocompromised patient. Am] OphthalmoI1999;127:93. 159. Britt ~' Alford CA: Cytomegalovirus. In: Fields BN, Knipe DM, Howley PM, eds: Virology, 3rd ed. Philadelphia, Lippincott-Raven, 1996, pp 1146-1178. 160. Gallant]E, Moore RD, Richman DD, et al: Incidence and natural history of cytomegalovirus disease in patients with advanced lmman immunodeficiency virus disease treated with zidovudine. ] Infect Dis 1992;166:1223. 161. Atherton SS, Newell CK, Kanter MY, et al: T cell depletion increases susceptibility to murine cytomegalovirus retinitis. Invest Ophthalmol Vis Sci 1992;33:3353. 162. Bale ]F, O'Neil ME, Folberg R: Murine cytomegalovirus ocular infection in immunocompetent and cyclophosphamide-treated mice: Potentiation of ocular infection by cyclophosphamide. Invest Ophthalmol Vis Sci 1991;32:1749. 163. Skolnik PR, Pomerantz R], de la Monte SM, et al: Dual infection of retina with human immunodeficiency virus type 1 and cytomegalovirus. Am] Ophthalmol 1989;107:361. 164. D'Amico DJ: Diseases of the retina. N Engl] Med 1994;331:95. 165. Tufail A, Moe AA, Miller M], et al: Quantitative cytomegalovirus DNA level in the blood and its relationship to cytomegalovirus retinitis in patients with acquired immune deficiency syndrome. Ophthalmology 1999;106:133. 166. Davis ]L, Feuer W, Culbertson WW, et al: Interpretation of intraocular and serum antibody levels in necrotizing retinitis. Retina 1995;15:233. 167. Knox CM, Chandler D, Short GA, et al: Polymerase chain reactionbased assays of vitreous samples for the diagnosis of viral retinitis. Use in diagnostic dilemmas. Ophthalmology 1998;105:37. 168. Holland GN, Tufail A, Jordan MC: Cytomegalovirus diseases. In: Pepose ]C, Holland GN, Wilhelmus KR, eds: Ocular infection and immunity. St. Louis, Mosby, 1996, P 1088. 169. Pollard RB, Egbert PR, Gallagher ]G, et a1: Cytomegalovirus retinitis in immunosuppressed hosts. 1. Natural history and effects of treatment with adenine arabinoside? Ann Intern Med 1980;93:655. 170. Collier AC, Coombs RW, Schoenfeld DA, et al: Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N Engl] Med 1996;334:1011. 171. Cameron DW, Heath-Chiozzi M, Danner S, et al: Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. Lancet 1998;351:543. 172. Carpenter CC, Fischl MA, Hammer SM, et al: Antiretroviral therapy for HIV infection in 1998: Updated recommendations of the International AIDS Society-USA Panel.]AMA 1998;280:78. 173. Reed]B, Schwab IR, Gordon], et al: Regression of cytomegalovirus retinitis associated with protease-inhibitor treatment in patients with AIDS. Am] Ophthalmol 1997;124:199. 174. Whitcup SM, Cunningham ET, ]r, Polis MA, et al: Spontaneous and sustained resolution of CMV retinitis in patients receiving highly active antiretroviral therapy. Br] Ophthalmol 1998;82:845. 175. Whitcup SM, Fortin E, Nussenblatt RB, et al: Therapeutic effect of combination antiretroviral therapy on cytomegalovirus retinitis. ]AMA 1997;277:1519. 176. van den Horn G], Meenken C, Danner SA, et al: Effects of protease inhibitors on the course of CMV retinitis in relation to CD4 + lymphocyte responses in HIV + patients. Br ] Ophthalmol 1998;82:988. 177. Komanduri KV, Viswanathan MN, Wieder ED, et al: Restoration of cytomegalovirus-specific CD4 + T-Iymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nat Med 1998;4:953. 178. Jabs DA, Bolton SG, Dunn ]P, et al: Discontinuing anticytomegalovirus therapy in patients with immune reconstitution after combination antiretroviral therapy. Am] Ophthalmol 1998;126:817. 179. Macdonald]C, Torriani F], Morse LS, et al: Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy. ] Infect Dis 1998;177:1182. 180. Vrabec TR, Baldassano VF, Whitcup SM: Discontinuation of maintenance therapy in patients with quiescent cytomegalovirus retinitis and elevated CD4+ counts. Ophthalmology 1998;105:1259.

181. Frame RD, Hutchins RK, Shakan K], et al: Progression of cytomegaloviral retinitis in a patient responding to highly active antiretroviral therapy. Invest Ophthalmol Vis Sci 1999;40:873. 182. Whitley R], Jacobson MA, Friedberg DN, et al: Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: Recommendations of an international panel. International AIDS Society-USA. Arch Intern Med 1998;158:957. 183. Verbraak FD, van den Horn G], van der Meer ]T, et al: Risk of developing CMV retinitis following non-ocular CMV end organ disease in AIDS patients. Br] Ophtllalmol 1998;82:748. 184. Felsenstein D, D'Amico D], Hirsch MS, et al: Treatment of cytomegalovirus retinitis with 9-[2-hydroxy-l-(hydroxymetllyl) ethoxymethyl]guanine. Ann Intern Med 1985;103:377. 185. Hardy WD: Combined ganciclovir and recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of cytomegalovirus retinitis in AIDS patients.] Acquir Immune Defic Syndr 1991;4(Suppl):22. 186. DrewWL, Ives D, Lalezari]P, et al: Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. Syntex Cooperative Oral Ganciclovir Study Group. N Engl ] Med 1995;333:615. 187. Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group: Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial. 4. Visual outcomes. Ophthalmology 1994;101:1250. 188. Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group: Mortality in patients with the acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. N Engl ] Med 1992;326:213. 189. Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group: Combination Foscarnet and ganciclovir tllerapy vs. monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. The Cytomegalovirus Retreatment Trial. Arch Ophthalmol 1996; 114:23. 190. Skoutelis AT, Murphy RL, MacDonell KB, et al: Indwelling central venous catheter infections in patients with acquired immune deficiency syndrome.] Acquir Immune Defic Syndr 1990;3:335. 191. Davis ]L, Taskintuna I, Freeman WR, et al: Iritis and hypotony after treatment with intravenous cidofovir for cytomegalovirus retinitis. Arch Ophthalmol 1997;115:733. 192. Lalezari]P, Stagg R], Kuppermann BD, et al: Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann Intern Med 1997;126:257. 193. Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group: Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: The HPMPC peripheral cytomegalovirus retinitis trial. A randomized, controlled trial. Ann Intern Med 1997;126:264. 194. Jacobson MA, Wilson S, Stanley H, et al: Phase I study of combination therapy with intravenous cidofovir and oral ganciclovir for cytomegalovirus retinitis in patients with AIDS. Clin Infect Dis 1999;28:528. 195. Martin DF, Kuppermann BD, Wolitz RA, et al: Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group. N Engl] Med 1999; 340:1063. 196. Cochereau-Massin I, Lehoang P, Lautier-Frau M, et al: Efficacy and tolerance of intravitreal ganciclovir in cytomegalovirus retinitis in acquired immune deficiency syndrome. Ophthalmology 1991; 98:1348. 197. Diaz-Uopis M, Espana E, Munoz G, et al: High dose intravitreal foscarnet in the treatment of cytomegalovirus retinitis in AIDS. Br ] Ophthalmol 1994;78:120. 198. Taskintuna I, Rahhal FM, Rao NA, et al: Adverse events and autopsy findings after intravitreous cidofovir (HPMPC) therapy in patients with acquired immune deficiency syndrome (AIDS). Ophthalmology 1997;104:1827. 199. Musch DC, Martin DF, Gordon]F, et al: Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. The Ganciclovir Implant Study Group. N Engl] Med 1997;337:83. 200. Davis ]L, Tabandeh H, Feuer ~' et al: Effect of potent antiretroviral therapy on recurrent cytomegalovirus retinitis treated with the ganciclovir implant. Am] Ophthalmol 1999;127:283.

CHAPTER 24: HERPESVIRUSES 201. Martin DF, Dunn JP, Davis JL et al: Use of the ganciclovir implant for the treatment of cytomegalovirus retinitis in the era of potent antiretroviral therapy: Recommendations of the International AIDS Society-USA panel [see comments]. Am J Ophthalmol 1999)27:329. 202. Perry CM, Balfour JA: Fomivirsen. Drugs 1999;57:375. 203. Piascik P: Fomiversen sodium approved to treat CMV retinitis. J Am Pharm Assoc 1999;39:84. 204. Freeman WR, Friedberg DN, Berry C, et a1: Risk factors for development of rhegmatogenous retinal detachment in patients with cytomegalovirus retinitis. Am J Ophthalmol 1993;116:713. 205. Davis JL, HummerJ, Feuer ~: Laser photocoagulation for retinal detachments and retinal tears in cytomegalovirus retinitis. Ophthalmology 1997;104:2053. 206. Azen SP, Scott IU, Flynn HW, Jr, et al: Silicone oil in the repair of complex retinal detachments. A prospective observational multicenter study. Ophthalmology 1998;105:1587. 207. Nasemann JE, Mutsch A, Wiltfang R, et al: Early pars plana \ritrectomy without buckling procedure in cytomegalovirus retinitisinduced retinal detachment. Retina 1995;15:111.

208. Carr A, Cooper DA: Restoration of immunity to chronic hepatitis B infection in HIV-infected patient on protease inhibitor. Lancet 1997;349:995. 209. Karavellas MP, Plummer DJ, Macdonald JC, et al: Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J Infect Dis 1999;179:697. 210. Welzl-Hinterkorner E, Tholen H, Sturmer J, et al: Bilateral cystoid macular edema following successful treatment of AIDS-associated CMV retinitis. Ophthalmologe 1999;96:87. 211. Canzano JC, Reed JB, Morse LS: Vitreomacular traction syndrome following highly active antiretroviral therapy in AIDS patients with cytomegalovirus retinitis. Retina 1998;18:443. 212. MocroftA, Vella S, Benfield TL, et al: Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 1998;352:1725. 213. Jabs DA: Ocular manifestations of HIV infection. Trans Am Ophthalmol Soc 1995;93:623. 214. Davis JL, Serfass MS, Lai MY, et al: Silicone oil in repair of retinal detachments caused by necrotizing retinitis in HIV infection. Arch Ophthalmol 1995;113:1401.

Aaron L. Sobol and Ramzi K Hemady

Rift Valley fever (RVF) is an epizootic acute febrile illness primarily affecting domesticated cattle. It is caused by an arthropod-borne plebovirus in the family Bunyaviridae. The virus can also infect humans, causing a spectrum of disease ranging from a mild constitutional illness to fatal complications including hemorrhagic fever and meningoencephalitis. I Reports of ocular manifestations in human outbreaks are well recognized as a significant cause of morbidity.

HISTORY The virus was first described in 1931 following an outbreak in cattle and humans in the Rift Valley in East Mrica. 2 Since then, there have been sporadic outbreaks in at least 25 Mrican countries, usually associated with periods of heavy rainfall, most recently in Kenya in 1998. 3 Until fairly recently, these outbreaks were thought to cause mortality in cattle and only a flulike illness in humans. During a South Mrican outbreak in 1950 there were an estimated 20,000 human infections but few deaths despite 100,000 sheep and cattle fatalities during the same period. However, the epidemic in South Mrica in 1974 to 1975 produced at lea&$ 70 human deaths, and the epidemic in Egypt in 1977· to 1978 produced 598 fatalities, highlighting the potentially fatal nature of this infection in humans. 4 Freed 5 and Schrire 6 first characterized ophthalmic complications from RVFvirus in 1951. Since then, many reports have been published describing a macular or paramacular syndrome of edema with exudative-type lesions and hemorrhage.

EPIDEMIOLOGY The Great Rift Valley is a geological depression extending more than 4830 km from Syria in southwestern Asia along the eastern Mrican coast to Mozambique in southeastern Mrica. Although the disease was first noted in this region of East Mrica, outbreaks have been seen throughout the continent. RVF has not been reported in cattle outside of Mrica and was localized to sub-Saharan Mrica until the 1977 outbreak in Egypt. There is a report of an international traveler in Canada diagnosed with RVF in 1979. 7

PATHOGENESIS The virus is transmitted by numerous species of mosquitoes, with the genera Culex and Aedes playing dominant roles in the viral cycle (Fig. 25-1). Culex spread the virus to humans and animals through blood meals. The cattle serve as a repository for amplification of the virus as uninfected mosquitoes that bite viremic vertebrates may become infected. The Aedes has been implicated in maintaining the epizootic outbreaks by depositing virus-laden eggs in soil that hatch when ground pools form during heavy rains. 8 , 9

In past outbreaks, the majority of the human infections were in farmers, farm laborers, and veterinary surgeons that handled the carcasses of infected cattle. A Senegali study showed that individuals in endemic areas who worked with livestock had a five- to six-fold risk of having positive RVF viral IgG over individuals who did not handle livestock. 8 A Kenyan task force found that contact with livestock was significantly associated with serologic . evidence of acute infection with RVF virus. 3 It appears that RVF is primarily spread to animals by mosquitoes; the method of transmission to humans is less clear. Besides arthropod vectors, there are indications that inhalation can be a route of transmission. Infection in humans exposed to aerosol contamination during animal slaughter or to infection by contact during meat preparation is well recognized. The virus has been experimentally transmitted through contaminated blood, and several laboratory workers have contracted the disease. The meat of affected animals is not infectious, and neither person-to-person nor nosocomial transmission have been documented,I, 10

CLINICAL CHARACTERISTICS Typical signs in animals include fever, weakness, anorexia, and evidence of abdominal pain. Lambs and calves are more susceptible to the fatal form of RVF than adults. Abortion may reach 100% and accounts for one of the major economic impacts of the outbreaks. The incubation periods in humans is generally from 3 to 7 days, followed by one of four clinical syndromes, the most common of which is an uncomplicated febrile illness with constitutional symptoms. This is characterized by abrupt onset of fever with a biphasic temperature curve, mimicking dengue fever. The main symptoms are headache, arthralgias, "back-breaking" myalgias, and gastrointestinal disturbances. The fever subsides in 12 to 36 hours, and the other symptoms are relieved within 4 days. Several authors have noted that. conjunctivitis and photophobia are common early symptoms, although anterior uveitis is relatively uncommon,u Ocular, hematologic, and neurologic involvement characterize the other three clinical syn.dromes, respectively. The ocular syndrome has been reported to be present in 1% to 20% of RVF infections, and the hematologic and neurologic forms have been reported in 0.2% to 2% of RVF infections. I, 3, 4, 8,12 Ocular involvement typically follows a brief febrile illness. Decreased visual acuity usually begins from 2 to 7 days after onset of fever. I3 Siam described the largest series of serologically proven RVF with ocular manifestations during the 1977 epidemic in Egypt,u The most common findings were bilateral macular and paramacular exudative-like lesions with retinal edema a11d hemorrhage. Some cases were associated with anterior inflammation or vitritis. Other finding!' included retinal vasculitis, ranging from sheathing of the arterioles in the area of the exudative lesions to a diffuse vasculitis.

CHAPTER 25: RIFT VALLEY FEVER Uninfected Culex Mosquito

Seasonal Rains

Infected Cow

Bloodmeal

tI

Infected Aedes Mosquito

Viral Laden Eggs in Soil

Mode of Transmission Uncertain Transovarial Transmission

Infected Culex Mosquito

FIGURE 25-1. Rift Valley fever virus life cycle.

The visual deficit appears to be related to the size and degree of vascular involvement, ranging from slight impairment to light perception. Although small case studies suggested that permanent visual deficit was unusual, larger studies have noted a 40% to 50% persistence of deficits despite resolution of retinal edema. 4 , 12 Fluorescein angiography typically showed delayed filling of both the retinal and choroidal circulation, although one small case series suggested sparing of the choroidal circulation. 5 There is obscured choroidal fluorescence in the area corresponding to the lesion and delayed peripapillary choroidal filling in the arteriovenous phase. Macular and paramacular leakage may be seen. Angiography following convalescence may show residual delay in peripapillary filling and loss of macular vessels. 14 Deutman and Klomp described a patient with severe macular lesions and serologic evidence suggestive of RVF, as well as bilateral optic nerve pallor. 15 The electroretinogram was almost unrecordable in one eye and somewhat better in the other. The visual-evoked potentials (VEP) were not recordable in one and only minimally recordable in the other. The electro-oculogram (EGG) was flat in both eyes and did not show any change in light adaptation. The hematologic complications consist of a generalized hemorrhagic state, including epistaxis, hematemesis, and melena. These complications usually occur within 2 to 4 days of an acute febrile illness. Liver function tests in affected patients have shown elevated serum transaminases, hyperbilirubinemia, and a prolonged prothrombin

time. Shock and hepatic insufficiency contribute to the high mortality rateP Meningoencephalitis is well recognized and typically presents 5 to 10 days following a febrile illness. Presentation includes changes in mental status, meningismus, and vertigo. Evaluation of cerebrospinal fluid shows pleocytosis with lymphocyte predominance and normal glucose and protein concentrations. 4 ,13

PATHOLOGY The RVF virus is a hepatotropic virus, and the most characteristic microscopic lesion is a diffuse focal hepatic necrosis. Eosinophilic granules may occur in the hepatocytes. Autopsies have shown diffuse petechial and ecchymotic hemorrhages in all organ systems. 4 There are no published reports describing ocular pathology.

DIAGNOSIS Diagnosis should be considered in the presence of animal outbreaks of RVF. Selective involvement of lambs and calves, high abortion rates, and characteristic liver lesions provide presumptive evidence but virus isolation is necessary to confirm the diagnosis. In Kenya in 1998, diagnostic confirmation was made by detection of IgM antibodies, virus isolation, reverse-transcriptase polymerase chain reaction for viral nucleic acid, or immunohistochemistry. 3 A fourfold or greater rise in hemagglutination-inhibition or complement fixation antibody titers to RVF virus was seen in six of eight patients with uncomplicated RVF and in five of five patients with meningoencephalitis. 13

25: RIFT VALLEY FEVER

DIAGNOSIS The differential diagnosis for RVF retinitis includes other viral entities such as measles, rubella, and influenza. These diseases can be differentiated from RVF by clinical history and serologic testing. Rickettsial infections have been reported to cause retinitis; a history of tick bites and antibody titers can aid in the diagnosis. Lyme disease can mimic RVF and can be ruled out with antibody titers. 6 Other hemorrhagic fever viruses have been reported to have ocular involvement. The hemorrhagic fever with renal syndrome is associated with two major causative viruses, the Hantaan virus and the Puumala virus. Hantaan disease has been associated with anterior uveitis during the acute febrile phase. 16 Marburg and Ebola viruses, of the family Filoviridae, have been implicated in multiple epidemics of hemorrhagic fever in sub-Saharan Mrica and in a primate import quarantine facility in Reston, Virginia. 16 About one half of the patients had conjunctivitis in the early febrile stage and late sequelae have included anterior uveitis. Marburg virus has been isolated from the anterior chamber nearly 3 months following disease onset. 16 Hemorrhagic fever in the United States is noted in the Hantavirus pulmonary syndrome, which has not been reported to have ocular complications. 16

TREATMENT No specific effective treatment has been demonstrated for the hemorrhagic or encephalitic complications of RVF. Ribavirin, an antiviral agent, and polyriboinosinicpolyribocytidylic acid, an interferon inducer, have shown encouraging results in experimental studies in animals, as has passive antibody transfusionY No treatment has yet been evaluated in a clinical setting, however. Epidemic disease is best prevented with vaccination of livestock. Live-attenuated and inactivated vaccines are available in Mrica for veterinary use. A single dose of the live-attenuated RVF MP-12 vaccine is immunogenic, nonabortogenic, and protective of the animal and fetus against experimental challenge with virulent virus. The duration of the protective response is unknown, and the vaccine is being tested for use in humans. An inactivated vaccine produced for the U.S. Army is available and recommended for exposed laboratory workers and veterinarians working in sub-Saharan Mrica. 18 There are no reported treatments for the ocular complications.

CONCLUSIONS Ocular complications occur in approximately 20% of cases of RVF, a viral epidemic illness predominantly distributed in sub-Saharan Mrica. The typical presentation includes unilateral or bilateral macular and paramacular exudates with edema, retinal hemorrhages, and vascular sheathing and occlusion. Anterior uveitis has been noted, and conjunctivitis and photophobia may be common presenting symptoms. Diagnosis is based on serologic testing. No specific effective treatment exists.

References 1. House JA, Turell MJ, Mebus CA: Rift Valley fever: Present status and risk to the western hemisphere. Ann N Y Acad Sci 1992;653:233-242. 2. Daubney R, Hudson JR, Garnham pc: Enzootic hepatitis or Rift Valley fever: An undescribed virus of sheep, cattle, and man from East Mrica. J Pathol 1931;34:545-549. 3. Centers for Disease Control: Rift Valley fever-East Mrica, 19971998. MMWR 1998;47:261-264. 4. McIntosh BM, Russell D, Dos Santos I, Gear JHS: Rift Valley fever in humans in South Mrica. South Mrican Medical Journal 1980;58:803-806. 5. Freed I, Rift Valley fever in man, complicated by retinal changes and loss of vision. S Afr MedJ 1951;25:930-932. 6. Schrire L: Macular changes in Rift Valley fever. S Mr Med J 1951 ;25:926-929. 7. Centers for Disease Control and Prevention: Rift Valley fever with retinopathy-Canada. MMWR 1980;28:607-608. 8. Wilson ML, Chapman LE, Hall DB, et al: Rift Valley fever in rural northern Senegal: Human risk factors and potential vectors. Am J Trop Med Hyg 1994;50:663-675. 9. Wilson ML: Rift Valley fever virus ecology and the epidemiology of disease emergence. Ann NY Acad Sci 1994;740:169-180. 10. Ghoneim NH, Woods GT, Rift Valley fever in its epidemiology in Egypt: A review. J Med 1983;14:55-75. 11. Siam AL, Meegan JM, Gharbawi KF: Rift Valley fever ocular manifestations: Observations during the 1977 epidemic in Egypt. Br J Ophthalmol 1980;64:366-374. 12. Arthur RR, El-Sharkawy MS, Cope SE, et al: Recurrence of Rift Valley fever in Egypt. Lancet 1993;342:1149-1150. 13. Laughlin LW, Meegan JM, Straugbaugh LJ, et al: Epidemic Rift Valley fever in Egypt: Observations of the spectrum of human illness. Trans R Soc Trop Med Hyg 1979;73:630-633. 14. Yoser SL, Forster, DJ, Rao, NA: Systemic viral infections and their retinal and choroidal manifestations. Surv Ophthalmol 1993; 37:313-352. 15. Deutman AF, Klomp Hl Rift Valley Fever retinitis. Am J Ophthal 1981;92:38-42. 16. Peters Cl Harrison's Principles ofInternal Medicine, 14th ed. New York, McGraw Hill, 1998, pp 1142-1147. 17. Peters q, Reynolds JA, Slone TW, et al: Prophylaxis of Rift Valley fever with antiviral drugs, immune serum, an interferon inducer, and a macrophage activator. Antiviral Res 1986;6:285-297. 18. Morrill, JC, Mebus, CA, Peters, Cl Safety and efficacy of a mutagenattenuated Rift Valley fever virus vaccine in cattle. Am J Vet Res 1997;58:1104-1109.

Erik Letko and C. Stephen Foster

DEFINITION Measles (rubeola) is an acute, highly contagious viral disease. The definition of "probable measles" proposed by the Centers for Disease Control and Prevention includes the following clinical signs and symptoms: (1) a generalized rash lasting 3 or more days, (2) a temperature greater than 101°F, and (3) cough, coryza, or conjunctivitis. 1

HISTORY From antiquity until the beginning of the 17th century, measles and smallpox were frequently confused. The first written record of measles comes from the 10th century by the Persian physician Rhazes. 2 But even Rl1.azes referred to the description of the disease by a famous Hebrew physician, El Yahudi, who lived 300 years earlier. Repeated epidemics of measles in Europe were reported in the 17th century.3 The first report on measles in America described an epidemic in Boston in 1657. 4 From that time onward, the reduction of epidemic intervals in Europe was noted as a consequence of rapid immigration to North America. The first epidemiologic data were reported in 1846 by Panum,5 who noticed that the incubation period for the disease was 14 days, that lifelong immunity followed recovery from the infection, and that spread was through human-to-hunian contagion via the respiratory route. It is evident that Shakespeare was aware of the latter in Coriolanus. 2 The first attempt to immunize against measles was performed by Home in 1758. 6 The pathognoIIlOnic exanthem for measles was precisely described by Koplik at the end of the 19th century.7-9 In 1954, measles agents were isolated in human and simian renal· cell cultures,10 and in 1963, the first inactivated and attenuated measles vaccines became available.D A nationwide immunization program was begun in the United States in 1965.

CONGENITAL Epidemiology During the pre-vaccine era, most persons contracted measles before reaching adulthood. Therefore, only four to six pregnancies per 100,000 were complicated by measles during this time period. 12 In the postvaccine era, the proportion of measles in pregnancy is larger. 13 Because of the low incidence of measles infection in adults, congenital measles is rare compared with acquired infection. Nevertheless, maternal measles can result in fetal death or congenital anomalies. 14, 15 The majority of women who contract measles during pregnancy do not have a history of vaccination against the virus. 14

Clinical Characteristics Infection during the third trimester of pregnancy causes spontaneous abortion in about 20% of women and may also result in premature birth. Newborns with congenital

measles infection may present with the following anomalies: cardiopathy, pyloric stenosis, genu valgum, deafness, mongolism, vertebral anomalies, cleft lip, cleft palate, or rudimentary ear. Ocular manifestations of congenital measles include dacryostenosis, cataract, and pigmentary retinopathy. Ophthalmoscopy reveals optic nerve head drusen and bilateral diffuse scattered pigmentary retinopathy with involvement of both the posterior pole and the retinal periphery.16 The retinopathy may be associated with retinal edema, macular star formation, and arteriolar attenuation. 17

Pathophysiology, Immunology, Pathology, and Pathogenesis Congenital and acquired measles infection is caused by a single-stranded RNA virus belonging to the genus Morbillivirus in the Paramyxoviridae family. The virion is circular or oval in shape and enveloped, and has a diameter of 120 to 250 nm. 1S , 19 Humans and monkeys are the only natural hosts of the measles virus. Congenital. measles infection is transmitted through the placenta and may result in fetal demise or serious congenital anomalies.

Diagnosis Diagnosis of congenital measles infection is made by history of maternal measles and the presence of congenital anomalies. The electroretinogram does not show any abnormalities; however, an enlarged blind spot in visual field may appear as a consequence of drusen of the optic disc. 16

Treatment Congenital measles is a self-limiting disease, and no specific treatment is available.

Prognosis The prognosis for patients with congenital measles depends on the extent and nature of congenital anomalies. Interestingly, the visual acuities in reported patients with congenital rubeola retinopathy have been normal. 16, 17

ACQUIRED "MEASLES Epidemiology Before the introduction of the measles vaccine, 95% of Americans were infected with measles by the age of 15 years. 20, 21 As a consequence of nationwide vaccination, there has been a marked decrease in the incidence of the disease, with a shift in the age of presentation from children to adolescents and young adults. 21 - 23 Despite the availability of measles vaccine in the United States, however, there are still large numbers of Americans who are susceptible to the disease. Complete eradication of the disease has not been achieved owing to several factors, including primary vaccine failure reported in 5% to 8%, lack of vaccination (i.e., parental apathy, contraindi-

26: MEASLES

cations based on existing medical conditions, or religious convictions), and importation of measles from other countries. IS, 24

Clinical Characteristics The mucosal involvement consists of a catarrhal reaction of the conjunctiva and respiratory mucosa, as well as petechial lesions of the palate and pharynx. One to two days before the onset of the rash, Koplik's spots appear. These are small, bluish-white dots surrounded by a red areola, typically localized on the buccal mucosa ?ppo~ite the lower molars, but their presence on the conJunctIVa, caruncle, vagina, rectum, and intestinal mucosa has been observed as wel1.2 5 The Koplik spots disappear by the second day following the skin eruption. The characteristic skin eruption starts as pink macules (discrete, irregular, and erythematous) behind the ear, on the forehead, a~d on the neck. They rapidly become maculopapular In nature and spread downward during the next 3 days to involve the face, trunk, arms, and legs. IS, 19, 26, 27 Conjunctivitis, together with cough and coryza,. are considered the classic triad in measles. However, conJunctivitis need not be clinically present in all affected patients. 2s It is usually mild, catarrhal, papillary, and nonpurulent. Pseudomembranes may occur,29 and in debilitated patients, severe, true conjunctival me.~branes m~y d.evelop.26 An associated epithelial keratitIs, presentI~1g III 76% of patients,30 is the most common ocular manIfestation in acquired measles infection. 2s-3l It is usually mild and bilateral. Keratitis begins lU the limbus, progresses centrally to the cornea, and usually does not affect the Bowman layer. The keratitis develops in the prodromal phase or at the time of the onset of the rash and resolves several days afterward. However, in some patients, it may persist as long as 4 months. 2s , 29, 31 Corneal sensation is unaffected, and the corneal lesions resolve without scarring. 32 Other, less common ocular findings include Koplik's spots, which may occur on the caruncle and on the conjunctiva, where they are also called Hirschberg's spotS. 19,26 Stimon's line is a sharply demarcated transverse linear injection of the lower lid margin present at the onset of conjunctivitis. 19 Blepharitis and gangrene of the eyelids are rare. 26 Rubeola retinopathy may occur either in presence or in absence of encephalitis, complicating acquired measles infection. 33 Patients may present with a sudden decreased vision bilaterally 6 to 12 days after the appearance of measles exanthem. 26 , 33 Acquired measles retinitis has been described and is characterized by clear media, blurry disc margins, diffuse retinal edema, attenuated arterioles, scattered retinal hemorrhages, and a starshaped macular edema. The following retinal findings were observed after the resolution of acute measles retinopathy: pale optic disc, parapapillary vascular sheathing, mild attenuation of arterioles, and secondary pigmentary retinopathy with a "bone corpuscle" or "salt;and-pepper" pattern. 33 A retinopathy described as pigmented paravenous retinoch~­ roidal atrophy with abnormal visual field and electroretInogram might develop several years after acute measles infection as a consequence of measles retinopathy.34

Pathophysiology, Immunology, and Pathogenesis The measles virus is highly contagious. Transmission of the virus in acquired disease occurs by the transfer of nasopharyngeal secretions directly or in airborne droplets from an infected individual to the mucous membranes of the upper respiratory tract or conjunctiva of a susceptible individual. IS, 19 Infected individuals may transmit the virus from 5 days after exposure to 5. days following the skin rash, which may appear 14 days after initial exposure. The prodromal period, 9 to 10 days after exposure, is the most contagious. IS, 19 The first contact with the highly infective virus is at the mucous membrane of the respiratory tract. The conjunctiva also might act as a portal of entry for the mea~les infection. 30 If it is not inactivated by mucus or speCIfic secretory immunoglobulin A antibodies, the virus enters the ciliated columnar epithelium. 35 During the primary viremia, 2 to 6 days after the infection, the virus is transported intracellularly within the formed elements ?f the blood. An extensive proliferation of virus follows III the reticuloendothelial system in the tonsils, spleen, liver, bone marrow, and other lymphoid tissues. The second viremia starts 10 days after the infection, with proliferation of the virus inside the leukocytes. Neutralizing antibodies appear 14. days after infection, at the time of the appearance of the rash. The ras~1 is a~ expression. of immunologic defense, and in patIents With severely Impaired cell-mediated immunity, a measles infection may run its course without the presence of rash. 36, 37 A more severe clinical course with higher incidence of complications such as pneumonitis and encephalitis has been observed in immunocompromised patients. 3s A single episode of infection with measles virus and successful vaccination with live attenuated measles vaccine confers lifelong immunity. The use of live attenuated measles vaccine induces active immunity in about 95% of susceptible individuals and should be provided for all individuals older than 12 months of age, because younger infants might still have circulating maternal neutralizing antibodies to measles. IS, 19,39,40 Histopathologically, Koplik's spots represent necrosis of the epithelium, and the skin rash shows multinucleated giant cells, parakeratosis, and dyskeratosis. 25 Multinucleated giant cells with eosinophilic cytoplasmic inclusion bodies appear not onl~ in the. epithelium but also in lymphoid tissues. InclusIOn bodIes may become visible 16 to 20 hours after infection in the cytoplasm and 96 to 120 hours after infection inside the nucleus. 36 In electron microscopic studies, inclusion bodies are visible as granular masses, with the characteristic measurements of the RNA helix.

Diagnosis Diagnosis of measles is made by observation of the sequence of clinical symptoms. The measles virus can be recovered from the nasopharynx, conjunctiva, lymphoid tissues, respiratory mucous membranes, urine, and blood for a few days before skin eruption and 1 or 2 days afterward}S, 19 Virus isolation in cell cultures has been achieved in monkey and dog kidney tissue, and chick

CHAPTER 26: MEASLES

embryo chorioallantoic membranes. Serum immunoglobulin M antibodies can be detected within 1 or 2 days after the onset of the skin rash. 18, 19 Peak titers of serum antibodies occur in 2 to 4 weeks. The complement-fixing antibodies may diminish gradually over a period of years. Virus-neutralizing and hemagglutination-inhibiting (HI) antibodies show an initial decrease in concentration for 2 to 6 months after the attainment of maximum titers but persist indefinitely thereafter. 18, 19 During the prodromal phase and early eruptive phase of measles, multinucleated giant cells with eosinophilic inclusions in both the nuclei and cytoplasm can be identified in sputum, nasal secretions, and urine. 18, 19 The diagnosis of measles retinopathy is made by the history of recent measles infection and ophthalmoscopic findings. Fluorescein angiography of· the fundus in patients with measles retinopathy reveals a generalized increased transmission of background choroidal fluorescence due to widespread pigment epithelial disturbance with characteristic salt and pepper pattern. Visual field was reported to be constricted and the ERG may reveal either normal or low activity.33 Retinal findings similar to macular star formation and pigmentary changes of the retina may be observed in patients with other viral infections such as mumps or influenza A. Measles retinitis may be distinguished from Leber's stellate idiopathic neuroretinitis and central serous chorioretinopathy by the absence of systemic symptoms.

Treatment Uncomplicated measles infection is usually a self-limiting disease, and supportive treatment is usually sufficient. However, in high-risk patients such as pregnant women, children younger than 1 year of age, and immunosuppressed patients, the course of measles infection can be altered by treatment with gamma-globulin 0.25 ml/kg of body weight if therapy is begun 6 days after exposure.1 8, 19,39 In patients with vitamin A deficiency, oral administration of vitamin A results in decreased mortality rate,4l Treatment of the ocular manifestations is symptomatic, with the use of topical antiviral or antibiotics to prevent ~econdary infections in patients with keratitis or conjunctivitis. A combination of systemic corticosteroids and antibiotics has been successfully used in treatment of measles retinopathy in one case. 33

Complications Systemic complications of measles infection include encephalitis, acute glomerulonephritis, disseminated intravascular coagulation, otitis media, laryngotracheitis, pneumonia, appendicitis, and myocarditis. 42 Keratitis in patients with secondary bacterial infections or in debilitated patients can become ulcerative with consequent corneal neovascularization, or it may become purulent, with progression to corneal perforation, panophthalmitis, and phthisis bulbi,26, 27 These severe corneal ul~er complications are most frequent in developing countries as a consequence of malnutrition, vitamin A deficiency, protein deficiencies, and racial, geographic, and cellular immunity factors. 43 , 44 Other uncommon ocular findings may be associated

with the central nervous system complications of rubeola such as optic atrophy, optic neuritis, papilledema, central retinal vein occlusion, neuroretinitis, chorioretinitis, extraocular muscle palsies, nystagmus, abnormal eye movements, and cortical blindness. 19

Prognosis In developing countries approximately 1 % of children with measles develop permanent ocular damage. 45 According to one study, 43.7% of students in blind school institutions in a developing country were blind as a consequence of measles infection. 46 The term postmeasles blindness (PMB) is restricted to the corneal complications of the disease. 3o Concomitant HSV infection, folk remedies, confluence of keratitis, and vitamin A deficiency are associated with poor visual prognosis. 47 In cases of measles retinitis the long-term prognosis is good. Mter an initial period of decreased visual acuity, the vision improves in subsequent weeks to months. However, the visual fields remain constricted and the ERG may not regain full activity.

SUBACUTE SCLEROSING PAN ENCEPHALITIS Epidemiology Subacute sclerosing panencephalitis (SSPE), first described by Dawson in 1933, is a chronic degenerative disease of the central nervous system complicating measles virus infection. 48 Its prevalence has been estimated at 3.5 cases per 10 million persons younger than 20 years. 49 The occurrence of SSPE in boys is approximately two times greater than that in girls,5o,51 with male-to-female ratio of 1.8:1. 50 The onset of SSPE is usually 6 to 7 years after acute measles, but later onset has been reported as well. 52 Individuals who had measles before the age of 2 years are at higher risk of developing SSPE. The majority of patients manifest neurologic signs before the age of 20 years.

Clinical Characteristics The typical clinical picture of SSPE has three stages. Behavioral changes and intellectual deterioration are present in the first stage. The second stage is characterized by extrapyramidal signs and cortical blindness. Dementia develops in the third stage, with death within 1 to 3 years of disease onset. Approximately 50% of patients develop ocular symptoms. 53-56 Ocular symptoms may precede neurologic manifestations by several weeks to 2 years.57 Maculopathy consisting of pigment epithelial changes and focal retinitis in 36% of patients is the most typical ocular finding 55 ,57-63 (Fig. 26-1; see also color insert). The retinitis can spread within several days from the macula to the posterior pole and peripheral retina. 52, 54, 64-67 Other ocular findings include disc edema, papillitis, optic nerve edema and pallor, retinitis, serous retinal detachment, retinal hemorrhage, chorioretinitis, vasculitis, preretinal membrane, retinal folds, macular hole, cortical blindness, hemianopsia, horizontal nystagmus, and ptosis.53-56, 58, 61, 62, 65, 66, 68 Characteristically, there is little or no vitreous inflamma-

CHAPTER 26: MEASLES

ment of the retinal pigment epithelium and choroid.58, 62 Histopathology shows necrotizing retinopathy with eosinophilic inclusion bodies in both the cytoplasm and nucleus of neuronal glial and pigment epithelial cells. In addition, depigmentation and proliferation of the pigment epithelium with or without lymphocytic infiltration in choroids is observed. 48 , 58, 60, 62, 66 Immunohistology reveals the measles virus antigen on nucleocapsids of the nuclear and cytoplasmic inclusions. 66 On electron microscopy, filamentous microtubular structures representing measles virus nucleocapsids of characteristic size are present in the retinal lesions, similar to those in the CNS.60, 62

Diagnosis

FIGURE 26-1. Ophthalmoscopic photograph, right macula. Note the well circumscribed, deep retinal opacification inferior to the fovea, with faint nerve fiber layer swelling extending from the lesion to the optic disk. (From Park DW, Boldt HC, Massicotte S1, et al: Subacute sclerosing panencephalitis manifesting as viral retinitis: Clinical and histopathologic findings. Am 1 Ophthalmol 1997;123:533-543. With permission from Elsevier Science.) (See Color insert.)

tion. 52 ,54-56, 58, 60, 64, 65, 68 The retinitis resolves, leaving retinal pigment epithelium mottling and scarring. 52 ,54, 59, 61, 62, 67, 68

Pathophysiology, Immunq,iogy, Pathology, and Pathogenesis The classic measles virus replicates by budding and fusion. Subacute sclerosing panencephalitis is caused by measles virus, so-called "slow virus," deficient of certain virion polypeptides, such as matrix (M), hemagglutinin (H), and fusion (F) proteins. These proteins are necessary for alignment of the virus along the host-cell plasma membrane and subsequent budding and release of the virus from the host cell. Defects in these proteins, particularly in M protein, allow the virus to stay in its intracellular form and to spread by cell-to-cell contact. 69-72 The disease is a true panencephalitis, affecting both gray and white matter. Immunohistochemical studies of brain tissue of SSPE patients has revealed increased expression of interleukin1 (IL-I), IL-6, tumor necrosis factor-a (TNF-a), interferon-)' (IFN-)'), IL-2, and lymphotoxin. 73 Interestingly, only IL-I and intercellular adhesion molecule 1 (ICAM1) were elevated in cerebrospinal fluid. 74 The way in which these cytokines reached the cerebrospinal fluid is not known. IFN appears to play an important role in the pathogenesis of SSPE. The intracellular virus can revert to the productive form in vitro on removal of IFN.75 And abnormally low IFN-a and IFN-13 levels were found in cerebrospinal fluid of patients with SSPE,76, 77 and their peripheral mononuclear cells failed to produce IFN in vitro. 78 However, an in vitro resistance of SSPE virus to IFN has been observed as well. 79 The virus in patients with SSPE is thought to reach the eye by hematogenous dissemination.61 In the eye, the virus primarily affects the retina, with secondary involve-

Diagnosis requires a high degree of suspicion and should be suspected in school-age children who exhibit unexplained, slowly progressive, cognitive, emotional, or neurologic dysfunction. The diagnosis is made by the presence of three of five criteria, which include (1) clinical course, (2) biopsy or necropsy results, (3) EEG pattern, (4) elevated globulin levels in cerebrospinal fluid, and (5) elevated levels of IgG measles antibodies in serum and cerebrospinal fluid. 50, 80 Absence of IgM measles antibodies provides evidence against a new, acute-onset infection. Ophthalmoscopic signs may appear before the development of the neurologic disease and do not necessarily correspond to a particular stage of neurologic impairment. Fluorescein angiography (FA) typically shows optic nerve staining, and precapillary arteriole and postcapillary venous occlusion with staining of the retinal lesions in the area of acute retinitis. 52,59 The retinal lesions may resolve, leaving retinal pigment epithelial window defects on FA.52 Ocular findings similar to those seen in SSPE might be observed in patients with multiple sclerosis (MS) or in patients with unexplained optic atrophy and retinitis. Differentiating features between MS and SSPE include the fact that MS is not a panencephalitis, and MRI in patients withMS usually reveals focal lesions of white matter. In addition, cystoid macular edema (CME) is common in patients with MS but has not been seen in patients with SSPE.

Treatment There is no definitive treatment for SSPE. However, intracameral IFN-a82-84 may induce remission or stabilize the clinical course. Potential resistance to IFN-a might be overcome by higher doses administered for a longer period of time. 82 Inosiplex, a 1:3 molar complex of inosine with dimethylaminoisopropanol-p-acetamidobenzoate, is a drug with both direct antiviral and immunomodulatory properties. 84 Early oral administration of inosiplex may delay the neurologic progression of the disease, with prolonged survivaJ.81, 84 Treatment with a combination of intravenous IgG and inosiplex has been reported in one case as well. 85 The clinical symptoms rapidly improved after the treatment; however, the high titer of antibodies persisted. The efficacy and mechanism of action of this therapy remain unclear.

CHAPTER 26: MEASLES

Prognosis SSPE is generally considered to be a progressive fatal disease within 1 to 3 years of first clinical signs and symptoms. 50 ,51 In addition to this classic clinical presentation, a chronic slowly progressive form, a fulminant form leading to death within several weeks, and a "stuttering" form with remissions and relapses have been reported. 50, 86 Spontaneous remission may occur in approximately 5% of patients. 87

CONCLUSION Measles infection can affect multiple ocular structures and produce devastating neurologic disease. Keratitis, the most common ocular sign, is benign in developed countries. However, in less developed countries it represents a common cause of blindness. Moreover, over a million children die each year asa result of measles in underdeveloped countries. Vaccination provided by the World Health Organization may reduce this morbidity and mortality. SSPE, the late manifestation of measles infection, is a rare, fatal disease with high incidence of necrotizing retinitis. Regrettably, there is no definitive treatment for SSPE thus far, and the disease is almost universally fatal.

References 1. Centers for Disease Control and Prevention: Case definitions for public health surveillance. MMWR 1990;39(no. RR-13):1-43. 2. Wilson GS: Measles as a universal disease. Am J Dis Child 1962;103:219-223. 3. Katz SL, Enders JF: Measles virus. In: Horsfal1YFL Jr, Tamm T, eds: Viral and Rickettsial Infections of Man, Philadelphia, lB. Lippincott, 1965, pp 784-801. 4. Caulfield E: Early measles epidemics in America. Yale J BioI Med 1943;15:531-536. 5. Panum PL: Observations made during the epidemic of measles on Faroe Island in the year 1846. Med Classics 1939;3:829-886. 6. Home F: Medical facts and experiments. London, A. Millar, 1759. 7. Koplik H: The diagnosis of the invasion of measles from a study of the exanthema as it appears on the buccal mucous membrane. Arch Pediatr 1896;13:918. 8. Koplik H: A new diagnostic sign of measles. Med Rec 1898;53:505. 9. Koplik H: The new diagnostic spots of measles on the buccal mucosa and labial mucous membrane. Med News 1899;74:673. 10. Enders JF, Peebles TC: Propagation in tissue cultures of cytopathogenic agents from patients with measles. Proc Soc Exp BioI Med 1954;86:277-286, 11. Krugman S: Present status of measles and rubella immunization in the United States: A medical progress report. J Pediatr 1971;78:116. 12. Gershon AA: Chickenpox, measles, and mumps, In: Remington JS, Klein JO, eds: Infectious diseases of the fetus and newborn infant. Philadelphia, WE Saunders, 1990, pp 395-:-445. 13. Centers for Disease Control. Measles-United States, 1990. MMWR 1991;40:369-372. 14. Eberhart-Phillips JE, Frederick PD, Baron RC, Mascola L: Measles in pregnancy: A descriptive study of 58 cases. Obstet Gynecol 1993;82:797-801. 15. Siegel M: Congenital malformations following chickenpox, measles, mumps, and hepatitis. Results of a cohort study. JAMA 1973;226:1521. 16. Metz HS, Harkey ME: Pigmentary retinopathy following maternal measles (morbilli) infection. Am J Ophthalmol 1968;66:1107. 17. Guzzinati GC: Sulla possibilita di lesioni oculari congenita da morbillo e da epatite epidemica. Boll Ocul (Italia) 1954;12:833-841. 18. Ray CG: Measles (rubeola). In: Thorn GW, et aI, eds: Harrison's Principles of Internal Medicine, 8th ed, vol. I. New York, McGrawHill Company, 1977. 19. Katz SL: Measles. In: Rudolph AM, Barnett HL, Einhord AH, eds: Pediatrics, 16th ed. New York, Appleton-Century-Crofts, 1977.

20. Collins SD, Wheeler RE, Shannon RD: Occurrence of whooping cough, chickenpox, mumps, measles, and German measles in 200,000 survey families in 28 large cities. Bethesda, Maryland, National Institute of Health, 1943. 21. Hinman AR, Brandling-Bennett AD, Nieburg PI: The opportunity and obligation to eliminate measles from the United States. JAMA 1979;242:1157-1162. 22. Hinman AR, Brandling-Bennett AD, Bernier RH, et al: Current features of measles in the United States. Epidemiol Rev 1980;2:153. 23. Measles-United States, 1977-1980. MMWR 1980;29:598-599. 24. Hinman AR, Eddings DL, Kirby CD, et al: Progress in measles elimination. JAMA 1982;247:1592-1595. 25. Bergstrom TJ: Measles infection of the eye. In Darrell RW (ed): Viral Diseases of the Eye. Philadelphia, Lea & Febiger, 1985, p 233. 26. Fedukowicz HB: Measles. In: External Infections of the Eye. 2nd ed. New York, Appleton-Century-Crofts, 1978, pp 214-216. 27. Hiles DA, Cignetti FE: Measles. In: Harley RD, ed: Pediatric Ophthalmology. Philadelphia, W.B. Saunders Company, 1975, p 683. 28. Deckard PS, Bergstrom TJ: Rubeola keratitis. Ophthalmology 1981;88:812-813. 29. Thygeson P: Ocular viral diseases. Med Clin North Am 1959;43:1419-1440. 30. Dekkers NWHM: The cornea in measles. In: Darrell RW (ed): Viral Diseases of the Eye. Philadelphia, Lea & Febiger, 1985, p 239. 31. Florman AL, Agatston HJ: Keratoconjunctivitis as a diagnostic aid in measles. JAMA 1962;179:568-570. 32. Doggart JG: Superficial punctate keratitis. Br J Ophthalmol 1933;17:65-82. 33. Scheie HG, Morse PH: Rubeola retinopathy. Arch Ophthalmol 1972;88:341-344. 34. Foxman SG, Heckenlively JR, Sinclair SH: Rubeola retinopathy and pigmented paravenous retinochoroidal atrophy. Am J Ophthalmol 1985;99:605-606. 35. Dawson CR: How does the external eye resist infection? (Editorial.) Invest Ophthalmol 1976;15:971-974. 36. Morgan EM, Papp F: Measles virus and its associated diseases. Bacteriol Rev 1977;41:636-666. 37. Scheifele DW, Forbes CE: The biology of measles in Mrican children. EastMr MedJ 1973;50:169-173. 38. Kaplan LJ, Daum RS, Smaron M: Severe measles in immunocompromised patient. JAMA 1992;267:1237-1241. 39. Immunization Practices Advisory Committee: Measles prevention. MMWR 1982;31:217-224, 229-231. 40. Krugman RD, Rosenberg R, McIntosh K, et al: Further attenuated live measles vaccines: The need for revised recommendations. J Pediatr 1977;91:766-767. 41. Barclay AJ, Foster A, Sommer A: Vitamin A supplements and mortality related to measles: randomized clinical trial. Br Med J 1987;294:294-296. 42. Cherry JD: Measles. In Feigin RD, Cherry JD, eds:· Textbook of pediatric infectious diseases, Vol II. Philadelphia, W.B. Saunders Co, 1992, p 1591. 43, Frederique G, Howard RO, Boniuk V: Corneal ulcers in rubeola. AmJ Ophthalmol 1969;68:996-1003. 44. Sandorf-Smith JH, Whittle HC: Corneal ulceration following measles in Nigerian children. Br J Ophtl1almol 1979;63:720-724. 45. Morley D: Severe measles in the tropics. Br Med J 1969;1:297. 46. Chirambo MC, Benezra D: Causes of blindness in students in blind school institutions in a developing country. Br J Ophthalmol 1976; 60:665. 47. Foster A, Sommer A: Corneal ulceration, measles, and childhood blindness in Tanzania. Br J Ophthalmol 1987;71:331. 48. Dawson JR Jr: Cellular inclusions in cerebral lesions of letl1argic encephalitis. AmJ Patl101 1933;9:7. 49. ModlinJF, Halsey NA, Eddins DL, et al: Epidemiology of subacute sclerosing panencephalitis. J Pediatr 1979;94:231. 50. Dyken. PR: Subacute sclerosing panencephalitis. Neurol Clin 1985;3:179. 51. Sussman J, Compston DAS: Subanlte sclerosing panencephalitis in Wales. QJ Med 1994;87:23. 52. Park DW, Boldt C, Massicotte SJ, et al: Subacute sclerosing panencephalitis manifesting as viral retinitis: clinical and histopathologic findings. AmJ Ophthalmol 1997;123:533. 53. Salmon JF, Pan EL, Murray AND: Visual loss with dancing extremities and mental disturbances. Surv Ophtl1almol 1991;35:299.

CHAPTER 26: MEASLES 54. Morgan B, Cohen DN, Rothner AD, et £11: Ocular manifestations of subacute sclerosing panencephalitis. AmJ Dis Child 1976;130:1019. 55. Robb RM, Watters GV: Ophthalmic manifestation of subacute sclerosing panencephalitis. Arch Ophthalmol 1970;83:426. 56. Hiatt RL, GrizzardHT, McNeer P, Jabbour JT: Ophthalmologic manifestations of subacute sclerosing panencephalitis (Dawson encephalitis). Trans Am Acad Ophthalmol Otolaryngol1971;75:344. 57. Zagami AS, Lethlean AK: Chorioretinitis as a possible very early manifestation of subacute sclerosing panencephalitis. Aust N Z J Med 1991;21:350. 58. DeLaey lJ, Hanssens M, Colette P, et £11: Subacute sclerosing panencephalitis: Fundus changes and histopathologic correlations. Doc Ophthalmol 1983;56:11. 59. Kovacs B, Vastag 0: Fluoroangiographic picture of the acute stage of the retinal lesion in subacute sclerosing panencephalitis. Ophthalmologica 1978;177:264. 60. Landers MB, Klintworth GK: Subacute sclerosing panencephalitis (SSPE). Arch Ophthalmol 1971;86:156. 61. Meyers E, Mailin M, Zonis S: Subacute sclerosing panencephalitis: Clinicopathological study of the eyes. J Pediatr Ophthalmol Strabismus 1978;15:19. 62. Nelson DA, Weiner A, Yanoff M, et £11: Retinal lesions in subacute sclerosing panencephalitis. Arch Ophthalmol 1970;84:613. 63. Otradovec J: Chorioretinitis centralis bei leucoencephalitis subacuta sclerotisans Van Bogaert. Ophthalmologica 1963;146:65. 64. Brudet-Wickel CLM, Hogweg M, DeWolf-Rouendaal D: Subacute sclerosing panencephalitis (SSPE). Doc Ophthalmol 1982;52:241. 65. Grayina RF, Nakarishi AS, Faden A: Subacute sclerosing panencephalitis. AmJ Ophthalmol 1978;86:106. 66. Font RL,jenis EH, Truck KD: Measles maculopathy associated with subacute sclerosing panencephalitis. Arch Pathol 1973;96:168. 67. LaPiana FG, Tso MOM, Jenis EH: The retinal lesions of subacute sclerosing panencephalitis. Ann Ophthalmol 1974;6:603. 68. Raymond LA, Kerstine RS, Shelburne SA: Praeretinal vitreous membrane in subacute sclerosing panencephalitis. Arch Ophthalmol 1976;94:1412. 69. Cattaneo R, Schmid A, Rebmann9G, et al: Accumulated measles virus mutations in a case of subacute sclerosing panencephalitis: Interrupted matrix protein reading frame and transcription alteration. Virology 1986;154:97. 70. Choppin PW: Measles virus and chronic neurological diseases. Ann Neurol 1981;9:17. 71. Hall WW, Lamb RA, Choppin PW: Measles and SSPE virus protein: Lack of antibodies to the M protein in patients with subacute sclerosing panencephalitis. Proc Natl Acad Sci USA 1979;76:2047. 72. Johnson KP, Norrby E, Swoveland P, et £11: Experimental subacute sclerosing panencephalitis: Selective disappearance of measles virus

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Erik Letko and C. Stephen Foster

Rubella is an acute, contagious, exanthematous disease caused by rubella virus.

HISTORY Two German physicians, De Bergen (in 1752),1 and Orlow (in 1758) ,2 provided the first clinical descriptions of rubella, calling the disorder Rotheln. The disease became known as German Measles in English speaking countries. A Scottish physician, Veale, used the name rubella for the first time in 1866. 3 In 1941, an Australian ophthalmologist, Gregg, noticed congenital defects in babies of mothers who contracted rubella during pregnancy.4 However, Gregg cited Mitchell, who first observed retinopathy in congenital rubella. Hiro and Tasaka in 1938 showed that rubella was caused by a virus. 5 The isolation of the virus in 1962 by Weller and Neva6 enabled vaccine development. Since 1969, live attenuated rubella vaccine has been available in the United States. 7

CONGENITAL RUBELLA

Epidemiology Epidemiologic data on congenital rubella had not been reported until 1966 when The National Register for Congenital Rubella was established. It is clear that the incidence rate depends on the month of the mother's pregnancy in which maternal infection occurs, as well as on the presence or absence of epidemics in each year. Thirtysix percent of maternal rubella between the 1st and 8th week of pregnancy ended in abortion or stillbirth, and 25% had gross fetal anomalies. 8 Fifty-two percent of the instances of maternal rubella occurring between 9th and 12th week resulted in the birth of babies with congenital defects, whereas the rate fell to 16% if the mother had become infected between 13 and 20 weeks of gestation. There were no such congenital defects reported if the maternal infection occurred after week 20 of pregnancy.8 In another study, a risk of 3% malformations and 4% stillbirth has been estimated if maternal rubella infection is contracted after 12 weeks of pregnancy.9

Clinical Characteristics The classic features of congenital rubella syndrome are manifested by hearing, ocular, and cardiac defects. 4, 10 However, anomalies may be present in other organ systems. l l Congenital malformations, including ocular anomalies associated with congenital rubella syndrome, can be present at birth, shortly after birth, or later in life. 12 , 13 The overall incidence of ocular anomalies is 30% to 78% (Table 27-1). Bilateral or unilateral deafness, the most common symptom, is present in 80% to 90% of infants with congenital rubella. Cataracts and microphthalmia are the most frequent cause of poor visual acuity.14 Patients with congenital rubella are at higher risk for developing diabetes and subsequent diabetic retinopathy.15

Pigmentary retinopathy, described as "salt and pepper," is one of the most common ocular manifestations of congenital rubella (Fig. 27-1). It usually remains stable throughout life, but in some patients, the retinopathy may become progressive and cause continual tissue destruction and scarring (Fig. 27-2) .16 Moreover, some eyes may develop pigmentary retinopathy later in lifeY The visual acuity in eyes with congenital rubella pigmentary retinopathy in the absence of other ocular symptoms is usually but not always good, with visual acuity as poor as 20/200 having been reported. 16 Subretinal neovascularization in the absence of a rupture of Bruch's membrane is a complication of pigmentary retinopathy. The neovascularization develops later in life and can cause either sudden loss of vision as a consequence of subretinal hemorrhage or gradual vision impairment due to disciform scarring in the macula. 18- 21 The electroretinogram (ERG) in such eyes remains normal. 22 Keratic precipitates are reported in eyes with cataracts after either cataract extraction or cataract resorption. Patients with congenital cataracts associated with congenital rubella syndrome may have an increased inflammatory response after cataract surgery, probably as a consequence of the virus persistence in the cataractous lens. 23

Pathophysiology, Immunology, Pathology, and Pathogenesis Fetal infection can develop by the ascending route from cervix as well as by primary placental infection. 24 , 25 Only newborns with congenital rubella syndrome who had ex-

TABLE 27-1. OCULAR MANifESTATIONS Of CONGENITAL RUBELLA SYMPTOM

Retinopathy Cataract Strabismus Nystagmus Microphthalmia Amblyopia Glaucoma Buphthalmos Lid defects Persistent hyaloid artery Iris coloboma Iris atrophy Optic atrophy Corneal haze Phthisis bulbi Dacryostenosis Keratoconus Keratic precipitates Aphakia Any eye disease

INCIDENCE (%)

REFERENCE

9-88 16-85 9-60 13-44 10-63 1-16 2-25

38, 62, 64, 68 38,69 61,69 38, 64 38, 69 14, 38 60 38 38 38 14, 64 38 14,38 38, 64 38 14,38,64 59 23 67,72 14,60, 65

11

10 9 1-5 7 4-9 1-25 7 2-5 rare rare rare

30-78

Adapted from Givens KT, Lee DA, Jones T, Ilstrup DM: Congenital rubella syndrome: Ophthalmic manifestations and associated systemic disorders. Br J Ophthalmol 1993;77:358-363.

CHAPTER 27: RUBELLA

FIGURE 27-1. A typical "salt-and-pepper" pigmentary mottling in congenital rubella. (Reprinted from Orth DR, Fishman GA, Segall M, et al: Rubella maculopathy. Br J Ophthalmol 1980;64:201-205, Fig. 3a, with permission of the editor.)

perienced rubella infection during the first 12 weeks of gestation showed significantly reduced levels of antibodies directed to both the E1 and E2 rubella virus epitopes. Asymptomatic newborns infected later than week 10 of gestation have normal levels of antibodies. 26 Rubella virus can persist in infants with congenital rubella as long as 4.5 years after their birth. 27 Defects in congenital rubella result from both specific cell damage and generalized vascular damage resulting in mitoti& arrest and reduction; that is, cellular necrosis and cellular deficiency with reduction in number of cells in organs. Disturbance of organogenesis, particularly in the first 16 weeks of pregnancy, and tissue destruction and scarring are the consequences of fetal rubella infection. 28-3o Termination of susceptibility in the second trimester is consistent with development of the fetal immune response and increased transfer of maternal IgG.30 The pathogenesis of rubella embryopathy has not been elucidated on a cellular level, but it is thought that the virus inhibits the cellular multiplication together with the establishment of persistent infection during organogenesis. Multiple organ damage is manifested shortly after the birth, but delayed manifestations several months or years later in life are reported as well. 24 A spectrum of delayed manifestations of congenital rubella is described in the literature. 23 , 29 Chronic persistence of the virus with extension of the infection, growth of the virus resulting in reduced growth rate and shortened lifespan of body cells, autoimmune response, genetic susceptibility, vascular damage by virus, and reactive hypervascularization are hypothesized to explain this phenomenon as well. 24 , 30 At autopsy, rubella virus has been isolated from clear lens of infants with congenital rubella syndrOlue 31 and from cataractous lens as late as 35 months of age. 32 Focal necrosis of the ciliary epithelium, pars plicata, and pars plana is considered to be characteristic of ocular rubella. 33 The histopathology of the iris stroma reveals atrophy, hypoplasia or absence of the dilator muscle and hypoplasia of the sphincter muscle of the iris, and vacuolization and focal necrosis of the pigment epithelium of the iris and ciliary body.33, 34 The absence of inflammatory

response suggests that these changes occur before the development of an immune response in the fetus. However, the presence of a nongranulomatous uveitis with lYJ-uphocytic infiltration of the anterior uvea, plasma cells, and histiocytes suggests that such changes must occur in later fetal life or in the early neonatal peliod. 35-36 The presence of pigment on the anterior lens capsule may further support this hypothesis. 20 A clinical correlation of active iritis has been described in one report. 37 Pigmentary retinopathy is indeed confined to the pigment epithelium and does not involve the neurosensory retina or underlying choroids capillaries. At histopathology, it is present as an uneven distribution of pigment in the cells of the retinal pigment epithelium. However, in later fetal life and in infancy, the underlying choroid may be infiltrated with lymphocytes, suggesting an inflammatory response. 38

Diagnosis The diagnosis of congenital rubella is made by the presence of maternal rubella infection and congenital anomalies. Detection of serum IgM antibodies to rubella is a useful diagnostic tool in children with anomalies from uneventful pregnancies. 39 Viral isolation from the nose, throat, urine, buffy coat of the blood, or cerebrospinal fluid is the best· method to prove congenital rubella. Monitoring the IgM antibodies after the birth can be helpful in questionable cases. If the level of IgM antibodies does not drop four- to eightfold by the age of 3 months and continues to fall to nondetectable levels, congenital rubella can be confirmed. Fluorescein angiography of the retina in patients with pigmentary retinopathy associated with congenital rubella reveals both hyperfluorescent and hypofluorescent areas due to the diffuse pigment epithelial mottling. The early venous stage of the fluorescein angiogram may show new vessels replete with discrete hyperfluorescence in the presence of subretinal neovascularization with subsequent leakage in the later phase of the study. Accumulation of fluorescein is seen beneath pigment epithelium

FIGURE 27-2. Congenital rubella. Diffuse pigment epithelial mottling with "salt-and-pepper" appearance, and a yellowish disciform scar. (Reprinted from Orth DR, Fishman GA, Segall M, et al: Rubella maculopathy. Br J Ophthalmol 1980;64:201-205, Fig. 2a, with permission of the editor.)

CHAPTER 21: RUBELLA

in cases of hemorrhage pigment epithelial detachment complicating subretinal neovascularization. In the presence of a disciform scar, the early phase of fluorescein angiography shows a pigment epithelial window defect secondary to the fibrotic tissue, whereas the late phase reveals an increased hyperfluorescence due to staining of the scar. lS- 21 The ERG in patients with pigmentary retinopathy is normal. Slight abnormalities may be present if subretinal hemorrhage develops. IS

Treatment Immune globulin given to women susceptible to rubella infection in the first 20 weeks of pregnancy or within 72 hours after the exposure may prevent both maternal and congenital infection. Most infants with congenital rubella are actively infected at the time of birth, that is, they are contagious and, therefore, must be placed in isolation until the viral cultures become negative. The treatment of congenital anomalies is symptomatic. It is obviously important to examine "normal" children born to mothers with maternal rubella infection during the first several years after birth because of a possible late manifestation of congenital rubella. Increased inflammation after cataract surgery typically responds well to topical steroid therapy.23 Photocoagulation should be considered in patients with subretinal neovascularization.

Prognosis The prognosis depends on the severity of congenital malformations and potential progression later in life. If the subretinal neovascularization, particularly with subretinal hemorrhage develops, the patients usually suffer from permanent decrease of vision because of the subsequent disciform scarring in the macula. However, involution of subretinal hemorrhage without disciform scarring with full restoration of visual acuity has been also reported. 4o

children. Prodromes can occur in adolescents and adults 1 to 5 days before the onset· of the rash. 46 The rubella exanthem appears first on the face and then spreads toward the hands and feet. The erythematous and maculopapular exanthem involves the whole body in 24 hours and disappears by the third day. In some individuals, the skin rash is not present. Lymphadenopathy is a major clinical manifestation of rubella. The occurrence of fever is variable. Arthritis, encephalitis, and thrombocytopenic or nonthrombocytopenic purpura can complicate the course of acquired rubella infection. Ocular manifestations of acquired rubella include conjunctivitis, epithelial keratitis, and retinitis. Conjunctivitis, the most common ocular finding in· acquired rubella, is present in 70% of patients. Epithelial keratitis, reported in 7.6% of patients, resolves without sequelae within one week. 47 , 34 Retinitis is a rare complication of acquired rubella. 4s ,49 Decreased vision is the major symptom. On examination, optic media are clear, but cells in the anterior chamber may be present. The retinal findings include dark gray atrophic lesions of the retinal pigment epithelium, flat detachment of the retinal neuroepithelium at the posterior pole, and bullous and diffuse detachment of the retina. A case of bilateral optic neuritis diagnosed 3 weeks after measles,mumps, and rubella vaccination is described in the literature as well. 5o

Pathophysiology, Immunology, Pathology, and Pathogenesis

Rubella infection is caused by rubella virus from the Rubivirus genus of the family Togaviridae.31 Humans are the only known vertebrate hosts, although animals can be experimentally infected. 51 The rubella virion is spherical, with a diameter of 60 to 70 nm. The virion contains three major polypeptides-E1, E2, and C.52 E1 and E2 are located on the viral surface membrane, and C is located in the nucleocapsid along with the genomic ACQUIRED RUBELLA RNA.52 Specific viral antigens can be identified by hemagglutination-inhibition, complement-fixation, neutralizaEpidemiology Before the initiation of widespread vaccination programs, tion, immunofluorescence, radioimmunoassay, precipitarubella epidemics occurred in 6- to 9-year intervals, with tion, platelet aggregation, latex agglutination, and passive each cycle over a 3- to 4-year periodY After the introduc- hemagglutinationY Rubella infection is characterized by tion of rubella vaccine in the United States, there has the appearance of IgM, IgG, and IgA antibodies in the been no nationwide epidemic of rubella reported. In serum. The IgM antibodies persist no longer than 8 weeks closed populations such as families, military training cen- after the onset of the infection. The IgA antibodies are ters, and institutions for the mentally handicapped, the elevated in the case of natural rubella infection or nasal infection will occur in 100% of susceptible individuals. 42 immunization.53 Cellular immune response and circulatThe highest attack rate occurred in the 5- to 9-year-old ing virus-antibody immune complexes are believed to children in the prevaccine era. However, in the postvac- cause skin rash and arthritis. Life-long persistence of cellcine era, 50% of rubella infection was reported in persons mediated immunity without reinfection is reported. 54 The older than 19 years of age. The vaccination programs rubella-specific response is suppressed during pregfocus on children to prevent epidemics and on young nancy.55 The infection is spread by the respiratory route. 56, 57 women of childbearing age to prevent maternal and congenital rubella, respectively.43,44 Rubella is usually a winter Respiratory epithelium of the nasopharynx is the primary and spring disease, but sporadic infections occur through- . site of inoculation. The virus then spreads to the regional out the year in large urban areas. 45 lymph nodes. Replication occurs in both respiratory epithelium and in lymph nodes, followed by viremia. Rubella virus has been isolated from lymph nodes, urine, cerebroClinical Characteristics The incubation period for acquired infection is 14 to 21 spinal fluid, conjunctiva, breast milk, synovial fluid, lung, days. Skin rash is the first sign of rubella infection in and skin at sites where rash was both present and absent. l l

CHAPTER 27: RUBELLA

Diagnosis The diagnosis of rubella can be difficult, because in some cases, there is a lack of pathognomonic findings. However, rubella usually occurs in epidemics, which makes the diagnosis easier. The rubella infection can be definitely confirmed by virus isolation or by serologic tests in uncertain cases. Fluorescein angiogram in patients with retinitis associated with acquired rubella infection shows hyperfluorescent areas with no leakage from the retinal vessels.

Treatment Treatment in patients with uncomplicated acquired rubella infection is symptomatic. The rubella retinitis and postvaccination optic neuritis respond well to systemic steroids.49, 50

Complications The course of acquired rubella can be complicated by arthritis, encephalitis, and thrombocytopenic purpura. l1 Persistent scotoma following optic neuritis after measles, mumps, and rubella vaccination is described in the literature. 50

Prognosis The prognosis in acquired rubella is excellent unless encephalitis or thrombocytopenic purpura develop. The retinitis typically resolves, leaving retinal pigment epithelial damage. The visual acuity usuaH¥ improves but does not always return to normal in each eye. 48 ,49 Rapid improvement of visual acuities is reported after optic neuritis following measles, mumps, and rubella vaccination. 50

CONCLUSIONS Maternal rubella is likely to cause damage to the fetus. Ocular manifestation and hearing loss are the most common manifestations of congenital rubella. Because of a potential progression or development of new symptoms, congenital rubella should be considered as a chronic disease capable of progressive damage, and patients with the disorder should be monitored regularly. Acquired rubella is usually harmless to the eye, although retinitis (rare), may affect vision. The diagnosis should be considered in patients with recent rubella infection who develop uveitis.

References 1. Griffith JPC: Rubella (Rotheln: German measles). With a report of one hundred and fifty cases. Medical Record 1887;32:11-41. 2. Wesselhoeft C: Rubella (German measles). N Engl J Med 1947;236:943-950, 978-988. 3. Veale H: History of an epidemic of Rotheln, with observations on this pathology. Edinb MedJ 1866;12:404-414. 4. Gregg NM: Congenital cataract following German measles in the mother. Transactions of the Ophthalmological Society of Austria 1941 ;3:35-46. 5. Hiro VY, Tasaka S: Die Rotheln sind eine Viruskrankenheit. Monattsschr Kinderheilk 1938;76:328-332. 6. Weller TH, Neva F: Propagation in tissue culture of cytopathic agents from patients with rubella-like illness. Proc Soc Exp BioI Med 1962;111:215-225. 7. Meyer HM, Hopps HE, Parkman PD, et al: Control of measles and rubella through use of attenuated vaccines. Am J Clin Pathol 1978;70:128.

8. Sallomi SJ: Rubella in pregnancy. A review of prospective studies from the literature. Obstet Gynecol 1966;27:252-256. 9. Cockburn WC: World aspects of the epidemiology of rubella. Am J Dis Child 1969;118:112. 10. Gregg NM: Further observations on congenital defects in infants following maternal rubella. Transactions of the Ophthalmological Society of Austria 1944; 4:119-125. 11. Cherry JD: Rubella virus. In: Feigin RD, Cherry JD, eds: Textbook of Pediatric Infectious Diseases, Vol II. Philadelphia, W.B. Saunders, 1992, pp 1922-1949. 12. Hancock MT, Huntley CC, Sever JL: Congenital rubella syndrome with immunoglobulin disorder. J Pediatr 1968;72:636-645. 13. Murphy AM, Reid RR, Pollard I, et al: Rubella cataracts. Further clinical and virologic observations. AmJ OphtllalmoI1967;64:11091119. 14. Givens KT, Lee DA, Jones T, Ilstrup DM: Congenital rubella syndrome: Ophtllalmic manifestations and associated systemic disorders. Br J Ophthalmol 1993;77:358-363. 15. Menser MA, Dods L, Harley JD: A twenty-five year follow-up of congenital rubella. Lancet 1967;ii:1347-1350. 16. Collis VB, Cohen DN: Rubella retinopathy: A progressive disorder. Arch Ophthalmol 1970;84:33-35. 17. Wolff SM: Ocular aspects of congenital rubella. In: Ryan SJ, Smith RE, eds: Selective Topics on the Eye in Systemic Disease. New York, Grune and Stratton, 1974, p 205. 18. Deutman AF, Grizzard WS: Rubella retinopathy and subretinal neovascularization. Am J Ophtllalmol 1978;85:82. 19. Frank KE, Purnell EW: Subretinal neovascularization following rubella retinopatlly. AmJ OphthalmoI1978;86:462. 20. Ortll DH, Fishman GA, Segall M, et al: Rubella maculopathy. Br J Ophthalmol 1980;64:201-205. 21. Slusher MM, Tyler ME: Rubella retinopathy and subretinal neovascularization. AmJ Ophthalmol 1982;14:292. 22. Krill AE: The retinal disease of rubella. Arch Ophthalmol 1967;77:445-449. 23. Boger WP: Late ocular manifestation in congenital rubella syndrome. Ophthalmology 1980;87:1244-1252. 24. Sever JL, SOUdl MA, Shaver KA: Delayed manifestations of congenital rubella. Rev Infect Dis 1985;7:S164. 25. Vaheri A, Vesikari T, Oker-Blom N, et al: Isolation of attenuated rubella-vaccine virus from human products of conception and uterine cervix. N EnglJ Med 1972;286:1071-1074. 26. Meitsch K, Enders G, Wolinsky JS, et al: The role of rubella-immunoblot and rubella-peptide-EIA for the diagnosis of the congenital rubella syndrome during the prenatal and newborn periods. J Med Virol 1997;51:280. 27. Shewmon DA, Cherry JD, Kirby SE: Shedding of rubella virus in a 4 1/2-year-old boy witll congenital rubella syndrome. Pediatr Infect Dis 1982;Sep-Oct:342-343. 28. Atreya CD, Lee NS, Forng RY: The rubella virus putative replicase interacts with the retinoblastoma tumor suppressor protein. Virus Genes 1998;16:177. 29. South MA, Sever JL: Teratogen update: The congenital rubella syndrome. Teratology 1985;31:297-307. 30. Webster WS: Teratogen update: Congenital rubella. Teratology 1998;58:13. 31. Bellanti JA, Artenstein MS, Olson LC, et al: Congenital rubella: Clinicopathologic, virologic and immunologic studies. Am J Dis Child 1965;110:464. 32. Menser MA, Harley JD, Hertzberg R, et al: Persistence of virus in lens for three years after prenatal rubella. Lancet 1967;2:387-388. 33. Boniuk M, Zimmerman LE: Ocular pathology in the rubella syndrome. Arch Ophthalmol 1967;77:455. 34. Zimmerman LE: Histopathologic basis for ocular manifestations of congenital rubella syndrome. AmJ Ophthalmol 1968;65:837. 35. Yanoff M, Schaefer DB, Scheie HG: Rubella ocular syndrome: Clinical significance of viral and pathological studies. Transactions of the American Academy of Ophthalmology and Otolaryngology 1968;122:1049. 36. Zimmerman LE, Font RL: Congenital malformations of the eye: Some recent advances in the knowledge of the pathogenesis and histopathological characteristics. JAMA 1966;196:684. 37. Krause AC: Congenital cataracts following rubella in pregnancy. Ann Surg 1945;122:1049. 38. Wolff SM: The ocular manifestations of congenital rubella. A pro-

CHAPTER 27: RUBELLA

39.

40.

41.

42.

43. 44.

45.

46. 47. 48. 49. 50.

51.

52.

53.

54.

spective study of 328 cases of congenital rubella.] Pediatr Ophthalmol 1973;10:101-141. Stiehm ER, Ammann A], Cherry]D: Elevated cord macroglobulins in the diagnosis of intrauterine infections. N Engl ] Med 1966;275:971-977. Bonomo PP: Involution without disciform scarring of subretinal neovascularization in presumed rubella retinopathy. A case report. Acta Ophthalmol 1982;60:141. Horstman DM: Rubella. In: Evans AS, ed: Viral Infections of Humans: Epidemiology and Control, 3rd ed. New York, Plenum Medical Book Company, 1990, pp 617-631. Horstman DM, Liebhaber H, LeBouvier GL, et al: Rubella: Reinfection of vaccinated and naturally immune persons exposed in an epidemic. N Engl] Med 1970;283:771-778. National Communicable Disease Center: Rubella Surveillance. Atlanta, GA, Centers for Disease Control, 1969. Hambling MH: Effect of a vaccination programme on the distribution of rubella antibodies in women of childbearing age. Lancet 1975;1:1130-1138. Communicable Disease Center: Provisional Information in Selected Notifiable Diseases in the United States and on Deaths in Selected Cities for Week Ended September 3,1964. MMWR 1964;13:349-360. Gross PA; Portnoy B, Mathies AW ]1', et al: A rubella outbreak among adolescent boys. Am] Dis Child 1970;119:326. Matoba A: Ocular viral infections. Pediatr Infect Dis 1984;3:358368. Gerstle C, Zim KM: Rubella-associated retinitis in adult. Report of a case. Mt Sinai] Med 1976;43:303. Hayashi M, Yoshimura N, Kondo T: Acute rubella retinal pigment epithelitis in an adult. Am] Ophthalmol 1982;93:285-288. Kazarian EL, Gager WE: Optic neuritis complicating measles, mumps, and rubella vaccination. Am] Ophthalmol 1978;86:544547. Plotkin SA: Rubella virus. In: Lenette EH, Schmidt]H, eds: Diagnostic Procedures for Viral and Rickettsial Infections. New York, American Public Healtll Association, 1969'¥p 364. Pettersen RF, Oker-Blom C, Kalkklnen N, et al: Molecular and antigenic characteristics and synthesis of rubella virus structural proteins. Rev Infect Dis 1985;7:S140. Ogra PL, Kerr-Grant D, Umana G, et al: Antibody response in serum and nasopharynx after naturally acquired and vaccine-induced infection witll rubella virus. N Engl] Med 1971 ;285: 1333. RossieI' E, Phipps PH, Weber ]M, et al: Persistence of humoral and

55.

56. 57. 58.

59.

60. 61. 62. 63.

64. 65.

66.

67. 68. 69. 70. 71. 72.

cell-mediated immunity to rubella virus in cloistered nuns and in schoolteachers.] Infect Dis 1981;144:137. Thong YH, Steele RW, Vincent MM, et al: Impaired in vitro cellmediated immunity to rubella virus during pregnancy. N Engl ] Med 1973;289:604. Green RH, Balsamo MR, Gilles ]P, et al: Studies of the natural history and prevention of rubella. Am] Dis Child 1965;110:348-365. Heggie AD, Robins FC: Natural rubella acquired after birth. Clinical features and complications. Am] Dis Child 1969;118:12-17. ArnoldlJ, McIntosh EDG, Martin F], Menser MA: A fifty-year followup of ocular defects in congenital rubella: Late ocular manifestations. Aust N Z] Ophyhalmol 1994;22:1. Boger WP, Petersen RA, Robb RM: Keratoconus and acute hydrops in mentally retarded patients with congenital rubella syndrome. Am ] Opthalmol 1981;91:213-223. Boniuk M: Glaucoma in the congenital rubella syndrome. Int Ophthalmol Clin 1972;12:121. Boniuk V: Systemic and ocular manifestations of the rubella syndrome. Int Ophthalmol Clin 1972;12:67. Boniuk V: Rubella. Int Ophthalmol Clin 1975;15:229. Fenner F: Classification and nomenclature of viruses. Second report of the International Committee on Taxonomy of Viruses. Intervirology 1976;7:1-115. Geltzer AI, Guber D, Sears ML: Ocular manifestations of the 19641965 rubella epidemic. Am] Ophthalmol 1967;63:221. Harley RD: Discussion comments in: Boniuk V, Boniuk M. The prevalence of phthisis bulbi as a complication of cataract surgery in tlle congenital rubella syndrome. Transactions of tlle American Academy of Ophthalmology and Otolaryngology 1970;74:360. Heggie AD: Pathogenesis of the rubella exanthem: Distribution of rubella virus in tlle skin during rubella with and without rash. ] Infect Dis 1978;134:74-77. Johnson BL, Cheng KP: Congenital aphakia: A clinicopathologic report of three cases.] Pediatr Ophthalmol Strabismus 1997;34:35, Krill AE: Retinopathy secondary to rubella. Int Ophthalmol Clin 1972;12:89. O'Neill ]F: Strabismus in congenital rubella. Arch Ophthalmol 1967;77:450. Seppala M, Vaheri A: Natural rubella infection of the female genital tract. Lancet 1974;1:46-47. Wolter]R, Insel PA, Arbor A, et al: Eye patllOlogy following maternal rubella.] Pediatr Ophthalmol 1966; 3:29. Wolter ]R, Hall RC, Masson GL: Unilateral primary congenital aphakia. Am] Ophthalmol 1964; 58:1011.

I Gurinder Singh

DEFINITION An ocular syndrome of macular scar, peripheral punchedout chorioretinal scars ("histo spots"), and pigmented peripapillary degeneration with clear vitreous is presumed to be associated with the fungus Histoplasma capsulatum, thereby its name, presumed ocular histoplasmosis syndrome (POHS). Accruing epidemiologic and immunologic evidence has supported the association of these ocular manifestations with systemic infection by this fungus. Still, the definite pathogenesis has eluded scientists. It appears to result from a complex and ill-defined interaction of the fungal pathogen and the body's immune reaction to it, presenting in a specific pattern in certain endemic areas in the United States. Systemic fungal infection by H. capsulatum is seen worldwide, but the ocular presentation in the form of POHS was thought to be a phenomenon seen only in certain parts of the United States. More recently, POHS has been reported in England and in Europe, where it is clinically indistinguishable from that seen in the United States, albeit with negative skin testing. POHS, also called presumed ocular;,.histoplasmosis or simply ocular histoplasmosis, is a distinct entity, distinguished from the exudative/productive H. capsulatum infection of ocular tissues that is part of disseminated histoplasmosis. The latter is a rare disease of infants with immature immune systems, of immunosuppressed adults, and, even more rarely, of adults without any known immune deficiency.l, 2 Systemic disseminated histoplasmosis can luanifest in three major forms: (1) mild influenza-like respiratory symptoms with fever, malaise, and fatigue; (2) acute progressive life-threatening disease; and (3) chronic granulomatous disease mimicking tuberculosis. The ocular manifestations in systemic disseminated histoplasmosis can include retinitis, optic neuritis, and uveitis. 3 It can present as panuveitis, vitl-itis, iritis, focal retinitis, and severe endophthalmitis. 4 It may even occur as an exogenous infection after intraocular surgery.5 H. capsulatum has been cultured and identified histopathologically from ocular tissue of patients with ocular involvement in disseminated histoplasmosis 6-9 but not in POHSI0 (as discussed later). This chapter will be limited to POHS without further elaboration on the ocular manifestations of disseminated systemic histoplasmosis.

HISTORY The first to identify an H. capsulatum infection was Darling, at the autopsy of a patient in 1906. 11 , 12 In 1942, Reid and colleagues 13 published the ocular findings in a patient dying of acute disseminated histoplasmosis. In 1951, Krause and Hopkins 14 reported a case of hemorrhagic retinitis and exudative chorioretinitis, which flared up with the histoplasmin skin test. On reviewing this case

report, SchlaegeP5 hypothesized that the choroiditis was probably associated with histoplasmosis. However, Woods and Wahlen16 were the first to describe an ocular syndrome of disciform macular detachment and peripheral chorioretinal scars in otherwise healthy adults. Schlaegel and Kenney17 added peripapillary atrophy and pigment changes to the features described by Woods and Wahlen, completing the classic triad of what we now know as POHS.

MYCOLOGY The causative organism H. capsulatum is a dimorphic fungus belonging to the class Ascomycetes. 1s It grows in the soil in the mycelial (mold) phase and inside animals or birds in the yeast phase. Primary histoplasmosis infection occurs typically by inhaling either microconidia (small spores), macroconidia (large spores), or mycelial (hyphae) fragments. These fragments penetrate the lungs but get entrapped in reticuloendothelial cells. An inflammatory reaction heals the infection and leaves small calcified lesions in lungs, liver, spleen, and lymph nodes that can be seen on radiologic examination. 19

EPIDEMIOLOGY

Geographic Distribution Systemic histoplasmosis is a worldwide phenomenon occuring between 45° north and 45° south of the equator. The mycelial form of this fungus grows in the upper 2 inches of the soil, fertilized by droppings of birds, chicken, and bats, along the rivers of central and southeastern United States, Central and South America, Asia, Italy, Turkey, Israel, England, Australia, Japan, and Puerto Rico. 20 However, POHS has been described primarily in the endemic areas of the valleys of the Ohio and Mississippi rivers (including Indiana, Ohio, Illinois, Kentucky, Tennessee, and Mississippi), in mid-Atlantic states such as Maryland, and in the San Joaquin Valley of California.21 Ocular findings mimicking POHS have been reported in England, Europe, and the Northwestern United States where histoplasmosis is not endemic.22-25

Prevalence The prevalence of POHS in the United States has been reported to be 1.6% in Ohi0 26 and 2.6% in western Maryland. 21 In a study done in Ohi0 26 (in an institutionalized population of 1417 adults, including whites and blacks, men and women), the prevalence of ocular histoplasmosis was 1.6%. Over 50% of this population reacted positively to a histoplasmin skin test. All of those who had signs of ocular histoplasmosis either reacted positively to the skin test or had radiographic findings consistent with systemic histoplasmosis infection. Twenty-two of 842 residents of Walkersville, Maryland,21 had ocular histo spots, giving a prevalence rate of 2.6%. Davidorf and Anderson

CHAPTER 28: PRESUMED _""'....,11.._...,. HISTOPLASMOSIS

found the prevalence to be as high as 12.9% in an "Earth Day epidemic" in an endemic area. 27 POHS has a prevalence of 0.5% among the blind in endemic areas of Tennessee. 28

Incidence Little is known about the overall incidence of ocular histoplasmosis, even in endemic areas in the United States, because most of the lesions are asymptomatic. POHS causes significant central visual impairment in at least 2000 young and middle-aged adults in the United States each year. 29 It is estimated that 1 adult in 40,000 in Tennessee will become legally blind from untreated POHS-related maculopathy.28 In this endemic area, POHS has an annual incidence of 2.8% among the blind. 28

Age Vision-threatening disciform ocular histoplasmosis is a disease of young adults in their thirties and forties, significantly more common in the population from 30 to 39 years of age. It is thought that asymptomatic ocular involvement by histoplasmosis in the form of atrophic chorioretinal scars occurs in early life but remains undetected until it becomes symptomatic or is detected on a routine eye examination. The median age of 36 is considered the most reliable estimate. 3o Hawkins and Ganley,31 in an epidemiologic study conducted in Washington County, Maryland, determined that the IS-year risk of visual impairment and blindness appears to be higher among 'adults aged 30 years and older who have only peripheral atrophic scars of POHS than among individuals living in the same endemic community but without such scars.

Sex and Race Ocular histoplasmosis presenting as atrophic peripheral and/or monocular macular scars is seen equally in men and women and in blacks and whites. But the disciform macular type of histoplasmosis is more commonly seen in whites, and considerably less commonly in blacks,32, 33 and bilateral macular involvement is seen more frequently in men than in women. 34

Involvement of the Second Eye The incidence of the development of a symptomatic disciform lesion in the second eye is considerable. The reported annual incidence of ocular histoplasmosis in the second eye varies from 1.7%,35 to 2%,36 to 12%,37 based on 40, 25, and 105 patients followed for a mean of 13, 10, and 2 years, respectively, in young adults. Older adults who already have a disciform lesion in one eye because of POHS are at low risk of developing a disciform lesion in the fellow eye later in life. 31

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peripheral histo spots. Another antigen, HLA-DRw2, has been found to have some apparent association with disciform macular lesions40 as well as in patients with exclusively peripheral histo spotsY Both B7 38 ,39 and DRw2 40 are two to four times more common among patients with macular disciform lesions, and DRw2 40 is twice as common among patients with only peripheral histo spots than among control populations. It is hypothesized that expression of both the B7 and the DRw2 alleles may predispose patients to exudative maculopathy and macular scarring. Another interesting observation is that POHS in black patients with disciform lesions shows no B7 association but a strong correlation with DRw2when compared with control populations. 32 In a recent study, immunophenotyping in POHS-like retinopathy has revealed no significant preferential expression. 42 Analysis of the T-cell receptor variable region and HLA typing have failed to reveal any links. All lymphocyte markers were unremarkable, with the exception of CD38, which was significantly raised compared with controls. 42 A type of multifocal choroiditis with panuveitis mimics POHS25,43 and occurs in nonendemic areas of the United States. 25 The clinical features of this entity resemble those of POHS, but the immunologic responses to histoplasma antigen do not. 25 These findings suggest that POHS seen in endemic areas and POHS-like retinopathy seen in nonendemic areas probably have different etiologic origins and are two different entities. 22- 25

CLINICAL CHARACTERISTICS A triad of disseminated choroiditis (histo spots), maculopathy (macular chorioretinal or disciform scar), and peripapillary chorioretinal degenerative changes (atrophic and pigmentary changes) constitutes the classic syndrome of presumed ocular histoplasmosis. Another characteristic finding of "clear vitreous" has been added to the syndrome; that is, the disorder is not accompanied by inflammation resulting in inflammatory cells in the vitreous. This constellation of clinical findings that identifies POHS has remained essentially unchanged since its originaldescription. At present, the clinical appearance of POHS includes multiple, small, atrophic, punched-out chorioretinal scars in the mid periphery and posterior pole (the histo spots), linear peripheral atrophic tracks or streaks of such scars, and peripapillary chorioretinal degeneration with or without choroidal neovascularization (CNV) in the macula. These discrete focal lesions occur frequently in both eyes without anterior segment or vitreous inflammation. These findings in a white, 20 to 50 years of age, who has lived in or visited the histoplasmosis endemic areas of the United States, and who may be HLA-B7 positive (for macular disease) further support the diagnosis of POHS.44

Histocompatibility Antigens

Disseminated Choroiditis

Histocompatibility antigen analysis in POHS patients suggests a potential immunogenetic predisposition for development of histo spots and disciform macular lesions. Godfrey and colleagues 38 and Braley and associates 39 found an association of human leukocyte antigen (HLA)B7 with macular histoplasmosis lesions, with a relative risk of 11.8. There is no association of this antigen with

Disseminated choroiditis usually goes undetected because of its asymptomatic peripheral lesions. It manifests as mild choroidal inflammation that is self-limiting, and as it heals it leaves behind histo spots. Rarely, choroiditis can cause photopsia by irritating the contiguous rods and cones. In the active acute stage, choroiditis lesions appear as small, yellowish gray, raised spots, scattered in the

CHAPTER 28: PRESUMED OCULAR HISTOPLASMOSIS SYNDROME

periequatorial region or posterior to the equator. The overlying retina may have a slight ground-glass-like haze from tissue swelling. These lesions resemble, and should be differentiated from, the nodules of miliary tuberculosis, sarcoidosis, nocardiosis, coccidioidomycosis, and cryptococcosis.

Histo Spots Disseminated choroiditis produces the typical histo spots. These are small, circular, depigmented, and atrophic chorioretinal scars, measuring about 0.2 to 0.7 disc diameter in size, and they may have a pigment clump in the center. 30 On average, these number between four to eight per eye, but the range is from 0 to 70. In two thirds of the cases, these spots are bilateral and randomly distributed throughout the mid periphery and posterior to the equator of all quadrants of the fundus (Fig. 28-1A,B). This might suggest hematogenous dissemination of the fungus or its antigen to the eye, because the greater number of scars occurs in areas of greater blood supply.30 In the acute stage, a slight yellowish swelling of the choroid and overlying retina gives a ground-glass-like haze to the retina and produces ill-defined edges to the spots (Fig. 28-1 C). In the atrophic stage, the spots look punchedout, with sharp edges, round or oval in shape, and with slight depression of the retinal pigment epithelium and choroid (Fig. 28-1D). The atrophic changes make the underlying choroidal vessels infrequently visualized

through these spots. Similar-looking lesions have been reproduced in animal models after intravenous injection of H. capsulatum. 45 Based on their clinical photographic appearance, the histo spots have been classified as typical or atypica1. 46 Typical histo spots are atrophic lesions, representing the inactive scar lesion, that have distinct borders, a punchedout appearance, and a uniformly flat or excavated bottom (Fig. 28-1A and D). Atypical histo spots, representing the acute active lesions, are creamy yellow lesions (Fig. 28-1 C) that are hyperfluorescent on fluorescein angiograms, with less distinct borders and a slightly elevated rather than an excavated appearance. 46 It has been sug~ gested that atypical histo spots in the macula may be more likely sites of development of subsequent CNV than are typical punched-out atrophic scars. 46

linear Streaks In 5% of POHS patients, histo spots occur in the equatorial ocular region arranged in a linear pattern, or streaks, running parallel to the ora serrata. 47 ,48 This finding is a fourth sign of the syndrome. These streaks consist of hypopigmented and hyperpigmented, circumlinear, peripheral chorioretinal scars, which are clumps of histo spots arranged in linear fashion (Fig. 28-2). These streaks have also been seen in the multifocal choroiditis and panuveitis syndrome that can in some respects mimic POHS,43 and in pathologic myopia. 22 ,49

FIGURE 28-1. A, Color fundus photograph illustrating juxtafoveal punched-out typical "histo spot." B, Peripheral "histo spot" in the same eye. C, Ground-glass-like macular "atypical histo spot" with ill-defined edges. D, Multiple macular "histo spots" in another patient. (See Color insert.)

CHAPTER 28: PRESUMED OCULAR HISTOPLASMOSIS SYNDROME

FIGURE 28-2. Color fundus photograph illustrating a clump of histo spots arranged in linear fashion in peripheral retina to constitute linear streaks. (See Color insert.)

Peripapillary Chorioretinal Degeneration/ Choroiditis/Atrophic Scarring/Pigment Changes Peripapillary chorioretinal degeneration, pigment changes, and atrophic scarring, presumably caused by an underlying choroiditis, are frequent diagnostic findings in the majority of patients with POHS. An atrophic depigmented area surrounds a pigmented crescent around the optic nerve head (Fig. 28-3A t~ C). These are asymptomatic lesions that appear as enlarged blind spots on perimetry. Rarely, these lesions appear to be nodular and can harbor subretinal neovascular membranes. The subretinal CNV can spontaneously bleed (Fig. 28-3D). Resultant hemorrhagic episodes because of CNV make these lesions symptomatic in 11 % of POHS patients. The hemorrhage surrounds the disc in most cases. Occasionally, it is limited to the nasal or temporal side. Subretinal hemorrhage leads to a detachment of the sensory retina that may extend into the macula and cause loss of vision (Fig. 28-3D). Peripapillary chorioretinal degeneration is seen in both eyes in about 70% of patients wh'o have associated macular disease, and in an additional 15% of patients in only one eye. 50 Peripapillary degenerative and atrophic pigment changes are seen in only 18% to 28% of patients who have just the peripheral histo spots and no macular involvement. 3o

Clear Vitreous Presumed ocular histoplasmosis does not cause associated vitreous inflammation. Clear vitreous is an important and integral part of the clinical appearance of POHS.51 Only rarely are cells ever seen in either the anterior chamber or the vitreous humor. When vitreous cells are seen, other entities, such as multifocal choroiditis and panuveitis syndrome, should be considered.

Maculopathy Most patients with POHS are diagnosed incidentally and are asymptomatic. Although usually a benign syndrome, POHS becomes symptomatic because of recurrence or reactivation of macular lesions. The symptoms include

waviness or distortion of linear contours, metamorphopsia, macropsia, and micropsia. The symptoms are similar to those of age-related macular degeneration, ocular migraine, and central serous choroidopathy. Patients with POHS often can tell when a recurrence or reactivation is beginning, before the signs become manifest enough for the ophthalmologist to see them. CNV in the macula can cause a sudden, abrupt decrease in central vision if the underlying CNV pushes the retina upward because of blood, fluid, or lipid deposits, giving the retina a gray-green, ground-glass appearance. Before the introduction of fluorescein angiography, CNV could not be differentiated from retinal pigment epithelial detachment and central serous choroidopathy. Probably for that reason, retinal pigment epithelial (RPE) de,.. tachment and central serouschoroidopathy were reported in 7% and more frequent hemorrhagic macular lesions were reported in 63% of patients. 52 Rarely, it may have associated vitreous hemorrhage. 53 In POHS eyes, the patients with macular histo spots have a 1 in 4 chance of recurrence in the macula over the ensuing 3 years. However, if no macular histo spots are present, then the chances of recurrence in the macula are only about 1 in 50. 54 It seems that atypical histo spots are more prone to develop CNV than regular atrophic typical histo spotS. 46 Recurrence or reactivation of macular lesion leads to severe visual impairment in 60% of the involved eyes, and only 10% to 15% of eyes maintain 20/20 vision after a 2-year period. An asymptomatic macular lesion in POHS may occur as an atrophic punched-out pigmented scar similar to the regular histo spot (see Fig. 28-1A): But the more commonly seen lesion that causes debilitating visual loss is a raised, heaped-up fibrovascular scar, referred to as a disciform macular scar (Fig. 28-4). It develops as a result of hemorrhagic retinal detachment and CNV. At times, CNVis difficult to diagnose on biomicroscopic exam alone because of absence of hemorrhage or pigmentation. 55 Rarely, subretinal neovascularization leading to disciform scar has been seen in the absence of previous pigmentary changes. This denotes a nidus of activity56 and invisible foci of choroidal inflammation in this disorder.57 The active disciform lesions appear to arise at the edge of old lesions,33 producing recurrence or the reactivation of the old atrophic scars. Therefore, the development of a disciform macular lesion in the second eye depends on whether there are old atrophic macular histo scars or not. In the absence of macular scars, the risk of a symptomatic lesion in the fellow eye is less than 1% per year of follow-up.36, 58 Submacular neovascularization in POHS leads toexudative maculopathy and macular detachment or swelling that heals with disciform scarring in the macular area. Visual loss is secondary to these macular changes. It is estimated that 1 in 1000 adults in an endemic area has disciform macular scarring in one eye,21,54 and 1 in 10 affected patients has bilateral macular scarring54 from POHS. One third of the patients diagnosed as having POHS develop bilateral CNV or disciform lesions within 1 to 7 years of follow-up.59 According to one estimate, POHS causes significant visual impairment in at least 2000 young and middle-aged adults in the United States

CHAPTER 28: PRESUMED OCULAR HISTOPLASMOSIS SYNDROME

FIGURE 28-3. A, and B, Color fundus photographs illustrating bilateral peripapillary chorioretinal degeneration in POHS. C, Peripapillary chorioretinal degeneration in another patient. D, Peripapillary CNV causing subretinal hemorrhage extending into the macular area. (See Color insert.)

each year. 60 Untreated subretinal CNV within the foveal avascular zone leads to a final visual acuity of less than or equal to 20/200 in two thirds of patients. 61 The risk of developing a disciform macular lesion has been reported to be as high as 25% when the atrophic scars are present in the macular region. This risk is reported to be only 1 in 50 if no macular scars are noted in POBS. 59 It has been well documented that 50% to

70% of untreated eyes have significant central visual loss (i.e., a final visual acuity of 20/200 or worse).29, 62 About 10% to 16% of patients with macular CNV, who are under 30 years of age, who have small submacular membranes with small involvement of the foveal avascular zone, and who have no vision loss in the other eye retain good functional vision (i.e., 20/40 or better) .29,62 Overall, the eyes with POBS carry excellent visual prognosis, except for the ones with macular lesions. Asymptomatic eyes without any ophthalmoscopic or angiographic evidence of focal macular or paramacular chorioretinal scars carry an excellent visual prognosis in patient with POBS.33 The high risk of developing a neovascular membrane in the contralateral eye, at the rate of 8% to 24% over a 3-year petiod,63, 64 justifies periodic examination and Alnsler grid testing in patients with macular POBS lesions. De novo CNV can develop in areas without preexisting atrophic histo spots or pigmentary lesions. 56, 65-70 Even patients without pre-existing macular lesions have a certain risk of developing CNV.I0

Spontaneous Improvement of Visual Acuity FIGURE 28-4. Color fundus photograph illustrating disciform macular scar in POHS. (See Color insert.)

An interesting phenomenon of spontaneousimptovement of visual acuity in 10 of 700 patients with POBS has been reported 71 and may follow active exudation. 72-75 Eleven of 12 patients who developed reactivation of in-

CHAPTER 28: PRESUMED OCULAR HISTOPLASMOSIS SYNDROME

flammatory lesions had resolution of the foci, documented by fluorescein angiography, With lessening of symptoms and improvement of visual acuity,76 despite the presence of CNV72 and macular scarring secondary to the CNV.29, 77, 78 This appears to be related to spontaneous involution of CNV. Visual recovery may also occur by development of eccentric fixation 79 or by reversal of an organic amblyopia with disappearance of central scotoma. 71 Visual improvement has been seen in response to corticosteroid treatment,58, 80 laser photocoagulation46 ,48, 63, 64, 73-75, 81-90 and submacular surgery.91-95 According to one study, 14% of eyes with active CNV, including some with foveal membranes, retained a visual acuity of 20/40 or better over a follow-up period that ranged from 12 to 109 months. 62 A pigment ring forms around the flbrovascular membrane and changes the leaking membrane to one that stains with fluorescein but does not leak. 72 The pigment ring and fibrosis contain the hemorrhaging and leaking vessels, and the subretinal fluid resolves with time, thereby producing spontaneous visual improvement. It is well documented that 7% of patients with subfoveal, subretinal neovascularization in POHS eyes have spontaneous visual improvement without any treatment. 91 As stated, it has also been documented that in many cases there is spontaneous involution of the subretinal CNV and excellent visual recovery without any treatment. 72 Patients who are young, who have good initial visual acuity at the time of ocular involvement, who have less than 50% of the foveal avasculiar zone involved in the process, and in whom the membrane extends less than 200 j-Lm beyond the center of the foveal avascular zone have a good visual prognosis. 29

Disappearing lesions The histo spots have been observed to enlarge in size and increase in number over a period of time. Similarly, the spots have been observed to decrease in size and even disappear. In a prospective clinical study, 12 patients developed active inflammatory lesions; 11 had spontaneous resolution of the foci with lessening of symptoms and improvement in visual acuity and fluorescein angiographic findings. 76 One of these 12 patients developed typical CNV about 8 months after the onset of symptoms. 76 The phenomenon of disappearing lesions has been well documented by both clinical and fluorescein angiographic examinations in animal lTIodels. 10, 96

PATHOGENESIS/PATHOPHYSIOLOGY/ IMMUNOLOGY/PATHOLOGY It is not known with certainty when and how the primary infection with H. capsulatum occurs in human beings. Indeed, it is not even certain that all cases with the clinical characteristics of POHS were ever even exposed to the microbe. One might logically speculate that exposure to other microbes could provoke the identical clinical response in a genetically susceptible individual, hence the appearance of the POHS picture in patients in England, Holland, and elsewhere. 22- 25 ,48 It is believed that primary infection is acquired early in life, probably during childhood to adolescence, through inhalation of microconidia (small spores) and/or macroconidia (large

spores). It begins as asymptomatic, systemic infection with the organism in the overwhelming majority of cases. Some patients develop a mild upper respiratory infection. The spore form of the fungus changes to its yeast phase within lung tissue. It spreads to other parts of the body via the blood stream. The organisms are entrapped in the reticuloendothelial tissues; dead or latent H. capsulatum cells are found in numerous organs at autopsy or as calcified spots on radiologic examinations. 68 Ocular histoplasmosis, however, does not become apparent until 10 to 30 years later. 97 POHS rarely follows disseminated infection with H. capsulatum or chronic pulmonary histoplasmosis. The foci with dead or latent organisms .later become sources themselves of subsequent asymptomatic transient episodes of H. capsulatum fungemia. Such episodes of fungemia may eventually seed the choroid to produce a multifocal granulomatous chorioretinitis that heals as atrophic histo scars as the host response rapidly destroys the organism.98-101 Hematogenous spread of H. capsulatum to th~ eye could explain its frequent bilaterality, the number and random distribution of histo spots throughout the fundus,30, 33 and the changing pattern of peripheral atrophic histo spots over many years. 66-68, 102 Inflammatory injury caused by H. capsulatum-induced chorioretinitis leads to damage to Bruch's membrane, RPE, and choriocapillaris. That may result in an atrophic scar, CNV formation, or exudative retinal detachment. The development of subretinal hemorrhage from either CNV or direct damage to the RPE or choriocapillaris persists for a while but eventually heals as a fibrovascular scar. The findings in animal models have been observed clinically in the devel~ opment of disciform maculopathy contiguous to atrophic scars in individuals with POHS.33,100 The reasons for abnormal vascular proliferation in the macular region are still unknown. It may be the unique anatomic characteristics of the macular tissue that induce a unique wound-healing response to injury caused by H. capsulatum. Also, as mentioned, based on the histocompatibility data, there seems to be a certain predisposition to develop atrophic scars (histo spots) rather than disciform lesions in the macula. HLA-B7-positive individuals are more predisposed to develop macular disciform lesions than peripheral atrophic chorioretinal scars. 39 HLADRw2-positive patients are more predisposed to have macular disciform or only peripheral lesionsY Similarly, the initial response to primary fungal infection is different. from the reactivation or re-exposure to the histoplasma antigens. Initially, the lesions are small and, most of the time, subclinical. However, re-exposure to histoplasma antigens induces vascular proliferation and symptomatic disciform lesions surrounding an atrophic scar.33 Other hypotheses proposed to explain the ocular response in POHS have included (1) larger initial inoculum of the fungus/ 03 , 104 (2) reinfection,16, 105 (3) hypersensitivity,16,97 and (4) the presence of other risk factors that compromise the vascular system106, 107 or the immune systelTI. 108

Animal Studies Much effort has been devoted to develop an adequate animal model of POHS in producing ocular lesions com-

CHAPTER 28: PRESUMED OCULAR HISTOPLASMOSIS SYNDROME

parable to those seen in humans; Histoplasmosis occurs naturally as choroiditis in cats and as retinitis in· dogs. l09 Initial animal experiments met with disappointment because intraocular inoculation of H. capsulatum in animals generally produced acute anterior segment· inflammation, extensive vitreous clouding, or some other features that were not characteristic of human POHS.110 Success was achieved only by the use of intravenous or intracarotid inoculations of H. capsulatum to produce acute choroiditis lesions that spontaneously and relatively rapidly resolved into lesions typical of human POHS, including peripapillary scarring, RPE defects, and punched-out atrophic histo spots, as well as "disappearing lesion," and minimal inflammatory reaction. 99 Hemorrhagic maculopathy has not been produced in animal models. 110 Subretinal neovascularization was observed in one eye of a nonhuman primate 1 year after injection with the organism. l l l This lesion was not seen with fluorescein angiography, presumably because of the presence of tight junctions and therefore no leakageyl It is important to understand that the organisms have not been demonstrated by culture or special stains in lesions present for longer than 6 weeks. 99 A feature common to all eyes studied, including those whose lesions were clinically inactive or had clinically disappeared, was the persistence of small foci of lymphocytes in the choroid. Damage to Bruch's membrane was observed in some specimens. It is postulated that these occult foci of lymphocytes appear beneath an intact and normalappearing RPE-Bruch's membrane crbmplex and retina, in areas where clinically disappearing lesions had been. They provide the potential site and source for reactivation of the so-called de novo lesions that can appear to arise from normal retina in humans with POHS.99 The persistence of these chronic inflammatory cells and foci, and not the organisms, throughout the choroid of apparently healed eyes leads to "new" lesions and subretinal CNV.99,110

DIAGNOSIS The diagnosis of POHS is essentially a clinical one, depending on the clinical appearance of characteristic punched-out histo spots in one or both eyes, peripapillary degeneration, pigment changes and histo scars, and linear tracks and streaks in the equatorial region, with or without macular atrophic or disciform scar. The syndrome has not fulfilled the requirements of Koch's postulates, and the dimorphic fungal organism has never been cultured from an individual with POHS or isolated from an eye with classical lesions of POHS. Instead, epidemiologic and skin testing evidence has been used to implicate this fungus as the etiologic agent of POHS. The definite etiology of POHS remains unproven. 2 Ocular lesions identical to POHS have been seen in patients in the United Kingdom, Europe, and elsewhere where H. capsulatum is not endemic and patients do not have any other signs of systemic infection. 22-25 Two tests that were done in the past to diagnose POHS but are not performed any more are the histoplasmin skin test and the histoplasma complement fixation test. The histoplasmin skin test is diagnostic of POHS. The reactivity to histoplasmin antigen usually appears early

after exposure to the fungus and persists for a lifetime. It is negative in 11 % of patients who have clinically typical POHS. At one time, it was considered the most valuable measure for the laboratory diagnosis of ocular histoplasmosis, but it is not performed today because of the risk of flare-up of a maculopathy, seen in 7% of patients who may have visible or invisible previous macular lesions. The complement fixation test for circulating antibodies against histoplasmin antigen has not been of much value in supporting the diagnosis because of its poor seropositivity. It is seropositive in only one third of patients with typical histoplasmosis choroiditis. 48 The following tests may help to support the diagnosis ofPOHS.

Chest X-Ray X-ray examination of the chest may show calcified lesions because of primary disseminated histoplasmosis infection. These findings in the presence of typical ocular signs of POHS in the eye(s) confirm the diagnosis. Similar calcific lesions are seen also in pulmonary tuberculosis, sarcoidosis, and some fungal infections.

HLA Typing As mentioned previously, the prevalence of histocompatibility antigens HLA-B7 and HLA-DRw2 among cases of POHS suggests a genetic predisposition for the development of peripheral histo spots and disciform macular scarring. Immunophenotyping in POHS-like retinopathy has revealed no significant preferential expression,42 and these analyses might be of help in differentiating POHS from POHS-like retinopathy. Similar observations have been reported from the nonendemic northwestern United States. 25

DIFFERENTIAL DIAGNOSIS The confluent type of circumpapillary choroiditis, white dots, pigment changes, scarring, and macular lesions may be confused with the following manifestations: Myopic Crescent. A myopic crescent is a pale crescent outside the scleral ring, usually on the temporal side, but it may become annular. It is usually bilateral. The thin pigment rim lies on its outer edge and not inside the crescent. Foster-Fuchs spots are degenerative macular lesions that could progress to disciform detachment. The atrophic scars are whiter, more punched out or scalloped, and located only near the posterior pole (unlike histo spots). The macular involvement occurs around age 30 to 50 years, and the eyes are myopic between - 3D to - 25D. Senile Halo. A senile halo usually forms a yellow-red or pale red crescent on the temporal side of the optic nerve head in the elderly as an aging change, and it is usually bilateral. Inferior Crescent. An inferior crescent is a white or yellow-white lesion, has a uniform border, is often slightly raised over the surrounding tissue, and has a thin rim of pigment on the outer rim beyond which the choroid itself is thinned. Peripapillary Choroidal Coloboma. An atypical, minimal, peripapillary choroidal coloboma can rarely lead to retinal detachment and can mimic findings of active histoplasmosis choroiditis. Coloboma can be dis tin-

CHAPTER 28: P·RESUMED OCULAR HISTOPLASMOSIS SYNDROME

guished from histo lesions by stereoscopic fundus photography and fluorescein angiography.112 Optic Nerve Drusen. Drusen of the optic nerve head are usually bilateral, glistening, raised lesions occurring over the disc surface and not on the disc margin, seen in younger patients in their teens and twenties, and there is usually a family history of drusen. The clinical appearance of drusen may simulate that of papillitis or papilledema. Drusen of the optic nerve may cause nerve fiber bundle defect on visual field examination. Rarely, drusen may cause hemorrhagic retinal detachment that may spread from nerve head to the macular area,113 and it becomes even harder to distinguish drusen from peripapillary histo scars. Usually, other histo spots do notaccompany drusen, except in endemic areas coincidentally. Multifocal Choroiditis and Panuveitis (MCP). MCP presents initially with small and discrete inflammatory lesions at the level of the choroid and RPE, along with little or no vitreous inflammation. Within weeks or a few months, patients with multifocal choroiditis routinely develop new spots on follow-up, have prominent vitreous inflammation, and often have progressive visual loss. There could be acute antibody production to EpsteinBarr virus in patients with multifocal choroiditis. Multiple Evanescent White Dot Syndrome (MEWDS). MEWDS has widely scattered, active gray-white lesions, early punctate and an often wreath-shaped pattern of hyperfluorescence in the area of activity, and a decrease in the electroretinogram a-wave. The fundus and visual functions return to normal in 7 t-t> 10 weeks. Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE). APMPPE presents as acute loss of vision occurring in one or both eyes of young people of either sex, with spontaneous recovery in a few weeks. Classically, circumscribed yellow-white lesions occur in the fundus at the level of the RPE. Initially, these lesions are hypofluorescent on fluorescein angiography; later they hyperfluoresce. There isa wide spectrum of presentation and clinical features of APMPPE. Punctate Inner Choroidopathy (PIC). PIC is a disease that affects the choroid and RPE and is most common in young women. The acute lesions are small (100 to 300 j.Lm), yellow, and moderately well defined. The lesions gradually become more atrophic and form deep cylindrical and discrete scars. Pigmented tissue occasionally fills the center of the cylindrical scar, making it appear less deep. There could be associated shallow serous retinal detachments over the PIC lesions without neovascularization, and these detachments gradually resolve. Patients with PIC have acute symptoms of blurred vision, flickering lights, and scotomas. In the acute phases of the disease, the patients can often outline scotomas that correspond to individual lesions. These acute lesions are hyperfluorescent in the early phase and then gradually leak in the late phase. Angioid Streaks. Angioid streaks are fundus findings in collagen tissue disorders such as pseudoxanthoma elasticum, senile elastosis, osteitis deformans, and EhlersDenlos syndrome. Peau d'orange skin changes precede fundus changes of angioid streaks in these conditions. The salmon-colored spots very closely resemble histo spots and may also have disciform macular detachment.

Rarely, drusen of the optic nerve may also be associated findings, along with angioid streaks. Granulomatous Fundus Lesions. Ocular presentations of toxoplasmosis, tuberculosis, coccidioidomycosis, syphilis, sarcoidosis, and toxocariasis may mimic granulomas and scarring seen in POHS. Clear vitreous without any signs of inflammation such as keratic precipitates, flare and cells, vitreous cells, and cotton-balls in vitreous distinguish POHS from the other granulomatous fundus conditions.

TREATMENT Laser Photocoagulation

Maumenee and Ryan87 and Watzke and Leaverton90 were the first to suggest the use of laser photocoagulation to treat POHS using xenon-arc photocoagulation. 88 , 90,113 In 1979, the Macular Photocoagulation Study (MPS) group, sponsored by the National Eye Institute, initiated its first prospective randomized multicenter controlled clinical trial, called the Ocular Histoplasmosis Study (OBS). The purpose of this trial was to determine whether argon laser photocoagulation was beneficial in preventing severe visual acuity loss in eyes with CNV secondary to POHS. The data from this study demonstrated definite effectiveness of argon laser photocoagulation in treating such membranes. 73 Mter an IS-month follow-up, it was demonstrated that only 9.4% of laser-treated eyes (11 of 117) had lost six lines or more of visual acuity from the baseline as compared with 34.2% of untreated eyes (39 of 114).73 Based on these encouraging results from the OHS, the MPS group recommended laser photocoagulation to be the treatment of choice. in treating subretinal CNV.73 For better selection of patients undergoing laser treatment, the subretinal neovascular membranes are classified 29 ,73 according to their location as follows: 1. Subfoveal membranes are the well-defined subretinal neovascular membranes that have fluorescein angiographic evidence of neovascularization extending under the center of the foveal avascular zone (FAZ) , with or without a pigment ring, blocked fluorescence, or blood (Fig. 2S-5A and B). 2. Juxtafoveal membranes are the well-defined subretinal neovascular membranes that have fluorescein angiographic evidence of neovascularization extending to 1 to 200 /-1m from the center of the FAZ, with or without pigment ring, blocked fluorescence, or blood extending closer or through the center of the fovea: The term also refers to a neovascular membrane more than 200 /-1m from the center of the FAZ and a pigment ring, blocked fluorescence, or blood extending up to 200 /-1m from the FAZ. 3. Extrafoveal choroidal neovascularization membranes (CNV) are the neovascular membranes that have the fluorescein angiographic evidence of the neovascularization extending more than 200 /-1m from the center of the membrane and no continuous pigment ring, blocked fluorescence; or blood.

Extrafoveal Laser Photocoagulation The eligibility criteria for the patients in the OHS included well-defined extrafoveal CNV that had a foveal or

CHAPTER 28: PRESUMED OCULAR HISTOPLASMOSIS SYNDROME

FIGURE 28-5. A, Color photograph illustrating macular choroidal neovascularization (CNV) in POHS. B, Fluorescein angiogram of the same eye to show CNV. (See Color insert.)

posterior edge more than 200 f.1m and up to 2500 f.1m away from the center of the FAZ, and a visual acuity in the affected eye of at least 20/100 or better. Other signs of PORS were also present in the affected eyes. The visual symptoms of subretinal CNV were decreased visual acuity, distortion on Amsler grid chart, uniocular diplopia, or metamorphopsia. Eligible eyes were randomized to argon laser treatment or to no treatment (the control group). Mter laser treatment, the eyes were re-examined twice a year to check visual acuity and to take colored photographs. Each eye had fluorescein angiography performed preoperatively, 6 and 12 months postoperatively, and annually thereafter. About 4 years after initiating this study, it was concluded by the MPS Data and Safety Monitoring Committee that argon laser photocoagulation was beneficial in preventing or delaying loss of visual acuity secondary to PORS, and no further patients were enrolled. The data gathered by the MPS group from 242 subjects (and 245 eyes) enrolled over a 4-year period demonstrated that the untreated eyes with extrafoveal CNV due to PORS had a 2.3 times greater risk of losing six or more lines of visual acuity when compared with laser-treated eyes. 73 On the MPS chart, a loss of six lines of visual acuity from the initial baseline (rather than final visual acuity) was equivalent to a fourfold increase in the minimal angle of resolution or visual angle. These encouraging results met with some pessimism when a large percentage (26%) of treated eyes developed recurrent neovascularization; 31 of the 40 recurrences were contiguous to a previously treated area. Also, new areas of CNV not contiguous to the laser scars developed in another 7% of laser-treated eyes. 75 Most. recurrences were seen early, about 22% occurring within 6 months, the figure increasing to only about 28% 2 years after treatment. 63 Despite these recurrences, the laser-treated eyes had significantly improved visual outcome compared with the untreated eyes. Long-term follow-up of 3 years revealed that the eyes with recurrences had an. average visual acuity of 20/60. These results were far superior to the natural course of the disease, and reinforced the beneficial effect of argon laser photocoagulation. In 1991, the MPS group reported its 5-year results of

laser photocoagulation treatment for extrafoveal CNV secondary to PORS.75 The group upheld its earlier recommendation that laser photocoagulation was beneficial in preventing severe visual loss from PORS. Untreated eyes had 3.6 times the risk of severe visual loss that laser-treated eyes had. Only 12% of laser-treated eyes demonstrated a decrease in visual acuity of six lines or more from baseline visual acuity, compared with 42% of untreated eyes. 75

Juxtafoveal Laser Photocoagulation The second trial by the MPS group was initiated in 1981 to evaluate the efficacy of krypton red laser photocoagulation in treating juxtafoveal neovascular disciform lesions secondary to PORS. Krypton laser treatment of PORSrelated CNV had been found effective in previous studies,u4--116 The eligibility criteria for this study included patients who had neovascular lesions of PORS with the foveal or posterior edge inside the FAZ but still not subfoveal. Precisely, it meant that the foveal-edge CNV was 1 to 199 f.1m from the center of the foveal avascular zone, or 200 f.1m or more from the center of the FAZ with blood and/or blocked fluorescence within 200 /-Lm of the center of the FAZ. These eyes were randomized for either krypton laser treatment or no laser treatment (the control group). One-year follow-up showed that only 6.6% of lasertreated eyes (8 of 121) had lost six or more lines of visual acuity as compared with 24.8% of untreated eyes (31 of 125). By 3 years after randomization, the corresponding values were 4.6% (3 of 64) and 24.6% (15 of 61). Based on these results, after a 4-year period in 1986, the MPS Data and Safety Monitoring Committee intervened, concluding from the accumulated data from 289 eyes enrolled that krypton laser-treated eyes were significantly less likely to lose visual acuity than were untreated eyes. 74 The 5-year follow-up revealed that only 12% of lasertreated versus 28% of untreated eyes had lost six or more lines from the baseline visual acuity.83 The problem of persistent CNVcontiguous with the laser-treated scar was again observed in. a large percent (33%) of laser-treated eyes. New, noncontiguous areas of CNV developed in an additional 2% of eyes. 83

CHAPTER 28: PRESUMED OCULAR HISTOPLASMOSIS SYNDROME

Summarizing the findings from three randomized clinical trials of krypton laser treatment ofjuxtafoveal neovascular lesions revealed that untreated eyes with POHS had 2.6 times higher unadjusted estimated relative risk of losing 6 lines of visual acuity than laser-treated eyes from the I-year through the 5-year examination period. s3 Accurate and complete krypton laser treatment of juxtafoveal CNV, particularly close to the foveal center, was found to lessen persistent CNVS1 and was required for the patient to have the best chance of avoiding further severe visual acuity loss.s5, S7 The Canadian Ophthalmology Study group, S9 in a multicenter, randomized, controlled clinical trial, found krypton red laser photocoagulation to be no better than argon laser when treating well-defined extrafoveal CNV. Nevertheless, in a nonrandomized retrospective analysis over an average follow-up of 9.6 years, it was found that laser photocoagulation of POHS-related juxtafoveal and extrafoveal CNV had long-term benefits in preventing severe visualloss.u 7 The results of this study revealed that the visual acuity of 20/40 or better was obtained in 71 % of eyes laser-treated for extrafoveal CNV and 68 % of eyes laser-treated for juxtafoveal CNV. Recurrent CNV was observed in 23% of laser-treated eyes during the mean follow-up of 9.6 yearsy7

Peripapillary laser Photocoagulation Results of laser treatment of extrafoveal or juxtafoveal peripapillary CNV, or CNV that was located nasal to the fovea, demonstrated beneficial ~ffects after 3 years of follow-up.s5 Mter a 3-year follow-up of laser-treated and untreated eyes with CNV nasal to the fovea or in the peripapillary area, 11 % of the laser-treated eyes (6 of 54) versus 41 % of the untreated eyes (21 of 51) had lost six or more lines of visual acuity. Among eyes with peripapillary CNV lesions, 14% of the treated eyes (3/22) versus 26% of the untreated eyes (6/23) had lost six or more lines of visual acuity after a 3-year follow-up. Among the eyes with nasal CNV lesions, 9% of the treated eyes (3/ 32) versus 54% of the untreated eyes (15/28) had lost six or more lines of visual acuity after 3 years offollow-up. Thermal damage to the optic disc and papillomacular nerve bundle is a serious potential risk of laser treatment

of peripapillary CNV and CNV lesions nasal to the fovea, respectively. However, based on these results, the MPS group recommended laser treatment for peripapillary CNV and CNV nasal to the fovea, because the risks of treatment were outweighed by the potential loss of vision caused by growth and extension of the membrane into the fovea. S5

Subfoveal laser Photocoagulation Encouraged by these results, a pilot study was undertaken to evaluate the effectiveness of laser photocoagulation in treating subfoveal CNV.uS However, there was difficulty in recruiting patients for this study because most of the eyes had already been treated before they could get· to the advanced stage of subfoveal membranes. It was hypothesized that most of the CNV originated outside the fovea as extrafoveal or juxtafoveal membranes and were treated before they could grow into the subfoveal region. Only 25 patients were enrolled in this study, and they had a fairly short follow-up. Laser treatment of subfoveal CNV offers little benefit when compared to the natural history of the disease without treatment. Investigators were initially encouraged by the results of the MPS study for subfoveal treatment of age-related macular degeneration. The data from this study demonstrated that laser photocoagulation of subfoveal membranes neither caused marked decrease rior significant increase in vision in the eyes evaluatedYs Nevertheless, laser treatment of subfoveal CNV would sacrifice central vision in 14% to 23% of eyes with POHS that, according to natural history studies, may retain vision of 20/40 or betterYs At present, laser photocoagulation is the treatment of choice in managing macular CNV.73 Laser photocoagulation is performed to destroy the entire net of CNV (Fig 28-6A and B). Various studies have demonstrated that photocoagulation does not prevent recurrences of CNV, but it helps to dry up the active primary or recurrent lesions. CNV is suspected from a pigment ring, retinal detachment, and subretinalor retinal hemorrhage. The CNV· is confirmed with fluorescein angiography before laser treatment. A recent angiogram is needed to localize the treatment area before performing the laser photocoagulation, because the CNV does change with time. 73

FIGURE 28-6. A, Macular CNV causing foveal/subfoveal hemorrhage. B, Same eye six months after laser photocoagulation treatment to extrafoveal CNV with persistent CNV inferotemporal to the foveal center.

CHAPTER 28: PRESUMED OCULAR HISTOPLASMOSIS SYNDROME

Long burns achieve more effective closure of the neovascular membranes but are a higher risk to the fovea. The end point is a uniformly white ring of coagulation around the membrane to enclose it. 48 ,73

Laser Photocoagulation for Persistent or Recurrent CNV Evaluation of MPS results indicated that additional laser treatment was required if fluorescein angiography revealed leakage from persisting or new vessels along or within the margin of the treatment scar. 73 Symptomatically, the laser photocoagulation may cause worsening of vision during the first week after treatment because of retinal swelling, which resolves with time. However, if the vision starts to worsen again, there is concern that the CNV has not been completely destroyed. Re-evaluation to make sure that all the CNV is destroyed is therefore essential. Immediately after laser treatment, the tissue coagulation blocks adequate assessment of CNV. Also, the extent of CNV is difficult to assess under retinal or choroidal hemorrhage. Therefore, it is recommended that all the area of hemorrhage be treated to ensure full treatment of the underlying CNV. The subretinal CNV that cannot be fully treated by photocoagulation carries a poor prognosis. 48 Partial photocoagulation of subretinal CNV was thought to worsen the visual outcome because of stimulating the remaining CNV to proliferate and cause hemorrhagingyg Schlaege188 has refuted this observation. Even partial treatment of a CNV compleX' within 3 months of its start helps to reduce the size of retinal detachment and decrease the size of related scotoma, and the vision improves. 88 Various protocols for the treatment of CNV associated with POHS have been suggested: Schlaegel advocated laser photocoagulation to begin at the end of the CNV distant from the fovea to determine the correct dosage of photocoagulation before moving around to the fovea side. The foveal edge of the CNV was treated with 0.2 seconds exposure time and 100-J.1m-sized severe burns. The rest of the CNV was treated with 0.5 seconds exposure time and 200-J.1m-sized burns. 48

Laser Photocoagulation Protocol Used by the MPS Group In the MPS study,73 photocoagulation of CNV was performed using the argon blue-green laser. Fluorescein angiogram was obtained within 72 hours before treatment in each patient. Retrobulbar anesthesia was given to ensure immobility of the eyeball during treatment. The goal of treatment was to obliterate the neovascular complex. The treatment was begun by placing a noncontiguous row of 100-J.1m light-intensity burns 100 J.1m to 125 J.1m beyond the neovascular complex at durations of 0.1 to 0.2 seconds. The CNV complex included the hyperfluorescent new vessels and any adjacent blood, pigment, or blocked fluorescence. Once the CNV complex had been outlined, the foveal edge was treated with overlapping 200-J.1m burns at duration of 0.2 seconds. Treatment was continued by placing overlapping 200-J.1m burns along the entire perimeter of the complex. Treatment was completed by placing overlapping 200-J.1m to 500-J.1m lesions

at duration of 0.5 seconds over the entire CNV complex. The final appearance was an intense white lesion. 73 There were two important exceptions to this protocol. First, when the foveal edge of the CNV complex was within 350 J.1m of the center of the FAZ, the edge could be treated with overlapping 100-J.1m burns instead of 200J.1m burns. Second, when the new vessel complex was 200 J.1m to 300 J.1m from the center of the FAZ, the intense lesion did not have to be extended a full 100 J.1m beyond the CNV complex. However, it was required that the entire complex be covered with intense coagulation. 73 Additional laser treatment was performed when fluorescein leakage indicated new vessels along or within the margin of the treatment scar. It was not performed when new vessels recurred within 200 J.1m of the center of FAZ.73

Complications of Laser Photocoagulation Laser photocoagulation is not a complication-free treatment for CNV in POHS. Scars from juxtafoveal laser photocoagulation have a tendency to expand and enlarge over time and involve the center of FAZ.120 Argon laserinduced scars have been observed to expand toward the foveal avascular zone at a rate of 152 J.1m per year for the first 2 years after laser treatment and 22 J.1m per year thereafter. 120 Mter 10 years of follow-up, it has been found that the average scar was 3.23 times larger than the original treatment area. Argon laser has caused a macular hole formation in a patient with POHS.120 Persistent or recurrent CNV contiguous with the laser treatment scar has been reported in 33% of laser-treated eyes,82 and an additional 2% of eyes developed new noncontiguous areas of CNV.82 Thermal damage to the disc· and papillomacular bundle is an additional potential complication of laser photocoagulation of peripapillary CNV and CNV nasal to the fovea. 85

Corticosteroids Inactive and scarred lesions in POHS do not need any treatment until signs of reactivation. The use of systemic or periocular corticosteroids is advocated in patients with subfoveal neovascular membranes or CNV and reactivation of macular lesions. It has been recommended that high-dose oral corticosteroids be used immediately upon finding symptoms of macular lesions, with continuation until laser photocoagulation is administered. 122 ,123 The rationale for using systemic or periocular corticosteroids is based on the presence of lymphocytic infiltrates in POHS lesions41 , 65 and the persistent foci of lymphocytes in the choroid. These lesions represent persistent low-grade inflammatory foci and probably reactivate the previously inactive histo spots and de novo lesions. Anti-inflammatory agents probably limit the inciting stimulus as well as reduce the resulting reparative process that leads to scarring. Sub-Tenon injection of corticosteroids should be considered if symptomatic macular disease is present and no CNV can be detected, or, if it is detected, it is not treatable by laser because of its proximity to fovea or being subfoveal. 1o On one hand, corticosteroids have been demonstrated in the past to have a beneficial effect in treating acute macular lesions and their reactivation, which can cause a

CHAPTER 28:

sudden drop in visual acuityY Prednisone 40 to 100 mg per datO to 50 to 120 mg every other day, by mouth, and long-acting steroid injections (40 mg of methylprednisolone acetate) 48 were started at the earliest signs that histo scar reactivation was threatening macular and central vision. On the other hand, it is felt that the final visual outcome is not affected by high-dose long-term steroid therapy once the CNV encroaches upon the foveal and juxtafoveal region. 29 In one study, with an average followup of 39 months, 81 % of eyes treated with corticosteroids had visual acuity worse than 20/40 (6/12), and almost 70% of these were 20/200 (6/60) or worse. 29 The beneficial role of corticosteroids has never been proven with controlled clinical trials. Corticosteroids do have a beneficial role in treating eyes that have POHS and CNV in the extrafoveaF3 and juxtafoveaF4 regions. Since the introduction of laser photocoagulation in managing extrafoveal and juxtafoveal lesions in POHS, the role of corticosteroids has diminished, and steroids are given only while preparing the patient for laser photocoagulation51 or to patients who cannot have the laser treatment because of the proximity of CNV to fovea or when it is subfoveal.

Complications

of Corticosteroids

Long-term use of oral corticosteroids carries its own side effects and complications. Repeated injections to the subTenon carry risks of orbital infection, blepharoptosis, baggy eyelids, scleral melt, steroid-induced glaucoma, and posterior subcapsular cataract fOfmation. 48

SubmacularlSubretinal Surgery Surgical removal of CNV is now possible. Subretinal surgery was first performed in 1980 by Machemer,92 but its application for removing CNV was introduced by Thomas and Kaplan in 1991. 95 Two patients with CNV caused by POHS (and resultant visual acuity of 20/400) were operated on successfully. Mter a short follow-up of 3 to 7 months, one patient recovered visual acuity to 20/20 and the second to 20/40. 95 This dramatic improvement in visual acuity has not been reported subsequently. Visual improvement by just two Snellen lines 1 week to 6 months after surgical removal of subfoveal CNV has been reported in 8 of 15 patients. 91 Also, recurrent neovascularization developed in 2 of the 15 eyes. 91 Subretinal membranes have been classified as type I, in which the predominance of the CNV resides below the RPE, and type II, in which the CNV resides between the neurosensory retina and the RPE.124 It is the latter type of CNV that appears most amenable to surgical extraction. 124 Thomas and coworkers have suggested two types of procedures on patients who have subfoveal CNV complex secondary to POHS.94 Either the choroidal circulation to the neovascular membranes could be disconnected, or the choroidal neovascular complex could be extracted through the retinotomy site after performing vitrectomy.94 Visual improvement by at least two Snellen lines was observed in 6 of 16 eyes followed 1 to 8 months and operated on by extraction of the CNV complex. None of the four eyes that had the membranes' choroidal circulation disconnected demonstrated any visual improvement. 123

"'1L ••:n,..",· .ILILO

OCU lAR.

LA:SM'QSIIS SYNDROME

More recently, in a nonrandomized, uncontrolled, retrospective study with an average follow-up of 10.5 months, about 31 % of 67 eyes with POHS-related subfoveal CNV achieved a visual acuity of 20/40 or better after undergoing subretinal surgery.93 Eyes with better preoperative vision (>20/100) had significantly better final visual acuity than the eyes with poor preoperative vision «20/ 200) .93 Recurrences of CNV were successfully treated with laser photocoagulation and thereby did not affect the final visual outcome. Similarly, a retrospective review of 67 eyes that had surgical removal of subfoveal CNV caused by POHS demonstrated that the ingrowth site of subfoveal CNV could be identified in the majority of eyes, and that a significant number of eyes with subfoveal CNV have an, extrafoveal ingrowth site. The eyes with an extrafoveal ingrowth site have a favorable visual prognosis after surgical removal of CNV. If the ingrowth site is subfoveal or not identifiable, the visual prognosis after surgery is guarded. 125 In another retrospective study, visual recovery after submacular surgery in POHS was associated with postoperative perfusion of the subfoveal choriocapillaris. 126 The best-corrected visual acuity was an improvement of at least two Snellen lines in 71 % of the perfused and 14% of nonperfused eyes. It remains to be seen if the development of techniques to maintain or re-establish perfusion of the subfoveal choriocapillaris after surgery could improve visual outcome in these eyes. 126 Another retrospective study demonstrated that the ingrowth site of subfoveal CNV was a predictor of visual outcome after submacular surgical excision of CNV. 125 If the ingrowth site of subfoveal CNV was extrafoveal, the surgical removal of CNV was favorable, but if the ingrowth site of CNV was subfoveal or not identifiable, the visual prognosis was guarded. 125 Subretinal microsurgery is still in its infancy and going through its developmental stages. Initial encouraging results have not been consistently reproduced. Appropriate case selection and surgical timing of intervention to maximize visual benefits from submacular surgery still need to be defined. Several points need to be considered before deciding on subretinal or subfoveal surgery to remove CNV in POHS. First, all surgeons have stressed the importance of choosing the prospective patients very carefully. Submacular surgery is not for all patients with POHS, or perhaps even for most. Initial results of surgical removal of CNV in age-related. maculopathy have not been impressive. 51 Patients may need replacement of their nonfunctioning or barely functioning RPE cells along with removal of subfoveal neovascular membrane. Second, surgical removal of subretinal or subfoveal neovascular membranes is followed by a high recurrence rate and the results do not outweigh the results of other therapeutic modalities, especially laser photocoagulationY Third, and finally, a confounding point is the spontaneous regression of neovascular membranes in some patients with POHS,particularly in the young who happen to be good candidates for surgery.51 A randomized, controlled, prospective, multicenter tri(il, the Submacular Study Trial (SST) was organized to evaluate subfoveal surgery for POHS. Specifically, this study evaluates subfoveal surgery and compares it to ob-

CHAPTER 28:

rnll:;.;;zI'Jluy.m:;lIJ

OCULAR HISTOPLASMOSIS SYNDROME

servation for the treatment of eyes with POHS and subfoveal CNV. Histopathologic and ultrastructural findings of surgically excised CNV from patients who had undergone submacular surgery demonstrated fibrovascular tissue, fibrocellular tissue, or hemorrhage in all cases. Vascular endothelium and RPE were the most common constituents of the CNV.61,127-129

Complications Surgery

of SubmacularlSubretinal

CNV secondary to POHS often arises from focal defects in Bruch's membrane and proliferates anterior to the RPE.124 This type of membrane may be removed with preservation of the underlying RPE and choriocapillaris requisite to restoring visual function. 130 Submacular surgerycarries all the risks of vitrectomy surgery. Retinal detachment, retinal tears without detachment, endophthalmitis, subretinal hemorrhage, cataract formation, and premacular fibrosis have been reported as complications of submacular surgery.130 Recurrent neovascularization after subretinal surgery is a common problem. Recurrence should be differentiated from persistence of CNV because of incomplete removal of CNV membranes. Early recognition of persistent or recurrent CNV may allow laser photocoagulation in. CNV away from the fovea for better visual prognosis. 131 Subfoveal recurrence is the most difficult to manage, making it an ideal clinical mode~ for testing antiangiogenic agents 131 because laser treatment of subfoveal CNV destroys the fovea and is not recommended. 132 Younger patient age and the absence of previous laser photocoagulation are factors associated with a favorable visual prognosis after submacular surgery to remove subfoveal CNV.133 As discussed previously, the ingrowth site of subfoveal CNV in POHS has been associated with visual prognosis after submacular surgical removal of CNV. Eyes with an extrafoveal ingrowth site have a favorable visual prognosis after the surgical removal of the CNV. If the ingrowth site is subfoveal or not identifiable, the visual prognosis after submacular surgery is guarded. 125 Despite good results, the appropriate management of patients with POHS and subfoveal CNV remains controversial.

Amphotericin B It is presumed that the ocular histoplasmosis syndrome is caused by previous exposure to the fungus H. capsulatum. Because no organisms have been identified in human histopathologic specimens and none are found in the animal model 6 weeks after infection,lO the use of antifungal amphotericin B has no role in the treatment of POHS or reactivated macular lesions.

CONCLUSIONS Although many questions remain unanswered concerning the cause of ocular histoplasmosis, the epidemiologic, immunologic, experimental, and histopathologic data and evidence make a fairly compelling case that the fungus H. capsulatum is the causative agent for the constellation of ocular lesions that is clinically recognized as POHS. On the basis of these data and evidence, it has been proposed to call the entity ocular histoplasmosis and

drop the term presumed. Nevertheless, the syn.drome of ocular lesions is still called presumed ocular histoplasmosis syndrome. Since the efficacy of laser photocoagulation in treating extrafoveal and juxtafoveal CNV lesions is proven in controlled clinical trials, there is some hope for the patients suffering from POHS. The high-risk patients who have lost vision in one eye are encouraged to self-monitor their reading vision and regularly use an Amsler grid chart with each eye independently. This is recommended to detect new patches of neovascularization that may arise, either in the eye already affected or in the fellow good eye. I"aser treatment is then recommended. Further research is needed to better understand the pathophysiologic process that results in CNV and to develop animal models to explore potential antiangiogenic drugs to intervene in that process.

References 1. Cohen PR, Grossman ME, Silvers DN: Disseminated histoplasmosis and human immunodeficiency virus. Int] Dermatol 1991;30:614622. 2. Katz B], Scott WE, Folk ]C: Acute histoplasmosis choroiditis in 2 immunocompetent brothers. Arch Ophthalmol 1997;115:14701472. 3. Specht CS, Mitchell KT, Bauman AE, et al: Ocular histoplasmosis with retinitis in a patient with acquired immune deficiency syndrome. Ophthalmology 1991;98:1356-1359. 4. Weingeist TA, Watzke RC: Ocular involvement by Histoplasma capsulatum. Int Ophthalmol Clin 1983;23:33-47. 5. Pulido ]S, Folberg R, Carter KD, et al: Histoplasma capsulatum endophthalmitis after cataract extraction. Ophthalmology 1990;97:217-220. 6. Craig EL, Suie T: Histoplasma capsulatum in human ocular tissue. Arch Ophthalmol 1974;91:285-289. 7. Goldstein BG, Buettner H: Histoplasmic endophthalmitis: A clinico-pathologic correlation. Arch Ophthalmol 1983;101:774-777. 8. Hoefnagels KL, Pijpers PM: Histoplasma capsulatum in a human eye. Am] OphthalmoI1967;63:715-723. 9. Klintworth GK, Hollingsworth AS, Lusman PA, Bradford WD: Granulomatous choroiditis in a case of disseminated histoplasmosis: Histologic demonstration of Histoplasma capsulatum in choroidal lesions. Arch Ophthalmol 1973;90:45-48. 10. Brown DM, Weingeist TA, Smith RE: Histoplasmosis. In: Pepose JS, Holland GN, Wilhelmus KR, eds: Ocular Infection and Immunity. St Louis, Mosby Year-Book, 1996, pp 1252-1261. 11. Darling ST: A protozoan general infection producing pseudo tubercles in the lungs and focal necrosis in the liver, spleen, and lymph nodes. JAMA 1906;46:1283. 12. Darling ST: Histoplasmosis: A fatal infectious disease resembling kala-azar found among natives of tropical America. Arch Intern Med 1908;2:107-123. 13. Reid JD, Scherer JH, Herbut PA, et al: Systemic histoplasmosis diagnosed before death and produced experimentally in guinea pigs. J Lab Clin Med 1942;27:419-434. 14. Krause AC, Hopkins WG: Ocular manifestations of histoplasmosis. AmJ OphthalmoI1951;34:564-566. 15. Schlaegel TF: Granulomatous uveitis: An etiologic survey of 100 cases. Trans Am Acad Ophthalmol Otolaryngol 1958;62:813-824. 16. Woods AC, Wahlen HE: The probable role of benign histoplasmosis in the etiology of granulomatous uveitis. Trans Am Ophthalmol Soc 1959;57:318-343. 17. Schlaegel TF, Kenney D: Changes around the optic nerve-head in presumed ocular histoplasmosis. Am J Ophthalmol 1966;62:454458. 18. Schwartz]: Histoplasmosis. New York, Praeger, 1981. 19. Baker RD: Histoplasmosis in routine autopsies. Am J Clin Pathol 1964;41:457-470. 20. Furcolow ML: Histoplasmosis. Clin Notes Resp Dis 1967;6:3. 21. Smith RE, Ganley JP: An epidemiological study of presumed ocular histoplasmosis. Trans Am Acad Ophthalmol Otolaryngol 1971 ;75:994-1005.

CHAPTER 28: PRESUMED OCULAR 22. Bottoni FG, Deutman AF, Aandekerk AL: Presumed ocular histoplasmosis syndrome and linear streak lesions. Br ] Ophthalmol 1989; 73:528-535. 23. Braunstein RA, Rosen DA, Bird AC: Ocular histoplasmosis syndrome in the United Kingdom. Br] OphthalmoI1974;58:893-898. 24. Suttorp-Schulten MS, Bollemeijer]G, Bos P], Rothova A: Presumed ocular histoplasmosis in the Netherlands- an area without histoplasmosis. Br] Ophthalmol 1997;81:7-11. 25. Watzke RC, Klein ML, Wener MH: Histoplasmosis-like choroiditis in a nonendemic area: The northwest United States .. Retina 1998;18:204-212. 26. Asbury T: The status of presumed ocular histoplasmosis: Including a report of a survey. Trans Am Ophthalmol Soc 1966;64:371-400. 27. Davidorf FH, Anderson ]D: Ocular lesions in the Earth Day 1970 histoplasmosis epidemic. Int Ophthalmol Clin 1975;15:51-60. 28. Olk R], Burgess DB, McCormick PA: Subfoveal and juxtafoveal subretinal neovascularization in the presumed ocular histoplasmosis syndrome. Visual prognosis. Ophthalmology 1984;91:15921602. 29. Feman SS, Podgorski SF, Penn MK: Blindness from presumed ocular histoplasmosis in Tennessee. Ophthalmology 1982;89:12951298. 30. Smith RE, Ganley]P, Knox DL: Presumed ocular histoplasmosis. II. Patterns of peripheral and peripapillary scarring in persons with nonmacular disease. Arch Ophthalmol 1972;87:251-257. 31. Hawkins BS, Ganley]P, for the Washington County Follow-up Eye Study Group: Risk of visual impairment attributable to ocular histoplasmosis. Arch Ophthalmol 1994;112:655-666. 32. Baskin MA, ]ampol LM, Huamonte FU, et al: Macular lesions in blacks with the presumed ocular histoplasmosis syndrome. Am] Ophthalmol 1980;89:77-83. 33. Gass ]DM, Wilkinson CP: Follow-up study of presumed ocular histoplasmosis. Trans Am Acad Ophthalmol Otolaryngol 1972;76:672-693. 34. Schlaegel TF, Weber ]C: Follow-up study of presumed histoplasmic choroiditis. Am] Ophthalmol 1971;71:1192-1195. 35. Watzke RC, Claussen RW: The loiig-term course of multifocal choroiditis (presumed ocular histoplasmosis). Am] Ophthalmol 1981;91:750-760. 36. Lewis ML, Schiffman ]C: Long-term follow-up of the second eye in ocular histoplasmosis. Int Ophthalmol Clin 1983;23:125-135. 37. Sawelson H, Goldberg RE, Annesley WH, Tomer TL: Presumed ocular histoplasmosis: The fellow eye. Arch Ophthalmol 1976;94:221-224. 38. Godfrey WA, Sabates R, Cross DE: Association of presumed ocular histoplasmosis with HLA-B7. Am] Ophthalmol 1978;85:854-858. 39. Braley RE, Meredith TA, Aaberg TM, et al: The prevalence of HLA-B7 in presumed ocular histoplasmosis. Am ] Ophthalmol 1978;85:859-861. 40. Meredith TA, Smith RE, Duquesnoy RJ: Association of HLA-DRw2 antigen with presumed ocular histoplasmosis. Am] Ophthalmol 1980;89:70-76. 41. Meredith TA, Green WR, Key SN, et al: Ocular histoplasmosis: Clinicopathologic correlation of 3 cases. Surv Ophthalmol 1977;22:189-205. 42. Hodgkins PR, Lane AC, Chisholm 1M, et al: Immunophenotyping in presumed ocular histoplasmosis-like retinopathy. Eye 1995;9:5663. 43. Dreyer RF, Gass ]DM: Multifocal choroiditis and panuveitis. A syndrome that mimics ocular histoplasmosis. Arch Ophthalmol 1984;102: 1776-1 784. 44. Hawkins BS, Alexander ], Schachat AP: Ocular histoplasmosis. In: Schachat AP, Murphy RB, Ryan S], eds: Retina, 2nd ed. St Louis, Mosby Year-Book, 1994, pp 1661-1675. 45. Wong VG: Focal choroidopathy in experimental ocular histoplasmosis. Trans Am Ophthalmol Soc 1972;70:615-630. 46. Macular Photocoagulation Study Group: Five-year follow-up of fellow eyes of individuals with ocular histoplasmosis and unilateral extrafoveal or juxtafoveal choroidal neovascularization. Arch Ophthalmol 1996;114:667-688. 47. Fountain ]A, Schlaegel TF: Linear streaks of the equator in presumed ocular histoplasmosis syndrome. Arch Ophthalmol 1981;99:246. 48. Schlaegel TF: Presumed ocular histoplasmosis. In: Tasman W, ]aegel' EA, eds: Duane's Clinical Ophthalmology. Philadelphia, J.B. Lippincott, 1989, vol 4, chapter 48.

LA~SMlOSliS SYNDROME

49. Spaide RF, Yannuzzi LA, Freund KB: Linear streaks in multifocal choroiditis and panuveitis. Retina 1991;11:229-231. 50. Schlaegel TF, Weber ]C, Helveston E, Kennedy D: Presumed histoplasmosis choroiditis. Am] Ophthalmol 1967;63:919-925. 51. Nussenblatt RB, Whitcup SM, Palestine AG: Ocular histoplasmosis. In: Nussenblatt RB, Whitcup SM, Palestine AG, eds: Uveitis: Fundamentals and Clinical Practice, 2nd ed. St Louis, Mosby Year-Book, 1996, pp 229-237. 52. Walma D, Schlaegel TF: Presumed histoplasmic choroiditis. Am] Ophthalmol 1964;57:107-110. 53. Kran.ias G: Vitreous hemorrhage secondary to presumed ocular histoplasmosis syndrome. Ann Ophthalmol 1985;17:295-298. 54. Schlaegel TF: Ocular Histoplasmosis. New York, Grune & St:ratton, 1977. 55. Rivers MB, Pulido ]S, Folk]C: Ill-defined choroidal neovascularization within ocular histoplasmosis scars. Retina 1992;12:90-95. 56. Ryan SJ: De novo subretinal neovascularization in the histoplasmosis syndrome. Arch Ophthalmol 1976;94:321-327. 57. Schlaegel TF: The concept of invisible choroiditis in the ocular histoplasmosis syndrome. Int Ophthalmol Clin 1983;23:55-63. 58. Schlaegel TF: In discussion of Gass]DM and Wilkinson CP: Followup study of presumed ocular histoplasmosis. Trans Am Acad Ophthalmol Otolaryngol 1972;76:693-694. 59. Martin DF, Whitcup SM: Syndromes of possible infectious origin. In: Tabbara KF, Hyndiuk RA, eds: Infections of the Eye. Boston, Little, Brown, 1996, pp 595-597. 60. Meredith TA, Smith RE, Braley RE, et al: The prevalence of HLAB7 in presumed ocular histoplasmosis in patients with peripheral atrophic scars. Am] OphthalmoI1978;86:325-328. 61. Grossnildaus HE, Hutchinson AK, Capone A], et al: Clinical pathologic features of surgically excised choroidal peovascular membranes. Ophthalmology 1994;101:1099-1111. 62. Kleiner RC, Ramer CM, Enger C, et al: Subfoveal neovascularization in the ocular histoplasmosis syndrome: A natural history study. Retina 1988;8:225-229. 63. Macular Photocoagulation Study Group: Recurrent choroidal neovascularization after argon laser photocoagulation for neovascular maculopathy. Arch Ophthalmol 1986;104:503-512. 64. Macular Photocoagulation Study Group: Argon laser photocoagulation for neovascular maculopathy: Three-year results from randomized clinical trials. Arch Ophthalmol 1986;104:694-701. 65. Irvine AR, Spencer WH, Hogan M], et al: Presumed chronic ocular histoplasmosis syndrome: A clinical-pathologic case report. Trans Am Ophthahnol Soc 1976;94:91. 66. Krill AE, Christi MI, Klien BA, et al: Multifocal inner choroiditis. Trans Am Acad Ophthalmol Otolaryngol 1969;73:222-245. 67. Lewis ML, Van Newkirk MR, Gass]D: Follow-up study of presumed ocular histoplasmosis syndrome. Ophthalmology 1980;87:390-399. 68. Schlaegel TF: The natural history of histo spots in the disc and macular area. Int Ophthalmol Clin 1975;15:19-28. 69. Smith RE, Ganley]P: The natural history of non-disciform ocular histoplasmosis. Can] Ophtl1almol 1977;12:114-120. 70. Watzke RC: Presumed histoplasmosis syndrome. Trans New Orleans Acad Ophthalmol 1983;31:89-96. 71. lost BF, Olk R], Burgess DB: Factors related to spontaneous visual recovery in the ocular histoplasmosis syndrome. Retina 1987;7:1-8. 72. Campochiaro PA, Morgan KM, Conway BP, Stathos J: Spontaneous involution of subfoveal neovascularization. Am] Ophthalmol 1990;109:668-675. 73. Macular Photocoagulation Study Group: Argon laser photocoagulation for ocular histoplasmosis: Results of a randomized clinical trial. Arch Ophtl1almol 1983;101:1347-1357. 74. Macular Photocoagulation Study Group: Krypton laser photocoagulation for neovascular lesions of ocular histoplasmosis: Results of a randomized clinical trial. Arch OphthalmoI1987;lQ5:1499-1507. 75. Macular Photocoagulation Study Group: Argon laser photocoagulation for neovascular maculopatl1y: Five-year results from randomized clinical trials. Arch Ophthalmol 1991;109:1109-1114. 76. Callanan D, Fish GE, Anand R: Reactivation of inflammatory lesions in. ocular histoplasmosis. Arch Ophthalmol 1998;116:470474. 77. Orlando RG, Davidorf EH: Spontaneous recovery phenomenon in the presumed ocular histoplasmosis syndrome. Int Ophthalmol Clin 1983;23:137-149. 78. Singerman L], Wong BA, Smith S: Spontaneous visual improve-

CHAPTER 28: PRESUMED OCULAR HISTOPLASMOSIS SYNDROME

79. 80. 81.

82.

83.

84.

85.

86.

87.

88. 89.

90. 91.

92. 93.

94.

95.

96.

97. 98.

99.

100.

101.

102.

ment in the first affected eye of patients with bilateral disciform scars. Retina 1985;5:135. Harris MJ, Robbins D, Dieter JM: Eccentric visual acuity in patients with macular disease. Ophthalmology 1985;92:1550. GassJDM: Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment, 3rd ed. St Louis, CV Mosby, 1978, pp 112-128. Macular Photocoagulation Study Group: Persistent and recurrent neovascularization after krypton laser photocoagulation for neovascular lesions of ocular histoplasmosis. Arch Ophthalmol 1989;107:344-352. Macular Photocoagulation Study Group. Krypton laser photocoagulation for idiopathic neovascular lesions: Results of a randomized clinical trial. Arch Ophtllalmol 1990;108:832-837. Macular Photocoagulation Study Group: Laser photocoagulation for juxtafoveal choroidal neovascularization. Arch Ophthalmol 1994;112:500-509. Macular Photocoagulation Study Group: Evaluation of argon green vs krypton red laser for photocoagulation of subfoveal choroidal neovascularization in the Macular Photocoagulation Study. Arch Ophthalmol 1994;112:1176-1184. Macular Photocoagulation Study Group: Laser photocoagulation for neovascular lesions nasal to the fovea: Results from clinical trials for lesions secondary to ocular histoplasmosis or idiopatllic causes. Arch Ophthalmol 1995;113:56-61. Macular Photocoagulation Study Group: The influence of treatment extent on tlle visual acuity of eyes treated with krypton laser for juxtafoveal choroidal neovascularization. Arch Ophthalmol 1995;113:190-194. Maumenee AE, Ryan SJ: Photocoagulation of disciform macular lesions in the ocular histoplasmosis syndrome. Am J Ophthalmol 1973;75:13. Schlaegel TF: Partial photocoagulation in the presumed ocular histoplasmosis syndrome. Perspect Ophthalmol 1977;1:25. The Canadian Ophthalmology Study Group: Argon green vs krypton red laser photocoagulation for extrafoveal choroidal neovascularization: One-year results in ocular his~Dplasmosis. Arch Ophthalmol 1994;112:1166-1173. Watzke RC, Leaverton PE: Light coagulation in presumed histoplasmic choroiditis. Arch Ophthalmol 1971;86:127. Berger AS, Kaplan HJ: Clinical experience with the surgical removal of subfoveal neovascular membranes: Short-term postoperative results. Ophthalmology 1992;99:969-975. Machemer R: Surgical approaches to subretinal strands. Am J Ophthalmol1980;90:81-85. Thomas MA, Dickinson JD, Melberg NS, et al: Visual results after surgical removal of subfoveal choroidal neovascular membranes. Ophthalmology 1994;101:1384-1396. Thomas MA, Grand MG, Williams DF, et al: Surgical management of subfoveal choroidal neovascularization. Ophthalmology 1992;99:952-968. Thomas MA, Kaplan HJ: Surgical removal of subfoveal neovascularization in the presumed ocular histoplasmosis syndrome. Am J Ophthalmol1991;111:1-7. Anderson A, Clifford W, Palvolgyi I, et al: Immunopatll010gy of chronic experimental histoplasmic choroiditis in tlle primate. Invest Ophtllalmol Vis Sci 1992;33:1637-1641. Ganley JP: Epidemiologic characteristics of presumed ocular histoplasmosis. Acta Ophtllalmol1973;119(suppl):1-63. Smith RE, Dunn S, Jester JV: Natural history of experimental histoplasmic choroiditis in the primate. I. Clinical features. Invest Ophthalmol Vis Sci 1984;25:801-809. Smith RE, Dunn S, Jester JV: Natural history of experimental histoplasmic choroiditis in tlle primate. II. Histopathologic features. Invest Ophthalmol Vis Sci 1984;25:810-819. Smitll RE, O'Connor GR, Halde Cj, et al: Clinical course in rabbits after experimental induction of ocular histoplasmosis. Am J Ophthalmol 1973;76:284-293. Smitll RE, Scalarone M, O'Connor GR, Halde CJ: Detection of Histoplasma capsulatum by fluorescent antibody techniques in experimental ocular histoplasmosis. AmJ Ophthalmol 1973;76:375380. Tewari RP, Sharma DK, Mathur A: Significance of tllY1nus-derived IJ1liphocytes in immunity elicited by immunization with ribosomes or live yeast cells of Histoplasma capsulatum. J Infect Dis 1978;138:605-613.

103. Davidorf FH: The role of T-IJ1liphocytes in the reactivation of presumed ocular histoplasmosis sCars. Int Ophthalmol Clin 1975;15:111-124. 104. Smith RE. Natural history and reactivation studies of experimental ocular histoplasmosis in a primate model. Trans Am Ophthalmol Soc 1982;80:695-757. 105. Smith RE, Macy JI, Parrett C, Irvine J: Variations in acute multifocal histoplasmic choroiditis in tlle primate. Invest Ophthalmol Vis Sci 1978;17:1005-1018. 106. Aronson SB, Fish MB, Pollycove M, Coon MA: Altered vascular permeability in ocular inflammatory disease. Arch Ophthalmol 1971 ;85:455-466. 107. Gamble CN, Aronson SB, Brescia FB: Experimental uveitis: 1. The production of recurrent immunologic (Auer) uveitis and its relationship to increased uveal vascular permeability. Arch Ophthalmol 1970;84:321-330. 108. Kaplan HJ, Waldrep JC: Immunologic basis of presumed ocular histoplasmosis. Int Ophthalmol Clin 1983;23:19-31. 109. Gwin RM, Makley TAJr, Wynlan M, et al: Multifocal ocular histoplasmosis in a dog and cat. J Am Vet Med Assoc 1970;176;638-642. 110. Foster CS, Sonntag HG: Essentials of microbiology in uveitis. In: Kraus-Mackiw E, 0' Connor GR, eds: Uveitis: PatllOphysiology and Therapy, 2nd ed. Stuttgart, Georg Thieme Verlag, 1986, pp. 29-46. Ill. Jester JV, Smith RE: Subretinal neovascularization after experimental ocular histoplasmosis sY1ldrome. Retina 1987;7:1-8. 112. Hayreh SS, Cullen JF: Atypical minimal peripapillary choroidal colobomata. Br J Ophthalmol 1972;56:86-96. 113. Wise GN, Henkind P, Alterman M: Optic disc drusen and subretinal hemorrhage. Trans Am Acad Ophthalmol Otolaryngol 1974;78:212-219. 114. Bird AC, Grey RHB: Photocoagulation of disciform macular lesions witll krypton laser. Br J Ophthalmol 1979;63:669-673. 115. Sabates FN, Lee KY, Ziemianski MC: A comparative study of argon and krypton laser photocoagulation in tlle treatment of presumed ocular histoplasmosis syndrome. Ophthalmology 1982;89:729-734. 116. Yassur Y, Gilad E, Ben-Sira I: Treatment of macular subretinal neovascularization with the red-light krypton laser in presumed ocular histoplasmosis syndrome. Am J Ophthalmol 1981;91:172176. 117. Cummings HL, Rehmar AJ, Wood VV], Isernhagen RD: Long-term results of laser treatment in the ocular histoplasmosis syndrome. Arch Ophthalmol 1995;113:465-468. 118. Fine SL, Wood VV], Singerman LJ, et al: Laser treatment for subfoveal neovascular membranes in ocular histoplasmosis syndrome: Results of a pilot randomized clinical trial. Arch Ophthalmol 1993;111:19-20. 119. Gass JDM: Choroidal neovascular membranes-Their visualization and treatment. Trans Am Acad Ophthalmol Otolaryngol 1973;77:310-320. 120. Shah SS, Schachat AP, Murphy RP, et al: The evolution of argon laser photocoagulation scars in patients with tlle ocular histoplasmosis syndrome. Arch Ophthalmol 1988;106:1533-1536. 121. LimJI, Schachat AP, Conway B: Macular hole formation following laser photocoagulation of choroidal neovascular membranes in a patient with presumed ocular histoplasmosis (letter). Arch Ophthalmol 1991;109:1500-1501. 122. Schlaegel TF: Treatment of the POHS. In: Schlaegel TF, ed. Ocular Histoplasmosis. New York, Raven Press, 1977, pp 209-259. 123. Schlaegel TF: Corticosteroids in the treatment of ocular histoplasmosis. Int Ophthalmol Clin 1983;23:111-123. 124. Gass JDM: Biomicroscopic and histopathologic consideration regarding tlle feasibility of surgical excision of subfoveal neovascular membranes. AmJ Ophthalmol 1994;118:285-298. 125. Melberg NS, Thomas MA, Burgess DB: The surgical removal of subfoveal choroidal neovascularization: Ingrowth site as a predictor of visual outcome. Retina 1996;16:190-195. 126. Akduman L, Del Priore LV, Desai VN, et al: Perfusion of the subfoveal choriocapillaris affects visual recovery after submacular surgery in presumed ocular histoplasmosis syndrome. Am J Ophthalmol 1997;123:90-96. 127. Grossniklaus HE, Green WR: Histopathologic and ultrastructural findings of surgically excised choroidal neovascularization. Submacular surgery trials research group. Arch Ophthalmol 1998; 116:745-749. 128. Makley TA, Craig EL, Worling K: Histopathology of ocular histoplasmosis. Int Ophthalmol Clin 1983;23:1-18.

CHAPTER 28: PRESUMED OCULAR HISTOPLASMOSIS SYNDROME 129. Saxe Sj, Grossniklaus HE, Lopez PF, et al: Ultrastructural features of surgically excised subretinal neovascular. membranes in the ocular histoplasmosis syndrome. Arch Ophthalmol 1993;111:8895. 130. Mann ES, Meredith TA: Ocular Histoplasmosis. In: Guyer DR, Yannuzzi LA, Chang S, et aI, eds: Retina-Vitreous-Macula. Philadelphia, W.B. Saunders, 1999, pp 178-188. 131. Melberg NS, Thomas lYrA, DickinsonjD, Valluri S: Managing recurrent neovascularization after subfoveal surgery in presumed ocular histoplasmosis syndrome. Ophthalmology 1996;103: 1064-1067. 132. Campochiaro PA: In discussion: Melberg NS, Thomas MA, Dickin-

son jD, Valluri S: Managing recurrent neovascularization after subfoveal surgery in presumed ocular histoplasmosis syndrome. Ophthalmology 1996;103:1067-1068. 133. Berger AS, Conway M, Del Priore LV, et al: Submacular surgery for subfoveal choroidal neovascular membranes in patients with presumed ocular histoplasmosis. Arch Ophthalmol 1997;115:991996.

Acknowledgments I wish to thank Malika Singh and Mani Singh for their support in completing this chapter.

I Elisabeth M. Messmer

Infectious chorioretinitis/endophthalmitis is defined by the pi'esence of actively replicating organisms within· the eye, associated with a variable degree of inflammation. VVhen the organisms are introduced into the eye from outside the body (e.g., at the time of ocular surgery or trauma) the infection is termed exogenous. An infection resulting from septic embolization (from extraocular sources) is termed endogenous. Fungal organisms, such as Candida species, are observed in endogenous and, less frequently, in exogenous ocular infections. 1 Intraocular candidiasis may produce a choroiditis and/ or retinitis that may break through to the vitreous and cause endophthalmitis. Candida chorioretinitis is defined as the presence of focal, deep, white, infiltrative, chorioretinal lesions with no evidence of direct vitreal involvement except a diffuse vitreous haze. Candida endophthalmitis is defined as (1) Candida chorioretinitis with extension of the surrounding inflammation into the vitreous, or (2) a vitreous abscess manifesting as intravitreal fluff balls. 2

In 1877, Grawitz was probably the ,~rst author to report ocular candidiasis in animal experiments. He injected C. albicans into the vitreous of rabbits, causing vitreous opacities and small, white preretinal "structures."3 The initial pathologic description of endogenous ocular candidiasis in humans was reported in 1943 by Miale." In 1958, Van Buren pltblished the first clinical report of a patient with multiple myeloma who developed Candida chorioretinitis. 5 Prior to the availability of adequate therapy, treatment for eyes with endophthalmitis was limited to minimizing the cosmetic deformity that resulted as the intravitreal abscess pointed and discharged its liquefied intraocular contents. 1 Almost all eyes with endophthalmitis evolved to complete blindness. Greater awareness of the disease entity, improvement of diagnostic tools, the development of new antifungal agents, alternative routes of antifungal administration, and refined surgical techniques contributed to a better functional outcome. Nevertheless, Candida endophthalmitis still carries a grave prognosis for the eye and, in cases of endogenous endophthalmitis, is even a marker for poor patient survival.

According to the results of the National Nosocomial Infections Surveillance System surveys conducted through 1992, Candida has become the fourth most common iSQlate recovered from blood cultures in the United States. 6 Rates of candidemia have also increased substantially in Europe. 7 Approximately half of all candidal infections occur in surgical intensive care units. 7 It has been~I"e­ ported that the species of Candida causing infection have shifted noticeably toward nonalbicans species. s, 9 DNA

typing has verified that transmission occurs from patient to patient and from health care worker to patient. 7 Among the numerous risk factors for endogenous candidiasis (including Candida endophthalmitis) are the use of antibiotics, indwelling catheters, hyperalimentation, cancer therapy, immunosuppressive therapy after organ transplantation, bone marrow transplantation, acquired immunodeficiency syndrome (AIDS), hospitalization in intensive care units, recent intra-abdominal surgery, candiduria, and colonization with Candida species. 7, 10-15 Ocular candidiasis has occurred as a complication of spontaneous abortion,16 as the only initial manifestation of pacemaker endocarditis,17 and after intravenous anesthesia with propofol,1s Candida endophthalmitis represents one of the most serious and increasingly common ocular complications of intravenous drug abuse. 15, 19-21 Fungal infection may result from contamination of the drug, syringes, needles, or the cotton used to filter the drug before intravenous injection. 20 , 21 Systemic fungal infections, especially candidiasis, have been increasingly encountered among high-risk neonatal patients. Candida sepsis was reported to occur in 3% to 4% of premature infants with a birthweight of under 1500 g.22,23 Further risk factors include extended antibiotic therapy, prolonged parenteral nutrition or use of fat emulsions, chronic artificial ventilation, and prior surgery.22, 24---27 In neonates with positive blood, urine, cerebrospinal fluid, or stool cultures of Candida albicans, Chen observed candidal meningitis in 55% and Candida endophthalmitis in 46% of infants. 28 Candida endophthalmitis, however, was also reported in otherwise healthy adults. 29 , 30 Exact numbers concerning the annual incidence of Candida endophthalmitis are not available. Fungal organisms, however, account for more than half of cases of endogenous endophthalmitis, with Candida albicans being responsible for 75% to 80% of cases. 31 , 32 Risk factors for exogenous Candida endophthahnitis include trauma and ocular surgery, especially cataract extraction with intraocular lens implantion 33-38 and perforating keratoplasty.39-42 Fungal endophthalmitis, especially that caused by candidal infection, is a frequent complication reported to occur in 9.9% to 45% of hospitalized patients with candi.. demia. lO , 11,43,44 In a study by Brooks, patient age, sex, underlying diseases, presence of Foley catheters, bacteremia, white blood cell count, use of multiple antibiotics, hyperalimentation, or surgery did not differ between the candidemic patients with and without Candida endophthalmitis. Moreover, groups were similar in number of sites colonized with yeast and species of Candida recovered. Io In a prospective multicenter study, Donahue and coworkers examined 118 patients with candidemia adequately treated with antifungal therapy. Candida chorioretinitis was seen in only 9% of patients. No patient was shown to progress to Candida ~ndophthalmitis.2

CHAPTER 29:

The presence of Candida endophthalmitis in ~ospita~­ ized patients is an important indica~or of ~ystemIc.cand~­ diasis, as evidenced by the pathologIc findmg of dIssemInated candidiasis in 78% of autopsy patients with Candida endophthalmitis. 29 The overall mortality of hospitalized patients with candidemia is high (53% to 61 %),12,13,45 with almost half the deaths occurring in the first week after candidemia begins. The mortality rate for patients with endogenous Candida eridophthalmitis is similarly high. Edwards and colleagues reviewed 76 cases of. Candida endophthalmitis and found an overall mortalIty of 50%.46 Menezes and associates reported an overall mortality rate of 77% of severely ill patients with Candida endophthalmitis, with an even higher mortality of 80% ~or intensive care patients. 12 Other authors found mortalIty rates ranging from 0% to 22% in their pa~ients ~th Candida endophthalmitis who were treated wIth vanous antifungal therapies with or without accompanying vitrectOlny or intravitreal antifungals. 13 , 29, 32, 47

CLINICAL CHARACTERISTICS Endogenous Candida Chorioretinitisl Endophthalmitis Ocular symptoms have been reported to be uncommon, especially in patients with peripheral chorioretinal Candida lesions or in moribund patients. Brooks noted the complete absence of visual symptoms even in patients with confirmed Candida endopht,llalmitis.lo Donahue and colleagues reported visual complaints in only 9 of .12 patients with ocular candidiasis. 2 ~atients wit~ Candzda endophthalmitis may complain of mIld ocular dIscomfort, red eye, floaters, and slowly progressing visu~l lo~s.2, 25, 48 Candida chorioretinitis, with focal, deep, whIte, Infiltrative chorioretinal lesions, is mainly bilateral, multiple (of;en including more than ten lesions), and predominantly observed in the posterior pole.2, 49 In 13 of 19. eyes with Candida chorioretinitis, additional fundus lesIOns, including nerve-fiber-Iayer infarcts, intraretinal hemorrhages, and white-centered hemorrhages (Roth spots), were present. 2 Whereas intraretinal hemorrhages ~r~ n?t usually the sole manifestation of intraocular candIdIasIs, nerve-fiber-Iayer infarcts and Roth spots are known to occur in hematogenously disseminated ocular infections. Moreover, Candida has been isolated from Roth spots,5,46 and therefore Roth spots could conceivably represent an early, nonspecific marker of Candida infection. 2 Neutropenia may inhibit the formation of typical Candida lesions in both animals and humans. 50 Candida endophthalmitis· presents as Candida chorioretinitis with extension of the surrounding inflaInmation into the vitreous, or vitreous abscess manifesting as intravitreal fluff balls. The vitreous opacities may be connected by strands producing a string-of.,.pearls appearance 15 (Fig. 29-1). Papillitis may be present. 48 Candida endophthalmitis follows a more indolent course than that of acute bacterial endophthalmitis. 25 Anterior segment pathology may include conjunctival hyperemia (only seen in 21 % of patients with ocular candidiasis by Donahue 2) anterior chamber cells, hypo. 2' -" '12 46 51 C orn eal . synec h·.c pyon, and postenor Iae .LOrmatIOn.

FIGURE 29-1. "String of pearls" appearance to the vitreal exudates in a patient with endogenous Candida endophthalmitis. (See Color insert.)

involveInent may result in suppurative keratitis with perforation. 26 Patients with endogenous Candida endophthalmitisresulting from intravenou~ drug abuse may present .~th. n~ clinical or serologic eVIdence of systeInIc candIdIasIs, suggesting that ocular candidiasis may have been caus.ed by transient candidemia. Anterior uveitis a~'ld extensIve vitreous involvement are common, and patIents do not necessarily show associated retinal lesions. 15 , 19 This may result in part from the fact that these patients seek treatment late, when retinal lesions have either resolved or been obscured by pronounced vitreous involvement. 15 Ocular findings in children with endogenous Candida endophthalmitis may mimic other .ocu~ar disoI~ders. Clinch and associates observed a localIzed Intralentlcular candidal abscess presenting as an infantile cataract with associated endophthalmitis in a 6-month~old infant. 25 Shields and coworkers report a systemically healthy 12month-old boy who developed ocular candidiasis simulating retinoblastoma. 3o Hypopyon formation; synec~iae, and the absence of a distinct ocular mass WIth calCIfications on ultrasound and computed tomographic examinations should differentiate endophthalmitis from retinoblastoma in most cases. 30

Exogenous Post-traumatic

Endophthalmitis

Fungal endophthalmitis is a rare but devast~ting com~li­ cation of penetrating ocular trauma. ForeIgn matenal contaminating the wound, especially wood or other vegetable matter, may harbor fungi. 52 ,53 Mycotic endophthalmitis occurring after trauma is often caused by septate filamentous fungi (e.g., Fusarium solani and Aspergillus species). Yeasts are rarely isolated. 53 The signs of infection frequently are obscured by tissue damage and inflammation as a result of the injury. Therefore, diagnosis and initiation of treatment are often delayed. These factors co~tribute to the overall poor prognosis associated with traumatic fungal endophthalmitis. 53

Postoperative Candida endophthalmitis is a rare complication of intraocular surgery, but it represents a potentially catastrophic

CHAPTER 29: CANDIDIASIS

evenL Endophthalmitis caused by coagulase-negative Staphylococcus species and Propionibacteriu1TL acnes must be included in the differential diagnosis of indolent subacute or chronic cases of postoperative uveitis. Cataract Surgery. Several cases of non-Candida 54- 55 and Candida endophthalmitis34, 35, 57 have been reported to have occurred secondary to contaminated solutions. Stern and associates describe a large group of patients who developed Candida parapsilosis endophthalmitis 1 to 18 weeks after cataract surgery as a result of contaminated intraocular irrigating solutions. Patients developed indolent inflamluation with a fibrinopurulent anterior chamber exudate and vitreous snowball opacities. 34 Discontinuation of topical steroid therapy led to a dramatic increase in intraocular inflammation and ocular discOlufort in most patients. 34 Delayed-onset pseudophakic endophthalmitis caused by C. parapsilosis has been reported in three patients 1 to 23 months following cataract extraction with posterior chamber intraocular lens implantation. The patients exhibited keratic precipitates, a white intracapsular plaque thought to contain sequestered organisms within the capsule, stringy white infiltrates in the anterior vitreous adjacent to the capsular remnants, and a mild diffuse vitreitis. 33 Perforating Keratoplasty. Candida albicans endophthalmitis has been reported following penetrating keratoplasty.39-42 Postkeratoplasty fungal endophthalmitis may originate from the operative site, cOJl-taminated solutions, culture media, and contaminated donor tissue. Up to 27% of eyes suitable for corneal transplantation have been found to harbor fungi,58 and cultures of donor rims as well as corneal storage media were positive for Candida species in most of the reported cases of fungal endophthalmitis following perforating keratoplasty.39-41 Patients with postkeratoplasty Candida endophthalmitis typically present with mild to moderate pain, purulent discharge, conjunctival injection, multiple fluffy infiltrates at the graft-host interface, or endothelial plaques associated with vitreitis. 39-41

Treated chorioretinal lesions may heal either as a faint gliotic scar, or as a focal defect in the pigment epithelium. 49 However, if left untreated, vitreous invasion with irreversible sequelae may eventuate, producing a vitreoretinal abscess with retinal necrosis, vitreal organization, tractional retinal detachment, cyclitic membrane formation, or phthisis bulbi. 15 , 32, 49, 50, 59-51 Even in treated cases, premacular scars may reduce visual acuity permanendy.15, 40, 48, 49 Postinflammatory fibrovascular membranes puckeringor tractionally detaching the macula may be surgically removed. McDonald and coworkers report on four eyes undergoing pars plana vitrectomy and membrane peeling after Candida endophthalmitis. Postoperative visual acuity ranged from 1/200 to 20/25, depending on the degree of macular pathology and the presence and location of full-thickness retinal scars.50 In rare cases, choroidal neovascular membranes may develop following endogenous Candida endophthalrriitis. 52

IMMUNOLOGY Candida albicans is normally present as an intestinal saprophyte in 20% to 40% of healthy individuals. Other Candida species may also be found in the gastrointestinal tract, although in lower concentrations. 53 In situations of internal environmental change, such as results from chronic use of antibiotics, indwelling catheters, hyperaliluentation, immunosuppressive therapy, or recent intraabdominal surgery, Candida may become pathogenic.48 Animal studies 45 , 54 and human histopathologic evaluations 45, 54, 55 have demonstrated the ability of Candida to spread hematogenously to the choroid and retina. Species of Candida other than C. albicans that are encountered in human disease include C. tropicalis, C. parapsilosis, C. krusei, C. stellatoidea, C. guilliennondii, C. lusitaniae, C. glabrata, C. pseudotropicalis, and C. rugosa. 55 Immunocompromised patients with hematologic malignancies are particularly prone to develop non-albicans candidal infections. 57 The relative resistance of the eye to non-albicans candidal involvement has been demonstrated in a rabbit model of endophthalmitis by Edward and colleagues.58 While C. albicans caused endophthalmitis at an inoculum of 105 colony-forming units (cfu)/ml, 108 cfU/IUl of C. tropicalis and C. stellatoidea were necessary to cause chorioretinal lesions. However, these concentrations did not cause endophthalmitis. C. parapsilosis, C. guilliermondii, and C. krusei were not pathogenic to the eye at the doses studied.58 In humans, Candida species reported to cause endogenous endophthalmitis include C. albicans, C. tropicalis, C. stellatoides, C. parapsilosis, and C. krusei. 31 Contradictory data are available in humans with respect to the incidence of endophthalmitis caused by different Candidal species. One study found that disseminated C. tropicalis was associated with a higher rate of endophthalmitis than was C. albicans (23% versus 6%) .59 Most other studies report the opposite, with the highest rate of endophthalmitis in C. albicans fungemia. 2, 10, 32, 43, 51, 55 In patients with intraocular candidiasis, C. albicans was the most common species isolated from blood (58 %), followed by C. tropicalis (14%), C. (Torulopsis) glabrata (14%), C. parapsilosis (9%), and other species (7%) in a study by Donahue. 2 Mter infection, Candida may persist in ocular tissues for a long time. C. albicans was isolated from a rhesus monkey eye 110 days after intravascular inoculation. 70 The reasons for the susceptibility of the retina to Candida infections compared with other organs are unclear. Fungal virulence may relate to the ability of the organism to produce pseudohyphae from blastospores that lodge in the deep capillary plexus of the retina and in the choriocapillaris. The production and localization of various phospholipases in the growing fungal buds suggest that phopholipid-rich tissues such as the retina and choroid may provide a substrate for yeast filamentation. 71 Much of the tissue destruction observed in fungal infection may be not so much the direct consequence of invasion but rather the effect of mediators of inflammation induced by the organisms. 72 The histopathologic examination of ocular Candida lesions may demonstrate a cOlubination of an acute nec-

CHAPTER 29: CANDIDIASIS

rotIzmg process and a chronic granulomatous reaction by histiocytes and round cells occurring primarily in the choroid. 26 , 46, 48, 49, 73 Colonies of Candida, identified by their characteristic budding pseudohyphae, may be found in the choroid, the retinal pigment epithelium, and Bruch's membrane. Extension into the subretinal space and into the retina occurs secondarily.48, '19 Retinal involvement is usually accompanied by a macrophage response in the overlying vitreous. 49 The internal limiting membrane of the retina provides no barrier to the spread of C. albicans, and if the lesion remains untreated, vitreous invasion may occur. 49 Vitreous lesions are composed largely of neutrophils, macrophages, and epitheloid cells, but they may also harbor Candida organisms. 15 , 46, 73, 74 In adults, immune responses to Candida organisms include monocytic and neutrophilic phagocytosis, along with intracellular killing of fungal organisms. 75 In addition, serum factors and lymphocytic function, particularly T lymphocytes, are important. The patient's immune status and the health of the affected eye modify the immune response to Candida. Moreover, the frequent use of corticosteroid eyedrops in the early postoperative period may mitigate signs and symptoms of infection. 40 Newborn infants are probably at higher risk for the development of Candida infections because of their normally deficient host immune system and the reduced killing ability of their leukocytes. 76, 77

DIAGNOSIS Candida endophthalmitis shoul¢ be suspected in any patient with one of the known predisposing conditions. The presence of the characteristic white chorioretinal lesions or puff-balI-like vitreous opacities is highly suggestive in the appropriate clinical setting. Because of the lack of clinical or laboratory parameters to distinguish between candidemic patients with and those without endophthalmitis, Brooks recommends early ophthalmoscopic examinations. In his experience, follow-up examinations are often helpful to the clinician in guiding antifungal therapy.1O Blood, urine, indwelling catheters, and any potential source of infection should be cultured. Additional examinations and tests are helpful in confirming the final diagnosis of ocular candidiasis.

Nonocular Cultures The significance of candidemia remains problematic. Positive fungal blood cultures may represent skin contamination without candidemia, true but transient candidemia without deep tissue invasion, or candidemia with deep tissue invasion. 43 A presumptive diagnosis of ocular candidiasis may be made if Candida is cultured from a source other than the eye (e.g., blood, urine, cerebrospinal fluid) in the presence of typical ocular lesions.Unfortunately, blood cultures are frequently negative in systemic candidiasis.73, 78

Antibody Testing The value of Candida antibody testing in serum as an aid in the early diagnosis of disseminated candidiasis remains questionable. Various methods of antibody determination with rather low sensitivity and specificity, including immunodiffusion, counterelectrophoresis, and latex agglutina-

tion (LA), have been employed. 79-82 According to Gentry and colleagues, LA is the most sensitive test for antibody determination. 79 LA titers are, however, rarely of benefit in predicting the presence of endophthalmitis in ocular candidiasis. 43 Mathis and associates observed a significant difference in the local production of specific antibodies in the anterior chamber between patients with Candida endophthalmitis and controls. They even report a correlation between the severity of uveitis and antibody titers. 83

Antigen Testing Determination of Candida antigen titers can offer significant clinical advantages to the treating physician. Some studies have shown relatively high sensitivity and specificity of antigen detection tests for invasive disease caused by Candida species. 84 Parke and coworkers demonstrated antigen titers indicative of disseminated disease in three of four patients with endogenous Candidaendophthalmitis. 43 In a study by Bailey and colleagues, however, all five patients with Candida endophthalmitis had a negative LA test for serum antigen. 85 Antigen titers may prove to be more sensitive than antibody titers, especially in immunocompromised patients, who are incapable of mounting an adequate antibody response to Candida.

Anterior Chamber Tap and Vitreous Aspiration Henderson and coworkers confirmed the diagnosis of candidiasis in 62% of eyes with vitreous aspiration, but they found anterior chamber aspiration to be a poor diagnostic technique. l l Axelrod and PeYInan succeeded in culturing Candida after aspiration from the vitreous in only one of six untreated rabbit eyes exogenously inoculated with Candida, although abundant organisms were demonstrated in all eyes microscopically after enucleation. 87 A random, or even a directed, aspiration can fail to produce positive Candida cultures or smears because of the sequestration of the organisms within large-diameter inflammatory nodules. 15 Thus, vitrectomy may be the only procedure that can reliably obtain Candida from an infected vitreous.

Pars

Vitrectomy

The goal of vitrectomy in eyes with Candida endophthalmitis is to confirm the presumptive clinical diagnosis and remove the intravitreal fungal mass and inflammatory debris while delivering safe and therapeutic doses of antibiotics to the infected eye. Diagnostic vitrectomy is especially valuable in a subgroup of patients with presumed localized intraocular infection without clinical or cultural evidence of disseminated disease. 32 A vitreous infusion suction cutter is necessary to remove formed vitreous for suspected fungal infection. One recOlnmended technique consists of culturing the harvested vitreous specimen under sterile operating room conditions. Samples, diluted by the irrigating solution, are passed through a disposable membrane filter system.88 Specimens are inoculated onto Sabouraud's agar, blood agar, and liquid brain-heart infusion with gentamicin at room temperature for fungal isolation. For rapid diagnosis, slides are prepared for GraIn staining, Giemsa staining, and modified Grocott's methenamine-silver (GMS)

CHAPTER 29: CANDIDIASIS

stain, and Cellufluor or Ca1cofluor white techniques for the identification of fungal elements. If retinoblastoma is a consideration, fine-needle biopsy, rather than vitrectomy, should beperformed. 30

DIAGNOSIS The differential diagnosis of Candida chorioretinitis includes necrotizing retinopathies caused by herpes viruses such as cytomegalovirus (CMV) , herpes simplex virus (HSV) , and varicella-zoster virus (VZV) , and the acute retinal necrosis syndrome (Table 29-1). Protozoan infections such as toxoplasmic retinochoroiditis or nematode infections (e.g., Toxocara canis) may simulate candidal chorioretinitis. Bacterial endophthalmitis and fungal uveitis caused by organisms other than Candida (e.g., Aspergillus sp., Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis) must be differentiated from ocular candidiasis. Choroidal granulomas (e.g., in ocular sarcoidosis) may mimic candidal chorioretinitis. Retinoblastoma and large cell lymphoma must be included in the differential diagnosis of ocular candidiasis. Even cottonwool spots may be confused with chorioretinal infection by Candida; however, their eventual regression over 5 to 8 weeks, depending on the underlying diagnosis, facilitates their diagnosis.

TREATMENT Endophthalmitis is a potentially devastating disease that requires aggressive management. Although the incidence of serious infections caused by Carcdida species is rising rapidly, the most appropriate management strategies for such infections remains severely limited because large controlled studies of the various approaches have not been performed. 68 The mainstay of treatment for Candida endophthalmitis has been a combination of systemic and intravitreal amphotericin B with or without pars plana vitrectomy.18, 49,51,61,68 Newly developed triazole compounds, such as fluconazole, are very promising agents for the therapy of systemic and ocular candidiasis. 89 - 93 Moreover, the removal of precipitating factors such as intravenous lines is extremely important.

Amphotericin B

Amphotericin· B was discovered in 195694 and was first used for the treatment of ocular candidiasis in 1960. 95 It acts by binding to cell membrane sterols, resulting in the leakage of cellular constituents and ultimately the death of the organism. 96 It is not absorbed by the gastrointestinal tract and must therefore be given intravenously. The TABLE 29-1. DIFFERENTIAL DIAGNOSIS OF OCULAR CANDIDIASIS Bacterial endophthalmitis Viral retinopathies (CMV, HSV, VZV) Acute retinal necrosis Toxoplasmic retinochoroiditis Toxocara canis chorioretinitis Aspergillosis Cryptococcosis

Histoplasmosis Blastomycosis Sarcoidosis Retinoblastoma Large cell lymphoma Cotton-wool spots

CMV, cytomegalovirus; HSV, herpes simplex virus; VZV, varicella-zoster/virus,

maximum recommended dose is 0.5 to 1.0 mg/kg/day for an average daily dose of 40 to 50 mg. Therapy should continue until the retinal lesions disappear completely or become small and/or are replaced by fibrous tissue. 32 Although amphotericin B is effective against a wide range of fungal pathogens, its systeluic use in treating fungal endophthalmitis is severely limited by poor ocular penetration. 97 ,98 Persistent intraocular infection has been reported in spite of an adequate course of treatment when the vitreous is involved. 15, 49 An additional drawback of systemic amphotericin B therapy is the wide spectrum of toxic side effects encountered, ranging from nausea, vomiting, and malaise, to anemia and renal failure. Moreover, a minimum dose of 750 to 1000 mg of amphotericin B is required for cure of candidal endophthalmitis. 15 , 46, 89 Systemically administered antimycotics are important not only to treat endophthalmitis but also in the treatment of systemic infections. 16, 32 If evidence of systeluic candidiasis is present, intravenous amphotericin B should be administered. For severe systemic infections, a combination of intravenous amphotericin B and another antifungal drug (e.g., flucytosine) is recommended by some authors because of their synergistic effect. 2o ,99 However, the increased risk of bone marrow suppression or diarrhea as a complication of the simultaneous use of these drugs must be weighed against the potential benefit. 99 The potential toxicity of amphotericin B has led to the development of lipid-associated preparations, including liposomal amphotericin B, amphotericin B colloidal dispersion, and amphotericin B lipid complex. These preparations are less nephrotoxic, but higher systemic doses than those of conventional amphotericin B are needed to achieve the same effect in invasive fungal infections.100-102 The efficacy of lipid-associated formulations of amphotericin B in the treatment of ocular candidiasis is under investigation. Studies have shown that amphotericin B can be delivered to the eye in effective concentrations by direct intravitreal injection. Doses of 5 and 10 /-Lg amphotericin B injected intravitreally into eyes of healthy rabbits did not cause retinal toxicity clinically, microscopically, or by electroretinography.103 The safety of intravitreal injection of amphotericin B in humans has been demonstrated in several case reports in which histopathologic confirmation of a cured infection, absent retinal toxicity, and normal electroretinograms following intravitreal amphotericin B injection are described. 34, 104, 105 A 10-/-Lg dose into a human eye would theoretically provide a concentration of 2.5 /-Lg/ml, which is effective against most fungal pathogens. 103 When there is no extraocular evidence of candidemia or candidiasis, local ocular treatment with intravitreal amphotericin B may be all that is required. 32

Flucytosine In an effort to avoid the toxicity of systemic amphotericin B administration, recent studies have evaluated the use of alternate systemic therapy with fluorinated pyrimidine (flucytosine) or imidazole compounds including ketoconazole or fluconazole .18, 32, 51, 73, 89-93, 99 Flucytosine is selectively taken up by susceptible fungi and deaminated to 5-fluorouracil, which blocks DNA and RNA synthesis. The suggested oral dose is 50 to 150 lUg/

zr

CHAPTER 29: CANDIDIASIS

kg/ day in four divided doses. It shows excellent oral absorption and ocular penetration, and it is active against C. albicans. 73 , 106 Systemic administration is relatively risk free, but bone marrow and liver toxicity can occur. Because of a significant incidence of primary resistance during therapy, flucytosine should not be used alone in disseminated disease.99

Imidazole derivates Imidazole derivates act by inhibiting membrane sterols in C. albicans; they have good antifungal activity, absorption, and ocular penetration with minimal toxicity. 107, lOS Fluconazole shows improved permeability into the vitreous compared to ketoconazole. It is the only antifungal that penetrates into cerebrospinal fluid. However, candidal resistance was reported in cases treated with imidazole compounds, and a patient developed Candida endophthalmitis while receiving fluconazole for the management of candidal pyelonephritis. l09 In a rabbit model, intravenous amphotericin B was superior to intravenous fluconazole in the treatment of Candida endophthalmitis. 110 Fluconazole appeared to be efficacious in treating endophthalmitis after 10 to 17 days of therapy, but this salutary treatment effect was lost by day 24, and fluconazole failedto eradicate C. albicans from the rabbit eyeYo Brod and colleagues, however, successfully treated five patients with systemic flucytosine (2 g every 6 hours), or ketoconazole (200 to 400 mg/d) in association with intravitreal amphotericin B injection. 32 They recommend this regimen especially for pat~nts without evidence of disseminated disease. 32 Christmas and Smiddy treated their patients suffering from endogenous Candida endophthalmitis with oral fluconazole (200 mg/d) and vitrectomy without intravitreal injection of antifungals. They also report clearance of infection and improvement of visual acuity in all six patients. 92 The successful use of oral fluconazole in a dosage of 200 to 800 mg PO daily for 2 to 4 months as the only treatment for endogenous Candida endophthalmitis has also been reported. IS, 73, S9-91 Other imidazole derivates, such as itraconazole, miconazole, and econazole, are also effective anticandidal substances, and they show good ocular penetration. Ill, 112 They are used in the treatment of keratomycosis,113-117 but therapeutic experience in the Inanagement of Candida chorioretinitis and endophthalmitis with these drugs is limited and anecdotal. 11S

Corticosteroids Intraocular and systemic corticosteroids have been suggested as a useful adjunctive treatment in cases of fungal endophthalmitis. 20 , 51, 119, 120 However, controversial opinions exist concerning their use in Candida endophthalmitis. Steroids may potentiate systemic candidiasis, but they may attenuate the inflammatory response in ocular candidal infection and may prevent vision-threatening sequelae.

Role of Vitrectomy Pars plana vitrectomy offers several theoretical advantages to the treatment of Candida endophthalmitis. In addition to obtaining vitreous biopsy to correctly identify the organism, vitrectomy physically removes a large mass of

invading organisms, thereby fulfilling the general surgical criteria of incision and drainage of an abscess. Huang and coworkers demonstrated that intravitreal amphotericin B combined with vitrectomy was more effective in reducing vitreous opacification than was the use of intravitreal amphotericin B alone in a rabbit model of exogenous Candida endophthalmitis. 121 In 1976, Snip and Michels reported the successful use of pars plan vitrectomy and intravitreal amphotericin B in the management of endogenous Candida endophthalmitis in a patient. 122 Furthermore, it has been shown that infected eyes treated with vitrectomy and intraocular antibiotics have a surprisingly greater number of negative cultures 1 week later than do those treated with intraocular antibiotics alone. 123 Vitrectomy also removes the scaffold on which fibrotic traction bands might develop, resulting in secondary traction retinal detachment. 12'1 Moreover, vitreous, as a potential barrier to the diffusion of large molecules such as amphotericin B, is eliminated. 122 Amphotericin clearance and toxicity in vitrectomized versus nonvitrectomized eyes was studied by Doft and coworkers 125 and Baldinger and colleagues. 126 The most rapid decay in amphotericin concentration from the vitreous cavity occurred in aphakic vitrectomized eyes, with a half-life of 1.4 days compated to aphakic normal eyes (4.7 days) and phakic Candida infected eyes (8.6 days). Therefore, readministration of intravitreal amphotericin may be necessary 3 to 4 days following vitrectomy if clinically indicated. 32 , 125 Toxicity of amphotericin was not increased in vitrectomized eyes?26 Pars plana vitrectomy and injection of intravitreal amphotericin B should be considered for moderate to severe vitreous involvement in an eye with presumed ocular candidiasis. Most authors reserve surgery for patients with a visual acuity of 20/400 or less, or when the fundus cannot be visualized due to severe vitreous involvement. 72 The best timing for surgical therapy, however, is still not known. It may well be that early vitrectomy combined with intravitreal injections of amphotericin B offers the best chance for functional improvement. 124 The role of intraocular lens removal or exchange remains controversial in the management of exogenous Candida endophthalmitis following cataract surgery.34, 35, 37 Successful sterilization of the vitreal cavity does not require routine intraocular lens removal, although recurrences are possible. 34, 35 Stern and colleagues recommend introcular lens explantation only when clinical response to pars plana vitrectomy and intravitreal alnphotericin B is inadequate. 34 In cases where white plaque lesions are present at the posterior lens capsule, a large capsulectomy is warranted. 33 Single case reports have been published on the treatment of Candida endophthalmitis in children. In contrast to adults, intravenous infusions with amphotericin B, sometimes combined with flucytosine without vitrectomy, seem to be effective in these cases. 27 , 2S, 127 Having been treated with systemic antifungals alone, 11 premature infants demonstrated minimal residual ocular pathology.127 This may be due to the newborns' immature immune system resulting in less vitreous reaction and postinflammatory sequelae.

Prophylaxis The ultimate goal is to prevent disease. Prophylactic administration of oral nystatin can reduce fungal coloniza-

CHAPTER 29: CANDIDIASIS

tion and infection in very low birthweight infants. 128 The risk of systemic candidiasis can be minimized in patients by. following good antibiotic use principles. Indwelling intravascular devices and indwelling bladder catheters should be avoided when possible. 99

PROGNOSIS Although rare, spontaneous resolution of endogenous Candida endophthalmitis has been reported.129-131 Usually, the outcome of candidal endophthalmitis is dependent on four main factors: the virulence of the organisms, the duration of the inflammatory response, the prompt diagnosis, and correct management. 39 Moreover, the functional result depends on the extent and site of involvement of the chorioretinal lesions. 25 , 27 In recent publications, . final visual acuity following endogenous Candida endophthalmitis ranged from no light perception and phthisis to 20/15. 19 ,20,32,73 In five cases with less than 2 months between onset of sYlnptoms and initiation of antifungal therapy, four had a final visual acuity of 20/50 or better, but none of the patients with a delay of more than 2 months had a visual acuity better than 20/80. 32 Another important factor in determining the final visual outcome is the presence of intercurrent complications such as retinal detachments. 32 Depending on the time to diagnosis and appropriate therapy, visual acuity after postsurgical Candida endophthalmitis ranges from 20/25 to phthisis with no light perception. Reasons for bad visual acuity following postsurgical Candida endophthalmitis ~inc1ude graft failure, secondary glaucoma, pupillary membrane, and macular scars. 33 ,38-41 Infantile Candida endophthalmitis seems to have a good ocular prognosis for children treated promptly with systemic antifungal therapy.127

CONCLUSIONS Ocular candidiasis is one of the infectious causes of uveitis. The presence of Candida endophthahnitis is a good indicator of a systemic fungal infection that carries a high mortality in seriously ill patients in intensive care units. 12 Since many of these patients may have negative blood cultures despite extensive visceral involvement, the ophthalmologic examination is an important adjunct in the diagnosis of systemic candidiasis,12 and serial ophthalmic examinations are an objective measure of therapeutic response. 2 As in any infectious uveitis, steroids can suppress inflammation, but eventually the ocular problem deteriorates. A high index of suspicion is necessary to trigger a decision and to proceed to diagnostic vitrectomy in patients with Candida endophthalmitis. A stepladder approach in treatment of ocular candidiasis may be useful. Mild cases of Candida chorioretinitis without evidence of systemic disease may be managed with oral azole derivates alone, whereas advanced cases of Candida endophthalmitis and patients with candidemia need systemic antifungals and intravitreal amphotericin B injections combined with pars plana vitrectomy.

References 1. Weissgold DB, D'Amico DJ: Rare causes of endophthalmitis. Int Ophthalmol Clin 1996;36:163-177.

2. Donahue SP, Greven CM, ZuravlefflJ, et al: Intraocular candidiasis in patients with candidemia. Clinical implications derived from a prospective multicenter study. Ophthalmology 1994; 101: 13021309. 3. Grawitz P: Beitrage zur systematischen Botanik der pflanzlichen Parasiten mit experimentellen Untersuchungen i\ber die durch sie bedingten Krankheiten. Virchows Arch Path Anat 1877;70:546588. 4. Miale JB: Candida albicans infection confused with tuberculosis. Arch Pathol Lab Med 1943;35:427-437. 5. Van Buren JM: Septic retinitis due to Candida albicans. AMA Arch Pathol 1958;65:137-146. 6. Jarvis VVR: Epidemiology of nosocomial fungal infections, with emphasis on Candida species. Clin Infect Dis 1995;20:1526-1530. 7. Edwards JE: International conference for the development of a consensus on the management and prevention of severe candidal infections. Clin Infect Dis 1997;25:43-59. 8. Wingard JR: Importance of Candida species other than C. albicans as pathogens in oncology patients. Clin Infect Dis 1995;20:115125. 9. Pfaller MA: Nosocomial candidiasis: Emerging species, reservoirs, and modes of transmission. Clin Infect Dis 1996;22:S89-94. 10. Brooks RG: Prospective study of Candida endophthalmitis in hospitalized patients with candidemia. Arch Intern Med 1989;149:22262228. 11. Henderson DK, Edwards JE, Montgomerie JZ: Hematogenous Candida endophthalmitis in patients receiving parenteral hyperalimentation fluids. J Infect Dis 1981;143:655-661. 12. Menezes AV, Sigesmund DA, Demajo WA, et al: Mortality of hospitalized patients with Candida endophthalmitis. Arch Intern Med 1994;154:2093-2097. 13. Wey SB, Mori M, Pf(lller MA, et al.: Hospital-acquired candidemia: The attributable mortality and excess length of stay. Arch Intern Med 1988;148:2642-2645. 14. Coskuncan NM, Jabs DA, Dunn JP, et al: The eye in bone marrow transplantation. VI. Retinal complications. Arch Ophthalmol 1994;112:372-379. 15. Aguilar GL, Blumenkrantz MS, Egbert PR, McCulley JP: Candida endophthalmitis after intravenous drug abuse. Arch Ophthalmol 1979;97:96-100. 16. Haskjold E, Lippe von der B: Endogenous Candida endophthalmitis. Report of two cases. Acta Ophthalmol 1987;65:741-744. 17. Shmuely H, Kremer I, Sagie A, et al: Candida tmpicalis multifocal endophthalmitis as the only initial manifestion of pacemaker endocarditis. AmJ Ophthalmol 1997;123:559-560. 18. Daily MJ, Dickey JB, Packo KH: Endogenous Candida endophthalmitis after intravenous anesthesia with propofol: Arch Ophthalmol 1991;109:1081-1084. 19. Sugar HS, Mandell GH, Shalev J: Metastatic endophthalmitis associated with injection of addictive drugs. Am J Ophthalmol 1971;71:1055-1058. 20. Elliott JH, O'Day DM, Gutow GS, et al: Mycotic endophthalmitis in drug abusers. AmJ Ophthalmol 1979;88:66-72. 21. Vastine DW, Horsley W, Guth SB, Goldberg MF: Endogenous Candida endophthalmitis associated with heroin use. Arch Ophthalmol 1976;94:1805. 22. Baley JE, Kliegman RM, Fanaroff AA: Disseminated fungal infections in very low-birth-weight infants: Clinical manifestations and epidemiology. Pediatrics 1984;73:144-152. 23. Johnson DE, Thompson TR, Green TP, et al: Systemic candidiasis in very low-birth-weight infants « 1.500 grams). Pediatrics 1984;73:138-143. 24. Weese-Mayer DE, Fondriest DW, Brouillette RT, et al: Risk factors associated with candidemia in the neonatal intensive care unit: A case-control study. Pediatr Infect DisJ 1987;6:190-196. 25. Clinch TE, Duker JS, Eagle RC, et al: Infantile endogenous Candida endophthalmitis presenting as cataract. Surv Ophthalmol 1989;34:107-112. 26. Michelson PE, Rupp R, Efthimiadis B: Endogenous Candida endophthalmitis leading to bilateral corneal perforation. Am J Ophthalmol 1980;80:800-803. 27. Palmer EA: Endogenous Candida endophthalmitis in infants. Am J Ophthalmol 1980;89:388-395. 28. Chen JY: Neonatal candidiasis associated with meningitis and endophthalmitis. Acta PaedJap 1994;36:261-265.

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57. McCray E, Rampell N, Solomon SL, et al: Outbreak of Candida parapsilosis endophthalmitis after cataract extraction and intraocular lens implantation. J Clin Microbiol 1986;24:625-628. 58. White JH: Fungal contamination of donor eyes. Br J Ophthalmol 1969;53:30. 59. EdwardsJE, Mongomerie JZ, Foos RYet al: Experimental hematogenous endophthalmitis caused by Candida albicans. J Infect Dis 1975;131:647-657. 60. McDonald RH, Bustros de S, Sipperley JO: Vitrectomy for epiretinal membrane with Candida chorioretinitis. Ophthalmology 1990;97:466-469. 61. Wolfensberger TJ, Gonvers M: Bilateral endogenous Candida endophthalmitis. Retina 1998;18:280-281. 62. Beebe WE, Kirkland C, Price J: A subretinal neovascular membrane as a complication of endogenous Candida endophthalmitis. Ann Ophthalmol 1987;19:207-209. 63. Cohen R, Roth FJ, Delgado E, et al: Fungal flora of the normal human small and large intestine. N EnglJ Med 1969;280:638-641. 64. Hoffmann DH, Waubke TH: Experimentelle Untersuchungen zur metastatischen Ophthalmie mit Candida albicans. Graefes Arch Ophthalmol 1961;164:174-196. 65. Edwards JR, Lehrer RI, Stiehm ER, et al: Severe candidal infections: Clinical perspective, immune defense mechanisms, and current concepts of therapy. Ann Intern Med 1978;89:91-106. 66. Joshi N, HamoryBH: Endophthalmitis caused by non-albicans species of Candida. Rev Infect Dis 1991;13:281-287. 67. Horn R, Wong B, Kiehn TE, Armstrong D: Fungemia in a cancer hospital: Changing frequency, earlier onset, and results of therapy. Rev Infect Dis 1985;7:646-655. 68. Edwards JE, Mongomerie JZ, Ishida K, et al: Experimental hematogenous endophthalmitis due to Candida: Species variation in ocular pathogenicity. J Infect Dis 1977;135:294-297. 69. McDonnell Pj;.McDonnell JM, Brown RH, Green WR: Ocular involvement in patients with fungal infections. Ophthalmology 1985;92:706-709. 70. Green MT, Jones DB, Gentry LO: Endogenous Candida endophthalmitis in the primate. Invest Ophthalmol Vis Sci 1978;17(s):229. 71. Wilhelmus KR: The pathogenesis of endophthalmitis. Int Ophthalmol Clin 1987;27:74-81. 72. Okada AA, D'Amico DJ: Endogenous endophthalmitis. In: Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology, vol 5. Philadelphia, W.B. Saunders, 1994, pp 3120-3126. 73. Robertson DM, Riley FC, Hermans PE: Endogenous Candida oculomycosis. Report of two patients treated with flucytosine. Arch Ophthalmol 1974;91 :33-38. 74. Cohen M, Edwards JE, Hensley TJ, Guze LB: Experimental hematogenous Candida albicans endophthalmitis: Electron microscopy. Invest Ophthalmol Vis Sci 1977;16:498-511. 75. Baley JE, Annable WL, I\liegman RM: Candida endophthalmitis in the premature infant. Pediatrics 1981;98:458-461. 76. Dossett JH: Microbial defenses of the child and man. Deficient host mechanism of the newborn. Pediatr Clin North Am 1972;19:355-372. 77. Xanthou M, Valassi-Adam E, Kintsonidou E, Matsaniotis N: Phagocytosis and killing ability of Candida albicans by blood leukocytes of healthy term and preteI'm babies. Arch Dis Child 1975;50:72-75. 78. Bielsa I, Miro JM, Herrero C, et al:Systemic candidiasis in heroin abusers. Cutaneous findings. IntJ Dermatol 1987;26:314-319. 79. Gentry LO McNitt TR, Kaufman L: Use and value of serologic tests for the diagnosis of systemic candidiasis in cancer patients: A prospective study of 146 patients. Curl' Microbiol 1978;1:239-242. 80. Meckstroth KL, Reiss E, Keller ]W, Kaufman L: Detection of antibodies and antigenemia in leukemic patients with candidiasis by enzyme-linked immunosorbent assay. J Infect Dis 1981;144:24-32. 81. Filice G, Yu B, Armstrong D: Immunodiffusion and agglutination tests for Candida in patients with neoplastic disease: Inconsistent correlation of results with invasive infections. J Infect Dis 1977;135:349-357. 82. Stickle D, Kaufman L, Blumer SO, McLaughlin DW: Comparison of a newly developed latex agglutination test and an immunodiffusion test in the diagnosis of systemic candidiasis. Appl Microbiol 1972;23:490-499. 83. Mathis A, Falecaze F, Bessieres MH, et al: Immunological analysis of the aqueous humour in Candida endophthalmitis. II: Clinical study. BrJ Ophthalmol 1988;72:313-316.

29: 84. Fung JC, Donta ST, Tilton RC: Candida detection system (CANDTEC) to differentiate between Candida albicans colonization and disease. J Clin Microbiol 1986;24:542-547. 85. Bailey ]W, Sada E, Brass C, Bennett JE: Diagnosis of systemic candidiasis by latex agglutionation for serum antigen. J Clin MicrobioI 1985;21:749-752. 86. Henderson DK, EdwardsJE, Ishida K, et al: Experimental hematogenous Candida endophthalmitis: Diagnostic approaches. Infect Immun 1979;23:858-862. 87. Axelrod AJ, Peyman GA: Intravitreal amphotericin B treatment of experimental fungal endophthalmitis. Am J Ophthalmol 1973;76:584-588. 88. Forster RK, Abbott RL, Gelender H: Management of infectious endophthalmitis. Ophthalmology 1980;87:313-319. 89. Alder ME, Vellend H, Neely DM, et al: Use of fluconazole in the treatment of candidal endophthalmitis. Clin Infect Dis 1995;20:657-664. 90. Laatikainen L, Tuominen M, Dickhoffvon K: Treatment of endogenous fungal endophthalmitis with systemic fluconazole with or without vitrectomy. AmJ Ophthalmol 1992;113:205-207. 91. LuttrullJK, Wan WL, Kubak BM, et al: Treatment of ocular fungal infection with oral fluconazole. Am J Ophthalmol 1995;119:477481. 92. Christmas NJ, Smiddy WE: Vitrectomy and systemic fluconazole for treatment of endogenous fungal endophthalmitis. Ophthalmic Surg Lasers 1996;27:1012-1018. 93. Del Palacio A, Cuetara MS, Ferro M, et al: Fluconazole in the management of endophthalmitis in disseminated candidosis of heroin addicts. Mycoses 1993;36:193-199. 94. Gold W, Stout HA, Pagano JF, Donovick R: Amphotericins A and B: Antifungal antibiotics produced by a streptomycete: 1. In vitro studies. In: Welch H, Marti-Ibanez F, eds: Antibiotics Armua119551956. New York, Medical Encyclopedia, 1956, p 579. 95. Louria DB, Dineen P: Amphotericin B in the treatment of disseminated moniliasis. JAMA 1960;174:273-279. 96. Medoff G, Kobayashi GS: Strategies in the treatment of systemic fungal infections. N EnglJ Med 1980;30f.145-155. 97. Green WR, Bennett JE, Goos RD: Ocular penetration of amphotericin B. A report of laboratory studies and a case report of postsurgical cephalosporium endophthalmitis. Arch Ophthalmol 1965;73:769-775. 98. Fisher JF, Taylor AT, Clark J, et al: Penetration of amphotericin B into the human eye. J Infect Dis 1983;147:164. 99. Behlau I, Baker AS: Fungal infections and the eye. In: Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology, vol 5. Philadelphia, W.B. Saunders, 1994, pp 3030-3037. 100. Presterl E, Graninger W: New aspects in the treatment of systemic mycoses. Wien Klin Wochenschr 1998;110:740-750. 101. Ng TT, Denning DW: Liposomal amphotericin B (AmBisome) therapy in invasive fungal infections. Evaluation of United Kingdom compassionate use data. Arch Intern Med 1995;155:10931098. 102. Kruger W, Strockschlader M, Russmann B, et al: Experience with liposOll1al amphotericin B in 60 patients undergoing high-dose therapy and bone marrow or peripheral blood stem cell transplantation. Br J Haematol 1995;91:684-690. 103. Axelrod AJ, Peyman GA, Apple DJ: Toxicity ofintravitreal injection of amphotericin B. AmJ Ophthalmol 1973;76:578....583. 104. Stern GA, Fetkenhour CL, O'Grady RB: Intravitreal amphotericin B treatment of Candida endophthalmitis. Arch Ophthalmol 1977;95:89-93. 105. Ho PC, O'Day DM: Candida endophthalmitis and infection of costal cartilages. Br J Ophthalmol 1981;65:333-334. 106. Bennett JE: Chemotherapy of systemic mycoses. N Engl J Med 1974;290:30-32. 107. Debryne D, Ryckelynck J: Pharmacokinetics of fluconazole. Clin Pharmacokinet 1993;24:10-27.

108. O'Day DM, Foulds G, Williams TE, et al: Ocular uptake of fluconazole following oral administration. Arch Ophthalmol 1990;108:1006-1008. 109. Nomura J, Ruskin J: Failure of therapy with fluconazole for candidal endophthalmitis. Clin Infect Dis 1993;17:888-889. 110. Filler SG, Crislip MA, Mayer CL, Edwards JE: Comparison of fluconazole and amphotericin B for treatment of disseminated candidiasis and endophthalmitis in rabbits. Arltimicrob Agents Chemother 1991 ;35:288-292. Ill. Savani DV, Perfect JR, Cobo LM, Durack DT: Penetration of new azole compounds into the eye and efficacy in experimental Candida endophthalmitis. Antimicrob Agents Chemother 1987;31:610. 112. Van Cutsem J: Oral, topical and parenteral antifungal treatment with itraconazole in normal and in immunocompromised animals. Mycoses 1989;32S:14-34. 113. Mohan M, Panda A, Gupta SK: Management of human keratomycosis with miconazole. Aust N ZJ OphthalmoI1989;17:295-297. 114. Ball MA, Rebhun WC, GaarderJE, Patten V: Evaluation ofitraconazole-dimethyl sulfoxide ointment for treatment of keratomycosis in nine horses. J Am Vet Med Assoc 1997;211:199-203. 115. Arocker-Mettinger E, Huber-Spitzy V, Haddad R, Grabner G: Keratomycosis caused by Candida albicans. Klin Monatsbl Augenheilkd 1988;193:192-194. 116. Gupta SK: Efficacy of miconazole in experimental keratomycosis. Aust N ZJ OphthalmoI1986;14:373-376. 117. Thomas PA: Mycotic keratitis-an underestimated mycosis. J Med Vet Mycol 1994;32:235-256. 118. Airas KA, Nikoshelainen J: Haematogenous Candida endophthalmitis after abdominal surgery. Acta Ophthalmol Copenh 1987; 65:450-454. 119. Schulman JA, Peyman GA: Intravitreal corticosteroids as an adjunct in the treatment of bacterial and fungal endophthalmitis. Retina 1992;12:336-340. 120. Coats ML, Peyman GA: Intravitreal corticosteroids in the treatment of exogenous fungal endophthalmitis. Retina 1992;12:46-51. 121. Huang K, Peyman GA, McGetrick J: Vitrectomy in experimental endoph thalmi tis: 1. Fungal infections. Ophthalmic Surg 1979; 10:84-86. 122. Snip RC, Michels RG: Pars plana vitrectomy in the management of endogenous Candida endophthalmitis. Am J Ophthalmol 1976;82:699-704. 123. Cottingham AJ, Forster RK: Vitrectomy in endophthalmitis. Arch Ophthalmol 1976;94:2078-2081. 124. Barrie T: The place of elective vitrectomy in the management of patients with Candida endophthalmitis. Graefes Arch Clin Exp Ophthalmol 1987;225:107-113. 125. Doft BH, Weiskopf J, Nilsson-Ehle I, Wingard LB: Amphotericin clearance in vitrectomized versus nonvitrectomized eyes. Ophthalmology 1985;92:1601-1605. 126. Baldinger J, Doft BH, Burns SA, Johnson B: Retinal toxicity of amphotericin B in vitrectomized versus non-vitrectomized eyes. Br J Ophthalmol 1986;70:657-661. 127. Armable WL, Kachmer ML, DiMarco M, DeSantis D: Long-term follow-up of Candida endophthalmitis in the premature infant. J Pediatr Ophthalmol Strabismus 1990;27:103-106. 128. Sims ME, Yoo Y, You H, et al: Prophylactic oral nystatin and fungal infections in very-Iow-birthweight infants. Am J Perinatal 1988;5:33-36. 129. Horne MJ, Ma MH, Taylor RF, et al: Candida endophthalmitis. Med J Aust 1975;1:170-172. 130. Dellon AL, Stark WJ, Chretien PB: Spontaneous resolution of endogenous Candida endophthalmitis complicating intravenous hyperalimentation. Am J Ophthalmol 1975;79:648-654. 131. Servant JB, Dutton GN, Ong-Tone L, et al: Candidal endophthalmitis in Glaswegian heroin addicts: Report of an epidemic. Trans Ophthalmol Soc U K 1985;104:297-308.

Richard R. Tamesis

Coccidioidomycosis is a disease produced by the soil fungus Coccidioides immitis. It is also called the San Joaquin Valley fever or valley fever. C. immitis is a dimorphic fungus, which means that it occurs in two forms: (1) growing as a mold with septate hyphae in soil and in culture, and (2) as a nonbudding spherule in host tissue. 1 It is identified by its appearance and by the formation of segmented arthrospores. The fungus grows in the topsoil layers in semiarid areas of the Western Hemisphere. Infection is caused by inhalation of airborne arthrospores that have been dislodged from the soil. The arthrospores form thick-walled spherules inside the host that then rupture and release endospores that spread locally and disseminate.

HISTORY Coccidioidomycosis affecting the external eye and orbit has been described since 1896, when the disease was first reported in the United States. 2 In 1948, Levitt reported what he believed to be a case of intraocular coccidioidomycosis in a patient with pulmonary coccidioidomycosis. 3 However, it was not until 1967, when Hagele reported a patient with endophthalmitis caysed by C. immitis, that a case of intraocular coccidioidorllycosis was confirmed by histopathology and culture before enucleation or death of the patient. 4

EPIDEMIOLOGY

c. immitis is endemic in the region known as the lower Sonoran Life Zone, which includes the San Joaquin Valley region of California and the Southwestern United States. The disease also occurs in the arid regions of Mexico, Central America, and parts of South America. In semiarid climates, winters with heavy rain, followed by hot, dry, dusty periods, favor the rapid multiplication of the arthroconidia. The seasonal occurrence of primary coccidioidomycosis increases during the summer and fall in the Southwestern United States, corresponding to the dusty time of the year.. Severe drought followed by heavy rainfall was identified as a factor associated with a 19911993 epidemic of coccidioidomycosis in California. 5 ,6 Outbreaks have also occurred following earthquakes, dust storms, and archeological excavations. 7- 9 Filipinos, blacks, Native Americans, Mexican Americans, and immunocompromised individuals such as the elderly population, neonates, and those with the acquired immunodeficiency syndrome (AIDS) are at higher risk for developing the disease. lO , 11 Meningitis, lymphadenopathy, and diffuse pulmonary disease are more commonly found in these patients. CLINICAL CHARACTERISTICS The lungs, skin, and central nervous system are most commonly affected in patients with coccidioidomycosis. Approximately 40% of infected individuals are symptom-

atic. 12 The vast majority of symptomatic patients present with a mild upper respiratory tract infection or a pneumonitis characterized by fever, cough, night sweats, and malaise approximately 3 weeks after exposure to the organism. Erythema nodosum or multiforme may appear anywhere from 3 days to 3 weeks after the onset of symptoms. Disseminated infection occurs in less than 1 % of patients with pulmonary coccidioidomycosis. 13 Ocular coccidioidomycosis is rare, even in disseminated disease, and can present as (1) intraocular disease producing iridocyclitis, choroiditis, and chorioretinitis, which can affect one or both eyes; and (2) external disease consisting of blepharitis, keratoconjunctivitis, phlyctenular conjunctivitis, granulomatous conjunctivitis, episcleritis, and scleritis, as well as optic atrophy, extraocular nerve palsies, and orbital infection. 2 , 14-16 Posterior segment involvement can manifest in four different ways: (1) diffuse choroiditis often associated with widely disseminated (and preterminal) systemic disease, (2) large, juxtapapillary choroidal infiltrates with variable involvement of the overlying retina that may be associated with retinal edema and hemorrhage, (3) spherical opacities of the macula or posterior pole at the level of Bruch's membrane and sensory retina associated with macular edema and exudates, and most commonly as (4) small, peripheral chorioretinal scars with central hypopigmentation resembling presumed ocular histoplasmosis scars. 17, 18 Vitreous cells and perivascular sheathing may also be present with posterior segment disease. About half of all patients present primarily with a granulomatous iridocyclitis without posterior segment involvement. Iris nodules containing the fungus may be seen. Spherules of C. immitis can be demonstrated from anterior chamber taps and iris biopsies in these patients. Although ocular coccidioidomycosis generally occurs in patients with disseminated disease, there are reports of intraocular coccidioidomycosis occurring in otherwise apparently healthy individuals. 19- 21

C. immitis produces pyogenic, granulomatous, and mixed reactions. 22 Polymorphonuclear leukocytes suppurate around infecting conidia and inside granulomas when the spherules rupture and release endospores. A granulomatous reaction develops around the developing spherules, which can be found inside foreign body giant cells. Fibrosis, necrosis, and calcification can occur. Intact cell-mediated immunity serves to limit further extension of these foci and is essential for the host to eliminate this organism. Patients deficient in cell-mediated immunity such as those with AIDS are at risk for developing the chronic and disseminated forms of the disease and may require prolonged therapy. They typically have high titers of complement-fixing anticoccidioidal antibodies with no delayed-type hypersensitivity on skin testing.

CHAPTER 30: COCCIDIOIDOMYCOSIS

Distribution of the endospores via the ophthalmic artery to. the short posterior ciliary and central retinal arteries can result in miliary retinal and choroidal granulomas. Choroidal granulomas are confined Inainly to the middle and large vessel layers. 23 Retinal granulomas are centered in the distribution of the central retinal artery. Anterior segment lesions demonstrate zonal granulomatous inflammation that can involve the uvea and angle structures.

DIAGNOSIS Patients living in endemic areas who show the characteristic chorioretinal lesions should be suspected of having the disease whether or not they have active intraocular inflammation. Chest x-ray studies may show pneumonitis or characteristic "coin lesions." Biopsy of skin lesions can be especially important in identifYing the organism in disseminated coccidioidomycosis. Confirmation of the diagnosis is generally based on histopathologic, cultural, or molecular evidences of C. im1Jlitis. The spherules are 30 to 60 fJum in size and appear flattened rather than globular. 24 They are refringent on direct examination and stain with periodic acid-Schiff. Theendospores are oval in shape. Culturing for the organism can be very dangerous because the mycelial form is highly infectious and requires special handling. Aqueous and vitreous biopsies can be examined directly for the organism by means of the Papanicolaou stain. 25 Iris biopsies of lesions and nodules can also help establish the diagnosis of ocular G,Occidioidal infection rapidly. Immunologic evidence for the diagnosis includes a positive serologic test for anticoccidioidal antibodies in serum, cerebrospinal fluid, vitreous, or aqueous by (1) detection of anticoccidioidal IgM using immunodiffusion, enzyme immunoassay (EIA) latex agglutination, or tube precipitin, or (2) detection of a rising titer of anticoccidioidal IgG by immunodiffusion, EIA, or complement fixation. 26 Serum IgM antibodies appear 1 to 3 weeks after the onset of symptoms in 75% of cases of primary infection and disappear within 4 months. 27 Three months after onset, 50% to 90% of the patients with symptomatic primary infections have complement-fixing serum IgG anticoccidioidal antibody. This antibody may last for 6 to 8 months, although it may occasionally persist longer at low levels even after the infection resolves successfully. A fourfold rising titer is of grave prognostic significance and indicates advanced disease. A falling titer indicates improvement. Negative serologic tests do not exclude the diagnosis of coccidioidomycosis, particularly if chronic pulmonary disease is present. A valid diagnosis of coccidioidal infection can be made by skin test conversion with the mycelial phase antigen coccidioidin (1:100 dilution) from negative to positive after the onset of clinical signs and symptoms. Spherulin (1:100 dilution), a parasitic phase antigen, may be a more sensitive reagent in detecting delayed hypersensitivity and is just as specific a coccidioidin. The antigen is applied intradermally (0.1 ml). Thirty-six hours is the optimal reaction time, although the readings are usually taken at 24 and 48 hours. Induration greater than 5 mm in diameter is considered a positive reaction. A positive skin test

indicates previous exposure or active disease and usually occurs a week after the developinent of symptoms in about 80% of patients. A negative skin reaction does not rule out coccidioidomycosis. Almost all symptomatic patients are positive a month after the onset of sYlnptoms. Anergy is common in disseminated disease. There is a low degree of cross reactivity with histoplasmosis and blastomycosis. 28 Positive skin tests do not affect serologic testing, although a positive coccidioidin skin test may induce antibodies that cross react with histoplasmin. 29 Skin testing is important primarily in assessing the cellular immunity status of a patient with documented coccidioidal disease and as an epidemiologic tool.

The cornerstones of therapy for coccidioidomycosis at the present time are amphotericin B and the triazoles fluconazole and itraconazole. The advantages of the triazoles over amphotericin B include oral administration and relative nontoxicity. Fluconazole is effective in treating progressive pulmonary and disseminated coccidioidomycosis. 30 There are, however, no comparative trials comparing amphotericin B to the triazoles in the treatment of coccidioidomycosis, and the triazoles are not currently approved by the U.S. Food and Drug Administration for the treatment of this disease. Miconazole has not been proved to beeffective.in treating intraocular coccidioidomycosis. 3! . Amphotericin B is the treatment of choice for coccidioidomycosis. It is administered intravenously at a dose of 1 mg/kg body weight per day. A total dose of 500 mg to 1500 mg can be given. Intraocular amphotericin B (5 fJug/0.1 ml) is administered during vitrectomy for suspected fungal endophthalmitis. Amphotericin B, however, has poor ocular and central nervous systeln penetration, retinal toxicity associated with intravitreal injection, and potentially serious dose-limiting systemic side effects. Fluconazole (Diflucan) is the drug of choice for coccidioidal meningitis. Oral administration results in high concentrations in the cerebrospinal fluid, the aqueous, vitreous, retina, and choroid. 32 , 33 It is given orally at a dose of 400 to 800 mg/day. It can be substituted for amphotericin B, but cases of treatment failure have been reported. 34 Intraocular coccidioidomycosis has been successfully treated using fluconazole as the primary agent. 35 The authors of that report believe that alnphotericin B should be reserved for patients who fail initial treatment with oral fluconazole. Itraconazole (Sporanox) has also been used in the treatment of coccidioidomycosis, and it has a response rate of 60% to 80%.36,37 It is taken orally at a dose of 200 mg twice daily. Its role in treating ocular coccidioidomycosis is unclear, although it has been used successfully in a uveitis patient with iris-biopsy confirmed coccidioidomycosis. 2! Acute treatment of progressive pulmonary and extrapulmonary coccidioidomycosis should be followed by long-term maintenance therapy because of a reported high relapse rate after treatment with both amphotericin B and the triazoles. 38 , 39 Fluconazole (200 to 400 mg daily), weekly amphotericin B, or itraconazole may be effective. Patients with meningitis and those with the

CHAPTER 30: COCCIDIOIDOMYCOSIS

acquired immunodeficiency syn.drome with progressive or disseminated coccidioidomycosis should continue with maintenance therapy for life. Complications of intraocular coccidioidomycosis include posterior synechiae, cataracts, scleral thinning and staphyloma formation, and secondary glaucoma. The posterior segment lesions can involve the macula and the optic nerve, with devastating consequences to the vision. Epiretinal membranes and serous retinal detachment can occur. Even with aggressive antifungal therapy, the eye can become hypotonous and painful and require enucleation.

PROGNOSIS Despite systemic antifungal therapy, meningeal involvement carries a grave prognosis. 4 0-41 In patients with AIDS, less than half respond to treatment, and the mortality rate can climb as high as 70% in those patients with diffuse pulmonary disease. 42 The prognosis of ocular coccidioidomycosis ultimately depends on the location and severity of the ocular lesions, as well as on prompt diagnosis and treatment of the systemic disease. In general, intravenous and intraocular amphotericin B can sterilize most cases of ocular coccidioidomycosis. However, the prognosis for patients with isolated anterior segment coccidioidomycosis is poor, with the majority requiring enucleation owing to blindness and pain. 21

CONCLUSIONS Coccidioidomycosis must be considered in the differential diagnosis of ocular inflammatory disease, especially in patients who have lived in or traveled through endemic areas. The absence of serologic evidence for coccidioidomycosis and lack of systemic manifestations do not rule out the diagnosis of coccidioidal infection. Biopsies of intraocular lesions, including vitreous and aqueous taps, provide rapid diagnosis and may be the most efficient method of facilitating appropriate treatment. Guidelines for therapy have not been clearly established owing to the rarity of the disease. Intravenous amphotericin B is the treatment of choice, although the triazoles such as fluconazole hold promise as a better tolerated form of treatment. The role of intraocular injections of amphotericin B in treating intraocular coccidioidomycosis is unclear, although it is given in suspected cases of fungal endophthalmitis. Patients may require prolonged systemic therapy to prevent relapse and require close collaboration between the ophthalmologist and infectious disease specialists. The prognosis for isolated anterior segment disease is poor, and the majority of these eyes may ultimately require enucleation.

References 1. Bennett JE: Coccidioidomycosis and paracoccidioidomycosis. In: Isselbacher Ig, Braunwald E, Wilson JD, et al (eds): Harrison's Principles of Internal Medicine. New York, McGraw-Hill Book Company, 1994, pp 857-858. 2. Rodenbiker HT, Ganley JP: Ocular coccidioidomycosis. Surv Ophthalmol 1980;24:263-290. 3. Levitt JM: Ocular manifestations in coccidioidomycosis. Am J Ophthalmol 1948;31:1626-1628.

4. Hagele AJ, Evans DJ, Larwood TR: Primary endophthalmic coccidioidomycosis. Report of a case of exogenous primary coccidioidomycosis of the eye diagnosed prior to enucleation. In: Aiello E (ed): Coccidioidomycosis. Tucson, University of Arizona Press, 1967, pp 37-39. 5. CDC: Update: Coccidioidomycosis-California, 1991-1993. MMvVR 1994;43:421-423. 6. Pappagianis D: Marked increase in cases of coccidioidomycosis in California: 1991, 1992, and 1993. Clin Infect Dis 1994;19(Suppl 1):Sl4-18. 7. Schneider E, Hajjeh RA, Spiegel RA, et al: A coccidioidomycosis outbreak following the Northridge, California, earthquake. JAMA 1997;277:904-908. 8. Flynn NM, Hoeprich PD, Kawachi MM, et al: An unusual outbreak of windborne coccidioidomycosis. N EnglJ Med 1979;301:358-361. 9. Werner SB, Pappagianis D, Heindl I, et al: An epidemic of coccidioidomycosis among archeology students in Northern California. N Engl J Med 1972;286:507-512. 10. Galgiani IN: Coccidioidomycosis: Changes in clinical expression, serological diagnosis, and therapeutic options. Clin Infect Dis 1992;14(Suppl 1) :S100-S105. 11. Granoff DM, Libke RD: Coccidioidomycosis in children. In: Feigin RD, Cherry JD (eds): Textbook of Pediatric Infectious Diseases. Philadelphia, WE Saunders Company, 1981, pp 1488-1500. 12. Drutz DJ, Cadanzaro A: Coccidioidomycosis. Am Rev Resp Dis 1978;117:559-585. 13. Ampel NM, Wieden MA, Galgiani IN: Coccidioidomycosis: Clinic update. Rev Infect Dis 1989;11:897-911. 14. Maguire LJ, Campbell RJ, Edson RS: Coccidioidomycosis with necrotizing granulomatous conjunctivitis. Cornea 1994;13:539-542. 15. Fusaro RM, Bansal S, Records RE: Some unusual periorbital dermatoses. Ann Ophthalmol 1988;20:391-393. 16. Mark AS, Blake P, Atlas SW, et al: Gd-DTPA enhancement of the cisternal portion of the oculomotor nerve on MR imaging. AJNR AmJ Neuroradiol 1992;13:1463-1470. 17. Blumenkranz MS, Stevens DA: Endogenous coccidioidal endophthalmitis. Ophthalmology 1980;87:974-984. 18. Lamer L, Paquin F, Lorange G, et al: Macular coccidioidomycosis. Can J Ophthalmol 1982;17:121-123. 19. Zakka KA, Foos RY, Brown ~. Intraocular coccidioidomycosis. Surv Ophthalmol 1978;22:313-321. 20. Rodenbiker HT, Ganley JP, Galgiani IN, et al: Prevalence of chorioretinal scars associated with coccidioidomycosis. Arch Ophthalmol 1981;99:71-75. 21. Moorthy RS, Rao NA, Sidikaro Y, et al: Coccidioidomycosis iridocyclitis. Ophthalmology 1994;101:1923-1928. 22. Irvine AR Jr: Coccidioidal granuloma of the lid. Trans Am Acad Ophthalmol Otolaryngol 1968;72:751-754. 23. Glasgow BJ, Brown HH, Foos RY: Miliary retinitis in coccidioidomycosis. AmJ Ophthalmol 1987;104:24-27. 24. Gori S, Scasso A: Cytologic and differential diagnosis of rhinosporidiosis. Acta Cytologica 1994;38:361-366. 25. Warlick l\tLA, Quan SF, Sobonya RE: Rapid diagnosis of pulmonary coccidioidomycosis. Cytologic vs potassium hydroxide preparations. Arch Intern Med 1983;143:723-725. 26. CDC. Coccidioidomycosis-Arizona, 1990-1995. JAMA 1997; 277:104-105. 27. Stevens DA: Coccidioides immitis. In: Mandell GL, Douglas RG Jr, Bennett JE (eds): Principles and Practice of Infectious Diseases. New York, John Wiley & Sons, Inc., 1985, pp 1485-1493. 28. Chick EW, Baum GL, Furculow ML, et al: Scientific Assembly statement. The use of skin tests and serologic tests in histoplasmosis, coccidioidomycosis, and blastomycosis, 1973. Am Rev Respir Dis 1973;108:156-159. 29. Pappagianis D, Zimmer BL: Serology of coccidioidomycosis. Clin Microbiol Rev 1990;3:247-268. 30. Catanzaro A, Galgiani IN, Levine BE, et al: Fluconazole in the treatment of chronic pulmonary and nonmeningeal disseminated coccidioidomycosis. Am J Med 1995;98:249-256. 31. Blumenkranz MS, Stevens DA: Therapy of endogenous fungal endophtllalmitis. Arch Ophthalmol 1980;98:1216-1220. 32. Tucker RM, Williams PL, Arathoon EG, et al: Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis. Antimicrob Agents Chemotller 1988;32:369-373. 33. O'Day DM, Foulds G, Williams TE, et al: Ocular uptake of flucona-

CHAPTER. 30: COCCIDIOIDOMYCOSIS

34. 35.

36. 37.

38.

zole following oral administration. Arch Ophthalmol 1990;108: 1006-1 008. Evans TG, Mayer J, Cohen S, et al: Fluconazole failure in the treatment of invasive mycoses. J Infect Dis 1991;164:1232-1235. LuttruU JK, Wan WL, Kubak BM, et al: Treatment of ocular fungal infections with oral fluconazole. Am J Ophthalmol 1995;119:477481. Graybill JR, Stevens DA, Galgiani IN, et al: Itraconazole treatment of coccidioidomycosis. AmJ Med 1990;89:282-290. Tucker RM, Denning DW, Dupont B, et al: Itraconazole therapy for chronic coccidioidal meningitis. Ann Intern Med 1990; 112:108-112. Dewsnup DH, Galgiani IN, Graybill JR, et al: Is it ever safe to stop

39.

40.

41. 42.

azole therapy for Coccidioides immitis meningitis? Arm Intern Med 1996;125:304-310. Oldgfield EG III, Bone WD, Martin CR, et al:Prediction of relapse after treatment of coccidioidomycosis. Clin Infect Dis 1997;25:12051210. Bouza E, Dreyer JS, Hewitt WL, et al: Coccidioidal meningitis: An analysis of thirty-one cases and review of literature. Medicine 1981;60:139-172. Kafka JA, Cataranzo A. Disseminated coccidioidomycosis in children. J Pediatr 1981;98:355-361. Fish DG, Ampel NM, Galciani IN, et al: Coccidioidomycosis during human immunodeficiency virus infection: A review of 77 patients. Medicine (Baltimore) 1990;69:384-391.

Katerina Havrlikova-Dutt

Cryptococcosis is a systemic infection caused by the saprophytic fungus Cryptococcus neoformans. It is known to affect mainly immunocompromised patients, although it can cause disease in an immunocompetent individual as well. Pulmonary and central nervous system (CNS) involvement make up the majority of cases. Cryptococcosis is the most common mycotic infection of the CNS, and ocular involvement occurs in 40% of patients with cryptococcal meningitis. 1 C. neoformans is a round, encapsulated yeastlike fungus that reproduces by budding. Staining with India ink and Wright's stain shows a large capsule surrounding a cell that has a single bud attached to a narrow bud base.

EPIDEMIOLOGY

c. neoformans is a worldwide saprobe, found in pigeon feces, pigeon nesting places, and contaminated soi1,2 Despite the high concentration of fungus in pigeon feces, the birds are not infected. 3 There is evidence that the disease occurs after the organism is aerosolized and inhaled. 4 Transmission from animals to humans or between humans has not been documented, although a case of cryptococcal endophthalmitis a~quired through a corneal transplant from a donor with active cryptococcosis has been reported. 5 There has also been a case report describing Cryptococcus laurentii keratitis spread by a rigid gaspermeable contact lens in a patient with onychomycosis. 6 Cryptococcosis is relatively rare in an immunocompetent host, but in patients with acquired immunodeficiency syndrome (AIDS), it is the fourth most common cause of life-threatening infections. 7 It can also be seen in other immunocompromised patients such as diabetic patients on long-term corticosteroids or individuals with polyarteritis nodosa, lymphoma, systeluic lupus erythematosus, Hodgkin's disease, organ transplant recipients, or other systemic diseases treated with immunosuppressive agents. CHARACTERISTICS Systemic involvement in cryptococcosis varies widely and includes meningitis, pneumonia, mucocutaneous lesions, multiple skin lesions, pyelonephritis, endocarditis, hepatitis, prostatitis, and ocular infection. In the population of patients with AIDS, C. neoformans is an important pathogen producing not only a variety of CNS and neurophthalmic complications (chronic meningitis being the most common) but also devastating disseminated systemic disease. Ocular manifestations are thought to arise via optic nerve extension from central nervous system involvementS, 9 but it appears that intraocular involvement can occur via hematogenous spread as well. 10 Ophthalmic manifestations of cryptococcosis include papilledema, optic neuropathy, chiasmal involvement, optic atrophy, cranial nerve palsies, nystagmus, internuclear ophthalmoplegia, choroiditis, retinis, uveitis, inflamma-

tory iris mass, keratitis, conjunctival granuloma, limbal nodules, phthisis bulbi, periorbital necrotizing fasciitis, orbital infection, exogenous endophthalmitis, and endogenous endophthalmitis. In most patients ocular involvement is associated with meningitis. Specifically, the ocular involvement usually follows meningitis, but a case of endogenous cryptococcal endophthalmitis without a preceding meningeal infection has been documented. The most common intraocular manifestation is chorioretinitis. The earliest sign is focal or multifocal choroiditis, in which yellowish to white, subretinal, slightly elevated lesions one fifth to one optic disc diameter in size are usually observed. Choroiditis is followed, in rapid succession, by inflammation of the retina, vitreous, and if the condition is left untreated, the anterior segment. Endogenous cryptococcal endophthalmitis was first reported in 1948,11 and since then, approximately 15 cases have been reported in the literature. 12- 2o The earliest symptom is blurred vision, followed by redness, pain, photophobia, flqaters, ocular injection, and profound visual loss. Patients with concomitant cryptococcal meningitis also suffer from headaches and nausea. Ophthalmic findings include injection, anterior chamber cell and flare, mutton fat keratic precipitates, posterior synechiae, yellow or white chorioretinal lesions, retinal perivascular sheathing, subretinal exudate or localized serous retinal detachment, vitreous cells, severe vitreous inflammation with fluffy exudates, preretinal or vitreous abscesses, retinal detachment, and phthisis bulbi. 12- 20 The outcome in cryptococcal endophthalmitis is generally rather poor, including blindness or enucleation. Because cryptococcosis affects mostly ilumunocompromised patients, the inflammation typical of uveitis in an immunocompetent individual may be lacking. It is important to keep in mind that primary choroidal lesions in patients with AIDS may herald severe systemic disseminated disease. Funduscopic examination may detect disseminated cryptococcal disease before other clinical manifestations, thereby allowing prompt institution of effective therapy. 10

C. neoformans is a budding, spore-forming yeast yielding yellow-tan colonies on culture media. Four serotypes (A, B, C, and D) have been identified based on capsular polysaccharide antigen determination with immunofluorescence or agglutination. Types A and D are most COlUmonly pathogenic: 21 Infection occurs via inhalation into the moist environment of the lungs, where the yeast enlarges and starts to bud. A thick polysaccharide capsule forms around each cell. This capsule is immunologically inert and provides protection from phagocytic cells, thus the inflammatory response to infection is variable. Hematogenous spread to the brain leads to cystic clusters of cryptococci associated with minimal inflalumatory re-

CHAPTER 31: CRYPTOCOCCOSIS

sponse. Neutrophils are first to home to the infected area, followed by the monocytes that predominate in the later inflammatory infiltrate. 22 Neutrophils and monocytes can ingest and kill cryptococci in vitro by using the myeloperoxidase-peroxide-halide system 23 or the neutrophil cationic proteins. 24 Encapsulated C. neoformans may be sufficiently large to preclude phagocytosis, but they can still be surrounded and killed by "rings" of lTIaCrOphages. 25 Macrophage activation requires functional, sensitized T cells. Natural killer cells,26 anticryptococcal antibodies,27 and T cells may all be involved in the host defense response.

DIAGNOSIS The diagnosis of cryptococcosis requires a high degree of suspicion and is often presumptive, depending on the clinical context. Definitive diagnosis requires identification of the organism in culture from infected tissue, blood, or body fluids. There are usually no abnormalities in routine blood tests. If signs of meningitis are present, cerebrospinal fluid (CSF) analysis, including cryptococcal antigen testing and fungal culture, should be performed. When the CNS is involved in immUnOCOlTIpetent patients, the CSF is almost always abnormal with an elevated opening pressure, elevated protein, hypoglycorrhachia at 50%, and 20 to 600 leukocytes/mm3 with lymphocyte predominance. In severely immunosuppressed patients, there are minimal to no abnormalities of the CSF. India ink smears of the CSF have positive results for cryptococcus in 50% of patients. Solution ID'ay be contaminated by nonpathogenic cryptococci; other fungi or artifacts may be mistaken for cryptococci as well. Centrifuged CSF specimens should be cultured on several different occasions, because negative results do not rule out the disease. Cryptococcal polysaccharide capsular antigen may be detected in the CSF or serum of 90% of patients with meningoencephalitis. 28 The antigen is detected by latex agglutination; false-positive results may occur in the presence of rheumatoid factor. Anticryptococcal antibodies are also detectable in healthy persons, so culture of cryptococcus remains the definitive diagnostic test. Cryptococcal serology and fungal cultures of blood, sputum, or urine are often helpful in patients with disseminated disease. 2 If the results of these tests are negative and clinical suspicion still exists, diagnostic vitreous tap, vitrectomy,24 fine-needle abscess biopsy,16 or eye wall biopsy29 can be performed.

DIAGNOSIS Multifocal choroiditis due to Pneumocystis carznzz cannot be distinguished from cryptococcocal uveitis by clinical examination alone. A history of P. carinii pneumonia and the use of aerosolized pentamidine in patients with AIDS should suggest the former diagnosis. Other opportunistic infections in AIDS patients, including toxoplaslTIosis, cytomegalovirus, and herpes simplex virus, all of which primarily infect the retina, should be excluded in cases of suspected C. neofonnans endophthalmitis. Tuberculosis, sarcoidosis, intraocular lymphoma, and uveitis caused by other fungal organisms should also be considered in the differential diagnosis.

Cryptococcal meningitis is usually fatal without systemic antifungal therapy, and even with treatment, the relapse rate is about 50% in patients with AIDS. Fluconazole (200 to 400 mg/ day) has been used as a long-term oral maintenance therapy in an attempt to prevent such recurrences. 22 ,29 Combined therapy with oral flucytosine (25 to 35 mg q, 6 h PO) and intravenous amphotericin B (0.4 to 0.6 mg/day) has been recommended as the treatment of choice for patients with disseminated or meningeal cryptococcosis. Oral fluconazole has been successful in some patients with AIDS, as well as others who cannot tolerate the renal toxicity and bone marrow suppression of the combined therapy. 23, 30 Treatment of endogenous cryptococcal endophthalmitis may require a combination of systemic antifungal agents, intravitreous amphotericin B, and pars plana vitrectomy. Patients with cryptococcosis should be evaluated every few months for at least 1 year after therapy, even if they are asymptomatic. The CSF, urine, and sputum should be cultured repeatedly. The outcome for an immunocompetent patient treated for a localized pulmonary infection is usually very good. The outcome for. immunocompromised patients can vary depending on a variety of factors. The mortality rate of immunocompromised patients who do not have AIDS and who have been treated for cryptococcal meningitis is approximately 25%. When predisposing factors- such as lymphoreticular malignancy or corticosteroid therapy are present, the mortality rate is 55%. After the initial treatment with amphotericin B, 20% to 25% of patients relapse. Of those cured, 40% suffer significant permanent sequelae, such as visual loss, cranial nerve palsies, lTIotor impairment, personality changes, and decreased mental function. The prognosis for patients with AIDS is very poor, because these patients are rarely completely cured. The treatment regimen is directed toward suppressing inflammation without interfering with treatment of concomitant diseases. 2 Despite its ubiquity throughout the world, C. neoformans is an uncommon cause of systemic or ocular disease in the immunocompetent patient. However, in the immunosuppressed host, particularly those individuals afflicted with AIDS, this fungus has become an important pathogen, producing potentially devastating CNS, ocular, and systemic disease. Diagnosis requires a high degree of clinical acumen in the correct clinical context, and despite aggressive treatment with systemic and/or intraocular antifungal agents, the prognosis is guarded. Nevertheless, early diagnosis and treatment of cryptococcosis can not only preserve the patients vision, but may also be life-saving, particularly in the managelTIent of patients with AIDS.

References 1. Lesser RL, Simon RM, Leon H, et al: Cryptococcal meningitis and internal ophthalmoplegia. Am J Ophthalmol 1979;87:682.

CHAPTER 31: CRYPTOCOCCOSiS 2. Behlau I, Baker AS: Fungal infections and the eye-cryptococcosis. In: Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology: Clinical Practice, 1st ed, Vol V. Philadelphia, WB Saunders, 1994, p 3045. 3. Littman ML, Walter JE: Cryptococcosis: Current status. Am J Med 1968;45:922. 4. Neilson JB, Fromtling RA, Bulmer GS: Cryptococcus neoformans: Size range of infectious particles from aerosolized soil. Infect Immun 1977;17:634. 5. Beyt BEJr, Waltman SR: Cryptococcal endophthalmitis after corneal transplantation. N Engl J Med 1978;298:825. 6. Ritterband DC, Seeder JA, Shah MK, et al: A unique case of C1yptococcus laurentii keratitis spread by a rigid gas-permeable contact lens in a patient with onychomycosis. Cornea 1998;17:115. 7. Eng RHK, Bishburg E, Smith SM, et al: Cryptococcal infections in patients witll the acquired immune deficiency syndrome. Am J Med 1986;81:19. 8. Eng RHK, Bishburg E, Smith SM, et al: Cryptococcal infections in patients witll tlle acquired immune deficiency syndrome. AmJ Med 1986;81:19. 9. Ofner S, Baker RS: Visual loss in cryptococcal meningitis. J Clin Neuroophthalmol1987;7:45. 10. Rostomian K, Dugel PD, Kolahdous-Isfahani A, et al: Presumed multifocal cryptococcal choroidopathy prior to specific systemic manifestation. Int Ophthalmol 1997;21:75. 11. Weiss C, Perry IH, Shevky MC: Infection of the human eye with Cryptococcus neofonnans (Torula histologica; Cryptococcus hO'lninis): A clinical and experimental study with a new diagnostic method. Arch Ophthalmol 1948;39:739-751. 12. Denning DW, Armstrong RW, Fishman M, et al: Endophthalmitis in a patient with disseminated cryptococcosis and AIDS who was treated 'with itraconazole. Rev Infect Dis 1991;13:1126. 13. Grieco MH, Freilich DB, Louria DB: Diagnosis of cryptococcal uveitis with hypertonic media. AmJ Ophtllalmol 1971;72:171. 14. Henderly DE, Liggett PE, Rao NA: Cryptococcal chorioretinitis and endophthalmitis. Retina 1987;7:75. 15. Hiles DA, Font RL: Bilateral intrf¥)cular cryptococcus Witll unilateral spontaneous regression: Report of a case and review of tlle literature. Am J Ophtllalmol 1968;65:98. 16. Hiss PW, Shields JA, Augsburger lJ: Solitary retrovitreal abscess as

17.

18. 19. 20.

21.

22.

23.

24. 25.

26.

27.

28. 29. 30.

the initial manifestation of cryptococcosis. Ophthalmology 1988;95:162. Malton ML, Rinkhoff JS, Doft BS, et al: Cryptococcal endophtllalmitis and meningitis associated with acute psychosis and exudative retinal detachment. AmJ Ophthalmol 1987;104:438. O'Dowd GJ, Frable ~: Cryptococcal endophthalmitis: Diagnostic vitreous aspiration cytology. Am J Clin Pathol 1983;79:382. Schields JA, Wright DM, Augsburger lJ, et al: Cryptococcal chorioretinitis. Am J Ophtllalmol 1980;89:210. Schulman JA, Leveque C, Coats M, et al: Fatal disseminated cryptococcosis following intraocular involvement. Br J Ophthalmol 1988;72:171. Diamond R: CryjJtococcus neofonnans. In: Mandell GC, Bennett JE, Dolin R, eds: Principles and Practice of Infectious Disease, 4tll ed. New York, Churchill-Livingstone, 1995, pp 2331-2340. Gadebush HH: Mechanisms of native and acquired resistance to infection with Cryptococcus neofonnans. CRC Crit Rev Microbiol 1972;1:311. Diamond RD, Root RK, Bennett JE: Factors influencing killing of Cryptococcus neofonnans by human leukocytes in vitro. J Infect Dis 1972;125:367. Ganz T, Selsted ME, Szklarek D, et al: Defensins: Natural peptide antibiotics of human neutrophils. J Clin Invest 1985;76:1427. Kalina M, KIetter Y, Aronson M: The interaction of phagocytes and the large-sized parasite, Cryptococcus neofonnans: Cytochemical and ultrastructural study. Cell Tissue Res 1974;152:165. Hidore MR, Murphy JW: Correlation of natural killer cell activity and clearance of Cryptococcus neoformans from mice after adoptive transfer of splenic nylon-wool-nonadherent cells. Infect Immun 1986;51:57. Nabavi N, Murphy JW: Antibody-dependent natural killer cell-mediated growtll inhibition of Cryptococcus neofonnans. Infect Immun 1986;51 :556. Benett JE, Bailey JW: Control for rheumatoid factor in the latex test for cryptococcosis. Am J Clin Pathol 1971 ;56:360. Peyman GA, Juarez CP, Raichand M: Full-thickness eye-wall biopsy: Long-term results in 9 patients. Br J Ophthalmol 1981;65:723. Golnik KC, Newman SA, Wispelway B: Cryptococcal optic neuropathy in the acquired immune deficiency syndrome. J Clin Neuroophthalmol 1991;11:96-103.

I Manolette Rangel Roque and C. Stephen Foster

Sporotrichosis is a chronic infectious disease caused by the filamentous branching fungus Sporothrix schenckii (Sporotrichum schenckii). It is characterized by subcutaneous, nodular granulomata, which are usually acquired by traumatic implantation through the skin. Ocular involvement ranges from simple conjunctivitis to fuhninant endophthalmitis.

The reported literature on sporotrichosis dates back to the turn of the 20th century. In 1809, Link, cited by Gordon,I described the genus Sporotrichum primarily as a saprophyte on wood. Schenck reported the first described clinical case in 1898. 2 He described a typical lesion occurring on a finger, followed by the formation of a nodular chain. As a result of his research, his name was attached to the organism. The first reported case of S. schenckii involving the eye or its adnexa was published in 1907 by Danlos and Blanc. 3 In that same year, DeBeurmann, Gougerot, and Laroche 4 cited a similar case with lid involvement. The first reported case of intraocular S. schenckii was published in 1909. 5 Morax then first isolated ocular S. schenckii in 1914. 6 In the 1940s, a large outbreak of nearly 3000 cases occurred in South African gold mines as a result of contaminated timber beams. 7 The latest reported case occurred in a patient with acquired immunodeficiency syndrome (AIDS) who had disseminated sporotrichosis with extensive cutaneous involvement. s

sippi rivers. This fungus is common in Mexico and Central America. It is a common saprophyte found in natural vegetation (soil,9-11 plants, thorns, wood, straw, reeds,7 etc.). There is a consequent high incidence of infection involving gardeners,I2 forestry workers,I3 agricultural workers, miners, meat packers, and sphagnum moss handlers. 14 Sporotrichosis also can be inoculated by insect stings, animal bites, and cat scratches, or by handling of contaminated fish. Pathogenic sporotricha have also been isolated from the hair of horses and other domestic animals and their excreta. I5

Mycology Sporothrix schenckii lives as a saprophyte on plants in many areas of the world. In nature and on culture at room temperature (25°C), the fungus grows as a beige-colored leathery mold that darkens to black with age (Figs. 32-1 and 32-2), but within host tissue or at 37°C on enriched media, it grows as a budding, cigar-shaped yeast (Fig. 32-3). It is identified by its appearance in mold and yeast forms I6 ,I7 (Figs. 32-4 and 32-5). The hyphae are 2 f-Lm in width; they are segmented and branched and produce oval conidia, which range from 2 to 6 f-Lm in longest diameter. IS

CLINICAL CHARACTERISTICS

Nonocular Disease

Sporothrix schenkii is distributed worldwide but is common in tropical or temperate regions. In the United States, the .majority of cases have been found in the Midwestern river valleys, especially those of the Missouri and Missis-

Lymphocutaneous infection is the most common form of sporotrichosis. 9, 10 At the site of entry (usually the hands), a small, painless, pink or purple, verrucous, nodular or ulcerative cutaneous lesion develops anytime from 1 week to several months later. It is a chronic subcutaneous nodular granuloma, usually with spreading lymphatic involvement, following trauma. The nodules may ulcerate and discharge a small amount of serosanguineous exudate.

FIGURE 32-1. Young colonies of Sporothrix schenckii remain white for some time at 25°C or when incubated at 37°C to induce its yeast phase. (Reprinted from http://Jungllsweb. utmb. edu/mycology/sporothrix. html, with permission from Medical Mycology Research Center, Depattment of Pathology, University of Texas Medical Branch.) (See color insert.)

FIGURE 32-2. Older colonies of Sporothrix schenckii turn black due to the production of dark conidia that arise directly from the hyphae. (Reprinted from http://fungusweb.utmb.edll/mycology/sporothrix.html, ,vith permission from Medical Mycology Research Center, Department of Pathology, University of Texas Medical Branch.) (See color insert.)

CHAPTER 32: SPOROTRICHOSIS

FIGURE 32-3. Sporothrixschenckii has a yeast form at 37°C. (Reprinted from http://fungusweb. utrnb.edu/mycology/sporothrix.htrnl, with permission from Medical Mycology Research Center, Department of Pathology, University of Texas Medical Branch.)

FIGURE 32-4. Conidia arising directly from the hyphae, and conidia arising on denticles from sympodial conidiophores are typical of Sporothrix schenckii. (Reprinted from http://fungusweb. utmb.edu/mycology/sj)orothrix.html, with permission from Medical Mycology Research Center, Department of Pathology, University of Texas Medical Branch.)

The primary lesion remains "fixed" in 23% of cases, without lymphatic involvement,19 originating from the extremities or the face, and persisting for years. These localized cutaneous lesions without lymphatic spread may appear nodular, crusted, weeping, or fungating or may resemble papillomata, folliculitis, or intertrigo. Sporotrichosis may be limited to the site of inoculation (plaque sporotrichosis) and manifests ctp a nontender, red, maculopapular granuloma, without associated systemic signs and symptoms. Disseminated sporotrichosis (lesions in more than one organ system) occurs after hematogenous 2o ,21 spread from a primary pulmonary or subcutaneous site, in an immunocompromised 22 host. When it occurs, it most commonly affects bones and joints. 9, 10 Reported manifestations of extracutaneous or disseminated sporotrichosis include fungal tendinitis, bursitis, arthritis, osteomyelitis, diffuse skin lesions, meningitis, ocular infection, and vocal cord granulomata. It has been observed in association

with corticosteroid use, sarcoidosis, diabetes mellitus, alcoholism, neoplasia, and AIDS.s, 22 Multifocal cutaneous sporotrichosis (skin infection beyond a single extremity) is extremely common in cases of dissemination. Except for a rilre primary pulmonary23 form of infection in which the organism is inhaled in endemic areas or by an immunocompromised host, sporotrichosis most commonly enters the body through the skin, usually in association with some episode of tralunatic implantation. Symptoms include the insidious onset of cough, sputum production, malaise, weight loss, low-grade fever, and occasional hemoptysis. A single, chronic, cavitary upper lobe lesion and hilar adenopathy are usually revealed on chest x-ray. 12 In the rare instance that the central nervous system is involved, focal or diffuse neurologic symptoms and headache and confusion may be present. An unusual case of lymphocutaneous sporotrichosis was seen in a man who engaged in self-tattooing of his

Conidiophore

Denticle

FIGURE 32-5. Sporothrix schenckii. (Reprinted from

Microconidia

http://www. asrnusa. org/edusrc/ library/ irnages/SMITH/ bnages/TMAGE1-ANJPG, with permission from Andrew G. Smith, M.D., and the AnIerican Society for Microbiology Instructional Library.)

"Fiowerettes", hyphae and conidia, diagnostic of Sporothrix

CHAPTER 32: SPOROTRICHOSIS

left foot. 24 He admitted to having mowed the lawn wearing only sandals on the same day that he tattooed his foot. Sporotrichosis can be seen in patients with other systemic illnesses. Three cases of coinfection with Leishmania have been described in Columbia. 25 The use of empirical treatments for leishmaniasis, such as poultices or puncturing of the lesion with thorns or wood splinters, was speculated to have caused the introduction of the Sporothrix. A woman with Cushing's disease presented with erysipeloid sporotrichosis. 26

Ocular Disease

In 1966, Alvarez and Lopez-Villegas 27 reported an ll-yearold mestizo boy with primary ocular sporotrichosis. The diagnosis was based on mycologic study of the biopsied left temporal bulbar conjunctiva. Conjunctival sporotrichosis may be a primary infection or may be secondary to involvement of the lid and face. The initial sign of infection in the skin of the eyelid is the appearance of a hard, spherical, movable, nontender nodule that later becomes attached to the skin. It is initially pink, then purple, and finally black and necrotic (sporotrichotic chancre). Multiple subcutaneous nodules appear along the course of the lymphatics draining the area. Numerous soft, yellow, granulomatous nodules, which may ulcerate, develop in the palpebral or bulbar conjunctiva of the involved eye. The conjunctival ulcers usually discharge a small amount of purulent material. Gross enlargement and occasional suppuration of preauricular and submandibular l)'lnph nodes occur. '0/ Most cases of ocular sporotrichosis· have an exogenous cause and are acquired through a traumatic injury to the conjunctiva,· cornea, or eyelids by a contaminated object. Witherspoon and associates 39 reported a case of exogenous S. schenckii endophthalmitis in a 13-year-old boy who was struck in his eye with a stick. They also reviewed previous cases of exogenous and endogenous ocular sporotrichosis, citing older reviews by Gordon in 1947, and Francois and Rysselaere in 1972. Most cases in the 1947 review were exogenous and involved the eyelids, conjunctiva, cornea, lacrimal excretory system, or orbit. But 14 of the 18 cases of intraocular sporotrichosis reported in the 1972 review were endogenous, resulting from disseminated sporotrichosis. The other 4 were cases of postoperative exogenous S. schenckii endophthahnitis following cataract surgery. Presenting s)'lnptoms in endogenous S. schenckii endophthalmitis include decreased vision, pain, and ocular redness. Most cases have signs of anterior segment inflammation, including granulomatous or nongranulomatous keratic precipitates, iris nodules, and hypopyon. Later sequelae may include posterior s)'l1.echiae, glaucoma, cataract, and phthisis bulbi. Posterior segment involvement may be manifested by choroiditis, vitritis, or a fluffy white retinal lesion. These latter cases of endogenous sporotrichosis can masquerade as idiopathic panuveitis or posterior uveitis; hence, it is important that the ophthalmologist keep in mind this and other causes of endogenous infectious uveitis. In 1993, Cartwright and coworkers 28 reported a 24year-old black male with S. schenckii endophthalmitis who presented without a history of trauma or systemic infec-

tion and was originally diagnosed with granulomatous uveitis that resulted in scleral perfo:ration. Most patients with endogenous S. schenckii endophthalmitis eventually require enucleation. One problem is that it is difficult to culture the organism from blood, urine, or intraocular fluids. Several cases in the Witherspoon study39 were not accurately diagnosed until enucleation had been performed. In addition, most of the previously reported cases occurred before amphotericin B or modern vitreoretinal surgical techniques were available. A recent case of endogenous S. schenckii endophthahnitis involved a 30-year-old man with AIDS and disseminated sporotrichosis. He had a granulomatous uveitis that worsened following topical and subconjunctival corticosteroid therapy. An aqueous aspirate was positive for S. schenckii, and the patient received treatment with intravitreous and intravenous amphotericin B. The patient's intraocular inflammation worsened despite negative repeat aqueous and vitreous cultures, and enucleation was eventually required.

PATHOLOGY Pathogenesis Traumatic implantation is the main mechanism for infection. Strains that multiply well at 25°C but poorly at 37°C can produce cutaneous lesions. Strains that multiply at both 25°C and 37°C are capable of producing lymphocutaneous or visceral disease. However, inhalation of spores is also known to cause a pulmonary form of disease.

Histopathology Histopathologic and electronmicroscopic examination of an eye with sporotrichosis reveals suppuration and granulomata, occasionally with caseating necrosis. Organisms morphologically compatible with S. schenckii have been demonstrated in the anterior chamber, vitreous cavity,29 retina,30 subretinal space, and retinal piglnent epithelium. 31 Additional histopathologic findings in other patients with S. schenckii endophthalmitis include a granulomatous necrotizing chorioretinitis 31 and intracellular fungi 32 within inflammatory cells. Scattered S. schenckii organisms with disrupted protoplasm 30 may occasionally be seen.

Immunology Historical attempts to demonstrate a positive reaction to the agglutination test have been dispelled by the fact that the spores have been similarly agglutinated by the serum of normal controls. S. schenckii can bind to fibronectin, laminin, and type II collagen; the organisms also show differences in binding capacity according to the morphologic form of the fungus. 33 The virulence of S. schenckii conidia may be determined by their cell wall composition. 34 Modern research has attempted to give the organism a molecular persona. Cell-mediated immunity is important in determining the extent of disease. S. schenckii is processed chiefly by the cellular limb of the immune system; therefore, the relative integrity of the cellular immune system will influence whether the disease remains localized or becomes disseminated.

CHAPTER 32: SPOROTRICHOSIS

The organism is rarely seen on direct examination of tissue. The positive diagnosis of sporotrichosis relies on the identification of the organism. 1 The most reliable means of identification is by culture. It grows well on Sabouraud's glucose agar or blood agar at 25°C. It is resistant to cycloheximide; therefore, Mycosel or Mycobiotic agar may be used for culture. Colony morphology is variable and may be white or pigmented, creamy, or shiny, depending on the strain and specimen type. Animal inoculation may also be performed for specific identification. S. schenckii can be very difficult to isolate frOlll blood, urine, or ocular fluid, thereby necessitating repeated diagnostic aqueous and vitreous aspiration and culture to isolate the organism. If there is another site of infection, such as a cutaneous lesion or fungal arthritis, biopsy or aspiration of that site with culture may be helpful. Careful examination of Gram's, periodic acid-Schiff, or Gomori methenamine silver stain, as well as immunofluorescence histologic studies of a tissue specimen, may reveal organisms, even when the cultures are negative. Also, specific serologic tests are available to identify antibodies to S. schenckii in blood or body fluid. Immunodiffusion, enzyme-linked immunosorbent assay (ELISA), or Western immunoblot testing can be performed on aqueous or vitreous fluid as well. Gallium and bone scans have been helpful in localizing areas of involvement in patients with disseminated sporotrichosis. Despite the well-known difficulties in determining an accurate and timely diagnosis, fine-needle aspiration cytology, l~ter confirmed by tissue biopsy and culture study, was performed and reported in 1999. 35

DIAGNOSIS Before the chain of lesions develops, there is nothing characteristic of the presentation that suggests sporotrichosis. Once the ulcers or chain of nodules appears, sporotrichosis should be suspected. All other causes of granulomatous lesions, however, should be investigated. Syphilis and tuberculosis may be ruled out on the basis of the clinical pictures and the specific lesions seen at biopsy and laboratory testing. Leprosy must also be excluded. In cases of conjunctival involvement, Parinaud's conjunctivitis should be considered and excluded. Other differentials worthy of consideration include causes of severe granulomatous inflammation such as sarcoidosis and fungal endophthalmitis caused by other organisms. The approach to treatment of sporotrichosis varies with the disease form. Administration of saturated solution of potassium iodide (SSKI) 1,36 is the treatment of choice for cutaneous disease. Oral potassium iodide is an effective, inexpensive treatment that has been the standard regimen for decades. Its antifungal effect is not well understood, and it has no direct effect on S. schenckii. It is taken orally in milk at an initial dose of 5 drops three times daily, increased by 4 to 5 drops per day up to 12 to 18 mllday12 (l drop equals 50 lull), or until signs of toxicity occur (e.g., lacrimation, salivation, parotid gland swelling, indigestion). When toxicity develops, the therapy should be stopped for a few days and restarted at a lower dose.

Local application of heat to the lesions may be helpful. A pustular, acneiform rash over the face and cape area of the trunk is not an infrequent finding, but it is not an indication to discontinue iodides; To avoid recurrence iodides should be continued for 4 to 6 weeks after clinical resolution. Disseminated or extracutaneous sporotrichosis is usually treated with intravenous amphotericin B (0.5 mg/ kg/ day). Flucytosine 37 has been effective in treating disseminated disease. Itraconazole is also very effective against both S. schenckii (in vitro) and disseminated sporotrichosis. Treatment with itraconazole has resulted in response rates of greater than 90%. As a result, itraconazole (200 mg once or twice daily) 17 is likely to become the drug of choice for both disseminated and nondisseminated forms of sporotrichosis, as most patients do not accept oral potassium iodide. 38 The patient presented by Witherspoon and associates 39 had exogenous S. schenckii endophthalmitis, and it was the first case to be successfully treated. The patient underwent pars plana lensectomy and vitrectomy, received topical amphotericin B, and had a repeat vitrectomy with injection of intravitreous amphotericin B. This was the first reported case of S. schenckii endophthalmitis treated with vitrectomy. The patient's vision improved frOlll light perception to 20/50. All previous cases of endogenous and exogenous S.schenckii endophthalmitis had resulted in enucleation. Successful treatment of endogenous S. schenckii endophthalmitis has not been reported.

PROGNOSIS Sporotrichosis in its cutaneous, lymphocutaneous, and mucocutaneous forms remits and relapses over years without therapy.12 Spontaneous cure has been reported in plaque sporotrichosis. 40 Most patients with sporotrichosis respond well to treatment, even when the disease has reached a fairly advanced state, provided that the deeper structures of the body are not yet involved. Involvement of the globe is evidence of deep invasion and indicates that the organism has reached the blood stream, unless a history has been elicited of direct perforation by the traumatizing and etiologic agent. 1

A high index of suspicion of the clinical entity of sporotrichosis is needed if a properly conducted early laboratory diagnosis is to be achieved. Positive diagnosis of sporotrichosis relies on identification of the organism. The most reliable means of identification is by culture. The treatment of choice for the cutaneous presentation is potassium iodide in its soluble form. For extracutaneous forms, aggressive treatment using systemic antifungal agents (amphotericin B and/or itraconzole), pars plana vitrectomy, and intravitreous amphothericin B is warranted.

References 1. Gordon DM: Ocular sporotrichosis. Arch Ophthalmol 1947;37:56. 2. Schenck BT: On refractory subcutaneous abscesses caused by a fungus, possibly related to the Sporotrochia. Bull Johns Hopkins Hosp 1898;9:286, as cited by Gordon DM: Ocular sporotrichosis. Arch Ophthalmol 1947;37:56. 3. Gordon DM: Ocular sporotrichosis. Arch Ophthalmol 1947;37:56.

CHAPTER 32: SPOROTRICHOSIS 4. DeBeurmann CL, Gougerot H, a11d Laroche: Gomme de 1£1 paupiere. Bull Mem Soc Med Hop Paris 1907;27:1046, as cited by Gordon DM: Ocular sporotrichosis. Arch Ophthalmol 1947;37:56. 5. DeBeurmann CL, Gouge-at H: Sporotrichose cachectisante martelle. Bllll Mem Soc Med Hop Paris 1909;26:1046, as cited in Duanes's Ophthalmology on CD-ROM. Philadelphia, LippincottRaven, 1996. 6. Morax V: Uveite sporotrichosique avec gomme sporotrichosique episclerale secondaire: Absence de route autre localization sporotrichosique decelable. Ann Ocul 1914;152:273, as cited in Duanes's Ophthalmology on CD-ROM. Philadelphia, Lippincott-Raven, 1996. 7. Mackenzie DWR: Subcutaneous mycoses. In: Stricldand GT, ed: Hunter's Tropical Medicine, 7th ed. Philadelphia, WB Saunders, 1991, pp 510-515. 8. Ware AJ, Cockerell q, Skiest DJ, Kussman HM: Disseminated sporotrichosis with extensive cutaneous involvement in a patient with AIDS. J Am Acad Dermatol 1999;40(2.2):350~355. 9. Wilson DE, Mann.IT, BennettJE, UtzJP: Clinical features of extracutaneous sporotrichosis. Medicine 1967;46:265. 10. Lynch PJ, Voorhees.IT, Harrell ER: Systemic sporotrichosis. Ann Intern Med 1970;73:23. 11. Chang AC, Destouet JM, Murphy WA: Musculoskeletal sporotrichoc sis. Skeletal Radial 1985;12:23. 12. Albert DM,Jakobiec FA, eds: Principles and Practice of Ophthalmology, on CD-ROM. Philadelphia, WB Saunders, 2000. 13. Powell KE, Talor A, Phillips BJ, et £11: Cutaneous sporotrichosis in forestry workers. Epidemic due to contaminated sphagnum moss. JAMA 1978;240:232. 14. Dixon DM, Salkin IF, Duncan RA, et £11: Isolation and characterization of Sporothrixschenchii from clinical and environmental sources associated with the largest U.S. epidemic of sporotrichosis, J Clin Microbial 1991;29:1106-1113. 15. McGrath H, Singer JI: Ocular sporotrichosis. Am J Ophthalmol 1952;35:102. 16. Pettit TH, EdwardsJEJr, Purdy EP, BullockJD: Endogenous fungal endophthalmitis. In: Pepose JS, Holland GN, Wilhelmus KR, eds: Ocular Infection and Immunity, 1st ed. Ml;ssouri, Mosby, 1996, pp 1278-1281. 17. Bennett JE: Miscellaneous mycoses and prototheca infections. In: Harrison TR, Resnick WR, Wintrobe MM, Thorn GW, et £11, eds: Harrison's Principles of Internal Medicine, 14th ed, on CD-ROM. New York, McGraw-Hill, 1998. 18. Rippon JW: The pathogenic fungi and the pathogenic Actinomycetes. In: Medical Mycology, 3rd eel. Philadelphia, WB Saunders, 1988. 19. BennettJE: Sporothrix schenchii. In: Pepoose JS, Holland GN, Wilhelmus KR, eds: Ocular Infection and Immunity. Missouri, Mosby-Year Book, 1996, p 1278. 20. Satterwhite TK, Kagler WV, Conklin RH, et £11: Dissemil1ated sporotrichosis. JAMA 1978;240:771. 21. Matthay RA, Greene WH: Pulmonary infections in the immunocom-, promised patient. Med Clin North Am 1980;64:529.

22. Bibler MR, Luber JH, Glueck HI, Estes SA: Disseminated sporotrichosis in a patient with HIV infection after treatment for acquired factor VIII inhibitor. JAMA 1986;256:3125. 23. Michelson E: Primary pulmonary sporotrichosis. Ann Thorac Surg 1977;24:83. 24. Bary P, Kuriata MA, Cleaver LJ: Lymphocutaneous sporotrichosis: A case report and unconventional source of infection. Cutis 1999;63(3) :173-175. 25. Agudelo SP, Restrepo S, Velez ID: Cutaneous New World leishmaniasis-sporotrichosis coinfection: Report of 3 cases. J Am Acad Dermatol 1999;40(6.1):1002-1004. 26. Kim S, Rusk MR, James WD: Eysipeloid sporotrichosis in a woman with Cushing's disease. J Am Acad Dermatol 1999;40(2.1) :272-274. 27. Alvarez RG, Lopez-Villegas A: Primary ocular sporotrichosis. Am J Ophthalmol 1966;62(1):150-151. 28. Cartwright MJ, Promersberger M, Stevens GA: Sporothrix schenchii endophthalmitis presenting as granulomatous uveitis. Br J Ophthalmol 1993;77:61-62. 29. Cassady JR, Foerster HC: Sporotrichum schenchii endophthalmitis. Arch Ophthalmol 1971;85:71. 30. Kurosawa A, Pollock SC, Collins MP, et £11: Sporothrix schenchii endophthalmitis in a patient with human immunodeficiency virus infection. Arch Ophthalmol 1988;106:376-380. 31. Font RL, Jakobiec FA: Granulomatous necrotizing retinochoroiditis caused by Sporotrichum schenhii: Report of a case including immunofluorescence and electron microscopical studies. Arch Ophthalmol 1976;94:1513. 32. Brod RD, Clarkson JG, Flynn HW Jr, et £11: Endogenous fungal endophthalmitis. In: Duane TD, Jaeger EA, eds: Clinical Ophthalmology, vol 3. Hagerstown, MD, Harper & Row, 1990. 33. Lima OC, Figueiredo CC, Pereira BA, et £11: Adhesion of the human pathogen Sporothrix schenchii to several extracellular matrix proteins. BrazJ Med BioI Res 1999;32(5):651-657. 34. Fernandes KS, Matthews HL, Lopes Bezerra LM: Differences in virulence of Sporothrix schenchii conidia related to culture conditions and cell-wall components. J Med Microbial 1999;48(2):195-203. 35. Zaharopoulos P: Fine-needle aspiration cytologic diagnosis of lymphocutaneous sporotrichosis: A case report. Diagn Cytopathol 1999;20(2):74-77. 36. Wescott BL, Nasser A, Jarolim DR: Sporothrix meningitis. Nurse Pract 1999;24(2):90, 93-94, 97-98. 37. Shelley WB, Sica PA JR: Disseminated sporotrichosis of skin and bone cured with 5-fluorocytosine: Photosensitivity as a complication. J Am Acad Dermatol 1983;8:229. 38. Wescott BL, Nasser A, Jarolim DR: Sporothrix meningitis. Nurse Pract 1999;24(2) :90, 93-94, 97-98. 39. Witherspoon DC, Kuhn F, Owens D, et £11: Endophthalmitis due to Sporothrix schenchii after penetrating ocular injury. Ann Ophthalmol 1990;22:385-388. 40. Bargman HB: Sporotrichosis of the nose with spontaneous cure. Can Med AssocJ 1981;124:1027.

Andrea Pereira Da Mala and Fernando Orefice

Toxoplasmosis is caused by the obligate intracellular protozoan Toxoplasma gondii. It has a universal distribution and a high serologic prevalence in all countries, but the incidence of Toxoplasma-induced disease is much lower. Although it affects humans and animals, the feline species is the only definitive host. Toxoplasmosis is the most common cause of posterior uveitis in the world,r-3 accounting for over 80% of the cases in some regions. 4,5 Recurrence of congenitally acquired toxoplasmosis,once blamed for almost all cases, is still the leading cause of Toxoplasma retinochoroiditis, but it is becoming increasingly clear that acquired ocular disease is more common than previously suspected. 6- 17 Although active Toxoplasma retinochoroiditis usually has a self-limiting course in immunocompetent patients, it can recur and lead to irreversible visual loss should ocular structures critical to good vision (the macula and the optic nerve) be involved. In the immunosuppressed host, Toxoplasma infection poses unique diagnostic and therapeutic challenges.

HISTORY Toxopla~ma gondii was discovered independently by two investigators in 1908. Alfonso Sp~endore in Brazil identified the organism in laboratory rabbits,18, 19 while Charles Nicolle and Louis Manceaux in Tunis observed the organism in the North Mrican rodent Ctenodactylus gondii. Nicolle and Manceaux named the parasite Toxoplasma gondii: Toxoplasma from the Greek word toxon, meaning arc, describing the small crescent shape of the parasites, and gondii from the animal in which it was found. 20 , 21 Both papers agreed in most of their observations, but it was Splendore who identified the schizogenous form of reproduction and the formation of true cysts. In the same year, Darling unwittingly described systemic toxoplasmosis at the Gorgas Hospital in PanalTIa. He reported a patient with acute myositis, but misdiagnosed it as sarcosporidiosis. Years later, Chaves-Carballo and Samuel reexamined the biopsy samples and concluded that the parasite was T. gondii. 22 Other reports followed, including Castellani (Ceylon, 1914) who attributed a case of fever and splenomegaly to a protozoan, which at the time he named Toxoplasma pyrogenes. 23 The first description of congenital toxoplasmosis with ocular involvement is attributed to JankCt. (Prague, 1923), who reported an II-month-old infant with hydrocephalus, microphthalmia, and a retinal "coloboma" in the macular region. Histopathologically, JankCt. identified an oval sporocyst containing numerous dark sporozoites within the outer layer of the choroid in this "colobomatous area. "24 The first photographic documentation of ocular toxoplasmosis was made in Brazil by Belfort Mattos in 1933 (Fig. 33-1). Acquired toxoplasmosis with ocular manifestations was not described until 1940, when Pinkerton and Weinman noted retinal lesions in a young adult with generalized disease. 25 Wilder demonstrated T. gondii

in stained sections of eyes with "intractable chorioretinitis." This resulted in a shift in the diagnostic mentality of posterior uveitis from tuberculosis being the most COlTImon agent to Toxoplasma as an important cause of posterior uveitis. 26 Diagnostic testing for toxoplasmosis was first attempted by Nicolau and Ravelo (1937), who used a complement fixation test to demonstrate the existence of anti- Toxoplasma antibodies. 27 However, their test proved to be of low reliability. The introduction of the Sabin-Feldman test in 1948 provided a sensitive and specific method for the detection of antibodies against T. gondii, allowing epidemiologic studies to be conducted. By 1960, toxoplasmosis was identified as the most common cause of posterior uveitis in the world. 28 It was not until 1970 that the feline species, primarily the domestic cat, was identified as the definitive host of T. gondii. 29 ,30

The Organism T. gondii is an obligate intracellular parasite that can be found in the host's tissues and body fluids, such as saliva, milk, semen, urine, and peritoneal fluid. The morphology of the T. gondii varies depending on the stage of the life cycle and habitat. It can present in three forms: the tachyzoite, bradyzoite, and sporozoite. The tachyzoite, also called trophozoite, is the infectious form responsible for the acute phase of the disease. It is approximately 3 by 7 /-Lm in length and 2 to 4 ~m in diameter, and it has the shape of a crescent. It was the form first observed by Nicolle and Manceaux that inspired the genus name Toxoplasma (Fig. 33-2). The tachyzoite, an obligate intracellular form, may enter the cytoplasmic vacuoles of any nucleated cell. It is mobile and quickly multiplies by endodyogeny until the cell ruptures, releasing more tachyzoites to infect other cells.

FIGURE 33-1. First photographic documentation of ocular toxoplasmosis. Taken by Waldemar Belfort Mattos, Brazil, 1933. (Courtesy of Rubens BelfOl~t Mattus Jr., M.D., Ph.D., UNIFESP, Brazil.)

CHAPTER 33: TOXOPLASMOSIS

FIGURE 33-2. Scanning electron photomicrograph of Toxoplasma 'gondii tachyzoites. (Courtesy of Rubens Belfort Mattos Jr., M.D., Ph.D., UNIFESP, Brazil.)

The tachyzoite encysts at the first sign of environmental stress such as the host immune response or the presence of antibiotic. The encysted form, known as the bradyzoite, begins to appear as soon as 1 week following infection. Bradyzoites divide slowly inside the cellular vacuole, which eventually becomes part of the cyst's capsule. The wall of a mature cyst is composed of a cOlubination of both host and parasitic components, so the bradyzoites are protected from the host's immune system. The cysts are very resistant and can remain dormant in "i' the host for years without tissue damageY Cysts have a predilection for tissues such as the retina, skeletal muscles, the central nervous system, and the heart, and they persist for the life of the host. They are approximately 10 to 100 fJvm in size and may contain up to 3000 bradyzoites (Fig. 33-3) .32 For reasons unknown, the cysts may rupture, causing reactivation of the disease and intense inflammation. Oocysts are produced only in the feline intestinal cells and are excreted in the feces. The oocyst is the most resistant form of the organism and may remain infectious

for up to 2 years in warm, moist soil. 32 They are oval and measure 10 to 12 fJvm in diameter. Within 1 to 21 days after shedding, the oocysts undergo sporulation and become mature, infective oocystS. 33 These mature forms contain two sporocysts, each of which contains four sporozoites. The ingestion of mature oocysts can cause infection in either an intermediate or the definitive host. Sporulation does not occur below 4°C or above 37°C, thus explaining the lower incidence of toxoplasmosis in areas with extreme temperatures.

life Cycle The life cycle of T. gondii is composed of two distinct phases: the asexual phase, which occurs in all hosts, and the sexual phase that happens only in the intestinal epithelium of the definitive host. Felines, especially domestic cats, are the only definitive host and they sustain both sexual and asexual reproduction. Humans and many other animals, such as cattle, pigs, sheep, and poultry, support asexual reproduction of T. gondii and constitute the intermediate host group.

FIGURE 33-3. Transmission electron photomicrograph of Toxoplasma gondii tissue cyst in mouse brain. (Courtesy of Fausto Araujo, Ph.D., United States.)

CHAPTER JJ: TOXOPLASMOSIS

The asexual cycle starts when a susceptible host ingests mature oocysts, tissue cysts contain bradyzoites, or tachyzoites are present in body secretions and raw meat. Tachyzoites that reach the stomach are destroyed by gastric acid, but. tachyzoites are very active and may penetrate the oral mucosa. Digestive enzymes break down the walls of both oocysts and tissue cysts, releasing sporozoites and bradyzoites. These organisms then enter cells of the intestinal tract and transform into rapidly multiplying tachyzoites that rupture the cells, releasing free tachyzoites. Extracellular tachyzoites or tachyzoites within leukocytes are transported throughout the body via the lymphatic system and bloodstream, and they can invade any organ or tissue. This initial infection characterizes the acute phase of the disease. Once infected, the host produces specific antibodies, which bind to the extracellular tachyzoites, initiating immune-mediated eradication of the free parasite. However, humoral immunity is ineffective against intracellular parasites and the cellular immune response is called upon to attack the parasitized cells, reducing intracellular multiplication and causing the tachyzoites to encystY When the immune system has eliminated the tachyzoites, symptoms disappear, and the chronic phase ensues. The sexual cycle takes place exclusively in the feline intestine, and it is unclear why this phase occurs only in members of the cat family. Cats may initially become infected by eating contaminated meat containing tissue cysts or by ingesting sporulated oocysts. In the cat's intestine, the tachyzoites invade the ~pithelial cells and start to multiply by schizogony. During this process, gametocytes are formed and fertilized to produce oocysts. The time interval between the infection and the appearance of oocysts in the feces depends on the form of the organism ingested and varies from 3 to 24 days. Excretion continues for up to 20 days, with shedding of as many as 12 million oocysts in a single day. In general, once a cat has cleared the initial infection it will not shed oocysts again. However, if the cat becomes infected with Isospora felis, recurrent oocyst shedding may occur. 34

Transmission The main mechanism of human infection is by ingestion of tissue cysts in raw or undercooked meat. In the United States, evidence of bradyzoites is seen in approximately 10% to 20% of lamb products and 25% to 35% of pork products, whereas the incidence in beef is only about 1%.35 Food may also be contaminated with oocysts, especially through dissemination by insects and by food handlers. The second important route of infection is contact with any material contaminated by infected cat feces, such as soil and cat litter. This may result in accidental ingestion or inhalation of oocysts. Infection may also be acquired through ingestion of unpasteurized goat's milk, raw eggs, or unwashed vegetables; transfusion of blood or leukocytes; organ transplantation; and laboratory accidents. 34--38 Transplacental transmission Inay occur if a woman is initially infected just before or during pregnancy. Women with positive serology before pregnancy have little or no chance of infecting their fetuses, although on rare occasions, women with chronic latent infection and per-

sistent parasitemia may have one or more affected children. 39 : 4o Reactivation of ocular toxoplasmosis during pregnancy does not increase the risk of congenital transmission in an immunocompetent woman,4l

As an obligate intracellular pathogen, T. gondii's reproductive success depends on its ability to penetrate host cells and evade cellular defenses. The tachyzoites actively secrete penetration-enhancing factors (PEFs) that interact with the cellular phospholipid bilayer and allow the organism to invade eukaryotic cells within 5 to 10 seconds. 42-44 During this active penetration, the tachyzoites become enveloped by part of the. cell membrane, inducing a new subcellular organelle, the parasitophorous vacuole. The tachyzoites induce molecular and morphologic changes in the parasitophorous vacuole, which prevent acidification and fusion with cellular lysozomes. 42 , 45-49 Maintenance of an alkaline pH (7.0 to 8.0) inside the vacuole is one of the main mechanisms that enable survival and replication of the tachyzoites. The activation of B cells and the humoral immune response is the first step toward control of the Toxoplas17w infection; this consists of the production of antiToxoplasma-specific immunoglobulin M (IgM), IgA, IgE, and IgG antibodies. Antibody binding to tachyzoites can result in lysis by the classical complement pathway, but more important, antibody-coated tachyzoites are unable to actively penetrate cells. Instead, these opsonized tachyzoites are recognized by phagocytic cells and are engulfed into phagolysosomes, resulting in destruction of the parasite. 49 ,50 Although the humoral response is important, it is not sufficient to eradicate the intracellular organism. Cellmediated immunity is the major mechanism involved in the resolution of the active disease,5l Indeed, a significant feature of the toxoplasmosis infection is the strong and persistent cellular immunity induced by the parasite. Evidence for the importance of cell-mediated immunity comes from immunocompromised patients in whom primary infection or reactivation of chronic T. gondii cysts often results in disseminated disease with a high mortality.52 The cellular immune response is characterized by activation of macrophages, natural killer (NK) cells, and T cells, and release of their cytokines. Macrophages are activated following phagocytosis of antibody-opsonized T. gondii, and they initiate the imlnune response by producing interleukin 12 (IL-12) and tumor necrosis factor alpha (TNF-a) .53,54 These monokines stimulate CD8 + T lymphocytes and NK cells to produce interferon-')' (IFN-')') .55 IFN-')' plays a key role in the immune response to T. gondii by enhancing the microbicidal activity of the macrophage. 55 ,56 Activated macrophages use toxic oxygen and nitrogen intermediates as well as products of arachidonic acid metabolism to enhance killing intracellular T. gondii. Other evidence suggests that IFN-')' Inay inhibit replication of Toxoplasma by tryptophan starvation in retinal pigment epithelial cells. 57 Monokines released by macrophages also stimulate CD4 + Th1 cells to produce IL2, which in turn activates cytotoxic T cells and NK cells to attack cells infested with T. gondii and free tachyzoites.

CHAPTER 33: TOXOPLASMOSIS TABLE 33-1. NAME

SAG1 SAG2 SAG3 GRA1 GRA2 GRA3 GRA4 GRA5 . ROP1 ROP2 MIC1 TUB1 TUB2

DTS1 NTP1

OF TOXOPLASMA GONDII GENES CLONED AND CHARACTERIZED THUS FAR OTHER NAMES

LOCALIZATION

KDA (SDS.PAGE)

REFERENCE

P30 P22 P43 P23, P27 P28

Surface Surface Surface Dense granule Dense granule Dense granule Dense granule Dense granule Rhoptry Rhoptry Micronemes Microtubules Microtubules

30 22 43 22, 23, 27 28, 28.5 30 40 21 60,60.5 54, 55 60

Secretory

63

172-175 173, 174, 176 173, 174, 177 178, 180 179,181-183 180, 184 180, 185 179, 186 183, 187 183, 188 189, 190 191 191 192 193, 194

P21 PEF P54, TG34 Alfa-tubulin Beta-tubulin DHFR NTPase

Modified from Joincr KA: Cell entry by Toxoplasma gondii: All paths do not lead to success. Res ImmunoI1993;144:34-38.

Conversely, stimulated CD4 + Th2 cells produce IL-4, IL5, and IL-I0, which modulate the activity of the cellmediated immune responses to prevent an excessive inflammatory response. 55 The inflammatory reactions in the eye are generally modified, because the eye is an immunologically privileged site; thus, the local ocular immune response tends to be suppressed to limit tissue damage. In the eye, inflammatory reactions are dominated by CDS + T cells and CD4 + Th2 cells due to constitutive expression of anti-inflammatory factors such as F~s, Fas ligand, and tumor growth factor beta (TGF-13).· T. gondii, however, seems to promote the production of factors, such as IFN-l' that abrogate this immune privilege. 55 , 58 The Toxoplasma organism has developed another strategy to evade host defenses. When tachyzoites encyst, the tissue cysts become invisible to the immune system, because the cyst wall incorporates cellular components derived from the host and thus is recognized as itself. Cysts may remain dormant for an indefinite period. Factors modulating the reactivation of cysts are poorly understood, but it seems· relatively clear that IFN-l' helps to prevent reactivation of chronic toxoplasmosis, possibly by inhibiting cyst rupture. 55 ,59 Immunosuppression, however (particularly the depletion of T-helper cells), allows the breakdown of tissue cysts and thus tachyzoite proliferation. Advances in the field of cellular biology of T. gondii have made possible the identification and purification of many cell surface antigens or secreted antigens from the tachyzoites (Table 33-1). The major surface antigen P30, for example, appears to have an important role in both immune and pathogenic mechanisms of the parasite. P30 may beinvolved in antibody-dependent, complement..,mediated lysis of the tachyzoites. 60 Another surface protein, p22, seems to be the target of cellular immune response,61 and the specific heat shock protein 70 (Hsp-70) may have an important role in the process of bradyzoite-tachyzoite conversion during the reactivation of chronic toxoplasmosis. 62

The T. gondii infection is one of the IllOSt common zoonoses in the world. 63 In all countries, a large percentage of

the population has chronic asymptomatic disease. The prevalence varies extensively in different regions, depending on socioeconomic, geographic, and climatic factors. A high prevalence is found in tropical areas close to sea level, and a lower prevalence is found in arid regions, in cold climates, and at high altitudes. These variations are related to environmental influences on the oocysts. In addition, the habit. of eating raw meat and the presence of the domestic cat greatly increase the incidence of Toxoplasma disease. The prevalence of seroconversion also increases with age. For example, in the United States, 5% to 30% of individuals 10 to 19 years old are seropositive, whereas up to 70% of those over age 50 years show serologic evidence of T. gondii exposure. 35 The general prevalence in the United States ranges from 30% to 70%.64-66 A comparison of positive serology for toxoplasmosis in different populations and geographic regions is shown in Table 33-2.

Congenital Toxoplasmosis Intrauterine toxoplasmosis infection deserves special at-, tention. Congenital infection has been estimated to affect 3000 infants born in the United States each year. 67 , 68 The prevalence of congenital disease parallels the rate of seropositivity (Table 33-3). Approximately 70% of women of child-bearing age in the United States are at risk of

TABLE 33-2. FREQUENCY OF POSITIVE SEROLOGY FOR TOXOPLASMOSIS IN DIFFERENT POPULATIONS POPULATION

Eskimos Navajo Indians England Finland Venezuela Austria Colombia United States Brazil France

POSITIVITY (%)

o 4

25 45 60 62 65 30-70 42-83 90

Modified from Orefice F, Bonfioli AA: Toxoplasmose. In: Orefice F, ed: Uveite clinica e cirurgica (in prelo). Rio de Janeiro, Brazil, Editora Cultura Medica, 1999; Orefice F, Belfort RJr: Toxoplasl11ose. In: Orefice F, Belfort R, eds: Uveitis. Sao Paulo, Roca, 1987.

CHAPTER 33: TOXOPLASMOSIS TABLE 33-3. PREVALENCE OF CONGENITAL INFECTION BY T. GONDII POPULATION

REFERENCE

Alabama England Scotland United States Czech Republic Australia Belgium Yugoslavia Switzerland Brazil France

Hunter et al, 1983 195 Jackson et aI, 1987]96 Williams et aI, 198p97 Alford, 1982]98 Palicka, 1982 199 Sfameni et aI, 1986200 Foulon et aI, 1984201 Logar et aI, 1992 202 Bornand, 1991 203 Camargo Neto, 197820 '1 Desmonts, 1983 205

CASES PER 1000 BIRTHS 0.12 0.07-0.25 0.46-0.93 1 1.6

2 2 3 3.5 4

7

contracting the disease,32 but the incidence of acquiring toxoplasmosis during pregnancy is only 0.2% to 1%.35 Among women who first contract toxoplasmosis during pregnancy, the chance of transplacental infection of the fetus is about 40%.69 The severity of congenital toxoplasmosis is inversely related to the time of gestational exposure. Vertical transmission is most frequent during the third trimester, when the fetus may be exposed to maternal blood. Fortunately, third-trimester infection usually results in a subclinical form of the disease. If, on the other hand, the infection occurs in the first trimester, it can result in spontaneous abortion or birth of an infant with severe disease. The transplacental infection rate is approximately 10% to 17% in the first trimester, 30% in the second trimester and 60% to 65% in the third trimester. 34, 41 Most auth~rities agree that transplacental transmission rates are lower if the mother receives treatment during pregnancy.70-73 However, a recent study claims that prenatal antibiotic therapy after toxoplasmosis infection during pregnancy has no impact on the fetomaternal transmission rate, but it does reduce the rate and severity of adverse sequelae among the infected infants. 74 Overall, retinochoroiditis is the most common manifestation of congenital infection, occurring in 70% to 90% of all cases. 64, 67 Most cases of congenital toxoplasmosis present as a subclinical or chronic infection. The newborn mayor may not have retinochoroidal scars (Figs. 33-4 and 33-5), intracranial calcifications (Fig. 33-6), or other sequelae of intrauterine infection. Mter months or even years, these children develop the signs and symptoms of central nervous system involvement, such as hydrocephalus or microcephalus, seizures, psychomotor retardation, development delay, and ocular disease with retinochoroidal lesions, strabismus, and blindness. The identification of subclinical infection is ilnportant, because early treatment improves the prognosis. 68 Some infants with congenital toxoplasmosis are born with clinical signs of active infection. They may present at birth with neurologic involvement or generalized disease, but the former is more frequent. The central nervous system involvement presents as encephalomyelitis, paralysis, meningismus, seizures, respiratory disturbances, hydrocephalus or microcephalus, intracranial calcifications, and failure to thrive. The generalized disease pre-

FIGURE 33-4. Typical wagon wheel appearance of a retinochoroidal lesion in congenital toxoplasmosis.

~ents with an exanthematous rash, petechiae, ecchymoses, ICterus, fever or hypothermia, anemia, lymphadenopathy, hepatosplenomegaly, pneumonitis, vOlniting, and c;liarrhea. This neonatal form is severe and patients frequently develop ocular ane}. neurologic sequelae even with treatment. The most common ocular sequelae are retinochoroidal scars, cataracts, microphthalmia, phthisis bulbi, strabismus, nystagmus, and optic atrophy. ?cca~ionally, the infant is normal at birth and develops actIve dIsease In the first few months of life. This form is more common in premature infants and results in severe disease, but it may also occur in full-term infants, in whom it is less severe.

Acquired Toxoplasmosis Typically, about 70% of immunocompetent patients who acquire toxoplasmosis are completely symptom free. Even when symptomatic, the disease is usually so mild and nonspecific that the diagnosis is difficult to make, and the condition is frequently unrecognized. The most common

FIGURE 33-5. Classic macular retinochoroidal lesion of congenital toxoplasmosis. (See color insert.)

CHAPTER 33: TOXOPLASMOSIS

manifestations IS variable, and ranges from days to years. 11-14. 17

Toxoplasmosis in Immunocompromised Patients

fiGURE 33-6. Contrast-enhanced CT scan demonstrating coarse intracranial calcifications, encephalomalacia and ventriculomegaly in congenital toxoplasmosis.

manifestation of acquired toxoplasmosis is l)Tlnphadenopathy affecting one or multiple lYJ-llph nodes. Cervical nodes are involved more frequently, followed by suboccipital, supraclavicular, axillary, inguinal, and mediastinal nodes. Involved lymph nodes are llsually bilateral, discrete, nontender, and nonsuppurative and they vary in firmness. About 20% to 40% of patients with lymphadenopathy also present with constitutional sYJ-llptoms resembling a mononucleosis-like illness. The sYJ-llptoms include headache, malaise, pharyngitis, fatigue, fever, and night sweats. A smaller proportion of sYJ-llptomatic patients may have a more florid picture including meningismus, meningoencephalitis, myalgias, arthralgias, abdominal pain, and a maculopapular rash that spares palms and soles. Acquired toxoplasmosis in an immunocompetent individual is usually benign and self-limiting, lasting about 2 to 4 weeks. However, malaise and lYJ-llphadenopathy may persist or recur in months. Rarely, the clinical manifestations may be very severe and include encephalopathy, pneumonitis, myocarditis, polymyositis, hepatitis, and splenomegaly, resulting in significant morbidity and even mortality. Acquired ocular toxoplasmosis was once thought to be relatively rare, as it was diagnosed only when the ocular disease occurred following an episode of acute symptomatic systemic disease. Because most acquired Toxoplasma disease is aSYJ-llptomatic, the true incidence of ocular toxoplasmosis in this setting is unclear, but current estimates range from 2% to 20%.3,7, S. 75 Evidence to support the hypothesis that acquired disease may often result in ocular toxoplasmosis comes from epidemiologiC studies demonstrating patients with elevated IgM and the frequentoccurrence of multiple siblings with ocular disease. 4, 5, S, 12, 15 When ocular disease occurs as a consequence of acquired toxoplasmosis, it can be simultaneous with the systemic disease or have a delayed onset. The time interval between the systemic disease and ocular

Immunocompromised patients are at increased risk for developing acute toxoplasmosis. The disease may be caused by reactivation of a chronic infection, or it may be an acquired infection. T. gondii causes a severe, fuhninant disease in immunocompromised individuals, including patients with human immunodeficiency virus (HIV) , transplant recipients, and, less frequently, l)Tlnphoma patients. 76 , 77 Toxoplasmosis in these individuals carries a poor prognosis and may be rapidly fatal if untreated. The parasite has an affinity for the central nervous system; consequently, the most common manifestation in patients with acquired immunodeficiency syndrome (AIDS) is intracranial involvement. Patients may present with diffuse neurologic dysfunction, seizures, or even focal neurologic signs due to encephalopathy, meningoencephalitis, and mass lesions. They also may develop multiple organ involvement, especially pneumonitis and myocarditis. Toxoplasma pneumonitis may be severe and rapidly progress to acute respiratory failure with hemoptysis, metabolic acidosis, hypotension, and occasionally disseminated intravascular coagulation. Ocular toxoplasmosis in AIDS patients is relatively uncommon and occurs in only about 1% to 3%,7s-s0 and of these cases up to 25% are thought to be the result of a newly acquired infection. s1 When Toxoplasma retinochoroiditis occurs in AIDS patients, it is frequently associated with encephalitis. In fact, 25% of AIDS patients with ocular toxoplasmosis also have intracranial involvement. Conversely, 10% to 20% of AIDS patients with intracranial toxoplasmosis also have ocular involvement. s2 One study found that, at autopsy, approximately 40% of all AIDS patients have intracranial Toxoplasma abscesses. 83 Thus, all AIDS patients who have ocular toxoplasmosis should undergo a complete neurologic evaluation, including computed tomography (CT) or magnetic resonance imaging (MRI) with contrast, and lumbar puncture. Unlike the situation in immunocompetent patients, most of the Toxoplasma retinal lesions in AIDS patients do not develop adjacent to old retinochoroidal scars. Instead, the lesions occur in a perivascular distribution, which suggests newly acquired infection or dissemination of parasites from other nonocular sites in the body.so, 81, S4 Retinochoroiditis in AIDS patients may have other atypical features, such as very large areas of severe confluent retinal necrosis,s5 as well as discrete single or multifocal lesions 79 , S6 and even bilateral active retinochoroiditis. 87 Ocular inflammation is variable and depends on the patient's lYJ-llphocyte count at the time of active disease. In general, AIDS patients who develop toxoplasmosis are still able to mount enough of a cellular immune response to produce the clinical findings of vascular sheathing, prominent vitritis, and intense anterior uveitis. 81 Ocular toxoplasmosis may follow a devastating course in AIDS patients, with inflammation extending into the orbit, causing orbital cellulitis and panophthalmitis. ss The clinical findings of Toxoplasma retinochoroiditis in AIDS patients may resemble a wide range of ocular

CHAPTER 33: TOXOPLASMOSIS

pathologies, and ocular ~oxo1?lasmo.sis shoL~ld always be suspected. The differentIal dIagnosIs may Include cytomegalovirus (CMV) retinitis, syphilitic retinitis, and progressive outer retinal necrosis (PORN). Howe:er,. toxoplasmosis retinochoroiditis :toes not ha:e. ~he sIgnI.ficant retinal hemorrhages seen In CMV retInItIs, nor IS the retinitis limited to the outer retinal layers, as in PORN. The utility of serologic testing in the diagnosis ~f AI~S patients for toxoplasmosis is que.stiona~le .. Ig
Ocular Toxoplasmosis The great majority of ocular toxoplasmosis is believed to occur as a consequence of reactivation of congenitally fiGURE 33-7. Active toxoplasma retinitis adjacent to a pigmented acquired infection. Congenital infection may account for juxtapapillary scar. Note also the small, active lesion along the superior branch of the temporal arcade. (See color insert.) about 80% to 98% of ocular disease. More than 82% of congenitally infected individuals not treated as infants will develop retinal lesions by the time they reach adoles- contrast, patients who present with newly acquired ocular cence. 68 Peripheral retinochoroidal scars are the most toxoplasmosis usually have unilateral, solitary, active lecommon ocular finding, occurring in 82% of patients. sions without evidence of previous retinochoroidal scarHowever, T. gondii has a strong predilection for the postering (Fig. 33-9). . rior pole, particularly the macular region; based on comClassically, the initial lesion starts in the superfiCIal parison of the total retinal area, macular l.esio~s are pro- retina. As the retinitis progresses, involvement of the portionally much more common, occurnng In 76% of full-thickness retina, adjacent choroid, vitreous, and even patients. 68 The reason for this is unclear, but some au- sclera may occur. Ophthalmoscopically, a yellowish-white thors suagest that the parasites first invade the eye or gray exudate is seen, with ill-defined borders caused through fhe posterior ciliary art~ries or the optic nerve. 55 , by surrounding retinal edema (Fig. 33-10). The size of 67, 80, 88 Invasion of the eye by way of the optic nerve may the lesion ranges from 1/10 of a disc diameter to two give rise to juxtapapillary Toxoplasma retino~ho~oiditis. quadrants of the retina. Slowly, the borders of the lesion Some other thoughts as to the macular predIlectIOn for become more defined, the exudates andvitritis diminish, Toxoplasma include the fact that there is ea:1ier vascul~ri­ and the lesion shows an elevated central area with a zation of the posterior pole than the penphery dunng whitish-gray to brown discoloration. Mter a variable time development and the fact that the fetal vasculature conperiod, pigmentation occurs, particularly in. the mar~ins tains end arterioles. In addition, there may be entrap- of the lesion. The time required for a retu10chorOldal ment of free parasites, or parasites within macrophages, lesion to heal varies, depending on the size of the lesion, in the terminal capillaries of the fovea. Ocular toxoplasmosis tends to be a recurrent disease, and two thirds of patients present with relapses. There are many theories as to the cause of recurrent Toxoplasma retinochoroiditis. Although it is unknown which mechanism or mechanisms are involved in the recurrence of retinochoroiditis, there are three main scenarios that may account for this phenomenon. The classic teaching has been that recurrence is the result of release of T. gondii from cysts. Cysts may rupture and release live organisms that actively invade the retina, or cysts may simply release antigens that stimulate an inflammatory retinochoroiditis. Alternatively, an autoimmune response may develop to retinal antigens such as the retinal S-antigen, which results in retinochoroiditis. 61 Finally, a novel theory suggests that some recurrences may be the .result ~f reinfection. It has been demonstrated that the ImmunIty from a primary Toxoplasma infection is not sufficient to prevent reinfection with a new strain of T. gondii. 90 Recurrent lesions frequently develop at the borders of old Toxoplasma retinochoroidalscars, so-called satellite fiGURE 33-8. Recurrent active retinitis distant from the primary piglesions (Fig. 33-7). Lesions may also recur in distant sites mented lesion. Note the primary lesion in the macula with evidence of away from the primary lesion (Fig. 33-8) or in th~ fellow prior recurrences along the inferotemporal arcade, ~s well as a small, eye. They are usually single, but they can be muluple. In active lesion along the supranasal arcade. (See color ll1sert.)

CHAPTER 33: TOXOPLASMOSIS

FIGURE 33-10. Active toxoplasma retinitis. Note the yellowish white appearance of the lesion with ill-defined borders due to surrounding retinal edema. There is associated phlebitis of the supratemporal arcade. (See color insert.) FIGURE 33-9. Unilateral, solitary, active lesion without evidence of chorioretinal scarring typical of acquired toxoplasmosis. (See color insert.)

the treatment delivered, the immunologic condition of the host, and the strain of T. gondii. 3 , 91, 92 A healed Toxoplasma scar typically has well-defined borders with central retinochoroidal atrophy and peripheral pigment epithelial hyperplasia. In the atrophic central area, either choroidal vessels or bare sclera may be observed. Healing Toxoplasma .lesions may be complicated by proliferative vitreoretinopathy, retinal gliosis, vascular shunts, and choroidal neovascular membranes (Fig. 3311A and B). The Toxoplasma scars themselves have variable appearances. The edges of the scar may present with a lobulated appearance, each lobule corresponding to a healed recurrence. The scar may also vary in depth, resulting from the different layers involved in the necrotizing process. Traction bands are also frequent, and they usually link an old scar to the optic disc (Franceschetti's syndrome) or to a neighboring scar (Fig. 33-12).

Vitritis is usually marked and is present in nearly all cases. When extensive vitritis is present, the active retinal lesion may have the classic ophthalmoscopic appearance of a headlight in the fog (Fig. 33-13). Vitreous involvement may occur as a localized or diffuse exudate, inflammatory cells, pigment, or hemorrhage. Vitreous opacities tend to be slowly reabsorbed and may persist for years after complete resolution of the retinal lesion. When there is severe and prolonged vitreous involvement, vitreous contraction, posterior vitreous detachment, or even retinal detachment may occur. Vascular involvement, which may occur either in the vicinity of the active lesion or in the distant retina, typically consists of a diffuse or segmental vasculitis produced by antigen-antibody complex deposition in the vessel wall, as well as localized mononuclear cell infiltrates (Fig. 33-14). The vasculitis involves primarily the veins, but arterial involvement is not uncommon. The vasculitis may result in complications such as retinal hemorrhage, vascular obstruction, vascular shunting, and even neovasculari-

FIGURE 33-11. A, Macular toxoplasma scar complicated by a choroidal neovascular membrane. Note the hemorrhage around the neovascular membrane. B, Late fluorescein angiogram hyperfluorescence of a choroidal neovascular membrane and blockage by the surrounding hemorrhage. (See color insert.)

CHAPTER 33: TOXOPLASMOSIS

FIGURE 33-12. Franceschetti's syn.drome, a traction band from the toxoplasma macular lesion to the optic nerve. (See color insert.)

zation. Kyrieleis arterialitis (the presence of exudates or periarterial plaques not associated with leakage or vascular obstruction) is also observed as an inflammatory response in ocular toxoplasmosis, and its pathogenesis is unknown (Fig. 33-15) .93 The anterior segment can also be involved with a granulomatous or nongranulomatous inflammatory reaction. This process is believed to develop as a result of a hypersensitivity reaction to Toxoplasma antigen, because live T. gondii has never been dem~nstrated in the anterior segment of an immunocompetent patient. The resulting anterior uveitis may be florid, and patients may develop "lllutton-fat" keratic precipitates, posterior synechiae, fibrin deposition, and Koeppe and Busacca nodules. Corneal edema may be present even in eyes with normal intraocular pressure due to endothelial dysfunction. The iridocyclitis is usually transient, but prompt therapy is necessary to avoid complications such as pupillary seclusion, rubeosis iridis, secondary glaucoma, and cataracts. Signs and symptoms of ocular toxoplasmosis vary with age. Children are generally referred to the ophthalmologist with complaints of decreased visual acuity, strabismus,

FIGURE 33-13. Active toxoplasma retinitis with marked vitritis producing the classic appearance of a headlight in the fog. (Courtesy of Maria Elenir F. Peret, M.D., COMG, Brazil.) (See color insert.)

FIGURE 33-14. Segmental arteritis associated with an active toxoplasma lesion in the vicinity of the vessel. The localized perivascular inflammatory accumulations may line up around the vessels and resemble a rosary. (See color insert.)

nystagmus, leukocoria, choroidal coloboma, and microphthalmia. Adolescents and adults typically complain of blurred vision and floaters. If the anterior segment is involved, pain, photophobia, and conjunctival hyperemia may be prominelit. The most common cause of visual loss in ocular toxoplasmosis is a macular scar, but other causes for substantial visual loss include dragging of the macula secondary to a peripheral lesion, retinal detachment, macular edema, optic atrophy, cataract, glaucoma, opacified media, amblyopia, and phthisis. Surprisingly, the presence of a .large congenital macular scar can be associated with remarkably good vision. 68

Atypical Forms PUNCTATE OUTER RETINAL TOXOPLASMOSIS

Punctate outer retinal toxoplasmosis is characterized by small multifocal gray-white lesions that develop in the deep layers of the retina and retinal piglllent epithe-

FIGURE 33-1 S. Toxoplasma periarterial plaques lmown as kyrieleis arterialitis. (See color insert.)

CHAPTER 33: TOXOPLASMOSIS

lilun 94,95 (Fig. 33-16A to D) . Acute lesions resolve, leaving behind fine, granular, white scars, but they frequently recur. Because the process is localized to the outer retinal layers, there is little or no overlying vitritis. There is usually significant optic nerve involvement and atrophy associated with the punctate outer retinal lesions. Thus, even without foveal lesions, these patients may suffer significant visual loss as a result of optic neuropathy. However, note that all five cases initially reported by Matthews and Weiter were treated, and all had a final visual acuity of 20/25 or better. In addition, many uveitis experts do not consider treatment for this form of Toxoplasma retinochoroiditis. . The punctate outer retinal form occurs most frequently in the first and second decades of life, and it can be congenital or acquired. It is bilateral in a third of the cases, and some patients present with classic Toxoplasma retinochoroiditis in one eye and the punctate form in the fellow eye (Fig. 33-17 A to D). The combination of T. gondii and host factors that result in the punctate outer retinal form rather than the classical form has not yet been elucidated. Furthermore, the reason a single patient should have the typical form in one eye and the punctate outer retinal form in the other eye is intrigtling. Perhaps this fonn is an immune phenomenon related to exposure of retinal antigens. Indeed, it has been demonstrated that patients with ocular toxoplasmosis develop both cellular and humoral im-

mune responses to retinal antigens. 96- 103 However, it is unclear what role, if any, autoimmune sensitization plays in the development of punctate outer retinal lesions. Clearly, this is an area deserving further study. Occasionally, the punctate outer retinal fonn is observed in the absence of typical Toxoplasma lesions in one or both eyes. If autoimmunity to retinal antigens truly is the cause of this entity, ·one must suppose a previous subclinical infection that has been overlooked. NEURORETINITIS

Toxoplasma neuroretinitis, previously known as Jensen's choroiditis, was attributed to tuberculosis. It typically consists of active lesions localized to the juxtapapillary .region, aggressively involving the retina and optic nerve (Fig. 33-18). Toxoplasma neuroretinitis initially presents as severe papillitis with disc hemorrhages, venous engorgement, and overlying vitritis (Fig. 33-19). Soon after, a juxtapapillary retinochoroiditis and macular star develop (Fig. 33-20). ToxojJlas17la neuroretinitis is an ophthalmic emergency and requires prompt treatment. NEURITIS

Papillitis in the presence of Toxoplasma retinochoroiditis is a relatively frequent finding. In this setting, there is optic nerve involvement associated with a distant retinal lesion (Fig. 33-21A and B). Some authors state that it simply constitutes a reactive edema of the optic disc, but

FIGURE 33-16. Right (A) and left (B) eyes of a patient with the punctate outer retinal form of toxoplasmosis. Note the small, multifocal, graywhite fine, granular scars in the deep layers of the retina and retinal pigment epithelium and the pale optic disc in the left eye. C, Red free photographs and fluorescein angiography demonstrating hypofluorescent lesions with hyperfluorescent borders. D, Indocyanine green angiography demonstrating hypofluorescence of the lesions throughout the examination with late trace of central staining.

CHAPTER 33:

FIGURE 33-17. A, Classic toxoplasma retinochoroiditis in the right eye. B, Left eye of the same patient demonstrating the punctate outer retinal form. Note the multiple active lesions in the posterior pole and associated temporal optic nerve atrophy. C, Late-phase fluorescein angiogram OD showing a mottled appearance of the lesion caused by pigment clumping and atrophy. D, Late-phase fluorescein angiogram OS showing multiple hyperfluorescent dots that correspond to tlle active lesions in the posterior pole.

FIGURE 33-18. Juxtapapillary active toxoplasma lesion witll severe involvement of the optic nerve. Note tlle severe papillitis and retinitis with hemorrhages. (See color insert.)

FIGURE 33-19. Initial presentation of toxoplasma neuroretinitis. Note papillitis with disc hemorrhages and venous engorgement prior to the development of retinochoroiditis. (See color insert.)

CHAPTER 33: TOXOPLASMOSIS

cataracts or intense vitritis in severe cases or because of clinical unimportance in asymptomatic or mild cases. ANTERIOR UVEITIS

A granulomatous iridocyclitis without evidence of retinal toxoplasmosis can develop in both immunocompetent and immunocompromised patients. 16 , 104 It is thought that the anterior uveitis is either a hypersensitivity reaction to Toxoplasma antigen or a Toxoplasma infection in the anterior segment. However, the parasite has never been demonstrated in the anterior segment of immunocompetent patients. FUCHS' HETEROCHROMIC IRIDOCYCLITIS

FIGURE 33-20. Toxoplasma neuroretinitis. Note the juxtapapillary active lesion and the deposits of hard exudate around the macula, forming a macular scar.

the markedly decreased visual acuity observed in some patients suggests that it is a true inflammation of the optic nerve. Like neuroretinitis, papillitis demands prompt therapy. MULTIPLE PSEUDORETINITIS

Multiple pseudoretinitis is characterized by the simultaneous presence of retinal lesions, which lil;ppear to be active. However, close observation reveals just a single active Toxoplasma lesion accompanied by noncontiguous areas of retinal .edema. Once the true active lesion heals, the pseudolesions completely disappear without scarring (Fig. 33-22A and B).

Some studies report an association between toxoplasmosis and Fuchs' heterochromic iridocyclitis (FHI), but a cause-and-effect relationship has not beer~ established.lOs-los The incidence of chorioretinallesions suggestive of toxoplasmosis in patients with FHI is higher than what would be expected from normal population figures and ranges between 8% and 65%.109 Several mechanisms have been proposed to explain the association between FHI and Toxoplasma retinochoroidallesions. One hypothesis suggests that primary retinochoroidal inflammation results in production of antibodies that cross-react with anterior segment antigens, causing a low-grade anterior uveitis (i.e., FHI) .109 Others posit that there is no statistically significant association between FHI and ocular toxoplasmosis. l1O UNILATERAL PIGMENTARY RETINOPATHY

Unilateral pigmentary retinopathy, like retInItls pigmentosa, has been reported as a sequela of chronic recurrent ocular toxoplasmosis. l l l

Complications PERIPHERAL LESIONS

Peripheral lesions simulating the snow-banking of pars planitis may be caused by toxoplasmosis. The incidence of these peripheral Toxoplasma lesions is probably underestimated because of difficult visualization associated with

The most common complication of ocular toxoplasmosis is secondary glaucoma. The glaucoma may be caused by mechanical obstruction of the trabecular meshwork with fibrin, inflammatory cells, or inflammatory debris. In these situations, the intraocular pressure is usually con-

FIGURE 33-21. A, Toxoplasma neuritis demonstrating papillitis associated with active retinochoroiditis. B, Late-phase fluorescein angiogram demonstrating leakage from the disc as well as the area of retinitis.

CHAPTER 33: TOXOPLASMOSIS

FIGURE 33-22. A, Toxoplasma multiple pseudoretinitis. Note the presence of a true active lesion inferior to the optic disc associated with an inferomacular area of retinal edema. B, Mter healing of the retinochoroidal lesion, the pseudolesion completely disappears without scarring. (Courtesy of Professor J. Melamed, UFRGS, Brazil.)

trolled by anti-inflammatory treatment. In cases with intense anterior uveitis, refractory glaucoma may develop as a result of synechial angle closure or seclusio pupillae with iris bombe. Other complications of ocular toxoplasmosis include cataracts, vitreous hemorrhage, proliferative vitreoretinopathy, retinal detachment, macular dragging, epiretinal membrane, cystoid macular edema, macular hole, retinovascular occlusion, vascular shunts, choroidal neovascular membrane, optic atrophy, and phthisis. Cataracts may result from severe vitreous inflammation or the use of local and systemic corticosteroids. Posterior subcapsular cataract is typical and usually occurs relatively early in the course of the disease; Vitreous hemorrhage and tractional or rhegmatogenous retinal detachment may result from proliferative vitreoretinopathy and contraction of vitreous bands. Proliferative vitreoretinopathy and tractional bands also may result in macular dragging. In addition, epiretinal membranes may develop, resulting in macular pucker and cystoid macular edema. Cystoid macular edema i~ also a response to the chronic inflammation. Occasionally, a macular cyst may develop, which, along with tangential traction on the retinal internal limiting membrane and the posterior hyaloid, predisposes to the formation of·a macular hole. Retinal hemorrhages may result from a retinal vein occlusion around or within active lesions. Both branch retinal vein occlusions and branch artery occlusions may occur when a vessel crosses an acute Toxoplasma lesion, but venous occlusions are more common. Arteriovenous shunts in the retina and chorioretinal vascular anastomosis may be seen as complications of vascular obstruction in ocular toxoplasmosis. Disruption of Bruch's membrane caused by the necrotizing retinochoroiditis promotes the development of choroidal neovascular membranes, which may develop adjacent to the retinal scar or at a distant location with feeder vessels originating from the scar. Optic nerve atrophy is associated with primary involve-

ment of the optic nerve, peripapillary'lesions, or lesions localized in the papillomacular bundle. In addition, punctate outer retinal toxoplasmosis is associated with frequent optic nerve atrophy. Finally, phthisis bulbi is a rare complication in the course of ocular toxoplasmosis, but it may occur in cases with inadequate treatment.

DIFFERENTIAL DIAGNOSIS Congenital toxoplasmosis of the newborn must be differentiated from the other infectious diseases of the TORCH group (rubella, cytomegalovirus, and herpes simplex virus as well as other congenital infectious diseases that may simulate toxoplasmosis, such as syphilis, tuberculosis, and AIDS). Important ocular entities that may be confused with congenital toxoplasmosis include coloboma, persistent hyperplastic primary vitreous, and retinoblastoma. Recurrent Toxoplasma lesions adjacent to retinochoroidal scars may resemble serpiginous choroiditis. However, in serpiginous choroiditis there is usually a single helicoid chorioretinal scar occurring in the peripapillary area and no significant inflammatory reaction of the anterior segment or vitreous. Other conditiOl)s that are important in the differential diagnosis of ocular toxoplasmosis are necrotizing retinitis caused by herpes viridae (cytomegalovirus, herpes simplex, herpes zoster), fungal retinitis (candidiasis, blastomycosis), septic retinitis,· ocular toxocariasis, sarcoidosis, syphilis, and tuberculosis. The atypical forms of ocular toxoplasmosis deserve distinct differential diagnoses. Punctate outer retinal toxoplasmosis must be distinguished from acute posterior multifocal placoid pigment epitheliopathy (APMPPE), punctate inner choroidopathy (PIC), and multifocal choroiditis, as well as diffuse unilateral subacute neuroretinitis (DUSN). In cases of Toxoplasma neuroretinitis, other causes of neuroretinitis, such as cat scratch disease and viral syndromes, must be excluded. Toxoplasma neuritis should be differentiated from the optic neuritis associated with sarcoidosis and CMV.

33: TOXOPLASMOSIS

Acute Toxoplasma lesions are characterized by cell death and focal necrosis resulting from replicating tachyzoites. There is an intense mononuclear inflammatory response, resulting in the formation of necrotizing granulomas in infected tissues. Tachyzoites are rarely visualized with routine histopathology; however, immunofluorescent techniques using Toxoplasma-specific antibodies can often detect the organism. In contrast to the intense inflammation produced by tachyzoites, tissue cysts containing bradyzoites cause little to no inflammation. In fact, it is thought that the bradyzoites are hidden from the immune system by their capsule, and that any inflammation around tissue cysts probably represents destruction of the residual tachyzoite antigens. Ocular toxoplasmosis may produce an inflammatory response to the invasive parasites, a hypersensitivity reaction to Toxoplasma antigens, or both. It is characterized by severe retinitis associated with coagulative necrosis within the retina and frequent secondary involvement of the choroid and even the sclera. 1l2 Intra- and extracellular tachyzoites, as well as cysts, are found most commonly in the inner retinal layers.ll s The inflammatory response to tachyzoites is largely composed of lymphocytes, plasma cells, macrophages, and epithelioid histiocytes. During the acute retinitis, there may be associated perivasculitis, choroiditis, vitritis, and iridocyclitis.ll 4 The inflammatory reaction of the iris, ciliary body, and vitreous is mainly composed of mononuclear cells. St"lfdies suggest that anterior uveitis, choroiditis, and vasculitis may be the result of a hypersensitivity reactionY5-117 This is supported by the fact that the inoculation of dead parasites in eyes of experimental immune animals can produce iridocyclitis, vasculitis, and choroidal inflammation, and T. gondii has never been demonstrated in the anterior segment of immunocompetent patientsY5 The retinitis, however, develops only in the presence of active proliferating tachyzoites.ll 6 As the inflammation subsides, often all that remains of the retinal and choroidal tissue is an atrophic scar. There is retinal pigment epithelial hyperplasia at the borders of the scar, and this is the usual location of tissue cysts. Tissue cysts can also be seen in distant areas of an unaffected retina with no associated inflammation or scarringYs Cysts lie dormant and are immunologically quiescent until they rupture and there is reactivation.

DIAGNOSIS

J

The definitive· diagnosis of toxoplasmosis is made by a direct demonstration of the organism in tissues or body fluids, by in vitro culture, by inoculation and culture in the mouse peritoneum, or by polymerase chain reaction(PCR). Direct demonstration of the parasite is easiest during the acute phase, when the trophozoites can be found in body fluids such as blood, cerebrospinal fluid, urine, and breast milk. The parasite in this phase can be identified microscopically after Giemsa staining. In the chronic phase, tissue cysts may be occasionally identified in biopsy samples by staining with hematoxylin and eosin or silver. Isolation of the parasite can also be accomplished by inoculation of infected secretions or tissues into the peritoneal cavity of mice. There, the parasites

multiply and then can be identified in the peritoneal fluid.ll g Alternatively, the mouse's anti-Toxoplasma serum titer can be evaluated 4 to 6 weeks after inoculation. Demonstration of the parasite through direct inoculation or through histopathologic identification has great diagnostic value but is generally not practical because it is difficult to grow the parasites in vivo and difficult to detect tachyzoites and tissue cysts histopathologically. Thus, these studies are not used routinely but are reserved for cases where the diagnosis is uncertain. In practice, the serologic methods are the main tools for confirming exposure to T. gondii in cases of suspected toxoplasmosis. Serology alone cannot make the diagnosis. The accuracy ofthe diagnosis, however, is complicated by the high prevalence of positive Toxoplasma titers in the human population. Although serial titers may be important to establish a diagnosis by demonstrating a rising titer, it is not necessary to repeat serologic testing during or after treatment, because serum titers do not correlate with recovery from infection. The serologic tests available for detection of Toxoplasma-specific antibodies include the Sabin-Feldman dye test, complement fixation (CF) test, hemagglutination test, immunofluorescence antibody test (IFAT), enzyme-linked immunosorbent assay (ELISA), immunoblotting (IB), and immunosorbent agglutination assay (ISAGA).

Sabin-Feldman Dye Test The Sabin-Feldman dye test is the standard to which all serologic tests performed to detect anti-Toxoplasma antibodies are compared. It is a neutralization test in which the patient's serum is incubated with complement and live Toxoplasrtya organisms, and a dye is employed to quantify the bound antibody. It allows early detection of the infection and has high sensitivity and specificity in both acute and chronic phases, but it is no longer used because it requires maintenance of live virulent parasites in the laboratory, and equally good, safer methods have been developed. Currently, the Sabin-Feldman dye test is restricted to research centers, as a method to standardize new tests.

Complement Fixation Test The CF test has a good sensitivity only when the level of circulating antibodies is high, which unfortunately delays the diagnosis in early infection. Complement fixation also cannot make the diagnosis in chronic disease (i.e., most cases). Thus, this test is useful only in combination with other tests. It is useful, however, to demonstrate rising titers when IFAT titers are already high. For example, an initially negative CF test becoming positive in the setting of a high, stable IFAT titer is indicative of active infection. CF studies are mainly used for acquired toxoplasmosis.

Hemagglutination Test The hemagglutination test has good sensitivity and specificity in the acute and chronic phases, but it does not detect early infection. Additionally, it is not accurate for the diagnosis of congenital toxoplasmosis and has large variations in the standard values depending on the laboratory. Therefore, it should be used in combination with other methods.

CHAPTER 33: TOXOPLASMOSIS

Immunofluorescence Antibody Test The immunofluorescence antibody test is a good method for the diagnosis of toxoplasmosis. It is easy to perform, detects early elevations in serum antibodies, and allows quantification of IgM and IgG levels. It has been the most commonly used test in the last two decades, but it has the disadvantage of equivocal results in the presence of cross-reactive antibody.120 Rheumatoid factor (IgM antiIgG) may result in a false-positive IgM test, suggesting acute infection, when in reality only IgG anti- Toxoplasma antibody is present. This results when anti-Toxoplasma IgG antibodies bind to the parasite antigens and rheumatoid factor cross-links these antibodies, producing a false-positive result during IgM anti-Toxoplasma testing. 121 , 122 Thus, it is essential to remove the rheumatoid factors, or, preferably, anti-IgG antibodies, from the serum in which IgM antibodies will be tested. Additionally, false-positive IgM and IgG titers can occur in the presence of antinuclear antibodies because the immunologic techniques are unable to differentiate some Toxoplasma antigens from proteins of human leukocyte nuclei.122-124 False-positive IgM titers may also result from cross-reactions with antibodies against cytomegalovirus, Epstein-Barr virus, hepatitis A, secondary syphilis, and others. Furthermore, false-negative IgM can result from inhibitory competition when there is excessive anti-Toxoplasma IgG.125 It is important to note that conventional techniques employed for indirect immunofluorescence begin at a serum dilution of 1:16 to avoid a low specificity. However, ocular disease may well be pFesent and not produce sufficient antibody to be detectable at a dilution of 1:16. Because any titer of antibody is significant for the diagnosis of ocular toxoplasmosis, it is important to test undiluted serum to avoid false-negative results. 126 In cases of suspected ocular toxoplasmosis with negative immunofluorescence titers, the Sabin-Feldman test, the ELISA, or both, should be performed before excluding the diag-

ity because only IgM of the test serUlll adheres to . plates precoated with anti-IgM antiserum. Consequently, rheumatoid factor, antinuclear antibodies, and others do not interfere with the results. 128, 129 The high sensitivity of the ELISA enables detection of IgM antibodies for many months after the acute phase; therefore, it is important to consider the level of IgM, not just the presence of IgM, as a marker of recent infection. 130 The ELISA is also able to determine the affinity of the serum antibodies for the antigen by washing with urea solution. If the infection occurred more than 6 months prior to obtaining the patient's blood for antibody testing, the antibodies are mature and have high affinity for the antigens, whereas serum antibodies present in acute infection tend to have a lower affinity and are more easily dissociated.

Immunosorbent Agglutination Assay The ISAGA is a method of immunocapture that allows the simultaneous detection of IgA and IgM anti-Toxoplasma antibodies. It has good sensitivity and specificity, allowing early diagnosis of congenital toxoplasmosis. In about 10% of cases when the IgM is not detectable in the serum, specific IgA antibodies can be found. 131 Usually, IgA disappears faster than IgM, so it is absent in chronic disease. Therefore, the simultaneous presence of IgA and IgM is useful to confirm acute infection, particularly in cases of suspected primary infection during pregnancy.

Immunoblotting Immunoblot (a type of western blot) has proven to be of equal or superior sensitivity when compared with the preceding tests, and it allows an earlier diagnosis of congenital toxoplasmosis (Table 33-4) .132 The Toxoplasma antigens p16, p32, p40, and p97 have been shown to be specifically recognized by low-affinity antibodies that are produced in early infection. I33

Interpretation of Serologic Results

nOSIS.

Enzyme-Linked Immunosorbent Assay The enzyme-linked immunosorbent assay is the test most widely used today. Like the Sabin-Feldman test, it has good sensitivity and specificity.127 The double-sandwich ELISA is superior to the IFAT with regard to IgM specific-

In the infant, the diagnosis of toxoplasmosis is determined by a combination of clinical and serologic features. As IgG is passively transmitted to the fetus, its detection does not have diagnostic value. Slowly, maternal IgG decreases in the infant's circulation, and it completely disappears within 18 months. Thus, the follow-up titers may be

TABLE 33-4. SENSITIVITY, SPECifiCITY, POSITIVE PREDICTIVE VALUE Of DiffERENT TECHNIQUES USED fOR DIAGNOSIS Of CONGENITAL TOXOPLASMOSIS AND CONCORDANCE WITH IMMUNOBLOTTING SENSITIVITY

SPECIFICITY

POSITIVE PREDICTIVE VALUE

CONCORDANCE WITH IB (%)

Culture in vitro

40.0

100

100

Inoculation in mice

62.5

100

100

IFAT (IgM) ELISA (IgM) ISAGA (IgM) IB (G + M + A)

7.4 29.6 44.4 92.6

97.8 97.8 95.7 89.1

89.6 97.2 93.5 92.4

69.2 (FB) 69.2 (AF) 91.7 (FB) 53.8 (AF) 50.0 62.5 72.9 100

TEST

IFAT, immunofluorescence antibody test; FB, fetal blood; ELISA, enzyme-linked immunosorbent assay; AF, amniotic fluid; ISAGA, immunosorbent agglutination assay; lB, immunoblotting. Modified from Chumpitazi BFF, Boussaid A, Pelloux H, et al: Diagnosis of congenital toxoplasmosis by immunoblotting and relationship with other methods. J Clin MicrobioI1995;33:1479-1485.

33: TOXOPLASMOSIS

diagn()stic. Serum titers that remain constant or increase in value after 1 week of life are diagnostic of fetal infection. However, the best serologic evidence of congenital toxoplasmosis is identification of IgM and IgA. A recently acquired infection will produce elevated titers of IgM, IgA, and IgE. In addition, the serUlll titer of IgG may be elevated or rising, but the affinity of these antibodies early in the course of infection is low. By contrast, in chronic cases low titer§ of high-affinity antiToxoplasma IgG are present. Because most of the cases of toxoplasmosis are evaluated in the chronic phase, a low IgG titer is expected. However, low IgG titers may also be a sign of recent infection. To differentiate between these two possibilities, serologic testing should be repeated at a tillle interval of 2 to 4 weeks. A rising titer is indicative of recent infection.

Polymerase Chain Reaction Recently, PCR has been used to demonstrate parasite DNA, and it has been especially useful in difficult cases. 134 PCR of the amniotic fluid has been used to diagnose intrauterine fetal infection.135-137 PCR has also been successfully used in the diagnosis of ocular toxoplasmosis using aqueous or vitreous samples. 13s , 139 PCR of the cerebrospinal fluid is useful for making the diagnosis of intracranial infection with Toxoplasma and may be particularly useful for evaluation of AIDS patients with suspected toxoplasmosis.

Additional Ancillary Evaluatipns Other laboratory and ancillary tests may assist in making the diagnosis of toxoplasmosis. Congenital disease can be present with anemia, thrombocytopenia, leukocytosis or leukopenia, atypical lymphocytes, and severe eosinophilia with values up to 30%. Similarly, acquired disease may produce atypical lymphocytes and moderate eosinophilia (5% to 10%). Elevated liver aminotransferases can be present. Evaluation of the cerebrospinal fluid in patients with encephalopathy or meningoencephalitis may demonstrate elevated intracranial pressure, xanthochromia, mononuclear pleocytosis, and elevated protein levels. Imaging studies (CT and MRI) are especially useful to identify cerebral calcifications, which occur in 32% to 87% of patients with congenital toxoplasmosis, and brain lesions in immunocompromised (AIDS) patients. ,n, 140

DIAGNOSIS OCULAR TOXOPLASMOSIS The diagnosis of ocular toxoplasmosis is usually based on clinical findings. Laboratory tests are helpful to support the diagnosis when the ocular manifestations are atypical. The diagnosis should not depend solely on serologic tests,

because the antigen load of a small, active lesion in one eye may not be enough to stimulate elevated systemic antibody titers. Indeed, in ocular toxoplasillosis there is a poor correlation between the senllll levels of antibody and active disease. It is not unusual to find low or negative IgM and IgG titers in patients with acute sYIllptomatic or recurrent ocular toxoplasmosis. For these reasons, undiluted serum should be used for the detection of antiToxoplasma antibody in ocular toxoplasmosis. In patients with atypical lesions, positive serology suggests only a presumptive diagnosis, because there is a high prevalence of anti-Toxoplasma antibodies in the human population. It is important to exclude other causes of focal retinochoroiditis, such as syphilis, tuberculosis, sarcoidosis, cytomegalovirus, fungal and viral infections, serpiginous choroiditis, and others. In patients whose diagnosis is unclear, the determination of anti- Toxoplas17w antibody titers in the aqueous humor can be elucidating. A comparison of serum levels of anti- Toxoplasma antibodies with the levels found in aqueous humor may identify intraocular production of antibodies, thus proving active ocular toxoplasmosis. This ratio, corrected for total protein concentration, is known as the coefficient of WitmerDesmonts (Table 33-5). When the coefficient of WitmerDesmonts is less than 2 in an immunocompetent patient, there is no active ocular toxoplasmosis. If the ratio is between 2 and 4, it is<suggestive of active ocular disease, and when the ratio is 4 or more it is considered diagnostic of active ocular toxoplasmosis.l4 1 Polyclonal B-cell activation is a possible source of error in this test.

Polymerase Chain Reaction Recently, PCR has become a powerful tool in making the diagnosis of ocular toxoplasillosis, especially if the serologic tests are equivocal. Aqueous or vitreous samples may be evaluated with high sensitivity and specificity for the presence of Toxoplasma DNA sequences using PCR.

Fluorescein Angiogram and Indocyanine Green In the early stages of toxoplasmosis, a fluorescein angiogram (FA) demonstrates central hypofluorescence because of blockage by the retinal inflammation in active Toxoplasma retinochoroiditis. Dye leakage occurs later, expanding from the margins of the lesion. Indocyanine green (ICG) of active lesions may show early hyperfluorescence or hypofluorescence with hyperfluorescence in the late phases (Fig. 33-23A to C). The retinochoroidal scars in the early phases of the FA may be seen as hypofluorescent due to blockage by retinal pigment epithelium (RPE) hypertrophy or as window defects due to RPE atrophy. Irregular RPE hypertrophy

TABLE 33-5. COEffiCIENT Of WITMER-DESMONTS Titer of antibody in aqueous humor* X Concentration of serum globulins Titer of antibody in serum* Concentration of aqueous humor globulins RESULTS

0.5 to 2 2 to 4 :::::4

No intraocular anti-Toxoplasma antibody production Suggestive of intraocular antibody production Diagnostic of intraocular antibody production

*The antibodies are determined by Sabin-Feldman dye test and the immunofluorescence antibody test.

CHAPTER 33: TOXOPLASMOSIS

FIGURE 33-23. A, Toxoplasma retinochoroiditis demonstrating the varied appearance of several healed scars and an area of active disease inferior to the macula. B, Red free photograph and fluorescein angiography demonstrating leakage at the site of active inflammation and blockage with peripheral staining of the scars. C, Indocyanine green angiography demonstrating early hypofluorescence with late leakage in the area of active retinitis and blockage with minimal peripheral staining of the scars.'.Note the area of bare sclera stains with both fluorescein and indocyanine green.

and atrophy may result in a mottled appearance of the lesion. The late phase of the angiogram demonstrates staining of the lesion margins. ICG stains of old lesions are hypofluorescent throughout the exam. In addition, FA and ICG are useful in the diagnosis of atypical presentations such as the punctate outer retinal form, because they highlight the lesions that follow the same fluorescence pattern as classic Toxoplasma lesions. The FA typically shows hyperfluorescence at the margins of the optic disc in patients with ToxojJlasma neuroretinitis and neuritis. The FA is also helpful in demonstrating associated features such as vasculitis, vascular occlusions, arteriovenous shunts within the retina, and retinochoroidal shunts, as well as macular edema and choroidal neovascular membranes. The ICG angiography is useful for the early diagnosis of recurrent ocular toxoplasmosis because it can identifY an area of reactivation not yet detectable by funduscopic exam or FA. FA and ICG are essential for the diagnosis and treatment of complications such as choroidal neovascularization.

THERAPY Medical Treatment of Toxoplasmosis Treatlnent of toxoplasmosis with pyrimethamine, sulfa, and corticosteroid has been elnployed since it was initially advocated in 1953 by Eyles and Coleman, and this continues to be the most common therapy used throughout the world. 142 In recent years, several new drugs have been

developed that are also effective for the treatment of toxoplasmosis. However, despite advances in research, an ideal therapy that destroys the tissue cysts and prevents recurrence has not been found. Currently, antimicrobial therapy is limited to treatment of active disease (i.e., the tachyzoites) . Antimicrobial therapy is absolutely required for systemic toxoplasmosis in newborns, pregnant women, and immunosuppressed patients, and in acute symptomatic disease. Patients with chronic toxoplasmosis do not require treatment when the disease is inactive, because no treatment is effective at eliminating the tissue cysts. In ocular toxoplasmosis, however, precisely when to apply therapy, for how long, and with what agents remain controversial. Because the active phase of ocular toxoplasmosis is self-limiting, some authorities believe that only vision-threatening lesions require treatment, and their indications for treatment are based on the location and severity of the acute focus. One recent study demonstrated no difference in time to resolution of active ocular lesions with or without pyrimethamine treatment; however, there was a significant reduction in the size of the resulting retinochoroidal scar in patients treated with pyrimethamine. 143 The generally accepted criteria for treatlnent include the following: A lesion affecting or near the optic nerve (within two disc diameters)

CHAPTER 33: TOXOPLASMOSIS

.. .. .. .. .. .. .. .. .. .. ..

prevent normal utilization of PABA for the synthesis of folic acid by the parasites. Sulfonamides and pyrimethamine are synergistic. Sulfonamides are distributed throughout all tissues of the body and readily enter body fluids, induding intraocular fluids. The concentration of sulfonamides in the eye reaches 50% to 80% of the simultaneous serum concentration. 144 Precipitation of sulfonamides in the urine may cause crystalluria, hematuria, and renal damage. Adequate hydration with oral fluids to maintain a urine output of at least 1500 mllday should avoid the problem. Patients with glucose 6-phosphate dehydrogenase deficiency should not use sulfa medications because of the potential for hemolytic anemia. Other idiosyncratic hematopoietic disorders can occur, induding acute hemolytic anemia in 0.05% and agranulocytosis in 0.1 % of patients. 144 Hypersensitivity reactions are quite variable and range from photosensitivity to a severe Stevensjohnson type of reaction involving skin and mucous membranes. The sulfonamides are contraindicated in the third trimester of gestation because they dislodge the fetal bilirubin from serum albumin, causing kernicterus.

A lesion within the temporal arcade A lesion that threatens a large retinal vessel A lesion that has induced a substantial hemorrhage A lesion with intense inflammatory reaction Extensive chronic exu<;lative lesions regardless of location Severe vitreous haze Loss of more than two lines in visual acuity Persistence of inflammation for more than· a month Congenital Toxoplasma retinochoroiditis in the first year of life A newborn diagnosed with congenital toxoplasmosis, regardless of the presence of ocular lesions Any lesion in an immunocompromised host

Although these treatment criteria are broad, some authorities believe that all active lesions should be treated. One reason for this recommendation is that active lesions, even those far from the macula, may be associated with decreased visual acuity because of macular edema, macular traction, severe vitritis, or retinal detachment. In addition, active lesions produce tachyzoites that may spread to distant retinal areas and encyst. Treatment of any active lesion reduces the number of tachyzoites and (theoretically) the chances of reactivation in crucial retinal locations. Specific therapy for toxoplasmosis indudes a wide variety of drugs (Table 33-6). Pyrimethamine and sulfonamides are two of the most commonly used antiToxoplasma agents. They act by inhib~ting the synthesis of folic acid, thereby impairing DNA synthesis (T. gondii must synthesize folates because the parasite lacks a transmembrane folate-transport system). Because folic acid antagonists act to inhibit DNA synthesis, they only prevent replication of the active parasite.

Folinic Add (Leucovorin) Folinic acid is used as an adjuvant in therapy with antifolate agents such as pyrimethamine. Folinic acid can be utilized by human cells but not by T. gondii and prevents bone marrow suppression caused by pyrimethamine and other folinic acid antagonists.

Clindamydn Clindamycin inhibits ribosomal protein synthesis and acts synergistically with pyrimethamine and sulfonamides. It has good ocular penetration and concentrates in the choroid. Clindamycin has been shown to reduce the number of tissue cysts in experimental animals, but it is undear if it decreases recurrence. 145 , 146 A skin rash occurs in 10% of the patients treated with dindamycin and diarrhea in 2% to 20%. Pseudomembranous colitis can develop in 0.01 % to 10% of patients treated with dindamycin, requiring immediate interruption of therapy and administration of vancomycin or metronidazole.

Pyrimethamine

Pyrimethamine interrupts the metabolic cyde of the parasite by inhibiting the dihydrofolate-reductase enzyme, thereby preventing the conversion of folic acid to folinic acid, which is essential in both DNA and RNA synthesis. Adverse effects of pyrimethamine indude dose-related bone marrow suppression (10%) with leukopenia, thrombocytopenia, and megaloblastic anemia, simulating fo- Spiramydn linic acid deficiency. It is reversible by interruption of Spiramycin is an antibiotic structurally similar to azithrotreatment or administration of folinic acid. Patients un- mycin. It is less effective but also less toxic than the der treatment should be followed by weekly complete combination of pyrimethamine with sulfadiazine, so it is blood cell counts, and pyrimethamine should be stopped the drug of choice during pregnancy. It achieves a high if the platelet count falls below 100,000/ml or the leuko- concentration in the placenta and has no reported teratocyte count falls below 4000 cells/ /-11. Folinic acid should genic effects. Spiramycin may reduce the incidence of be used simultaneously with pyrimethamine therapy to congenital transmission. This antibiotic can be obtained help prevent these hematologic problems. Pyrimeth- only with special permission through the Food and Drug amine is contraindicated in the first trimester of preg- Administration (FDA) in the United States, but it is availnancy because of potential teratogenicity. Pyrimethamine able in most other countries. treatment has been shown to minimize the size of the retinochoroidal scar that forms with resolution of the Atovaquone active lesion. 143 Thus, it is important in the treatment of , Atovaquone interferes in the mitochondrial electrical Toxoplasma lesions in the macular area. transport chain of T. gondii. This drug has potent action against tachyzoites, including those of very virulent Sulfonamides strains, and it has been shown to reduce the number of Sulfonamides are structural analogues and competitIve cerebral tissue cysts after acute or chronic infection in antagonists of paraminobenzoic acid (PABA) and thus the hamster mode1. 147 Atovaquone has been successfully I

CHAPTER 33: 33-6. DRUGS USED

THE TREATMENT Of OCULAR TOXOPLASMOSIS

DRUG

DOSAGE

NOTES

Pyrimethamine

Adults: 100 mg loading dose, followed by 25 mg/day for 30-60 days Children: 4 mg/kg loading dose followed by 1 mg/ kg/ day divided in 2 doses Newborns should be treated daily for the first 6 mo and then 3 times/wk for their first year of life. Dosage: 1 mg/kg/ day divided into 2 doses. Adults: 2 g loading dose followed by 1 g every 6 hI' for 30-60 days Children: 100 mg/kg/ day divided every 6 hI' Newborns should be treated daily for their first year of life. Dosage: 100 mg/kg/ day divided into 2 doses. 5-20 mg/day during pyrimethamine therapy, depending on neutrophil count 300 mg every 6 hours for 30-40 days Children: 16-20 mg/kg/ day divided every 6 hI'

Reversible dose-related bone marrow suppression Simultaneous administration of folinic acid Follow weekly with CBC Contraindicated in the first trimester of pregnancy (potential teratogenicity) Minimizes the size of retinochoroidal scar

Sulfadiazine

Folinic acid Clindamycin

Spiramycin

Pregnancy: 500 mg every 6 hr for 3 wk; regimen may be repeated after 21 days. Adults: 500-750 mg every 6 hI' for 30-40 days Children: 100 mg/kg/ day divided every 6 hr

Atovaquone

750 mg every 6 hI' for 4-6 wk

Tetracycline

500 mg every 6 hI' loading dose, followed by 250 mg every 6 hr for 30-40 days

Minocycline Clarithromycin

100-200 mg/ day for 30-40 days 1 g every 12 hI' loading dose followed by 500 mg every 12 hF for 4 wk

Azithromycin

500-1000mg/day for 3 wk

Trimethoprim/ sulfamethoxazole Prednisone

160/800 mg (one tablet) every 12 hrs for 30-40 days Adults: 40-100 mg/day Children: 1-2 mg/kg/ day

Adverse effects: photosensitivity, Stevens:Johnson syndrome, crystalluria, and hematologic problems Contraindicated in the third trimester of pregnancy (kernicterus) and during breast feeding Hemolytic anemia if G6PD deficient Synergistic with pyrimethamine Prevents bone marrow suppression when administered as an adjuvant of pyrimethamine therapy Adverse effects: skin rashes, diarrhea, and pseudomembranous colitis Synergistic with pyrimethamine and sulfonamides Drug of choice during pregnancy Reduces the incidence of congenital transmission In utero treatment of infected fetus improves visual outcome Not FDA approved Synergistic action with pyrimethamine, sulfadiazine, and clarithromycin No serious adverse effects Take with food to increase bioavailability Contraindicated during pregnancy and in childhood (brown discoloration of the teeth and depression of bone growth) Adverse effects: phototoxicity and audiovestibular toxicity Not FDA approved for children Syl1.ergistic action with pyrimethamine, sulfadiazine, and minocycline Synergistic action with pyrimethamine, sulfadiazine, dapsone, and IFNI' Significantly less effective than the combination of pyrimetllamine and sulfadiazine. Indicated in active disease involving the posterior pole or optic nerve or if there is severe vitreous inflammation. Start at tlle same time or within 48 hours of initiating antimicrobial therapy, and taper off before discontinuation.

CBC, Complete blood count; G6PD, glucose-6-phosphate dehydrogenase; FDA, U.S. Food and Drug Administration.

applied in the treatment of ocular toxoplasmosis, but unfortunately it has not proven effective for preventing recurrence. There are no reports of seriously· adverse effects except for a transient maculopapular rash. Administration with food increases the bioavailability of atovaquone. Atovaquone acts synergistically with pyrimethamine, sulfadiazine, and clarithromycin, and it may be useful in reducing the dose and toxicity of these drugs in the treatment of patients with AIDS and toxoplasmosis.

Tetracyclines Tetracycline and its derivatives, particularly minocycline, are alternatives in the treatment of toxoplasmosis. They cause phototoxicity and audiovestibular toxicity. Tetracyclines are contraindicated during pregnancy and in childhood because of resultant brown discoloration of the teeth and depression of bone growth. Long-term minocycline therapy has been recommended for massive, chronically active retinochoroidal granulomas. 82

Clarithromydn Clarithromycin is a derivative of erythromycin and is effective against T. gondii. It works synergistically with pyrimethamine, sulfadiazine, and minocycline. Clarithromycin is not approved by the FDA for children.

Azithromydn Aiithromycin inhibits ribosomal protein synthesis. It is more active against T. gondii than the other macrolides, such as roxithromycin and spiramycin. AzithrOlnycin is effective against the encysted forms of the parasite (the bradyzoites) in vitro and is currently being tested clinically. 148, 149 It has synergistic action when associated with pyrimethamine, sulfadiazine, dapsone, and IFN-j'.

Trimethoprim and Sulfamethoxazo/e The combination of trimethoprim with sulfamethoxazole (Bactrim) has been used in the treatment of toxoplasmosis in humans. The sulfamethoxazole inhibits the incorpo-

CHAPTER JJ: TOXOPLASMOSIS

ration of PABA in the synthesis of folic acid, whereas trimethoprim prevents reduction from dihydrofolate to tetrahydrofolate. This combination is significantly less active than the combination of pyrimethamine and sulfadiazine but may still be effective in the treatment of toxoplasmosis. Opremcak and colleagues have reported that 16 patients had improvement in vision and resolution of their retinochoroiditis when Bactriln was used, alone or in. combination with clindamycin or steroid. Two. patients were allergic to the medication. 150

Trovafloxadn Trovafloxacin is a new fluoroquinolone with potent activity against T. gondii. 151 It acts synergistically with clarithromycin, pyrimethamine, and sulfadiazine. 152 It seems to be a promising agent in the treatment of toxoplasmosis in immunocompromised patients.

Additional Antimicrobial Therapy Other antibiotics, such as roxithromycin, rifabutin, and rifapentine have shown efficacy in the treatment of toxoplasmosis.153-155 They have synergistic actions and are useful in combination with other agents, such as pyrimethamine and sulfadiazine. They allow dosage reduction of the drugs, providing significant reduction of adverse effects. IL-12 has been used with atovaquone and clindamycin to potentiate the effect of these drugs against T. gondii. This combination causes a significant increase in the levels of IFN-)' produced by the ho~t.156 IFN-)', TNF-a, IL2, and IL-12 have been proposed for trials in patients with Toxoplasma encephalitis. 157 Dideoxyinosine (DDI) is a drug used against HIV, which is active against T. gondii. It has been shown to reduce the number of bradyzoites in the brains of chronically infected Inice. 15S

Corticosteroids When there is potential for serious visual impairment due to posterior pole or optic nerve involvement or severe vitreous inflammation, systemic corticosteroids are added to the treatment regimen. The corticosteroids decrease the inflammatory response and therefore reduce the adverse sequelae such as cystoid macular edema, vitritis, retinitis, and vasculitis. The need for a delay in starting systemic steroid therapy is controversial. The introduction of corticosteroids may begin concomitant with antimicrobial therapy or may be delayed by 12 to 48 hours to achieve therapeutic levels of the antimicrobial drugs. Corticosteroids should be tapered off about 2 weeks before discontinuing the anti-Toxoplasma therapy. They should not be used without simultaneous antimicrobial cover. Paradoxically, devastating anterior and posterior inflammation can occur following corticosteroid monotherapy.159, 160 Topical corticosteroids are used for anterior uveitis, but periocular injections are contraindicated to avoid local immunosuppression and uncontrollable disease. 161

Treatment Failures Despite adequate treatment, some patients continue to have chronic active retinitis. This may be the result of a particularly virulent strain of T. gondii, or it may be be-

cause of a localized immune or even an autoimmune phenomenon. Many studies have demonstrated both a cellular and a humoral immune response to retinal antigens in the setting of ocular toxoplasmosis. 96-103 Although it is unclear what role the immune system plays in chronic active retinitis, immune-mediated disease should be considered if active retinitis persists for more than 4 months on appropriate antibiotics. In addition, evidence of immune sensitization to retinal antigens supports the use of corticosteroid acutely to minimize exposure to and stimulation by retinal antigens. Clinical evidence supporting the role of the immune system in persistent retinitis comes from patients with ocular toxoplasmosis who are corticosteroid dependent. Occasionally, patients with ocular toxoplasmosis respond to treatment including corticosteroid, but when the corticosteroid is withdrawn, active retinitis recurs despite continuous antibiotic administration. Although the reason for this recurrence has not been determined, it may possibly be explained by three different mechanisms. First and most likely, this "reactivation" phenomenon may simply demonstrate immune reactivity to persistent T. gondii antigens remaining in the tissues. Second, it may represent a form of localized autoimmunity. Third, the diagnosis of toxoplasmosis may be erroneous.

Surgical Treatm~nt of Ocular Toxoplasmosis Laser Photocoagulation Laser photocoagulation in the treatment of ocular toxoplasmosis has a limited role. Although photocoagulation may destroy cysts and tachyzoites and inhibit the spread of infection, its effectiveness is limited. Laser photocoagulation may be considered for recurrences during pregnancy, cases of drug intolerance, lesions associated with choroidal neovascular membranes, and cases that fail to respond or are resistant to medical therapy. Complications of laser photocoagulation are numerous, including retinal and vitreous hemorrhage, epiretinal membrane, and choroidal neovascular membrane formation. Laser photocoagulation is not recommended as prophylaxis because of dubious efficacy and potential complications, and because tissue cysts are often present in a normallooking retina. The pattern of photocoagulation employed consists of a triple row of coalescent burns encircling the lesion and confluent burns to the central area (Fig. 33-24A and B). FA should be performed 1 month after laser photocoagulation, and areas of leakage should be retreated. Occasionally, laser photocoagulation cannot be performed because of media opacity. In these cases, cryotherapy has been tried. Cryotherapy, however, is often not able to reach the typical posterior location of the lesions in Toxoplasma retinochoroiditis, and it has its own complications.

Pars Plana Vitrectomy Pars plana vitrectomy may be useful for removal of persistent vitreous opacities or to relieve vitreoretinal traction that may lead to retinal detachment. Epiretinal Iuembrane peeling combined with or without lensectomy may

CHAPTER 33: TOXOPLASMOSIS

fiGURE 33-24. A, Active toxoplasma lesion resistant to prolonged medical therapy. Note that the visual acuity measured 20/70. B, The same eye after laser photocoagulation. Note the well-defined, slightly pigmented borders of the lesion. The visual acuity improved to 20/30. (Courtesy of Professor Sue! Abl~amra, USP, Brazil.) (See color insert.)

be needed to restore visual acuity. Vitrectomy is also believed to remove antigenic proteins, immunoactivating factors, and inflammatory cells from the vitreous. Specific antimicrobial and anti-inflammatory therapy should be administered preoperatively and maintained postoperativelyy3 In the case of choroidal neovascular membranes, surgical removal has been attempted, but whether there was an improvement in visual acuity is questionableY

Therapeutic Regimens Currently, there are many po~ible therapeutic ?ptions for the treatment of toxoplasmosis, each with Its own advantages and disadvantages. We favor the use of pyrimethamine, sulfadiazine, clindamycin, folinic acid, and prednisone for vision-threatening ocular toxoplasmosis in the absence of contravening factors. The optimal duration of specific therapy has not been clearly defined. However, we treat for at least 30 to 60 days in an immunocompetent patient. A positive response to treatment is defined as a sharpening of the borders of the retinochoroidal lesions and improvement of vitreous haze. When therapy is complicated by adverse effects or proves to be ineffective after 4 months, a change in therapy is recommended. Pregnant women need a special regimen, because the most efficient drugs used for the treatment of toxoplasmosis are potentially harmful to the fetus and the mother. Pyrimethamine is potentially teratogenic and should be avoided, particularly in the first trimester. Sulfadiazine is discouraged in the third trimester because it competes with bilirubin for serum proteins, causing kernicterus. Spiramycin is considered the safest drug during pregnancy and should be combined with sulfadiazine in the first two trimesters and with pyrimethamine in the second and third trimesters. Folinic acid should be added if pyrimethamine is included in .the regimen. Spiramycin is not available in the United States but may be acquired from the FDA by special request. When a pregnant woman acquires toxoplasmosis, spiramycin in combination with pyrimethamine or sulfadiazine may be administered for a 3-week period. If the response is not adequate, the regimen can be repeated after 21 days. Prednisone can be introduced if needed.

Studies demonstrate that antibiotic therapy administered to mothers during pregnancy decreases the percentage of children who will develop retinochoroidal scars during the first and second years of life. 58, 70-72 Close follow-up with an obstetrician is essential. The newborn with a diagnosis of congenital toxoplasmosis also requires special consideration. Typically, infants present with inactive chorioretinal scars or no lesions at all, but active retinochoroiditis may develop at any time of life. Recent studies demonstrated that the recurrence rate of ocular toxoplasmosis in untreated or undertreated infants is 40% to 67%,41,58 Early and prolonged antibiotic therapy throughout the whole first year of life reduces the severity of ocular disease and reduces the recurrence rate to 4% to 13%.58 These data support the notion that infants with congenital toxoplasmosis should be treated in utero as well as during the entire first year of life regardless of the presence or activity of retinochoroidal lesions.58, 70-73 The suggested regimen is a combination of pyrimethamine, sulfadiazine, and folinic acid. A new approach to congenital toxoplasmosis is PCR of the amniotic fluid to establish the diagnosis and initiation of treatment in utero for infected fetuses. 152 , 153 In immunocompromised patients, any active retinal lesion deserves treatment because of the high risk of disseminated disease and its complications. A regimen similar to that used for immunocompetent patients may be used for immunosuppressed individuals, with the following modifications. Pyrimethamine may be avoided to prevent further bone marrow suppression and because of its antagonistic action against zidovudine, a retroviral agent often used in the treatment of AIDS.154 These patients also have a high incidence of allergic reactions, especially to the sulfonamides. Corticosteroids are not recommended, because the immune response is already compromised, and marked inflammation is often not present in HIV-infected individuals. Lifelong maintenance therapy to prevent relapses is required. Lower dosages of pyrimethamine combined with sulfadiazine or clindamycin may be used for this purpose.1 55 The prognosis of ocular toxoplasmosis (that does not involve the optic nerve or the central Inacula) is favorable

CHAPTER 33: TOXOPLASMOSIS

in most cases, because the active disease is self-limiting. In. some cases, however, sequelae such as a macular retinochoroidal scar, severe vitreous haze, glaucoma, macular edema, epiretinal membrane, choroidal neovascularization, and retinal detachment may cause severe loss of vision. Factors that lead to a worse visual prognosis are large lesions, proximity to the fovea, and a long duration of disease. Early diagnosis and appropriate treatment are essential to minimize complications and loss of vision.

PREVENTION Measures for the prevention of toxoplasmosis are primarily directed toward prevention of primary infection. Prevention is crucial for seronegative pregnant WOlnen and immunocompromised patients. Important measures to prevent infection include the following: .. Meat should be cooked to 60°C (140°F) for at least 15 minutes or frozen to temperatures below - 20°C for at least 24 hours to destroy the cysts. .. Any contact with cat feces should be avoided. .. Hands should be washed after touching uncooked meat and after contact with cats or soil that could be contaminated with cat feces. .. Consumption of raw eggs and nonpasteurized milk, particularly goat's milk, should be avoided. .. Fruits and vegetables should be adequately washed before ingestion. .. Daily cleaning of cat litter box removes the oocysts before they become infectious, because they need 1 to 3 days after excretion to undergo sporulation. This duty should be performed only by a nonpregnant individual. .. Blood transfusions and organ transplants from seropositive donors should be avoided if the recipient is seronegative. Extensive research throughout the world has been aimed toward developing an effective vaccine against toxoplasmosis. Currently, there is a vaccine composed of attenuated tachyzoites that has been used in sheep to prevent abortion due to toxoplasmosis.1 66 Vaccination with live tachyzoites, however, is inappropriate in humans. Vaccination with an immunostimulating complex preparation of T. gondii antigens has been studied and it seems to induce some immunity in mice. 167 Nearly total protection was observed after immunization with P30 either incorporated into liposomes1 68 or in conjunction with QuilA. 169 Because the most common transmission route of toxoplasmosis is oral, an interesting new approach consists of trials of oral vaccination,49 which can be combined with adjuvants such as cholera toxin, which is known to enhance the secretory IgA response. Secretory IgA is responsible for a first-line mucosal immunity in the gut and may inhibit organisms before they gain entrance into the circulation. Additionally, oral immunization tends to be both practical and safe in terms of side effects. 17o Other promising work is based on recombinant antigens from different forms of the parasite to produce a vaccine. l7l

CONCLUSION Toxoplasmosis is a recurrent and progressively destructive ocular and systemic disease, with potentially blinding and

even fatal consequences. Fortunately, the Inechanisms of disease transmission are well known, allowing the formulation of primary prevention strategies. Once chronic infection has been established and the tissue form has encysted, there is no effective treatment to eradicate the organism. The host immune system plays a vital role in modulating the course of disease. Tissue cysts lie dormant, awaiting the chance to reactivate when immune surveillance falters. Advances in research and treatment continue to be made, improving our ability to prevent, diagnose, and control this disease.

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CHAPTER JJ: TOXOPLASMOSIS 78. Jabs DA, Green WR, Fox R, et al: Ocular manifestations of acquired immunodeficiency syndrome. Ophthalmology 1989;96:1092-1099. 79. Friedman AH: The retinal lesions of the acquired immune deficiency syndrome. Trans Am Ophthalmol Soc 1984;82:447-491. 80. Tabbara KF: Ocular toxoplasmosis (review). Int Ophthalmol Clin 1990;14:349-351. 81. Holland GN, Engstrom RE, Glasgow BJ, et al: Ocular toxoplasmosis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 1988;106:653-667. 82. Khanna A, Goldstein DA, Tessler HH: Protozoal posterior uveitis. In: Yanoff M, Duker JS, eds: Ophthalmology, 1st ed. St. Louis, Mosby, 1999. 83. Henin D, Duyckaerts C, Chaunu MP, et al: Etude neuropathologique de 31 cas de syndrome d' immuno-depression acquise. Rev Neurol (Paris) 1987;143:631-642. 84. Mom-thy RS, Rao NA: Posterior uveitis. In: Wright KW: Textbook of Ophthalmology on CD-ROM. New York: Williams & Wilkins, 1997. 85. Holland GN: Ocular toxoplasmosis in the immunocompromised host. Int Ophthalmol 1989;13:399-402. 86. Schuman JS, Friedman AH: Retinal manifestations of the acquired immune deficiency syndrome (AIDS): Cytomegalovirus, Candida albicans, Cryptococcus, toxoplasmosis and Pneumocystis cannii. Trans Ophthalmol Soc UK 1983;103:177-190. 87. Heinemann MH, GoldJMW, MaiselJ: Bilateral toxoplasma retinochoroiditis in a patient with acquired immune deficiency syndrome. Retina 1986;6:224-227. 88. Moorthy RS, Smith RE, Rao NA: Progressive Ocular Toxoplasmosis in Patients with Acquired Immunodeficiency Syndrome. Am J Ophthalmol 1993;115:742-747. 89. Manschot WA,Daamen CBF: Connatal Ocular Toxoplasmosis. Arch Ophthalmol 1965;74:48-54. 90. Araujo F, Slifer T, Kim S: Chronic infection with Toxoplasma gondii does not prevent acute disease or colonization on the brain with tissue cysts following reinfection with different strains of the parasite. J Parasitol 1997;83:521-522. 91. Rothova A, Meenken C, Buitenhuis HJ, et al: Therapy of ocular toxoplasmosis. Am J Ophthalmol 1993;113:517...:.523. 92. Ghosh M, Levy PM, Leopold IH: Therapy of toxoplasmosis uveitis. AmJ Ophthalmol 1965;59:55. 93. Rodenhauser JH: Clinical findings and pathogenesis of Kyrieleis' discontinuous reversible arteriopathy in uveitis. Klin Monatsbl Augenheilkd 1969;155:234-243. 94. Doft BH, Gass DM: Punctate outer retinal toxoplasmosis. Arch Ophthalmol 1985;103:1332-1336. 95. Matthews JD, Weiter lJ: Outer retinal toxoplasmosis. Ophthalmology 1988;95:941-946. 96. Nussenblatt RB, Mittal KK, Fuhrman S, et al: Lymphocyte proliferative responses of patients with ocular toxoplasmosis to parasite and retinal antigens. AmJ Ophthalmol 1989;107:632-641. 97. Abrahams IW, Gregerson DS: Longitudinal study of serum antibody responses to retinal antigens in acute ocular toxoplasmosis. AmJ Ophthalmol 1982;93:224-231. 98. Whittle RM, Wallace GR, Whiston RA, et al: Human antiretinal antibodies in toxoplasma retinochoroiditis. Br J Ophthalmol 1998;82:1017-1021. 99. Kijlstra A, Hoekzema R, Van del' Lelij A, et al: Humoral and cellular immune reactions against retinal antigens in clinical disease. Curl' Eye Res 1990;9(suppl):85-89. 100. Froebel KS, Armstrong SS, Cliffe AM, et al: An investigation of the general immune status and specific immune responsiveness to retinal (S)-antigen in patients with chronic posterior uveitis. Eye 1989;3:263-270. 101. Gregerson DS, Abrahams IW, Thirkill CE: Serum antibody levels of uveitis patients to bovine retinal antigens. Invest Ophthalmol Vis Sci 1981;21:669-680. 102. Rahi AH, Addison DJ: Autoimmunity and the outer retina. Trans Ophthalmol Soc U K 1983;103:428-437: 103. Abrahams IW, Gregerson DS: Longitudinal study of serum antibody responses to bovine retinal S-antigen in endogenous granulomatous uveitis. BrJ Ophthalmol 1983;67:681-684. 104. Rehder JR, BurnieI' MB Jr, Pavesio CD, et al: Acute unilateral toxoplasmic iridocyclitis in AIDS patients. Am J Ophthalmol 1988;106:740-741. 105. De Abreu MT, Belfort R, Hirata PS: Fuchs' heterochromic cyclitis and ocular toxoplasmosis. AmJ Ophthalmol 1982;93:739-744.

106. Arffa RC, Schlaegel TF: Chorioretinal scars in Fuchs' heterochromic iridocyclitis. Arch Ophthalmol198 Ll;102:1153-1155. 107. Saraux H, Laroche L, Le Hoang P: Secondary Fuchs' heterochromic cyclitis: A new approach to an old disease. Ophthalmologica 1985;190:193-198. 108. Schwab IR: The epidemiologic association of Fuchs' heterochromic iridocyclitis and ocular toxoplasmosis. Am J Ophthalmol 1991;111:356-362. 109. Rutzen AR, Raizman MB: Fuchs' heterochromic iridocyclitis. In: Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology, vol 1. Philadelphia, W.B. Saunders, 1994, pp 503-516. 110. La Hey E, Rothova A, Baarsma GS, et al: Fuchs' heterochromic iridocyclitis is not associated witll ocular toxoplasmosis. Arch Ophthalmol 1992;110:806-811. 111. Silveira CM, Belfort R Jr, Nussenblatt R, et al: Unilateral pigmentary retinopathy associated witll ocular toxoplasmosis. Am J Ophtllalmol 1989;107:682-684. 112. Tabbara KF: Disruption of the choroidoretinal interface by toxoplasma. Eye 1990;4:366-373. 113. Tamesis RR, Foster CS: Toxoplasmosis. In: Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology, vol 2. Philadelphia, W.B. Saunders, 1994, pp 929-933. 114. Zimmerman LE: Ocular pathology of toxoplasmosis. Surv Ophtllalmol 1961;6:832-876. 115. Webb RM, Tabbara KF, O'Connor GR: Retinal vasculitis in ocular toxoplasmosis in nonhuman primates. Retina 1984;4:225-231. 116. Newman PE, Ghosheh R, Tabbara KF, et al: The role ofhypersensitivity reactions to toxoplasma antigens in experimental ocular toxoplasmosis in nonhuman primates. Am J Ophthalmol 1982;94:159-164. 117. Connor GR: The influence of hypersensitivity on the pathogenesis of ocular toxoplasmosis. Trans Am Ophthalmol Soc 1970;68:501547. 118. McMenamin PG, Dutton GN, Hay J, Cameron S: The ultrastructural patl1010gy of congenital murine toxoplasmomic retinochoroiditis. Part 1: The localization and morphology of toxoplasma cysts in tlle retina. Exp Eye Res 1986;43:529-543. 119. Kean BH, Sun T, Ellswortll RM: Color Atlas/Text of Ophthalmic Parasitology. New York, Igaku-Shoin, 1991, pp 9-21. 120. Kelan AE, Ayllon-Leindl L, Labzoffsky NA: Indirect fluorescent antibody method in serodiagnosis of toxoplasmosis. Can J MicrobioI 1962;8:545. 121. Fuccillo DA, Madden DL, Tzan N, Sever JL: Difficulties associated with serologic diagnosis of Toxoplasma gondii infections. Diagn Clin Immunol1987;5:8-13. 122. Weiss MJ, Velazquez N, Hofeldt AJ: Serologic tests in the diagnosis of presumed toxoplasmic retinochoroiditis. Am J Ophthalmol 1990;109:407-411. 123. Ara~o FG, Barnett EV, Gentry LO, Remington JS: False-positive anti-toxoplasma fluorescent-antibody tests in patients with antinuclear antibodies. Appl Microbiol 1971 ;22:270-275. 124. Naot Y, RemingtonJS: An enzyme-linked immunosorbent assay for detection of IgM antibodies to Toxoplasma gondii: Use for diagnosis of acute acquired toxoplasmosis. J Infect Dis 1980;142:757-766. 125. Pyndiah N, Krech U, Price P, Wilhelm J: Simplified chromatographic separation of immunoglobulin M from G and its application to toxoplasma indirect immunofluorescence. J Clin Microbiol 1979;9:170-174. 126. Weiss MJ, Velazquez N, Hofeldt AJ: Serologic tests in the diagnosis of presumed toxoplasmic retinochoroiditis. Am J Ophthalmol 1990;109:407-411. 127. Schlaegel TF Jr: Ocular Toxoplasmosis and Pars Planitis. New York, Grune & Stratton, 1978, pp 138-172. 128. Naot Y, Desmonts G, Remington JS: IgM enzyme-linked immunosorbent assay test for tlle diagnosis of congenital toxoplasma infection. J Pediatr 1981;98:32-36. 129. Tomasi JP, Schlit AF, Staatbaeder S: Rapid double sandwich enzyme-linked immunosorbent assay for detection of human immunoglobulin anti-Toxoplasma gondii antibodies. J Clin Microbiol 1986;24:849-850. 130. Guimaraes 0, Orefice F, Mineo JR, Brandao E: Reacoes de imunofluorescencia indireta e de ELISA na deteccao de anticorpos IgG and IgM no soro de pacientes portadores de retinocoroidite ativa e cicatrizada supostamente toxoplasmica. Rev Bras Oftal 1991;49:241-346.

CHAPTER JJ: TOXOPLASMOSIS 131. KatinaJA, Orefice F, Mineo JR: Anticorpos IgA especificos no soro e humor aquoso de pacientes com uveite de provavel etiologia toxoplasmica. Rev Bras Oftal 1992;51:209-216. 132. Chumpitazi BFF, Boussaid A, Pelloux H, et al: Diagnosis of congenital toxoplasmosis by immunoblotting and relationship with other methods. J Clin Microbiol 1995;33:1479-1485. 133. Yamamoto Yl, Mineo JR, Meneghisse CS, et al: Detection in human sera of IgG, IgM and IgA to excreted/secreted antigens from Toxoplasma gondii by use of dot-ELISA and immunoblot assay. Ann Trop Med Parasitol 1998;92:23-30. 134. Brezin AP, Egwuagu CE, Burnier M Jr, et al: Identification of Toxoplasma gondii in paraffin-embedded sections by the polymerase chain reaction. AmJ Ophthalmol 1990;110:599-604. 135. Hohlfeld P, Daffos F, CostaJM, et al: Prenatal diagnosis of congenital toxoplasmosis with a polymerase-chain-reaction test on amniotic fluid. N EnglJ Med 1994;331:695-699. 136. Thulliez P, Daffos F, Forestier F: Diagnosis of toxoplasma infection in the pregnant woman and the unborn child: Current problems. ScandJ Infect Dis Suppl 1992;84:18-22. 137. Forestier F, Hohlfeld P, Sole Y, Daffos F: Prenatal diagnosis of congenital toxoplasmosis by PCR: extended experience [letter]. Prenat Diagn 1998;18:407-409. 138. Manners RM, O'Connell S, Gay EC, et al: Use of the polymerase chain reaction in the diagnosis of acquired ocular toxoplasmosis in an immunocompetent adult. Br J Ophthalmol 1994;78:583-584. 139. Aouizerate F, Cazenave J, Poirier L, et al: Detection of Toxoplasma gondii in aqueous humor by polymerase chain reaction. Br J Ophthalmol 1993;77:107-110. 140. CouvreurJ, Desmonts G: Congenital and maternal toxoplasmosis: A review of 300 congenital cases. Dev Med Child Neurol 1962;4:519. 141. Desmonts G: Definitive serological diagnosis of ocular toxoplasmosis. Arch Ophthalmol 1966;76:839-851. 142. Eyles DE, Coleman N: Syn.ergistic effect of sulphadiazine and daraprin against experimental toxoplasmosis in the mouse. Antibiot Chemother 1953;3:483-490. 143. Rothova A, Meenken C, Buitenhui'S' HJ, et al: Therapy for ocular toxoplasmosis. AmJ Ophthalmol 1993;115:517-523. 144. Mandell GL, Sande Iv1A: Antimicrobial agents. In: Gilman AG, Goodman LS, Ralf TW, Murad F, eds: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 7th ed. New York, Macmillan, 1985, p 1098. 145. Hofflin JM, Remington JS: Clindamycin in a murine model of toxoplasmic encephalitis. Antimicrob Agents Chemother 1987;31 :492-496. 146. Tabbara KF, Dy-Liacco J, Nozik RA, et al: Clindamycin in chronic toxoplasmosis: Effect of periocular ir~jections on recoverability of organisms from healed lesions in the rabbit eye. Arch Ophthalmol 1979;97:542-544. 147. Gormley PD, Pavesio CE, Minnasian D, Lightman S: Effects of drug therapy on toxoplasma cysts in an animal model of acute and chronic disease. Invest Ophthalmol Vis Sci 1998;39: 1171-1175. 148. Huskinson-Mark J, Aral~o FG, Remington JS: Evaluation of the effects of drugs on the cyst form of the Toxoplasma gondii. J Infect Dis 1991;164:170-171. 149. Farthing C, Rendel M, Currie B, Seidlin M: Azithromycin for cerebral toxoplasmosis. Lancet 1992;339:437-438. 150. Opremcak EM, Scales DK, Sharpe MR: Trimethoprim-sulfamethoxazole therapy for ocular toxoplasmosis. Ophthalmology 1992;99:920-925. 151. Khan AA, Slifer T, Araujo FG, Remington JS: Trovafloxacin is active against Toxoplasma gondii. Antimicrob Agents Chemother 1996;40: 1855-1859. 152. Khan AA, Slifer T, Araujo FG, et al: Activity of trovafloxacin in combination with other drugs for treatment of acute murine toxoplasmosis. Antimicrob Agents Chemother 1997;41:893-897. 153. Aral~o FG, Khan AA, Remington JS: Rifapentine is active in vitro and in vivo against Toxoplasma g01Idii. An.timicrob Agents Chemother 1996;40:1335-1337. 154. Araujo FG, Slifer T, Remington JS: Rifabutin is active in murine models of toxoplasmosis. Antimicrob Agents Chemother 1994;38:570-575. 155. Aral~o FG, Suzuki Y, Remington JS: Use of rifabutin in combination with atovaquone, clindamycin, pyrimethamine, or sulfadiazine for treatment of toxoplasmic encephalitis in mice. Eur J Clin Microbiol Infect Dis 1996;15:394-397.

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FG, Hunter CA, Remington .IS: Treatment with interleukin 12 in combination with atovaquone or clindamycin significantly increases survival of mice with acute toxoplasmosis. Antimicrob Agents Chemother 1997;41:188-190. Hunter CA, Subauste CS, Remington JS: The role of cytokines in toxoplasmosis. Biotherapy 1994;7:237-247. Sarciron ME, Lawton P, Saccharin C, et al: Effects of 2', 3'-dideoxyinosine on Toxoplasma gondii cysts in mice. Antimicrob Agents Chemother 1997;41:1531-1536. Nicholson DH, WoIchok EB: Ocular toxoplasmosis in an adult receiving long-term corticosteroid therapy. Arch Ophthalmol 1976;94:248-254. Sabates R, Pruett RC, Brockhurst RJ: Fulminary ocular toxoplasmosis. AmJ Ophthalmol 1981;92:497-503. O'Connor GR, FrenkelJI\.: Editorial: Dangers of steroid treatment in toxoplasmosis. Periocular injections and systemic therapy. Arch Ophthalmol 1976;94:213. Couvreur J: Problems of congenital toxoplasmosis. Evolution over four decades. Presse Med 1999;28:753-757. Russo M: Toxoplasmosis in pregnancy. Prevention, diagnosis, and therapy. Recenti Prog Med 1994;85:37-48. Israelsky DM, Tom C, Remington JS: Zidovudine antagonizes the action of pyrimethamine in experimental infection with ToxojJlasma gondii. Antimicrob Agents Chemother 1989;33:30-34. Morlat P, Leport C: Prevention of toxoplasmosis in immunocompromised patien~s. An.n Med Interne (Paris) 1997;148:3, 235-239. Dubey JP: Prevention of abortion and neonatal death due to toxoplasmosis by vaccination of goats with the nonpathogenic coccidium Hammondia hammondi. AmJ Vet Res 1981;42:2155-2157. Uggla A, Araujo FG, Lunden A, et al: Immunizing effects in mice of two Toxoplasma gondii ISCOM preparations. J Vet Med 1988;B35:311-314. Bulow R, Boothroyd JC: Protection of mice from fatal Toxoplasma gondii infection by immunization with P30 antigen in liposomes. J Immunol 1991;147:3496-3500. Khan IA, Ely KI-I, Kasper LH: A purified parasite antigen (P30) mediates CD8 + T cell immunity against fatal Toxoplasmagondii infection in mice. J Immunol 1991;147:3501-3506. Kraehenbuhl JP, Neutra MR: Molecular and cellular basis of immune protection of mucosal surfaces. Physiol Rev 1992;72:853879. Alexander J, Jebbari H, Bluethmann H, et al: Immunological control of Toxoplasma gondii and appropriate vaccine design. Curl' Top Microbiol Immunol 1996;219:183-195. Burg JL, Perelman D, Kasper LH, et al: Molecular analysis of the gene encoding the mcyor surface antigen of Toxoplasma gondii. J Immunol 1988;141:3584-3591. Couvreur G, Sadak A, Fortier B, Dubremetz JF: Surface antigens of Toxoplasma gondii. Parasitology 1988;97:1-10. Handman E, Goding JW, Dubremetz JF: Detection and characterization of membrane antigens of Toxoplasma gondii. J Immunol 1980;124:2578-2583. Tomavo S, Schwarz RT, Dubremetz JF: Evidence for glycosyl-phosphatidylinositol anchoring of Toxoplasma gondii major surface antigens. Mol Cell BioI 1989;9:4576-4580. Prince .JB, Auer KL, Huskinson J, et al: Cloning, expression, and eDNA sequence of surface antigen P22 from Toxoplasma gondii. Mol Biochem Parasitol 1990;43:97-106. Cesbron-Delauw MF, Tomavo S: Unpublished observation. Cesbron-Delauw MF, Guy B, Torpier G, et al: Molecular characterization of a 23-kilodalton major antigen secreted by Toxoplasma gondii. Proc Nat Acad Sci 1989;86:7537-7541. Charif H, Darcy F, Torpier G, et al: Toxoplasma gondii. Characterization and localization of antigens secreted from taquizoites. Exp Parasitol 1990;71:114-124. Achbarou A, Mercereau-Puijalon 0, Sadak A, et al: Differential targeting of dense granule proteins in the parasitophorous vacuole of Toxoplasma gondii. Parasitology 1991;103:321-329. Mercier C, Lecordier L, Darcy F, et al: Molecular characterization of a dense granule antigen (GRA2) associated with the network of the parasitophorous vacuole in Toxoplasma gondii. Mol Biochem Parasitol 1993;58:71-82. Prince JB, Aral~o FG, Remington JS, et al: Cloning of cDNAs encoding a 28-kilodalton· antigen of Toxoplasma gondii. Mol Biochem Parasitol 1989;34:3-13.

CHAPTER 33: TOXOPLASMOSIS 183. Leriche MA, Dubremetz JF: Characterization of the protein contents of rhoptries and dense granules of Toxoplasma gondii tachyzoites by subcellular fractionation and monoclonal antibodies. Mol Biochem Parasitol 1991;45:249-260. 184. Bermudes D, Joiner KA: Unpublished observation. 185. Mevelec MN, Chardes T, Mercereau-Puijalon 0, et al: Molecular cloning of a gene encoding GRA4, a Toxoplasma gondii dense granule protein recognized by mucosal IgA antibodies. Mol Biochem Parasitol 1992;56:227-238. ·186. Lecordier L, Mercier C, Torpier G, et al: Molecular structure of a Toxoplasma gondii dense granule antigen (GRA5), associated with the parasitophorous vacuole membrane. Mol Biochem Parasitol 1993;59:143-153. 187. Ossorio PN, Schwartzman JD, Boothroyd JC: A Toxoplasma gondii rhoptry protein associated with host cell penetration has unusual charge asymmetry. Mol Biochem Parasitol 1992;50:1-16. 188. Saavedra R, Demeuter F, Decourt JL, Herion P: Human T-cell clone identifies a potentially protective 54-kDa protein antigen of Toxoplasma gondii cloned and expressed in Escherichia coli. J Immunol 1991;147:1975-1982. 189. Achbarou A, Mercereau-Puijalon 0, Autheman JM, et al: Characterization of microneme proteins of Toxoplasma gondii. Mol Biochem Parasitol 1991;47:223-233. 190. Fourmaux MN, Mercereau-Puijalon 0, Dubremetz JF: Unpublished observation. 191. Nagel SD, BoothroydJC: The a and [3 tubulins of Toxoplasma gondii are encoded by single copy genes containing multiple introns. Mol Biochem Parasitol 1988;29:261-273. 192. Roos D: Unpublished observation. 193. Johnson AM, Illana S, McDonald PJ, Asai T: Cloning, expression and nucleotide sequence of the gene fragment encoding an antigenic portion of the nucleoside triphosphate hydrolase of Toxoplasma gondii. Gene 1989;85:215-220.

194. Orefice F, Belfort R Jr: Toxoplasmose. In: Orefice F, Belfort R, Roca S, eds: Uveitis. Sao Paulo, 1987. 195. Hunter K, Stagno S, Capps E, Smith RJ: Prenatal screening of pregnant women for infections caused by cytomegalovirus, Epstein-Barr virus, herpesvirus, rubella, and Toxoplasma gondii. Am J Obstet Gynecol 1983;145:269-273. 196. Jackson MH, Hutchison WM, Siim JC: A seroepidemiological survey of toxoplasmosis in Scotland and England. Ann Trop Med Parasitol 1987;81:359-365. 197. Williams KA, ScottJM, Macfarlane DE, et al: Congenital toxoplasmosis: A prospective survey in the west of Scotland. J Infect 1981;3:219-229. 198. Alford CA: An epidemiologic overview of intrauterine and perinatal infections of man. Mead Johnson Symp Perinat Dev Med 1982;21:3-11. 199. Palicka P: [Incidence of congenital toxoplasmosis in the Czech population] Cesk Epidemiol Mikrobiol Imunol 1982;31:290-297. 200. Sfameni SF, Skunie IJ, Gilbert GL: Antenatal screening for congenital infection with rubella, cytomegalovirus and Toxoplasma. Aust N ZJ Obstet GynaecoI1986;26:257-260. 201. Foulon W, Naessens A, Volckaert M, et al: Congenital toxoplasmosis: A prospective survey in Brussels. Br J Obstet Gynaecol 1984;91:419-423. 202. Logar J, Novak Antolic Z, Zore A, et al: Incidence of congenital toxoplasmosis in the Republic of Slovenia. Scand J Infect Dis 1992;24:105-108. 203. BornandJE, PiguetJD: [Toxoplasma infestation: Prevalence, risk of congenital infection and development in Geneva from 1973 to 1987.] Schweiz Med Wochenschr 1991;121:21-29. 204. Camargo ME, Leser PG, Kiss MH, Amato Neto V: Serology in early diagnosis of congenital toxoplasmosis. Rev Inst Med Trop Sao Paulo 1978;20:152-160. 205. Desmonts G: [Detection of toxoplasmosis by agglutination of parasites. Value of a very sensitive antigen in the search for specific immunoglobulins G]. Ann BioI Clin (Paris) 1983;41:139-143.

I

I

I

Jesus Merayo-Lloves, Cindy M. Vredeveld, and Albert T. Vitale

Ocular disease caused by the free-living amebae Acanthamoeba and Naegleria is an uncommon but severe and progressive, potentially blinding infection. It usually affects the cornea but could also involve the sclera, uveal tract, and other ocular tissues. Early diagnosis is the most important prognostic indicator of successful outcome, so clinical suspicion should be high for patients with painful corneal inflammation of atypical course, whether or not they wear contact lenses, and laboratory confirmation should be sought. Amebiasis is an intestinal infection caused by Entamoeba histolytica. Only 10% of affected individuals demonstrated clinical manifestations (including dysentery and liver abscesses). Ocular infection is rare.

Historical Background Free-living Acanthamoeba (ameba from the Greek <X/-LOL[3T), change 1) was described in 1775 by Von Rosenhof2 and characterized by an irregular, sluggish, flowing "mneboid motion."3 In 1930, Aldo Castellani4 described the morphological characteristics; Culbertson in 1950 observed brain lesions in mice and monkeys; and Flower reported the first fatal human infection in 1965. 5 The first cases of confirmed Acanthamoeba infection of the eye were reported in 1973 by Jones and colleagues6 at the Ocular Microbiology and Immunology Group meeting, with clinical descriptions of keratitis and uveitis. The first published paper on its morphology appeared in 1975. 7 During the 1980s and 1990s, there was an emergent epidemic of Acanthamoeba keratitisS in contact lens wearers. Since then, improved education of clinical ophthalmologists has resulted in better prevention, earlier diagnosis, and more aggressive treatment, so the incidence of Acanthamoeba keratitis has declined, and the prognosis and visual outcome have improved. 9,IO

Microbiology These amebae are pathogenic and opportunIStlC freeliving protozoa that belong to the phylum Sarcomastigophom. There are two genera, Acanthamoeba and Naegleria, and Acanthamoeba has five species, A. castellanii, A. polyphaga, A. culbertsoni, A. rhisodes, and A. hatchettiY' 12 The only Naegleria species known to cause human infection (meningoencephalitis) is N.Iowleri. 5 Acanthamoeba can cause ocular infection and rare diseases affecting the lungs, skin, and central nervous system,S, 13 but it is also isolated from nasal and oral mucosae of healthy people. 1'1 The characteristics of Acanthamoeba species have been described,15 but species differentiation is of limited clinical importance. Acanthamoeba accounts for the largest population of

protozoa. It is ubiquitous, found in virtually every climate,12 and has been isolated in many water sources, including municipal water supplies and bottled drinking water. Acanthamoeba has also been found on contact lenses and in contact lens solutions. 2,16-1S Acanthamoeba has a biphasic life cycle. The motile, replicating, infective form (trophozoite) has pseudopodia and spike-shaped projections (acanthopodia) that constitute the locomotor organelles and enable it to attach to surfaces, phagocytizing bacteria and other cells. 16 When environmental conditions are adverse or there are no nutrients,17 the trophozoites secrete a rich protein outer wall (ectocyst) and. a cellulose inner wall (endocyst) and the amebae enter the dormant (cyst) phase 12 by a morphologic change in which both walls meet at various points called ostioles. Cysts are resistant to heat, cold, pH, and medical therapy; they are able to survive the attack of the immune system for months and may becOlne airborne. Under favorable conditions, the trophozoites emerge from the cyst through an ostiole (within 3 days) .13, 14 Unlike the free-living amebae, the intestinal protozoan Entamoeba histolytica causes an infection, amebiasis. Ninety percent of infected individuals are asymptomatic. There is a wide spectrum of clinical manifestations, from dysentery to abscesses in the liver and other organsY Healthy individuals are commonly exposed to Acanthamoeba species and a high percentage of the population has positive antibodies. 19 All types of water and soil are natural reservoirs,ll and cysts may be airborne. 14 Humans are the definitive hosts. ll Keratitis is the most common human disease caused by amebae. 2 The first case was presented in 1973, followed by several case reports with ocular trauma and water exposure in cOlnmon. 2, S, 9, 12, 13 In 1984, the first case of Acanthamoeba keratitis in a contact lens wearer was reported, and by 1989 more than 250 such cases had been collected by the Centers for Disease Control,2, S Eighty-five percent of infections were in contact lens wearers,20 with an estimated incidence in this epidemic period from 1.6 to 2.5 per Inillion contact lens wearers in the United StatesS and 1 per 10,000 in the United Kingdom. 9 Interestingly, the increased incidence of Acanthamoeba keratitis paralleled that of bacterial keratitis among contact lens wearers. S,21 This epidemic has been a lesson to the ophthalmic community: New technologies can be associated with unforeseen complications. s, 19 Risk factors for Acanthamoeba include contact lens wear (specifically, improper contact lens use and hygiene and the use of homemade saline solutions), corneal trauma, and exposure to contaminated water. 2, 9, 13, 22 About 10% of the world's population is infected with E. histolytica, with a high incidence in developing tl-opical countries. Groups at risk in developed countries include

CHAPTER 34: FREEaliVING AMEBAS AND AMEBIASIS

travelers, homosexual men, immigrants, and institutionalized personsY In the reported ocular cases, trauma and fecal-ocular infection were predispositions to infection. 23 Patients with amebic dysentery may develop intermediate uveitis,32 and examination of stool specimens will disclose the amebae.

lanii elaborates plasminogen activator, a substance not detected in the nonpathogenic forin. Some authors ascribe a role to plasminogen, with the subsequent activation to plasmin, in the promotion of parasite penetration into the corneal epithelium. 29 Entamoeba histolytica can affect the eyes through disselnination from systemic amebiasis,30 or it may be the host immunoresponse that is responsible for ocular disease. 31 - 33

Pathogenesis Ocular infection by free-living amebae depends on inoculation with virulent protozoa and the presence of a suitable environment for growth and host response. 12 , 13 funebae can reach the ocular surface through contalninated contact lenses or contact lens material, trauma, and contaminated water. Once the parasite reaches the corneal surface, it must remain in contact and eventually penetrate. 12 , 13 Trophozoites bind to corneal epithelium by a mannose-binding protein. 24 Recent articles address the role of lecithin-mediated adhesion and a contact-dependen t metalloproteinase in the cytopathogenic mechanism. 25 This union can induce cytolysis or apoptosis of the target cell and may exacerbate the pathogenic cascade by initiating the release of cytolytic factors. 26 Once in the stroma, amebae secrete collagenolytic enzYlnes that contribute to the dissolution of the stromal matrix. 27 Although protozoa can penetrate intact corneal epithelium,21 clinical and experimental data support the association of Acanthamoeba keratitis with epithelial damage and hypoxia, punctate epithelial eposions, and microscopic epithelial breaks l2 , 13 related to contact lens wear and trauma. ful0ther possible factor in the pathogenicity of Acanthamoeba is the presence of bacterial colonization of the ocular surface. The coinfection rate with bacteria has been reported to be as high as 58%. In a rat model of Acanthamoeba keratitis, when the cornea is infected with avirulent bacteria an enhancement of the disease develops.13 Additionally, endosymbiosis has been reported between Acanthamoeba and bacteria. 12 Thus, bacteria may Inodify the pathogenicity of Acanthamoeba. Host response is mediated by the humoral and cellular branches of the immune system and by complement activation. A11tibodies to this ubiquitous parasite may develop from environmental exposure, and they may act by opsonization, fixation of complement on the amebic membrane, and toxin neutralization. 13 But the role of mucosal immunity seems to be of greater importance. Only topical immunization (which increases local IgA) protects animals from disease, despite high levels of serum antibodies. lO Mucosal IgA does not affect the viability of Acantha1Tweba, but it seems to prevent infection by inhibiting parasite binding to the corneal epithelium. 28 The cellular response to infection is mainly polymorphonuclear, with a paucity of macrophages and lymphocytes. This response is important -in the eradication of trophozoites; however, cysts may resist this assault, survive for long periods of time, and reactivate infection under favorable conditions. Acanthanweba is capable of complement activation by the alternative pathway, which may lead to the production of inflammatory mediators,13 a possible explanation for damage to ocular tissue. The pathogenic form of A. castel-

Histopathology Polymorphonuclear leukocytes in the external part of the stroma are the primary immune cells in the first stages of the disease, as in other parasitic infections. Neutrophils are followed by macrophages, with a near absence of lymphocytes. There is necrosis and often a lack of neovascularization. 13 In advanced stages, Wessley's ring results from stromal precipitation of immunocomplex, which is often associated with properdin-mediated activation of the alternative pathway of complement. 12 Eye adnexa affected by amebiasis show necrosis and abundant E. histolytica. 12

Acanthamoeba I<:eratitis Acanthamoeba keratitis begins with an insidious onset of symptoms and signs that may emerge slowly, over several weeks, or worsen rapidly.13 Patients are typically young, immunocompetent individuals of either sex, with a history of contact lens wear, exposure to contaminated fluids or a foreign body, or minor trauma. 2 However, some patients may demonstrate none of the apparent risk factors, which could delay the diagnosis. 9 Patients typically complain of severe pain and tearing in one eye (rarely bilateral) far out of proportion with clinical observation. 2,9 The spectrum of clinical signs ranges from superficial erosions or microcyst edema to full-thickness corneal abscess. Dendritic epitheliopathy is common and could be misdiagnosed as herpes simplex keratitis. 2,9,12 Radial keratoneuritis (perineural infiltrates), when present, is highly suggestiveY As the disease progresses Wessley's ring could be present as well as subepithelial infiltrates caused by a delayed immunologic reaction. 12 A distinctive feature is the absence of corneal neovascularization,13 but vessels may be seen in the final stages covering centralleukomas. 9

Scleritis Scleritis has been observed in 11 %34 to 40%35 of cases, usually when the diagnosis was delayed for more than 2 months. 9,36 Scleral inflammation is characterized by severe ocular pain, deep scleral vascular engorgement, and scleral nodules. 13 Mter resolution, scleral ectasia may occur. 37 In most cases, scleritis is probably an immunologically driven response rather than a direct infection. 13

Uveitis A11terior chamber inflammation occurs in 5% of cases that are diagnosed early, but it rises to 79% when diagnosis is delayed more than 2 monthsY Hypopyon is present

CHAPTER 34: FREE-LIVING AMEBAS AND AMEBIASIS

in late stages in 46% of patients. 34 A recent report found a granulomatous reaction involving anterior chalnber stroma caused by Acanthamoeba. 3S Chorioretinitis in the contralateral eye of a patient with Acanthamoeba keratitis has been reported. 39

Complications Elevated intraocular pressure and cataracts are occasionally seen in patients with severe and prolonged ocular inflammation. 34 Six percent of patients diagnosed early (in less than 30 days) developed glaucoma, compared with 21 % of those diagnosed late (more than 2 months after the onset of symptoms). Similarly, only 3 % of patients diagnosed early, compared with 38% of those diagnosed late, developed cataracts. 9 This proves the importance of early recognition and treatment.

Ocular Diseases Associated with Amebiasis There are only occasional reports of eye infection by E. histolytica. Beaver reported a case with amebiasis of the eyelid and conjunctiva that was extended to the orbit. No intraocular disease was present. The risk factors were feco-ocular inoculation and trmuna. 30 Amebiasis has been associated with central serous chorioretinitis. 31 Rodger and colleagues reported an association between dysentery and intermediate uveitis. 32 In cases of dysentery, Entamoeba can be found in stool samples, but this is not always true in the case of hepatic cysts. 40

DIAGNOSIS Clinical awareness has been heightened by concerted educational efforts during the last decade among ophthalmologists and within the public sector,S leading to earlier diagnosis, often before the hallmark signs appear, and reducing the risk of late complications.S, 12, 13 Physicians should be suspicious of Acanthamoeba when a chronic keratitis persists despite adequate topical therapy, even in patients with no risk factors for the infection (10% of ameba keratitis patients are non-contact lens wearers).9 Diagnostic tests include in vivo confocal microscopy, corneal cultures, microscopic observation of corneal scrapings, polymerase chain reaction (PCR) of infected samples, and testing of contact lenses and contact lens solutions.

In Vivo Confocal Microscopy Confocal microscopy is a noninvasive method of magnification with sufficient spatial resolution to reveal trophozoites and cysts from the human cornea in vivo and to detect trophozoites in migration through corneal nervesY Moreover, corneal examination with tandem scanning confocal microscopy has been associated with a marked increase in the detection of Acanthamoeba, suggesting that the disease is more prevalent than once suspected. 42

laboratory Diagnosis Several laboratory techniques and protocols have been described. 2, 9, 12, 13, '13, 44 In this chapter, special attention Will be given to the Moorfields Eye Hospital protocol.9, 44

Before samples are taken, patients should discontinue any previous treatment in order to increase the yield of positive results. Corneal scrapings should be aggressively taken. If there is a high clinical suspicion and cultures are negative, corneal biopsy is indicated. Biopsy can be performed with a 2- to 3-mm trephine from an area of infiltration outside the visual axis. 9, 13 Samples are divided into two parts. One part, to be used for histopathology, is immediately fixed in formaldehyde 9 or methyl a1cohop3 for 3 to 5 minutes. The other part is placed on 11.011.nutrient agar, with or without Escherichia coli overlay (E. coli may be added later) , for culture. If the culture cannot be done immediately, transport in physiologic serum (0.9%) or in ameba transport Inedia. Large volumes of contact lens solution can be filtered with a 5-f-Lm polycarbamate membrane filter, with the filter upside-down for processing. Corneal biopsy may be processed for electron microscopy. All samples should be examined for bacteria, fungi, and virus. 9, 13 A new technique for cytology identification has been described recently by Gardner and associates. 45

Histopathology More than 15 stains including Giemsa, periodic acidSchiff, methylene blue, and ca1cofluor white may be used to demonstrate Acanthamoeba. A solution containing 0.1 % ca1cofluor white (which stains cyst and fungi) with a 0.1 % counterstain of Evans blue (which stains trophozoites) is one recommended method. 46 The method employed at the Moorfields Eye Hospital is an immunoperoxidase staining using a polyclonal antibody against Acanthamoeba. 9 ,44

Culture Although Acanthamoeba can grow on blood or chocolate agar, cultures should include non-nutrient agar with an E. coli overlay. Culture plates should be sealed to prevent evaporation and the loss of the organisms from dryingY Plates are incubated at 3°C over 72 hours. If growth is not detected by day 6, plates are moved to 22°C because some amebae grow better at low temperature. Plates are observed for up to 3 weeks if there has been no previous growth. 9 Wavy tracts or irregularly shaped trophozoites may be observed. 9, 13

Polymerase Chain Biology

m'IIl::
Polymerase chain reaction using primers for Acanthamoeba ribosomal RNA is a rapid, sensitive, and specific method for detecting Acanthamoeba from epithelial corneal specimens. 47 PCR has the advantage of allowing rapid, sensitive, and specific diagnosis with an extremely low number of parasites. Recently, PCR has been used to confirm confocal microscopic observations of Acanthamoeba. 4S PCR and other antibody marker techniques do not differentiate pathogenic from nonpathogenic Acanthamoeba, so a differentiation marker based on a colorimeter assay for protease activity is a good complement to these techniques. 49

Diagnosis Differential diagnosis should include herpetic, fungal, bacterial, or sterile contact lens-related keratitis. 13 Topical

34: fR.EE-LiVING AMEBAS AND

,1'''UVUII:::CIII-'l.,;;:U.;;II

anesthetic-abuse ring keratitis has been misdiagnosed as Acanthamoeba keratitis. 50 ,51

Treatment of ocular infection by Acanthamoeba is difficult because the cyst form can be highly resistant to treatment. Resistance to therapy and in vitro activity do not always correlate with in vivo effectiveness. 9 For this reason, most protocols have been established empirically and modified by trial and error. The goals of therapy are to eradicate the parasite, control inflammation, control pain, and treat complications. Surgery can be successful if the eye is free of inflammation. New therapies, such as immunization against Acanthamoeba and the induction of protective mucosal IgA, could prove to be successful in the future. 52

Medical Treatment

Antiamebic Agents Several agents have been tested for antiamebic effectY Aminoglycosides (neomycin, paromomycin) and imidazoles (miconazole, clotrimazole) probably have limited effectiveness, and aminoglycosides are toxic to epithelium, so they are not recommended. 53 According to the experience of the Moorfields Eye Hospita1,9 a combination of a biguanide and a diamidine, both of which are able to kill cysts, are the drugs of choice. Among the biguanides, 0.02% chlorhexidine and 0.02% polyhexamethyl biguanide (PHMB) are recommended. Diamines available in Europe are propamidine isethionate aJ1.d hexamidine (Desomedine, Chauvin, France).9 '

Treatment Protocol Hay and coworkers experienced success with the use of topical propamidine isethionate 0.1 % (Brolene, RhonePoulenc RoeI', Eastbourne, May and Baker, UK) and 0.02% chlorhexidine. Additionally, the combination of polyhexamethylene biguanide 0.02% (Cosmocil, Zeneca Pharmaceuticals, Wilslow, UK) with propamidine (Brolene) is a well-tolerated, nontoxic, and effective treatment. 54 Both drops are applied hourly day and night for 2 days. On days 3 to 6, medication is given hourly during the daytime OIily. Propamidine may generate epithelial toxicity, which is reversible with discontinuation of the drops for several days.54 Therapy is then reestablished on an individual basis with instillation every 3 hours and treatment continuing for 6 to 8 weeks after resolution of the inflammatory signs or after cessation of topical steroid therapy (if used) .55 Some authors recommend maintenance therapy once or twice daily for at least 1 year after the signs of active infection have resolved. 13 Other treatments include cycloplegia or oral flurbiprofen (50 to 100 mg) up to three times a day for analgesia and for treating scleritis when necessary.55

Topical Corticosteroids for Control of Inflammation Corticosteroids are usually not necessary in cases diagnosed early, as these will usually respond to antiamebic therapy. Fulcher and Dart do not recommend their· use until the patient has had 2 weeks with amebicidals. 9 Corti-

costeroids should be maintained until inflammatory activity is abolished. Antiamebic therapy should be continued at least 6 weeks after cessation of steroids. 9 Corticosteroids are effective for controlling pain and anterior chamber inflammation, which, if uncontrolled, eventually results in corneal perforation or secondary glaucoma. Until future studies clarifY the role of topical corticosteroids, their use in selected patients is justified. 56

Treatment of Scleritis, Limbal Inflammation, and Pain Nonsteroidal anti-inflammatory drugs (NSAIDs; flurbiprofen 50 to 100 mg three times a day) are effective in the treatment of limbal inflammation and scleritis. Scleritis may eventually become a severe complication, and oral steroids or oral cyclosporine A is necessary to control inflammation. In these cases, antiamebic treatment should be complemented with systemic triaconazole. 9 Pain usually responds to NSAIDs or corticosteroids. 9 For intense discomfort, narcotics may be required, and there are reports of modified retrobulbar injection of alcohol to achieve adequate analgesia. 12

Surgical Cryotherapy

Keratoplasty

Epithelial debridement may enhance the medical therapy for Acanthamoeba keratitis. Penetrating keratoplasty is indicated only in patients with vision-impairing corneal scarring once the infection has been resolved and there is no sign of active inflammation.13, 57 Graft survival is excellent for quiet eyes. 57 In addition, keratoplasty is indicated when active inflammation and infection are present as a therapeutic effort to preserve eye integrity and to treat corneal perforation. 9, 57 In these cases, cryotherapy should be performed with a freeze-thaw-refreeze of the peripheral host cornea. 58 Medical antiamebic treatment and topical steroids should be maintained. 9 Recurrences are common and typically result in graft failure. 57 Asymptomatic carriers can be treated with luminal agents such as iodoquinol, 650 mg three times a day for 20 days, diloxanide, or paromomycin (500 mg three times a day for 10 days). Acute colitis has a good prognosis when treated with metronidazole (750 mg by mouth for 5 to 10 days) and luminal agents. Liver abscesses can be treated with metronidazole, tinidazole, or ornidazole along with luminal agents. l l Because 85% of Acanthamoeba keratitis cases occur in contact lens wearers, preventive measures target these individuals and the eye care practitioners involved in contact lens fitting. 9, 13 Successful prevention depends on the compliance of patients with the proper use and care of contact lenses, including the disposal of single-use lenses after each wearing. 8 Preventive action should be taken in all steps of contact lens use: hand washing, lens cleaning, lens disinfection, rinsing, and storage. Proper cleaning removes debris and bacteria and reduces the risk of amebae adhesion. 13

CHAPTER 34: FREE-LIVING AMEBAS AND AMEBIASIS

Most commercially available solutions, used at appropriate concentrations and times, are effective in killing Acanthamoeba,13 but disinfection with wet heat or hydrogen peroxide in two steps, with 4 hours of disinfection followed by neutralization with a catalytic agent, is recommended. 9 Hydrogen peroxide 3% in one step is not enough to kill cysts and trophozoites and chloride solutions kill only bacteria and trophozoites but not cysts, so they are not recommended. 9 Disinfected contact lenses can be recontaminated if the wearer uses homemade saline solutions that contain tap water or nonpreserving saline solution in a squirt bottle. It is preferable to preserve rinse solution or nonpreserving solution in an aerosol container. In addition, contact lenses can be contaminated by exposure to water while swimming, bathing, or using hot tubs. Contact lens cases are an important reservoir of Acanthamoeba and bacteria. Aggressive cleaning of all surfaces of these cases with very hot water, followed by air drying, can eradicate trophozoites and cysts. 9 Contact lens wearers should consider replacing cases often.

PROGNOSIS One of the most important causes of poor visual outcome is late diagnosis, causing delay in the delivery of specific therapy.12 Bacon and colleagues reported that all eyes treated within 1 month of the onset of symptoms had final visual acuity of 20/40 or better, whereas only half of patients who received treatment late in the course of infection achieved visual acu~ty of 20/40. 9,12,59 The chances of treatment success are reduced with inadequate treatment and the use of topical steroids before diagnosis. 9 Good prognosis after keratoplasty is possible only if the eye is quiet prior to surgery. When inflammation is persistent and remains untreated, cataract and glaucoma are present in 57% of cases and surgical treatment has a poor outcome. 59

CONCLUSIONS Acanthamoeba keratitis is a disease that has been observed

for the last two decades, and it is now recognized worldwide. Ocular infection remains difficult to diagnose and treat. Preventive actions should be taken by contact lens wearers, who are most commonly affected by the disease. Additionally, ophthalmologists should consider Acanthamoeba early in any case of atypical keratitis, because early diagnosis and treatment can greatly improve recovery and visual outcome. Diagnosis can be simplified with the use of confocal microscopy and PCR techniques. Until the discovery of better antibiotic treatments, early and aggressive use of biguanides and management of the associated inflammation should be the standard treatment.

References 1. Diccionario de la Lengua Espanola. Real Academia Espanola. Madrid, Espasa-Calpe, 1992. 2. Alizadeh H, Niederkon JY, McCulley jP: Acanthamoebic keratitis. In: Pepose jS, Holand GN, Wilhemus KR, eds: Ocular Infection and Immunity. St. Louis, Mosby, 1996, pp 570, 1062-1071. 3. Sanahan jF, ed: Bailey & Scott's Laboratory Methods for Diagnosis of Parasitic Infections. St. Louis, Mosby-Year Book, 1994, pp 776861.

4. Castellani A: An amoeba found in cultures of yeast: Preliminary note. j Trop Med Hyg 1930;33:160. 5. Visvesvara GS: Pathogenic and opportunistic free-living amoebae. In: Murray PR, ed: Manual of Clinical Microbiology. Washington, DC, ASM Press, 1995, p 1196. 6. jones DB, Robinson NR, Visvesvara CS: Paper presented at the Ocular Microbiology and Immunology Group Meeting, Dallas, TX; September 1973. Cited in: jones DB, Visvesvara GS, Robinson RN: Acanthamoeba polyphaga keratitis and Acanthamoeba uveitis associated with fatal meningoencephalitis. Trans Ophthalmol Soc UK 1975;95:22. 7. Nagington j, Watson PG, Playfair Tj, et al: Amoebic infection of the eye. Lancet 1974;2:1537-1540. 8. Schaumberg DA, Snow KK, Dana MR: The epidemic of Acanthamoeba keratitis. Where do we stand? Cornea 1998;17:3. 9. Fulcher T, Dart jKG: Queratitis pOl' acantomoeba. In: Duran de la Colina j, ed: Complicaciones de las Lentes de Contacto. Madrid, Tecnimedia Editorial, 1998, p 263. 10. McCuley jP, Alizadeh H, Niederhorn JY: Acanthamoeba keratitis. CLAO j 1995;21:73. 11. Reed SL: Amoebiasis and infection with free living amoebas. In: Braunwald E, Isselbacher Kj, Petersdorf RG,. et aI, eds: Harrison's Principles of Internal Medicine. New York, McGraw-Hill, 1994, p 883. 12. Frangie jP, Moore MB: Parasitic infections including Acanthamoeba. In: Leibowitz HM, Waring III GO, eds: Corneal Disorders. Clinical Diagnosis and Management. Philadelphia, W.B. Saunders, .1998, p 719. 13. Rutzen AR, Moore MB: Parasitic infections. In: Kaufman HE, Barron BA, McDonald MB, eds: The Cornea. Butterworth-Heinemann, 1998, p 311. 14. Rivera F, Medina F, Ramirez P, et al: Pathogenic and free-living protozoa cultured' from the nasopharyngeal and oral region of dental patients. Environ Res 1984;33:428. 15. Byers Tj, Bogler SA, Burianek LL: Analysis of mitochondrial DNA variation as an approach to systematic relationships in the genus Acanthamoeba. j Protozoal 1983;30:198. 16. Visvesvara GS: Classification of Acanthamoeba. Rev Inf Dis 1992;13:S3691. 17. Badenoch PR: The pathogenesis of Acanthamoeba keratitis. Aust N Zj OphthalmoI1991;19:9. 18. Stapleton F, Seal DV, Dart J: Possible environmental sources of Acanthamoeba species that caused keratitis in contact lens wearers. Rev Infect Dis 1991;13:390. 19. Cerva L: Acanthamoeba culbertsoni and Naegleria fowleri: Occurrence of antibody in man. j Hyg Epidemiol Microbiol Immunol 1989;33:99-103. 20. Stehr-Green jK, Bailey TM, Visvesvara GS: The epidemiology of Acanthamoeba keratitis in the United States. Am j Ophthalmol 1989;107:331. 21. Poggio EC, Glymm Rj, Schein OD, et al: The incidence of ulcerative keratitis among users of daily wear and extended wear soft contact lenses. N Englj Med 1989;321:779. 22. Mathers WD, Sutphin jE, Lane jA, Folberg R: Correlation between surface water contamination with amoeba and the onset of symptoms and diagnosis of amoeba-like keratitis. Br j Ophthalmol 1998;82:1143. 23. Osato MS: Parasitic keratitis and conjunctivitis. In: Smolin G, Thoft RA, eds: The Cornea. Boston, Little, Brown, 1994, p 253. 24. Yang ZT, Cao ZY, Panjwani N. Patll0genicity of Acanthamoeba keratitis carbohydrate-mediated host parasite interactions. Infect Immun 1997;65:439. 25. Cao Z, jefferson DM, Panjwani N. Role of carbohydrate adherence in cytopathogenic mechanisms of Acanthamoeba. j BioI Chem 1998;273:15838-15845. 26. Leher H, Silvany R, Alizadeh H, et al: Mannose induces the release of cytopathic factors from Acanthamoeba. Infect Immun 1998;66:510. 27. He YG, Niederkon JY, McCulley jP, et al: In vivo and in vitro collagenolytic activity of Acanthamoeba castellanii. Invest Ophthalmol Vis Sci 1990;31:2235. 28. Leher HF, Alizadeh H, Taylor WM, et al: Role of mucosal IgA in tlle cesistance to Acanthamoeba keratitis. Invest Ophth. Vis Sci 1998;39:2666. 29. Van Klink F, Alizadeh H, Stewart GL: Characterization and patho-

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45. Gardner LM, Mathers WD, Folberg R: New technique for the cytologic identification of presumed Acanthamoeba from corneal epithelial scrapings. AmJ Ophthalmol 1999;127:207. 46. Wilhelmus KR, Osato MS, Font RL, et al: Rapid diagnosis of Acanthamoeba keratitis using calcofluor white. Arch Ophthalmol 1986;104:1309. 47. Lehmann OJ, Green SM, Morlet N, et al: Polymerase chain reaction analysis of corneal epithelial and tear samples in the diagnosis of Acanthmnoeba keratitis. Invest Ophthalmol Vis Sci 1998;39:1261. 48. Nelson SE, Mathers R, Folberg R: Confirmation of confocal microscopy diagnosis of Acanthamoeba keratitis using polymerase chain reaction analysis. Invest Ophthalmol Vis Sci 1999;40:S263. 49. lilian N, Jarroll EL, Panjwani N, Paget TA: Proteases: A marker for differentiation of pathogenic and nonpathogenic Acanthamoeba. Invest Ophthalmol Vis Sci 1999;40:S262. 50. Varga JH, Rubinfield RS, Wolf TC: Topical anesthetic abuse ring keratitis. Report of four cases. Cornea 1997;16:424. 51. Kim JY, Choi YS, Lee JH: Keratitis from corneal anesthetic abuse after photorefractive surgery keratectomy. J Cataract Refract Surg 1997;23:447. 52. Alizadeh H, He Y, McCulley JP, et al: Successful immunization against Acanthamoeba keratitis in a pig model. Cornea 1995;14:180. 53. Varga JH, Wolf TC, Jensen HG, et al: Combined treatment with propamidine, neomycin and polyhexamethylene biguanide. Am J Ophthalmol 1993;115:466. 54. Hay S, Kirkness C: Successful medical therapy of Acanthamoeba keratitis with topical chlorhexidine and propamidine. Eye 1997;10:413-421. 55. Duguid GM, Dart JKG, Morlet N, et al: Outcome of Acanthamoeba keratitis treated with polyhexamethyl biguanide and propamidine. Ophthalmology 1997;104:1587. 56. Park DH, Palay DA, Daya SM, et al: The role of topical corticosteroids in the managl';ment of Acanthamoeba keratitis. Cornea 1997;16:277. 57. Flicker LA, Kirkness C, Wright P: Prognosis of keratoplasty in Acanthamoeba keratitis. Ophthalmology 1993;100:105. 58. Binder PS: Cryotherapy for medically unresponsive Acanthamoeba keratitis. Cornea 1989;8:106. 59. Bacon AS, Dart JKG, Fliker LA, et al: Acanthamoeba keratitis: The value of early diagnosis. Ophthalmology 1993;100:1238.

Ron Neumann

Giardiasis is an infection of the small intestine caused by the flagellated protozoan Giardia lamblia. It is associated mainly with diarrhea, malabsorption, and weight loss.

EPIDEMIOLOGY The pathogen is found in all climates and spreads by a variety of routes. Person-to-person spread in day care centers for children and nursing homes has been demonstrated. A common source of spread is contaminated water. Rarely, food contamination after cooking may also be associated with Giardia epidemics. Breakdowns of community water filtration systems have been associated with Giardia outbreaks in communities, and indeed, Giardia is the most frequent cause of waterborne diarrhea in the United States. Animal infections may also contribute to surface water contamination, posing risks for campers who are not mindful of the risk of drinking untreated water. Giardia is a frequent source of diarrhea in campers returning from endemic areas and travelers to areas where water treatment and hygienic practices are impeded. The incubation period is 7 to 21 days, so it is common for infected travelers to develop symptoms and require medical treatment seve~al weeks after returning home. This longer incubation period serves to distinguish giardiasis from more explosive diarrhea caused by toxigenic Escherichia coli and other forms of infectious traveler's diarrhea with shorter incubation periods. l , 2

The Organism The organism may exist as a motile, flagellated, pearshaped trophozoite, 12 to 15 mm in length, or as a toughwalled oval cyst. The organism has two nuclei with prominent karyosomes and four pairs of flagella with two ventral suckers. The cyst of the parasite is oval and measures 10 to 20 mm in its longest diameter. Each cyst has four nuclei but no flagella or suckers. On excystation, the organism becomes a trophozoite with two nuclei and starts dividing by binary fission. In the intestine, the trophozoites may either attach to the microvilli of the intestinal epithelium using an attaching disc or may be free in the mucus layer just above the epithelium. As the trophozoites are carried into the colon, they encyst and pass into the environment. The cysts are protected from many environmental hazards including chlorine concentrations typical to treated municipal water supplies. Ten to twenty-five cysts may be enough to infect a subject drinking contaminated water. The acidic environment of the stomach activates the cysts, which develop into trophozoites that cause active infection. Typically, Giardia do not leave the gut and do not penetrate extraintestinal tissues. The jejunum is the main site of infection. Infected jejunal mucosa ranges in appearance from normal to marked

subtotal mucosal atrophy with submucosal inflammatory cell infiltration, reduced villus height, and elongated crypts. Epithelial cells beneath overlying adherent tTOphozoites are deformed with blunting of the individual microvilli. Host humoral and cellular immune responses occur, but their roles in protection as well as pathogenesis are unclear. The increased prevalence of giardiasis in persons with immune deficiency syndromes argues for the role of immunity in host defense.

CLINICAL MANIFESTATIONS Infection can be asymptomatic. Clinical illness, however, is associated with some or all of the following: diarrhea, abdominal cramps, flatulence, nausea, excessive fatigue, bloating, anorexia, and chills. Reversible lactase deficiency and malabsorption of fat and vitamin B I2 have been documented. The infection is frequently self-limited, but a prolonged, indolent illness with progressive weight loss is possible.

DIAGNOSIS The diagnosis is established by observing cysts or trophozoites in stools or trophozoites in small bowel contents. The organism may be excreted in stool intermittently, and its identification may therefore be elusive. Repeated negative stool examinations may not rule out the diagnosis. Common practice dictates three stool specimens for a negative conclusion to be drawn. The small bowel contents may be sampled by tube aspiration or by passing a string that will absorb sufficient jejunal fluid for examination. Microscopic examination of a wet preparation of jejunal contents usually reveals motile organisms when infection is present. For extreme cases, small bowel biopsy may be performed. Hematologic values are normal. Occasionally, it may be justified to treat patients when clinical suspicion is high even when laboratory evaluations are repeatedly negative. Mepacrine hydrochloride, 100 mg three times per day for 5 to 7 days, or metronidazole, 400 mg three times per day for 5 days, is recommended by the British National Formulary. One course of treatment will suffice for most patients, but some need a second course. Treatment of infected persons in highly endemic areas is of questionable value because reinfection occurs readily when water supplies are contaminated. All infected persons in nonendemic regions should be treated. 3 , 4 (The general information on giardiasis is based on reference 4, which is also recommended for furtller reading.) Few investigators have suggested the association of giardiasis and ocular morbidity, supporting their claim with circumstantial data of simultaneous occurrence of Giardia in the stool and ocular disease. The ocular manifestations

35: GIARDIA LAMBLIA

may be secondary to hypersensitivity reactions to Giardia antigen, because the parasite has never been found in extraintestinal tissues. Anterior uveitis, choroiditis,5 retinal pigmentary socalled salt-and-pepper alterations 5,7 and ocular vitelliform macular lesions have been blamed on Giardia. Earlier publications associated chorioretinal edema and retinal hemorrhages to Giardia. s Relating an infectious agent to specific manifestations that occur remote from the infected tissues is extremely difficult. Furthermore it may be impossible when only a minor percentage of the infected population develops these manifestations of a possible hypersensitivity mechanism. Knox and associates 5 presented three patients with uveitis who did not respond well to corticosteroids. Two patients had hazy vitreous and yellow-white deposits around thickened retinal vessels with sheathing and iridocyclitis. The third patient had evidence of retinal arteritis without vitritis or anterior uveitis. Giardia lamblia was found in the stools of these patients. Only one of the three patients improved following combined antiparasitic and corticosteroid therapy. The authors presented a thorough review of the literature, including three French articles that also described various ocular manifestations such as macular edema, anterior uveitis, retinal hemorrhages, neuroretinitis, and vitreous hemorrhage presumed to be secondary giardiasis. One of the authors also described 18 additional patients seen by him with a wide variety of ocular manifestations (e.g., iridocyclitis, toxoplasma-like retinitis, retinal arteriti~ pars planitis, keratitis, episcleritis, exudative retinal detachment, amebic choroiditis, chorioretinal atrophy, and nutritional amblyopia) and positive Giardia stool tests. A major parameter not mentioned in this article is the prevalence of giardiasis in their population base that did not suffer from ocular manifestations. Also, the prevalence of giardiasis in their overall ophthalmic inflammatory disease patient base was not addressed. It can be argued that their presented data merely reflect widespread giardiasis in their area at the time of their publication with no definitive causative role of the parasite to the ocular disease. Two large controlled studies of ocular manifestations in Giardia-infected children originated in Italy.5, 7 In the first,5 ophthalmic evaluation was added to the medical examination of 90 children with symptomatic giardiasis. Ten patients had ocular manifestations. Eight of these children presented with a diffuse salt-and-pepper appearance of the fundus with retinal pigment epithelial involvement in the midperiphery of both eyes. In one of the eight children, atrophic areas of the retinal pigment epithelium were noted, as well as small, hard exudates in one eye. Of the remaining two children, one had evidence of chorioretinitis, and the other had hyperemia of the optic nerve head. Mter therapy, patients were followed for 1 year. The child with chorioretinitis improved and apparently recovered after additional treatment with systemic corticosteroids. The retinal pigment epithelial changes in the other patients remained the same. None of the additional 200 children with gastrointestinal symptoms unrelated to giardiasis had evidence of salt-and-pepper changes or any other ocular manifestations.

The second, more recent study? involved 141 children with active or past giardiasis diagi'losed on the basis of microscopic examination of stool specimens or duodenal secretions. Fifty-three children were newly diagnosed and were untreated, 50 had active infections in spite of metronidazole therapy, and 38 had been successfully treated, with negative stool specimens for 1 to 3 years. Salt-andpepper retinal changes were seen in 28 (19.9 %) of the patients (similar distribution of retinal changes was observed in the three patient groups). None of these patients had electroretinographic changes. Five pairs of siblings were found to have retinal changes. In all groups, children who had retinal changes were consistently younger than those with normal retinas. Active choroiditis or other foci of ocular inflammation were not observed in this series. The authors concluded that asymptomatic, nonprogressive retinal lesions are particularly common in younger children with giardiasis. This risk did not seem to be related to the severity of the infection, its duration, or the use of metronidazole but may reflect a genetic predisposition. Of importance is the fact that none of these children had ocular inflammatory manifestations. These two publications,5, 7 while clearly associating saltand-pepper retinal pigmentation to giardiasis, are much less supportive of the association of true ocular inflammation with Giardia infection. The pathomechanism of these pigmentary changes is not clear, and the role of inflammation in their evolution is questionable. The fact that the original observation was repeated only in a few case reports despite the worldwide distribution of Giardia infection raises doubt as to the conclusion made in some publications referring to Giardia as a causative agent of ocular inflammation. A typical case presented in the Hebrew literature 9 describes a 24-year-old man diagnosed with unilateral acute anterior uveitis that responded poorly to topical and systemic corticosteroid therapy. On admission, examination of the left eye was remarkable for a moderate anterior inflammatory response without structural alterations. The vitreous was clear, but macular edema and partially pigmented nasal choroidal focus of inflammation were observed. Repeated stool tests were notable for the finding of Giardia cysts. The authors did not observe any response to systemic and topical steroid therapy until metronidazole was added to the therapeutic regimen. The exact regimen of systemic steroids in the first two weeks of therapy was not specified, and it can be argued that boosting the dose of oral prednisone to 60 mg in the last week resulted in effective anti-inflammatory treatment. Moreover, follow-up was limited to 3 months. These limitations make it difficult to assess the role of the intestinal infection in the development of the uveitis. Despite these limitations it should be noted that ocular inflammation is common in a variety of intestinal diseases. Uveitis associated with inflammatory bowel syndromes is well known. Also infectious intestinal diseases such as Shigella, Yersinia, Klebsiella, and Salmonella may be followed by Reiter's syndrome. The possible alteration of the normal role of the gut in the induction of immune tolerance in chronic intestinal infections may explain extraintestinal hypersensitive responses. Thus, it can be

CHAPTER JS: GIARDIA

concluded that although theoretical background does exist to support the causative association of Giardia intestinal infection and ocular inflammation, actual data to support this point are scarce. In our view, the current knowledge does not justify the routine testing for Giardia cysts in the stool of all chronic uveitis patients. It may be justified in those idiopathic cases in which diagnosis does not become apparent despite repeated testing for all other uveitis etiologies relevant for the case and any sort of gastrointestinal symptoms exist. It may also be considered for those patients who do not respond to corticosteroids and for travelers to endemic areas. Duodenal biopsy and culture should be reserved only for those who present with gastrointestinal complaints compatible with the diagnosis of giardiasis. It may also be justified for uveitis patients with idiopathic salt-and-pepper retinal changes. Treatment should be reserved for those patients who are positively diagnosed with the parasite.

LMIVIDB.-SM

References 1. Flanagan PA: Giardia-diagnosis, clinical course and epidemiology. Epidemiol Infect 1992;109:1. 2. Hopkins RS, Juranek DD: Acute giardiasis: An improved clinical case definition for epidemiologic studies. Am J Epidemiol 1991;133:402. 3. Sullivan PS, DuPont HL, Arafat RR, et al: Illness and reservoirs associated with Giardia lamblia infection in rural Egypt: The case against treatment in developing world environments of high endemicity. AmJ Epidemiol 1988;127:1272. 4. Cecil RL, Bennett JC, Plum F: Cecil Textbook of Medicine. Philadelphia, WE Saunders, 1996. 5. Knox DL, King J Jr: Retinal arteritis, iridocyclitis, and giardiasis. Ophthalmology 1982;89:1303. 6. Mantovani PM, Giardino I, Magli A, et al: Intestinal giardiasis associated with ophthalmologic changes. J Pediatr Gastroenterol Nutr 1990;11:196. 7. Corsi A, Nucci C, Knafelz D, et al: Ocular changes associated with Giardia lamblia infection in children. Br JOphthalmol 1998;82:59. 8. Caroll ME, Anast BP, Birch CL: Giardiasis and uveitis. Arch Ophthalmol 1961;65:775. 9. Gelfer S, Scharf J, Zonis S, Mertzbach-D: Acute uveitis associated with Giardia lamblia infection. Harefuah 1984;107:75.

Tomas Padilla, fr.

DEFINITION Trypanosomiasis is a protozoal parasItIc infection that includes two varieties: Mrican trypanosomiasis, also called sleeping sickness, and Chagas' disease or American trypanosomiasis. Trypanosomiasis is caused by Trypanosoma brucei rhodesiense in tropical East Mrica and by T. brucei gambiense in West and Central Mrica. Mrican trypanosomiasis is transmitted by the bite of an infected tsetse fly found only in that continent. Chagas' disease is caused by Trypanosoma cruzi and is spread by blood sucking triatomine insects. Trypanosomiasis is a systemic illness characterized early on by enlargement of the lymph glands and progresses to involve many different organ systeills. The end organ most frequently involved in Mrican trypanosomiasis is the central nervous system (CNS), whereas in Chagas' disease, the heart and hollow viscera are most often affected.

HISTORY Mrican trypanosomiasis has been known in West Mrica since records were kept approximately 600 years ago and had been known in the early days of the slave trade. 1 It is believed that the gambiense variety~is evolutionarily older than the rhodesiense subspecies. 2 There are two theories on the evolution of the two subspecies. One holds that rhodesiensedeveloped as the gambiense variety spread southeastward. Another holds that T. b. brucei and T. b. rhodesiense developed independently from a common ancestor. 3 The Brazilian physician Carlos Chagas first reported American trypanosomiasis in 1909, although the disease had also been around for centuries. Chagas' disease was originally an infection of wild animals of the American continent with apparently multiple foci. It became a zoonosis when the reduviid insect vectors adapted to human dwellings. 4 In humans, the disease is present from Chile to the United States.

EPIDEMIOLOGY Mrican trypanosomiasis is transmitted cyclically by various species of Glossina (tsetse fly) and by other blood sucking Diptera during epidemics. Natural populations of Glossina are generally resistant to infection by T. brucei, and only the parasites that have invaded the salivary glands of Glossina are infective to mammals. Human trypanosomiasis is restricted to the tropics, where annual rainfall exceeds 500 mm. The Western form, caused by T. brucei gambiense, has a range that includes the tropical rain forests and surrounding savanna. The other form, caused by T. b. rhodesiense is restricted to the eastern third of Mrica from the northern boundary of South Africa to Ethiopia. It caused major depopulation in many East Mrican regions early in the 20th century and was practically eliminated during the years 1960 to 1965. From 1970 onward, there occurred a major recrudescence in most of· the old foci, and prevalence levels in the mid

1990s were similar to those of the 1930s, especially in countries like Angola and the Democratic Republic of Congo. The number of reported cases in 1995 was 25,000. However, because 55,000,000 people are exposed to the risk of infection and only 4,000,000 are under surveillance, it is estimated that the number of cases is in the vicinity of 300,000 to 500,000. 5 The disease is also epidemic in Sudan and Uganda. It is endemic in Cameroon, the Central Mrican Republic, Chad, Congo, Cote d'Ivoire, Guinea, and Tanzania,. where its prevalence is increasing. 6 Human Mrican trypanosomiasis is focal and rural. Humans are the principal reservoir of infection of T. b. gambiense, whereas domestic cattle and wild animals are more iIllportant reservoirs of T. b. rhodesiense. It is estimated that 16 to 18 million people are infected with Chagas' disease, and of these, 50,000 die each year. Most T. cruzi infections are located in 21 endemic countries of Central and South America, where 100 million people, or 25 % of the population, are at risk of contracting the disease. Chagas' disease is transmitted in several ways in both rural and urban centers. The traditional rural pattern was changed by migration to the cities that occurred in the 1970s and 1980s. Humans and various species of wild and domestic animals constitute the reservoir and the triatomine insects are the vectors. These blood-sucking insects find a favorable habitat in the crevices, walls, and roofs of the houses of the poor in rural areas and urban slums. Another mode of transmission is through the use of unscreened blood for transfusions; the incidence of contamination with T. cruzi is between 1.7% and 53.0% in blood banks in some selected cities of Central and South America. 7

African trypanosomiasis begins with the painful bite of a tsetse fly that produces a chancre after 1 to 2 weeks. Several weeks later, other symptoms such as fever, rashes, myalgias and joint pains, headaches, extreme fatigue, and swelling of the hands and periocular areas occur. Winterbottom's sign, prominent supraclavicular or posterior cervical lymphadenopathy, may be seen. As the illness progresses, weight loss is common. In more advanced stages, the parasite invades the central nervous system. When this happens, personality changes, irritability, loss of concentration, dysarthria, gait disturbances, and seizures can occur. Sleep disturbances in the form of insomnia and daytime drowsiness, from which the disease derives its name, are common. If the condition is left untreated, death occurs within several months to years after infection. S Daniels first reported ocular lesions attributed to human Mrican trypanosomiasis in 1915. 9 These lesions consist of a bilateral, diffuse interstitial keratitis accompanied by neovascularization affecting all layers of the cornea, a

CHAPTER 36: TRYPANOSOMIASIS

mild iritis, and periocular congestion. Severe scarring and corneal necrosis may evolve in some cases. They were later noted to be due to other causes such as the toxic effects of trypanocidal drugs or concurrent conditions such as onchocerciasis and trachoma. 10- 13 Various animal studies involving dogs, cats, and other domesticated animals demonstrated ocular lesions due to different species of Trypanosoma in the form of corneal opacities, blepharitis, conjunctivitis, and keratitis. 14 In his 1974 study, Ikede reported that sheep infected with T. brucei developed lesions in the lids, conjunctiva, cornea, retina, optic nerve and extraocular muscles, and he found organisms in the aqueous and interstitial tissues surrounding the eye. The most dramatic clinical change though, was found in five animals 1 to 3 weeks before death. This consisted of bilateral hypopyon visible through an intact cornea. This hypopyon appeared as a milky white exudate that covered the pupil and progressed to fill the entire anterior chamber. This change was associated with lacrimation and photophobia. Similar changes were noted in the anterior chambers of cats infected experimentally with T. brucei in a study done by Mortelmans and Neetens in 1975. 15 Chagas' disease, on the other hand, starts after the bite of a reduviid insect that has become infected following a blood meal from another animal or person already affected by the disease. The victim frequently rubs the site of the bite and smears insect feces containing the parasites into the bite wound, open cuts, the eyes, and other mucous membranes. Often, an insectbite is not necessary to contract the disease. NumerCfus insects present in the ceilings and rafters of domiciles can drop feces into the mouths and eyes of people who are sleeping or facing upward. Romaiia's sign, or local perioi-bital swelling at and around the site of a bite where insect feces was rubbed into the eye, was first described in Argentina by Cecilio Romana in 1963. 16 Other routes of transmission include congenital transmission, infection at parturition, ingestion of infected breast milk or uncooked food contaminated with insect feces, or by blood transfusions and organ transplantation. There are three recognized stages of Chagas' disease. 17 The most recognizable manifestation of the acute stage is Romaiia's sign. Other signs and symptoms at this time may include fatigue, fever, loss of appetite and vomiting, rashes, lymphadenopathy, and hepatosplenomegaly. Infants and very young children can develop cerebral edema leading to increased intracranial pressure and death. Symptoms of the acute stage occur in 1 % of cases, last for 4 to 8 weeks and disappear, even without treatment. The intermediate stage occurs 8 to 10 weeks after infection, during which time people are asymptomatic but demonstrate antibodies to T. cruzi and often the presence of low-level parasitemia. Ten to twenty years after infection, signs and symptoms of the chronic stage may appear in some individuals. Most commonly, these include cardiomyopathy and heart failure or enlargement of the upper and lower digestive tract (megadisease) producing constipation and dysphagia. Koberle in 1974 suggested that the dilatation and elongation of sections of the gastrointestinal tract and cardiomyopathy associated with the chronic stage had a neurogenic origin

through denervation from the destruction of sympathetic and parasympathetic ganglia. IS The eye is an important portal of entry for T. cruzi into the body. However, other than Romaiia's sign, there have been few reports of ocular lesions associated with Chagas' disease. In 1997, Frohlich and colleagues reported, that out of 79 chagasic patients, only six had parafoveal retinal pigment epithelial defects and one case had distinct pigment epithelial atrophy.19 These lesions did not cause a significant loss of vision. In a follow-up study in 1998, they reported another two patients out of 23 who showed intraocular manifestations. These consisted of one case of fibrae medullares and one case of pigment dispersion. They concluded that the intraocular findings associated with Chagas' disease were rare, harmless postinflammatory changes. 2o

PATHOLOGY Mter skin inoculation through the bite of the Glossina fly, Mrican trypanosomes multiply in the subcutaneous tissues. From there, they proceed to the blood and lymph nodes, during which time they multiply exponentially for 1 to 3 days. They then disappear from the blood stream but then recover to produce successive waves of parasitemia. This phenomenon is possible because of antigenic variation wherein the parasite is able to evade the immune system of the host by producing different, variable glycoprotein surface antigens during each successive wave of parasitemia. 21 The clinical symptoms accompanying each bout of infestation correspond to malarialike symptoms and influenza, with fever occurring at the height of the parasitemic wave. 22 The immune response to trypanosomal antigens is massive, sometimes with detrimental side effects to the host. The most prominent feature is the increased concentration of serum IgM due to the sequential production of early antibodies against the various surface antigens. Circulating IgG-antigen complexes are also found repeatedly during the course of infection resulting in immune lysis of the parasite. A 41- to 46-kDA molecule called trypanosome-released lymphocyte triggering factor may selectively activate CD8 + T cells to produce interferon-gamma that activates macrophages but may concurrently promote parasitic multiplication. Macrophages also bind and destroy parasites in the presence of antibodies. They synthesize large quantities of tumor necrosis factorex. (TNF-ex.), which promotes parasite destruction but at the same time increases the severity of clinical symptoms. In addition to cytokines and prostaglandins, macrophages also produce antiparasitic nitric acid, which also induces immunosuppression. 23 Other immunologic findings associated with the disease include high levels of rheumatoid factor, heterophile antibody and the presence of many autoantibodies, especially anti-liver and anti-Wassermann antibodies. 22 One of the effects of macrophage-released substances is the alteration in the permeability of the blood-brain barrier. Trypanosomes and inflammatory cells then invade the meninges through the cerebrospinal fluid to produce a progressive meningoencephalitis with perivascular cuffing with histiocytes, lymphocytes, and plasmocytes. Using magnetic resonance imaging (MRI), the

CHAPTER 36: TRYPANOSOMIASIS

spread can be traced from the meninges to the choroid plexus and periventricular ependymal cells,24 and the tuberoinfundibula and thalamic-hypothalamic areas. This area of involvement accounts for the disruption in the normal sleep-wake cycle and hence the name, sleeping sickness. Antibodies to CNS components like galactocerebrosides, neurofilaments, and tryptophane are seen in cerebrospinal fluid, and their presence offers a link to the profound demyelination found in the late stages of the disease. 23 Sabbah and associates 24 reported late cortical and subcortical atrophy in one. patient but did not mention any visual disturbances. The pathology caused by T. cruzi in Chagas' disease is somewhat different from that caused by T. brucei.. Lesions in the CNS are not prominent except in infants, young children, and immunodeficient patients, and most can be found in the peripheral nervous system, specifically the ganglia. This process leads to organ dilatation, producing megaviscera and cardiomegaly.25 Koberle noted that the total number of ganglion cells in the heart, colon, and esophagus of chagasic patients was significantly less than that of nonchagasic patients or chagasic patients whose organs were not involved. He also noted that the organ that is more frequently innervated, the heart, is the one most often involved. I8

DIAGNOSIS The preliminary diagnosis of trypanosomiasis may sometimes be made clinically by obtaining a detailed history and physical examination, with specia'F emphasis on travel to or residence in an endemic area and noting any conspicuous lymphadenopathy. Definitive diagnosis is based solely on the presence of trypanosomes through analysis of blood, cerebrospinal fluid, or the biopsy of a chancre, if one is present. In the field, the card agglutination test for trypanosomiasis (GATT) is most often used as an antibody-screening test. This test is performed using a drop of freshly collected heparinized blood. 26 The blood samples that screen positive may then be subjected to further tests such as examination of thick blood films, the use of microhematocrit centrifugation, and miniature anion exchange chromatography and polymerase chain reaction (PCR) .27 Others have suggested that the quantitative buffy coat (QBC) technique, developed for the diagnosis of malaria, may also be another test suitable for in-field screening programs. 28 Lejon and colleagues29 have proposed the use of a semiquantitative enzyme-linked immunosorbent assay (ELISA), using the variable surface glycoprotein of T. b. gambiense as antigen for the detection of antibodies, mostly IgG1, IgG3, and IgM isotypes, in serum and cerebrospinal fluid in determining the clinical stage of sleeping sickness. 29 Also, others have recommended that in poorly equipped laboratories, the diagnosis of CNS involvement can be confirmed by the pleocytosis and elevation of cerebrospinal fluid total protein and IgM levels. 30 The diagnosis of acute Chagas' disease is achi~ved in a manner similar to that of sleeping sickness, with direct microscopic examination of anticoagulated blood or a QBC preparation for mottle trypanosomes. History and physical examination are important, especially in the differential diagnosis of organ dilatation in the chronic

stage. Serologic tests such as immunohemagglutination, indirect immunofluorescence assay, and ELISA31 may be performed to detect the presence of parasite-specific immunoglobulin. Gomes and associates 32 showed that an optimized PCR protocol was very sensitive in detecting the presence of T. cruzi in chronic chagasic patients compared with hemoculture and complement mediated lysis. However, because of different end-organ involvement in Chagas' disease as compared with sleeping sickness, the analysis of cerebrospinal fluid is not as crucial.

TREATMENT There are only a few established drugs today used to treat trypanosomiasis, and most of them were discovered more than 40 years ago. Their mechanism of action is largely unknown except for eflornithine, which is a suicide inhibitor of ornithine decarboxylase. Drawbacks of these drugs include poor oral absorption, systemic toxicity, short duration of action, low efficacy, and the emergence of trypanosomalresistance. 33 Chemotherapy is one aspect of attempts to control morbidity and mortality in trypanosomiasis. Pentamidine and suramin are most often used for prophylaxis and treatment during the early stages of the disease when the CNS is not involved. 34,35 Another class of drugs belonging to the melaminyl group, represented by melarsoprol, is useful in treating all st~ges of trypanosomiasis and is the drug of choice when the CNS is involved. The World Health Organization recommends initial treatment with suramin, followed by three courses of melarsoprol. However, because of melarsoprol toxicity, 5% of treated patients develop arsenical encephalopathy that is often fata1. 23 In some studies, a 7-day intravenous course of eflornithine has been successful following a relapse after melarsoprol treatment failure. 36 Research on alternative trypanocidal drugs continues and some have reported that substrate analogs of 5'-Deoxy-5' (methylthio)adenosine or MTA show promise as novel drugs against trypanosomiasis. 37 Another front in the struggle for control of trypanosomiasis involves new technology, vector control and public health measures. Conditions that aggravate the problem include war and civil disturbances, economic problems with the dismantling of disease control programs, and reduced health financing owing to lack of funds. 38 Methods other than drugs currently used to help control the spread of the disease include the breeding of trypanosotolerant livestock and vector control through the use of insecticides, traps, targets, and new bait technology. Some have offered the principle of integration as a means of controlling the spread of the disease: existent antitrypanosomal control measures consolidated and integrated with rural development and with control measures for other diseases. 39 Traditionally, Chagas' disease had no known safe and effective cure for the chronic stage and no drug destroys T. cruzi in vivo. 40 Recently, benznidazole was found to be effective in the treatment of the acute and early chronic phase of T. cruzi infection. The antitrypanosomal activity of benznidazole stems from its inhibition of ergosterol synthesis. Studies in 1996 confirmed the efficacy of benznidazole treatment at 5 to 8 mg/kg/day for a period

CHAPTER 36: TRYPANOSOMIASIS

of 60 days, which resulted in a 55.8% rate of negative seroconversion of specific antibodies.'ll,.42 However, a recent study showed that azole resistance in T. cruzi in vitro develops rapidly. 43 As previously mentioned, Mrican trypanosomiasis, if left untreated, causes meningoencephalitis in which sleep-wake cycle disturbances are prominent. In addition, there is progressive confusion, slurred speech, seizures, and gait disturbances. The parasites may reach the brain parenchyma through the choroid plexus orVirchowRobin spaces. 25 Other organ systems are also affected, and the patient may show hematologic abnormalities such as anemia, cardiovascular and endocrine disorders, and renal dysfunction. If the condition is allowed to progress, death inevitably results. The most common complication arising from treatment of trypanosomiasis is arsenic encephalopathy or post-therapeutic reactive encephalitis (PTRE). This occurs in 5% to 10% of patients treated with melarsoprol. 24 Ocular involvement manifesting as a bilateral, diffuse, interstitial keratitis has been described as a rare manifestation of· sleeping sickness. 9 Chagas' disease affects primarily the ganglion cells of the upper and lower digestive systems and the heart, resulting in megaviscera and cardiomegaly. Current treatment offers limited success, especially if it is started late in the chronic stage. Most cases of death from Chagas' disease result from heart failure. As mentioned earlier, reports in the literature of ocular involvement other than Romafia'ssign are rare; they comprise mostly retinal pigme~t epithelial defects that have no bearing on visual functioning.

CONCLUSION Trypanosomiasis is a public health concern of epidemic proportions in certain regions of tropical Mrica. It has shown a resurgence during the past 20 years such that its prevalence has reached proportions not seen since the 1930s. It is mostly a meningoencephalitic process that causes large segments of affected populations to become nonproductive members of society; this happens when the parasite reaches the brain and causes the individual to become somnolent and withdrawn-hence, the term Mrican sleeping sickness. Treatlnent is available and can be effective if given early. Reports of ocular involvement in humans with trypanosomiasis were made mostly early in the 20th century, although they were later attributed to the effects of trypanocidal drugs or other parasitic infections. However, animal studies have shown that the parasite can invade intraocular structures and cause an intense uveitic reaction. American trypanosomiasis is caused by Trypanosoma cruzi and is most prevalent in sections of Central and South America. People living in thatched, adobe, or mud houses are at greatest risk for contracting the disease because these habitats offer the reduviid insects a favorable place to live and breed. In the eye, retinal pigment epithelial disturbances have been reported in patients with Chagas' disease but these disturbances are not known to contribute to visual impairment. Romafia's sign, characterized by intense periocular soft tissue inflammation at the site of inoculation by insect feces, is the most

visible sign of an acute infection that can still be treated. Unfortunately, not all Chagasic patients Inanifest this sign, and often, the disease progresses unnoticed until the chronic stage. In the acute stage, medications such as benznidazole offer some hope of a cure but little except symptomatic relief can be offered to those in the chronic stage.

References 1. Nash TAM: Mrica's Bane: The Tsetse Fly. Collins, London, 1969. 2. Baker JR: Speculations on the evolution of the family Trypanosomatidae Doflein. Exp Parasitol 1901; 13:219-233. 3. Baker JR: Epidemiology of African Sleeping Sickness. Symposium on Trypanosomiasis and Leishmaniasis. Venezuelan Academy of Sciences and La Trinidad Medical Center, Caracas, 1974. 4. Zeled6n R: Epidemiology, Modes of Transmission, and Reservoir Hosts of Chagas' Disease, Venezuelan Academy of Sciences and La Trinidad Medical Center, Caracas, 1974. 5. World Health Organization Communicable Disease Surveillance and Response. Mrican trypanosomiasis: The Disease (http:// 101010. who. int/emc/diseases/tryp/trypanodis. htm). Lyon, France, Department of Communicable Disease Surveillance and Response, World Health Organization, 2000. 6. World Health Organization Communicable Disease Surveillance and Response. Mrican trypanosomiasis: Geographical Distribution (http://www. who. int/ernc/diseases/tryp/trypanogeo. html). Lyon, France, Department of Communicable Disease and Surveillance, World Health Organization, 2000. 7. World Health Organization Division of Control of Tropical Diseases. Chagas Disease: Burdens and Trends ( http://www. who. intictd/chagas/ burdens.htm). Geneva, Switzerland, World Health Organizatiori, 2000. 8. Bryan R, Waskin J, Richards F, et al: Mrican trypanosomiasis in American travelers: A 20-year review. In: Steffen R, Lobel HO, Hayworth J, Bradley DJ, eds: Travel Medicine. Berlin, SpringerVerlag, 1989, pp 384-388. 9. Daniels CW: Eye lesions as a point of importance in directing suspicion to possible trypanosome infection. Ophthalmoscope 1915; 13:595-597. 10. Van den Branden F, Appelmans M: Les troubles visuels au COllI'S du traitement de la trypanosomiase humaine par la tryparsamide (tryponarsyl, trypotan, novatoxyl). Bruxelles Medical 1934; 15:1405-1421. 11. Scott JW: Eye changes in trypanosomiasis. Journal of Tropical Medicine and Hygiene 1944;47:15-17. 12. Ridley H. Ocular lesions in trypanosomiasis. Ann Trop Med Parasitol 1945; 39:66-82. 13. Debeir 0: Ocular disturbances and toxic amblyopia in the course of sleeping sickness. Bureau Permanent Interafricain de la Tse-Tse et de la Trypanosomiase No. 200/T 7pp. (Abstracted in Tropical Diseases Bulletin, 1953; 51:150-151). 14. Ikede BO: Ocular lesions in sheep infected with Trypanosoma brucei. J Comp Pathol 1974; 84:203-213. 15. Mortelmans J, Neetens A: Ocular lesions in experimental Trypanosoma brucei infection in cats. Acta Zool Pathol Antverp 1975; 62:149172. 16. Romaila, C: Enfermedad de Chagas, Buenos Aires, Lopez Libreros, Argentina, 1963. 17. Centers for Disease Control and Prevention. Chagas DiseaseAmerican trypanosomiasis ( http://www. cdc.gov/ncidod/dpd/pamsites/ chagasdisease/factshCchagas_disease.htm). Division of Parasitic Diseases, National Center for Infectious Diseases. Atlanta, Georgia, Centers for Disease Control, 1998. 18. Koberle, F. Pathogenesis of Chagas' disease. Symposium on Trypanosomiasis and Leishmaniasis, Venezuelan Academy of Sciences and La Trinidad Medical Center, Caracas, 1974. 19. Frohlich SJ, Mino de Kaspar H, Peran R, et al: [Intraocular involvement of Chagas' disease (American trypanosomiasis). Studies in Paraguay/South America.]. Ophtl1almologe 1997;94:206-210. 20. Frohlich SJ, Mino de Kaspar, H, Peran R, et al: [Eye involvement in Chagas disease (American trypanosomiasis). Studies in Paraguay 1996-1997]. Ophthalmologe 1998;95:168-171. 21. Vincendeau P, Okomo-Assoumou MC, Semballa S, et al: Immunol-

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22.

23. 24. 25. 26.

27.

28.

29.

30.

31.

ogy and immunopathology of Mrican trypanosomiasis. Med· Trop 1996;56:73-78. De Raadt P: Immunity and antigenic variation: Clinical observations suggestive of immune phenomena in Mrican trypanosomiasis. Symposium on Trypanosomiasis and Leishmaniasis, Venezuelan Academy of Sciences and La Trinidad Medical Center, Caracas, 1974. Dumas M, Bouteille B: Human African trypanosomiasis. C R Seances Soc BioI Fil 1996;190:395-408. Sabbah P, Brosset C, Imbert P, et al: Human African trypanosomiasis: MR!. Neuroradiology 1997;39:708-710. Chimelli L, Scarvalli F: Trypanosomiasis. Brain Pathol 1997;7:599611. Pansaerts R, Van Meirvenne N, Magnus E, et al: Increased sensitivity of the card agglutination test CATT/ Trypanosoma brucei gambiense by inhibition Of complement. Acta Trop 1998;70:349-354. Kanmogne GD, Asonganyi T, Gibson WC: Detection of Trypanosoma brucei gambiense in serologically positive but aparasitaemic sleepingsickness suspects in Cameroon, by PCR. Ann Trop Med Parasitol 1996;90:475-483. Ancelle T, Paugam A, Bourlioux F, et al: Detection of trypanosomes in blood by the Quantitative Buffy Coat (QBC) technique; experimental evaluation. Med Trop 1997;57:245-248. Lejon V, Bilscher P, Magnus E, et al: A semi-quantitative ELISA for detection of Trypanosoma brucei gambiense specific antibodies in serum and cerebrospinal fluid of sleeping sickness patients. Acta Trop 1998;69:151-164. Miezan TW, Meda HA, Doua F, et al: Assessment of central nervous system involvement in gambiense trypanosomiasis: Value of the cerebro-spinal white cell count.Trop Med Int Health 1998;3:571575. VasquezJE, KrusnellJ, Om A, et al: Serological diagnosis of T1-ypanosoma rangeli infected patients. A comparison of different methods and its implications for the diagnosis of Chagas' disease. Scand J Immunol 1997;45:322-330.

32. Gomes ML, Galvao LM, Macedo AM, et al: Chagas disease diagnosis: Comparative analysis of parasitologic; molecular and serologic methods. AnlJ Trop Med Hyg 1999;60:205-210. 33. Wang CC: Molecular mechanisms and therapeutic approaches to the treatment of Mrican trypanosomiasis. Annu Rev Pharmacol Toxicol 1995;35:93-127. 34. Dumas M, Bouteille B: Current status of trypanosomiasis. Med Trop 1997;57 (Supply) :56-69. 35. Doua F, Miezan TW, Sanon Singaro JR, et al: The efficacy of pentamidine in the treatment of early-late stage Trypanosoma bnle cei gambiense trypanosomiasis. Am J Trop Med Hyg 1996;55:586588. 36. Khonde N, Pepin J, Mpia B: A seven day course of eflornithine for relapsing Trypanosoma brucei gambiense sleeping sickness. Trans R Soc Trop Med Hyg 1997;91:212-213. 37. Bacchi Gj, Sanabria K, Spiess AJ, et al: In vivo efficacies of 5'methylthioadenosine analogs as trypanocides. Antimicrob Agents Chemother 1997;41:2108-2112. 38. Smith DH, Pepin J, Stich AH: Human Mrican trypanosomiasis: An emerging public health crisis. Br Med Bull 1998;54:341-355. 39. Holmes PH: New approaches to the integrated control of trypanosomiasis. Vet Parasitol 1997;71:121-135. 40. Peters W: Drug resistance in trypanosomiasis and leishmaniasis. Symposium on Trypanosomiasis and Leishmaniasis. Venezuelan Academy of Sciences and La Trinidad Medical Center, Caracas 1974. 41. Levi GC, Lobo 1M, Kallas EG, et al: Etiological drug treatment of human infection by Trypanosoma cruzi. Rev Inst Med Trop Sao Paulo 1996;38:35-38. 42. De Andrade AL, Zicker F, De Oliveira RM, et al: Randomized trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet 1996;348:1407-1413. 43. Buckner FS, Wilson AJ, White TC, et al: Induction of resistance to azole drugs in Trypanosoma cruzi. Antimicrob Agents Chemother 1998;42:3245-3250.

Isabelle Cochereau and Thanh Hoang-Xuan

The first case of histologically proven Pneumocystis cannii choroidopathy was reported by Macher and colleagues in 1987 in a patient with the acquired immunodeficiency syndrome (AIDS).l The number of new cases reported in patients infected with the human immunodeficiency virus (HIV) has increased but remained 10w. 2-4 The widespread use of P. cannii pneumonia (PCP) prophylaxis with oral trimethoprim-sulfamethoxazole led to a decrease, a few years later, in the incidence of P. carinii choroidopathy. The recent advent of highly active antiretroviral therapy (HAART), which restores immunity in HIV-infected patients, induced a sharp drop in the incidence of all AIDSassociated opportunistic infections, particularly PCP. However, it remains crucial not to misdiagnose P. cannii choroidopathy, because it is a sign of life-threatening disseminated infection that requires systemic therapy.

PCP is an opportunistic infection usually limited to the lungs. It occurs in immunodeficient patients, especially subjects infected by HIV. Historically, the huge rise in the incidence of PCP was one of the features that led to the description of the acquired imml.l:pe deficiency syndrome. PCP is by far the most frequent opportunistic infection in HIV-infected patients, and it is a diagnostic criterion for AIDS. 5 PCP has also been described in HIV-seronegative immunodeficient patients. Patients at risk for PCP are those with lymphocytic leukemia, l)'luphoma, hypogammaglobulinemia, and allogeneic bone marrow transplantation, and those on high-dose immunosuppressive therapies for cancer, transplantation, or immunologic disorders. 6 Extrapulmonary Pneumocystis carinii infection is located mainly in the lymph nodes and spleen, although cases of liver, bone marrow, gastrointestinal tract, heart, hard palate, th)'l"oid, and choroid involvement have been described. One case of Pneumocystis carinii infection of the orbiC and one case of infection of the conjunctivaS have been reported in patients with AIDS. Pneumocystis carinii choroidopathy has been reported only in HIV-infected patients, at an estimated incidence of only 1 % before the HAART era. 4 , 9, 10 Unlike PCP, which occurs at an early stage of the disease when the CD4+ T-lymphocyte count is about 200/mm 3 , the choroidopathy occurs in patients in the later stages of HIV infection, when the CD4 + T-cell count is less than 501 mm3 . 10 The life expectancy of patients with Pneumocystis carinii choroidopathy is usually only a few months. 9 , 11, 12

to infect distant organs, in particular the choroid. The incidence of Pneumocystis cannii choroidopathy has fallen sharply since the widespread introduction of systemic PCP prophylaxis with oral trimethoprim-sulfamethoxazole. Pneumocystis cannii is an opportunistic fungus of low virulence, found in the extracellular spaces 'of infected tissues. As no reliable serologic antigenic test is available, the diagnosis of PCP is based on the detection of the parasite in various specimens, usually bronchoalveolar lavage (BAL) fluid, with special stains (Comori methenamine silver and Ciemsa) or indirect immunofluorescence. BAL examination is occasionally negative in patients receiving prophylaxis with inhaled pentamidine.

Postmortem histopathologic examination of patients with Pneumocystis carinii choroidopathy has disclosed choroidal infiltrates containing eosinophilic, acellular, and foamy material,l, 11, 16 Electron microscopy shows many Pneumocystis carinii cysts and trophozoites in choroidal infiltrates.u

Pneu1Jwcystis carinii choroidopathy is usually discovered incidentally when routine fundus examination discloses one to several yellow-white plaquelike deep lesions (Figs. 37-1 and 37-2) located under the vessels. These are slightly elevated, round or polylobar in shape, they are 0.5 to 6 disc diameters in size,l, 9,11,13 and they become confluent. 16 They are located mainly in the posterior pole up to the equator, but they are never anterior to it. 9 In the absence of treatment, the leading edge of the infiltrate progresses at an estimated 0.5 disc diameter per month. 9 The choroidopathy is bilateral in 76% of patients. 9 Typically, these choroidal lesions induce no significant visual disturbances, even if they are located beneath the fovea. 9 However, visual acuity may be reduced when they

ETIOPATHOGENESIS In the AIDS setting, Pneumocystis carinii choroidopathy occurs mainly in patients who have received primary or secondary PCP prophylaxis with aerosolized pentamidine. 9 , 10,13,14 As aerosolized pentamidine does not diffuse systemically from the lungs, Pneumocystis cannii is able

FIGURE 37-1. Choroidal lesions due to Pneu11locystis cannii infection.

CHAPTER 37: PNEUMOCYSTOSIS

FIGURE 37-2. Pneumocystosis. Red-free photograph.

are associated with serous retinal detachment. 17 Visual field examination discloses a depression corresponding to the choroidal lesions. 9 Inflammation of the anterior chamber and vitreous is usually absent, in part because cell-mediated immunity is severely depressed. Fluorescein angiography of the lesions shows hypofluorescence in the early phases (Fig. 37-3), and homogenous staining associated with indistinct borders in the later phases (Fig. 37-4) .9,11,13,16

DIAGNOSIS The diagnosis of Pneumocystis carinii choroidopathy is based on clinical andangiographic signs, a history of progressive PCP or aerosolized prophylaxis, and the efficacy of presumptive therapy. Choroidal biopsy is not performed in patients with suspected Pneul1wcystis carinii choroidopathy, because of the risk of retinal complications.15 An extensive systemic work-up is mandatory when Pneumocystis carinii choroidopathy is suspected, including chest radiographs, liver function tests, arteriolar blood-gas measurements, lactic dehydrogenase assay, computed tomography of the lungs and abdomen, and BAL.

FIGURE 37-3. Pneumocystosis: Early phase of the angiogram. Hypofluorescence of choroidal lesions.

FIGURE 37-4. Pneumocystosis. Late phase of the angiogram. Hyperfluorescence of choroidal lesions.

The differential diagnoses include tuberculous choroiditis; toxoplasmosis; candidiasis; cryptococcosis; MycobacteriU1n avium-intmcellulare infection; lymphoma; histoplasmosis; systemic immunologic diseases such as sarcoidosis, Vogt-Koyanagi-Harada syndrome, and sympathetic ophthalmia; and inflammatory choroidopathies. 12 , 15 Distinguishing Pneumocystis carinii choroidopathy from tuberculous choroiditis can be particularly difficult, as tuberculosis and pneumocystosis both occur at an early stage of HIV infection, disseminate to the same distant organs, and induce no inflammation of the aqueous humor or vitreous. However, choroidal tuberculous lesions typically appear as elevated orange masses that can raise the vessels,18 they are round but not polylobular, and they are often smaller than the lesions caused by Pneumocystis carinii choroiditis; in addition, the former tend to increase in size and thickness, whereas the latter increase in surface area only. On the angiogram, late staining of tuberculous foci is less marked and less homogeneous than that of Pneumocystis carinii choroidopathy. The isolation of Mycobacterium tuberculosis from BAL specimens or other specimens is of value; otherwise, a therapeutic test should be performed. At the early clinical stage, toxoplasmosis might also be considered in the differential diagnosis. However, later in this disease, the signs rapidly become specific and differ from those of Pneumocystis carinii choroidopathy. Fundus examination discloses fluffy borders, satellite vasculitis, vitritis around the focus, and an inflammatory reaction in the vitreous and anterior chamber. 19 ,20 The angiograms show hyperfluorescence, starting at the borders of the lesion in the early phases and extending toward the center in the late phase. Concomitant central nervous system toxoplasmosis is frequent, whereas involvement of the lung is uncommon. Candidiasis is easily distinguished from pneumocystosis by its rapid extension from the lesion into the vitreous, and by inflammation of both the vitreous and the aqueous humor. The posterior lesions of progressive outer retinal necrosis (PORN) progress more rapidly, become confluent,

37:

eventually involve the whole retina, and profoundly compromise vision. 21 Mycobacterium, avium-intmcellulare choroidal lesions have not been clearly characterized. The mycobacterium has been identified as a pathogen together with Pneumocystis carinii in some lesions. 12 , 22 Choroidal lesions are rare in cryptococcosis. They occur in patients with generalized cryptococcosis or cryptococcal meningitis. L)'lllphoma induces lesions that are more yellow, lllore elevated, and thicker, and that have fluffier borders. The extraocular involvement is also different from that of pneumocystosis. 23 Histoplasmosis is rare and is found in patients who have lived in areas endemic for histoplasmosis. 24 The lesions are smaller, being less than one disc diameter in size. Other choroidopathies unrelated to HIV infection can occur, but their incidence is very low, especially in these immunodeficient patients who cannot mount a significant inflammatory reaction. Even if the ocular lesions are as)'lllptomatic, Pnewnocystis carinii choroidopathy necessitates systemic treatment because it is a marker of a disseminated life-threatening infection. Induction therapy comprises systemic trimethoprim (15 mg/kg daily) and sulfamethoxazole (75 mg/kg daily) or pentamidine (4 mg/kg daily)1jl for at least 3 weeks. 9 , 11, 13, 17 The high frequency of systemic adverse reactions to these drugs necessitates careful monitoring. During systemic therapy, the choroidal lesions become paler and disappear very slowly, after several weeks, leaving small pigmentary changes not associated with visual sequelae. 9 Secondary prophylaxis consists of oral trimethoprimsulfamethoxazole 25 for as long as the immunodeficiency remains severe. Primary prophylaxis, which is indicated for patients with low CD4 + T-cell counts, also consists of oral trimethoprim-sulfamethoxazole. 26 Aerosolized pentamidine should be used only as adjunctive therapy to prevent pneumocystosis in special cases. Prompt recognition of Pneumocystis carinii choroidopathy in HIV-infected patients is mandatory, as it is a sign of disseminated life-threatening infection. Its detection requires regular ocular examination because it is usually as)'lllptomatic. The incidence of Pneumocystis carinii choroidopathy is now very low because of routine primary pneumocystosis prophylaxis with oral trimethoprim-sulfamethoxazole, and because of the restoration of immunity produced by HAART. However, a further rise in its incidence may occur in the coming years if resistance to HAART increases.

References 1. Macher AM, Bardenstein DS, Zimmerman LE, et al: Pnewnocystis earinii choroiditis in a male homosexual with AlDS and disseminated pulmonary and extrapulmonary P caTinii infection. N Engl J Med 1987;316:1092.

2. Jabs DA: Ocular manifestations of acquired immune deficiency syndrome. Ophthalmology 1989;96:1092-1099. 3. Jabs DA: Ocular manifestations of HIV infections. Trans Am Ophthalmol Soc 1995;93:623-683. 4. Hodge WG, Seiff SR, Margolis TP: Ocular opportunistic infection incidences among patients who are HIV positive compared to patients who are HIV negative. Ophthalmology 1998;105:895-900. 5. Murray JF: NHLBI workshop summary: Pulmonary complications of the acquired immunodeficiency syndrome. Am Rev Respir Dis 1987;135:504-508. 6. Sekpowitz KA: Pneumocystis eaTinii pneumonia in patients without AlDS. Clin Infect Dis 1993;17(suppl 2):S416-422. 7. Friedberg DN, Warren FA, Lee MH, et al: Pnewnocystis eaTinii of the orbit. AmJ Ophthalmol1992;113:595-596. 8. Ruggli GM, Weber R, Messmer EP, et al: PneumoGystis eaTinii infection of the conjunctiva in a patient with acquired immune deficiency syndrome. Ophthalmology 1997;104:1853-1856. 9. Shami MJ, Freeman W, Friedberg D, et al: A multicenter study of Pnewnocystis choroidopathy. Am J Ophthalmol 1991;112:15-22. 10. Sha BE, Benson CA, Deutsch T, et al: Pneumocystis eaTinii choroiditis in patients with AlDS: Clinical features, response to therapy, and outcome. J Acquir Immune Defic Syndr 1992;5:1051-1058. 11. Rao AN, Zimmerman PL, Boyer D, et al: A clinical, histopathologic, and electron microscopic study of Pnewnocystis em-inii choroiditis. AmJ Ophthalmol 1989;107:218-228. 12. Morinelli EN, Dugel PD, Riffenburgh R, et al: Infectious multifocal choroiditis in patients with acquired immune deficiency syndrome. Ophthalmology 1993;100:1014-1021. 13. Dugel PD, Rao NA, Forster DJ, et al: Pneu'l7locystis eaTinii choroiditis after long-term aerosolized pentamidine therapy. Am J Ophthalmol 1990;110:113-117. 14. Sneed SR, Blodi CF, Berger BB, et al: Pneu'l7locystis em-inii choroiditis in patients receiving inhaled pentamidine. N Engl J Med 1990;322:936-937. 15. Freeman WR, GrossJG, LabelleJ, et al: Pneu'l7locysris eannii choroidopathy. A new clinical entity. Arch Opththalmol 1989;107:863-867. 16. Holland GN, MacArthur LJ, Foos RY: Choroidal PCP. Arch Ophthalmol 1991;109:1454-1455. 17. Foster RE, Lowder CY, Meisler DM, et al: Dnifocal presentation, regression with intravenous pentamidine, and choroiditis recurrence. Ophthalmology 1991;98:1360-1365. 18. Muccioli C, Belfort R: Presumed ocular and central nervous system tuberculosis in a patient with the acquired immunodeficiency syndrome. AmJ Ophthalmol 1996;212:217-219. 19. Holland GN, Engstrom RE, Glasgow BJ, et al: Ocular toxoplasmosis in patients with the acquired immunodeficiency· syndrome. Am J Ophthalmol 1988;106:653-667. 20. Cochereau-Massin I, LeHoang P, Lautier-Frau M, et al: Ocular toxoplasmosis in human immunodeficiency virus-infected patients. Am J Ophthalmol 1992;114:130-135. 21. Forster DJ, Dugel PD, Frangieh GT, et al: Rapidly progressive outer retinal necrosis in the acquired immunodeficiency syndrome. Am J Ophthalmol 1990;110:341-348. 22. Whitcup SM, Fenton RM, Pluda JM, et al: Pneu'l7locystis earinii and NIyeobaeterium avium-intmeellulare infection of the choroid. Retina 1992;12:331-335. 23. Rivero ME, Kuppermann BD, Wiley CA, et al: Acquired immunodeficiency syndrome-related intraocular B-cell lymphoma. Arch Ophthalmol 1999;117:616-622. 24. Specht CS, Mitchell KT, Bauman AE, et al: Ocular histoplasmosis with retinitis in a patient with acquired immune deficiency syndrome. Ophthalmology 1991;98:1356-1359. 25. Hardy WD, Feinberg J, Finkelstein DD, et al: A controlled trial of trimethoprimsulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis earinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med 1992;327:1842-1848. 26. Schneider MM, Hoepelman Al, Eeftinck-Sckattenkerk JK, et al: A controlled trial of aerosolized pentamidine or trimethoprimsulfamethoxazole as primary prophylaxis against Pnewnocystis carinii pnemnonia in patients with human immunodeficiency virus infection. N EnglJ Med 1992;327:1836-1841.

Tanana Romero-Rangel and C. Stephen Foster

Toxocariasis is an infectious disease caused by the invasion of tissue by larvae of Toxocara canis or Toxocara cati, nematode parasites commonly present in the small intestine of dogs or cats, respectively. The infection in humans is most frequently caused by T. canis. Toxocara larvae are capable of living in many "accidental" hosts, including man, who becomes infected from ingesting the ova from soil contaminated by dogs or cats. Toxocara larvae may migrate through the body, invading many different organs. Clinically, human infestation can take three different forms. The two classical expressions are visceral larva migrans (VLM) and ocular toxocariasis. The third clinical manifestation, described more recently, has been called covert toxocariasis. The severity of the disease varies with the number of larvae in the tissues and the immune response of the individual.

The Organism The biology aild morphology of T. canis and T. cati are similar. 1 Three lips around the mouth, a small intestinal tract, posterior excretory columns, and prominent cervical alae in both sexes are anatomic'Eharacteristics that are helpful for making the correct identification and differentiation from other parasites. They are similar to Ascaris lumbricoides in appearance but only a quarter to half its size; males are 7 to 9 cm and females are 10 to 17 cm long. Adult worms live in the small intestine of dogs and cats for around 4 months. Adult T. canis produces 200,000 eggs per day. Eggs of Toxocara are spherical, light brown, and protected by a thick, rough, proteinaceous coat with vitelline membranes. This coat may serve as protection for the larvae, allowing fertilized eggs passed in the feces to survive for months and even years. Development of the second-stage larvae takes 5 to 6 days under favorable conditions of temperature, humidity, and aeration.

Life Cydein Natural Host Dogs may acquire the intestinal infection in five different ways: (1) by ingestion of infective embryonated eggs with stage 1 larvae encapsulated inside, (2) by ingestion of infective second-stage larvae infesting the meat of a rodent, (3) by ingestion of advanced-stage larva from the feces or vomit of prenatally infected pups, (4) by transmammary passage of larvae in milk from a lactating bitch to nursing puppies, and (5) by transplacental migration. In cats, transplacental migration has not been proved. 2 The infective eggs, with first- and second-stage larvae, hatch in the intestine and liberate the third-stage larvae, which penetrate the intestinal wall. Once located in the intestinal wall, the larvae are able to reach the lymphatics and blood vessels, initiating the systemic migration. Toxocara larvae pass through the portal circulation and migrate via the liver and heart to alveolar capillaries. The

fate of ingested larvae depends on the age and immunity of the host. In puppies, which are more frequently infected, the larvae are able to complete a migratory and developmental cycle. The worms hatch and migrate through the portal system and undergo transtracheal migration. The third-stage larvae are coughed up and aspirated, and they mature into sexually differentiated forms in the small bowel. If the host is an older puppy or an adult dog, particularly with some immunity acquired from past infectiop, the larvae do not complete the lung migration. They wahder through the body, eventually becOlning inactive, encysting as second-stage larvae in the tissues. Inactive larvae may be reactivated when a bitch becomes pregnant; they reenter the circulatory system and are carried to the placenta. The larvae pass through the placenta and grow to adult worms in the pups. Most puppies acquire the infection prenatally. However, they generally expel the worms before reaching adulthood. The animal may be asymptomatic or suffer lack of appetite, abdomen enlargement, internal abscess, ec;:>sino.. philia, and toxocarid pneumonia. 3

Human Infestation Humans acquire the infection by eating contaminated soil (geophagia) containing Toxocara larvae, or by ingestion of contaminated meat. Children who eat dirt (pica) or who are in close contact with puppies are at particular risk of acquiring the disease. The larvae are not able to complete their normal life cycle in humans because they cannot migrate out of the human lungs to return to the intestine. As the adult worms do not develop in humans, examination of the stool for ova and parasites is unproductive diagnostically. In the human intestine, the second-stage larvae migrate through the intestinal wall and enter the bloodstream via the portal circulation, traveling then to small vessels of target organs, where they encyst. Once in the tissue, the larvae are encysted by a focal granulomatous reaction, where they can remain alive for months or even years. These granulomas are most commonly found in the brain, liver, lung, and eye.'!

CLINICAL MANIFESTATIONS The most frequently recognized clinical manifestation of Toxocara invasion is the VLM syndrome. The first case was reported by Beaver and colleagues,5 who demonstrated the presence of T. canis, by liver biopsy, in one child with chronic eosinophilia, cough, pulmonary infiltration, fever, and hepatomegaly. Since this initial study, it has been shown that the VLM is usually caused by the migration of second-stage T. canis larvae or, in some cases, by other nematodes. VLM is typically seen in young children (1 to 4 years of age) with a history of pica. 6 Generally, the course of the disease is subclinical, but it can be symptomatic with ~arious clinical manifestations and levels of severity. Varia-

38: OCULAR TOXOCARIASIS

tion in VLM presentations has been suggested to be caused by factors such as patient age, number of larvae ingested, distribution of larvae, and host response. When symptoms are present, general symptoms and clinical signs such as fever, coughing or wheezing, malaise, irritability, weight loss, hepatomegaly, and pruritic eruptions and nodules over the trunk and legs are commonly seen. During the acute stage, laboratory investigation may reveal leukocytosis from 30,000 to 100,000/mm3, with 50% to 90% eosinophils. Peripheral eosinophilia has been correlated with the parasitic burden of Toxocara larvae and canbe seen for months or years after the acute presentation. 7 Therefore, eosinophilia does not implicate, necessarily, an active process. Serum immunoglobulins IgG, IgM, and IgE are usually elevated. Interestingly, antiA and anti-B titers are positive in some c::hildren with VLM. This can be explained, probably, by' the presence of Toxocara antigens, which stimulate isohemaglutinins. s Chest radiographs may show pulmonary infiltrates. However, severe respiratory distress is rare. Central nervous system manifestations such as encephalitis, cerebral eosinophilic granulomata, and seizures (usually of the petit mal type) can be observed. Since most patients with VLM are asymptomatic, the prognosis is generally excellent. However, clinically manifest cases can leave permanent structural damage to the involved tissues. Additionally, in rare cases, death of patients with severe VLM can occur, usually secondary to central nervous system or myocardial involvement. Brown9 summarized 245 repli1rted cases of ocular T. canis. He identified ocular toxocariasis as an entity different from VLM, describing the course of the disease and the clinical presentation of each. Cases of ocular toxocariasis differ from classical VLM in that patients are generally older (mean age, 4 to 8 years) and healthy, and they usually have just one eye affected (often infected by one larva). Since inflammation may not be a prominent feature, the lesion is often discovered during an evaluation of leukocoria, strabismus, or decreased vision, or on routine examination. Ocular involvement is usually not present in cases of VLM, and VLM is rarely seen in cases of ocular toxocariasis. However, some cases of ocular toxocariasis have been reported as having symptoms of VLM.I0 Recently, some cases of irritable bowl syndrome have been attributed to toxocariasis. The diagnosis has been made based on the levels of leukocytes, eosinophils, and enzyme-linked immunosorbent assay (ELISA) titers, and it has been called covert toxocariasis. l l , 12

HISTORY Calhoun visualized a nematode larva invading the eye for the first time in 1937. 13 The localization of the larva on the lens allowed a clear identification of the larva as Ascaris. The clinical presentation was characterized by severe keratitis and iridocyclitis associated with secondary glaucoma and dislocation of the lens in the right eye of an 8-year-old child. The larva was found to be disintegrating, so an attempt to recover it intact was unsuccessful. Histopathology of the lesion of ocular toxocariasis was described prior to the recognition of its typical clinical

appearance. Wilder, in 1950, observed a comlnon inflammatory pattern characterized by an eosinophilic abscess surrounded by epithelioid and giant cells in 46 eyes, all of which had a similar clinical presentation with a white pupillary reflex. 14 These cases had been previously diagnosed as pseudoglioma, Coats' disease, endophthalmitis, and (in most cases), retinoblastoma. The pathologic findings Were of special interest because they appeared similar to those associated with helminth infections elsewhere in the body. Therefore, multiple sections of the tissue were obtained. Nematode larvae or their residual hyaline capsules were found in 24 eyes. The 22 remaining eyes had a similar pathologic appearance, but larval remnants were not found. Wilder named the entity nematode endophthalmitis. At that time, the larvae found in Wilder's series were believed to be a hookworm. It was not until 6 years later that Nichols,15 while reviewing this series, determined that the larvae present in five eyes were in fact T. canis. Ashton 16 reported the clinical and histopathologic findings of the· first four cases of ocular toxocariasis in Great Britain. The eyes had been enucleated because the fundus lesions appeared to be similar to those of retinoblastoma. Ashton described a distinct, second form of the disease characterized by a solitary retinal tumor with slight evidence of inflammation. In one of the cases, in addition to the retinal granuloma, an eosinophilic abscess within the anterior vitreous was detected, as in a previous case reported by Irvine and Irvine. 17 Ashton suggested that the diversity of the clinical. picture depended on the site of localization of the larva, the severity of the individual reaction, and the stage at which the eye was examined. He also commented on the importance and necessity of serial sections for histologic diagnosis in any eye of a young person having an unexplained granulomatous reaction, particularly with an eosinophilic component. Duguid identified T. canis larvae in tWo eyes, and fragments thought to be T. canis in four other eyes in histopathologic studies of patients with chronic endophthalmitis. 1S , 19 He emphasized the importance of suspicion for T. canis as a cause of chronic endophthalmitis in children, along with other known etiologic agents of chronic uveitis. In addition, he discussed the clinical features of the posterior retinal granuloma and chronic endophthalmitis, which were the two most common types of ocular lesions seen in association with ocular toxocariasis in 28 cases described at the Institute of Ophthalmology of London. 20 Subsequently, a variety of clinical presentations were reported. 20 , 21 Wilkinson and Welch 22 reported their experience with 40 patients having presumed or proven intraocular Toxocara, in which 17 patients, including one with bilateral involvement, had a peripheral inflamInatory mass on clinical presentation. They emphasized the importance of differentiating these lesions from congenital and developmental anomalies, as most of the patients in previous reports and in their series were children. O'Connor 23 discovered nine patients with peripheral retinal masses joined to the disc by retinal folds while studying 20 uveitis cases. He observed a tubelike structure under the retina, spreading from the disc to the periph-

)CUlAR TOXOCARIASIS

and thought that this clinico,:ific for Toxocara infection. Sub\dings such as hemorrhages, ffuse retinal lesions with assoutic atrophy, and narrowing ) been described. 24

"",.sIS is a common infectious disease, seen tIle world. Brown summarized 403 cases of _"rtoxocariasis reported in 73 papers from 19 countrles. 25 Most papers were reported from the United States (224), Great Britain (144), and Australia (7 cases). In the United States, the population of the southeastern area has been found to be at especially high risk for acquired toxocariasis. It is thought that the actual prevalence of ocular toxocariasis is higher than the reported prevalence in the literature. Factors such as lack of clinical suspicion, subclinical infection in a large number of patients, limited availability of ophthalmic pathologists, and the difficulty in identifYing the larvae in pathologic specimens in some cases are among the factors responsible for the underdiagnosis. Toxocara larvae have been found in both rural and metropolitan areas. It has been reported that 10% to 32% of soil samples collected from parks, playgrounds, and other public places in the United States are contaminated with Toxocara eggs. The incidence of infected puppies has been estimated to be from 33 % in London to 98% in Columbus, Ohio, to 100% i~Brisbane, Australia. 26 Contact with dogs, especially puppies, is a well-known risk factor for ocular toxocariasis. 6 However, some patients do. not have a history of exposure to dogs or cats. It is especially important, therefore, for the ophthalmologist to remember that the most common route of infection is the ingestion of soil contaminated with Toxocara larvae. The patient and parents must be questioned about possible geophagia. Although young children (4 to 8 years old) are more commonly affected, cases of adults with ocular toxocariasis have been reported. 27 , 28 Studies performed in different populations have shown a varied prevalence of seropositivity for Toxocara antibodies. Study of a group of 333 kindergarten children with no ocular or systemic manifestations of toxocariasis disclosed that 106 children (32%) had a positive antibody titer equal to or greater than 1:16 by ELISA assay, and 77 (23%) had titers equal to or greater than 1:32. 29 The large number of healthy children with positive titers for Toxocara in this study shows that the presence of a positive titer should be interpreted with caution, particularly in areas where toxocariasis is widely prevalent. For exaInple, an extremely high prevalence was found in a population from Reunion (an island in the Indian Ocean) ,30 in which the sera of 387 persons over 15 years old were analyzed by Western blotting using T. canis excretory-secretory larval antigens; 92.8% of the sera analyzed demonstrated positive Toxocara titers. Pollard and coworkers 31 found positive ELISA titers in 37 of 41 patients (90%) with suspected ocular toxocariasis. One of these patients, with a 1:16 positive ELISA titer, was found to have retinoblastoma upon enucleation. 32 This case underscores the importance of excludA/

ing retinoblastoma in patients who are seropositive for the Toxocara parasite, particularly in populations with a high prevalence of toxocariasis. For this reason, it is of extreme importance to perform a complete laboratory investigation, correlating serum ELISA titers with risk factors, clinical findings, and standardized echography, and to obtain aqueous and vitreous ELISA titers, to differentiate between these two entities.

IMMUNOPATHOLOGY Definitive diagnosis of ocular toxocariasis requires the identification of the larva. Unfortunately, in most specimens the organism has been entirely destroyed. Moreover, if the larva is present, multiple sections of the specimen may be required to find it. This is in part because of the small size of the organism (18 to 21 microns), approximately two to three times the size of a red blood cell. For this reason, a presumptive diagnosis may be made based on the characteristic tissue reaction. 33 The most common finding in enucleated eyes with ocular toxocariasis is a chronic sclerosing vitritis with a secondary total retinal detachment. Less commonly, Toxocara larvae produce a localized retinochoroidal lesion. The underlying retinal pigment epithelium (RPE) is generally involved, with atrophy, hyperplasia, and breaks in Bruch's membrane. The organism induces a focat necrotizing granulomatous inflammation with varying degrees of intraocular disorganization, characterized by an aggregation of eosinophils, epithelioid cells, multinucleated giant cells, plasma cells, and lymphocytes surrounding the larva or its remnants. Plasma cells are the most common inflammatory cell in the infiltrate (Fig. 38-1) . The presence of inflammation in the absence of the larvae or their remnants has suggested that secreted surface antigens are responsible for the inflammatory reaction. 34 The idea that there is production of localized antibody in ocular toxocariasis has been strongly supported by (1) the observation of higher antibody titers in vitreous and aqueous humor than in the serum, (2) the

FIGURE 38-1. Histopathology of chorioretinal granuloma in a patient whose eye was enucleated secondary to chronic endophthalmitis and irreparable retinal detachment, ultimately shown to be secondary to toxocariasis. Note the complete loss of choroidal or retinal architecture with the granulomatous inflammatory infiltrate. (See color insert.)

CHAPTER 38: OCULAR TOXOCARIASIS

presence of plasma cells in the infiltrate, and (3) a serum T. canis antibody detected by ELISA that is fourfold lower in patients with ocular infestation than in patients with systemic VLM. The. result may be a local production of small amounts of antibody in the eye, with subsequent lower circulating titers. 35 , 36 In addition, local antibody production has been suggested by the Goldman-Witmer coefficient in patients with ocular toxocariasis. The ratio is considered significant if it is above 4; any ratio less than 1 is considered negative, and between 1 and 4 is considered indeterminant. The Goldman-Witmer coefficient is represented by the following equation, in which AH is aqueous humor and VF is vitreous fluid: Antibody titer AH or VF X _T_o_ta_l_I.h1.g_G_AH __o_1_'VF_ Antibody titer serum Total IgG serum The Splendore-Hoeppli phenomenon denotes an eosinophilic precipitate that can be observed around the Toxocara larva. This phenomenon is not specific to the Toxocara organism, as it has been seen around certain other parasites. Rockey and colleagues 37 studied the interaction in culture of eosinophils and humoral factors from ascaridinfected guinea pig eye with second-stage larvae of Toxocara canis and Ascaris suum, which are closely related phylogenetically and antigenically. They observed that the eosinophils adhered firmly to the surface of the larvae, to a larval sheath, or to atta~hed eosinophils. Furthermore, they noted the presence of soluble factors in the anterior chamber that had been shown to be important for the adhesion of eosinophils to a parasite surface membrane, and for the cytotoxicity and killing of parasites by eosinophils in tissue culture. These factors include IgG, IgE, eosinophil stimulation prOluoter, complement, eosinophil chemotactic factor of anaphylaxis, tetrapeptides, histamine, hydrogen peroxide, and superoxide anions. The time of appearance of aqueous hUluor IgE antibody corresponded to a rapid increase in the intraocular eosinophil infiltrate after a single intraocular infection with second-stage larvae. 37 A strong hypersensitivity reaction with local IgE production, as well as the presence of eosinophils and antigenic stimulation in Toxocara parasitosis, were also found in a clinical study of patients with focal chorioretinitis clinically suggestive of intraocular parasitosis, who had undergone vitrectomy for retinovitreous complications. The values of IgE in two patients with ocular toxocariasis were extremely high (520 and 1074 mg/dl); the corresponding serum titers were 64 and 17, indicating local synthesis of IgE in the vitrectomy fluid. In other ocular parasitic infections, such as toxoplasmosis, high levels of IgE in the vitreous have not been observed. This illustrates that there are different immunologic responses for different parasitic agents in intraocular parasitosis.

common manifestation when syruptoms are present. Generally, the youngest children do not report visual changes, even if visual acuity is profoundly affected. Thus, diminished visual acuity is frequently detected in a routine examination. Other clinical manifestations such as strabismus and leukocoria are commonly observed. Toxocara larvae may involve diverse ocular tissues. The different forms of the ocular disease result from the same pathogenesis. The larvae reach the eye via the bloodstream and become encysted in the ocular tissues. The most commonly affected tissue is the retina, which is frequently affected by a granulomatous reaction located in the posterior pole or in the periphery.16 COffiluonly, posterior pole toxocariasis lesions are white or gray, round, and elevated (Fig. 38-2). The diameter is generally one or two disc diameters in size. They may be centered anywhere in the posterior pole, including in juxtapapillary and subfoveallocations. A crescent-shaped dark area, possibly representing a larva, is sometimes seen in the lesions. Depending on the number of larvae and the anatomic location, there may be minimal or luassive vitreous inflammation. The predominance of peripheral granuloma, which appears as a hazy, white, elevated reaction in the peripheral fundus, associated with retinal folds that may extend from the peripheral mass to the optic nerve head, has been observed in,some studies (Fig. 38-3). Gillespie alid coworkers 38 found a peripheral granuloma to be the most common finding. Wilkinson and We1ch 22 described peripheral involvement in 44% of eyes with ocular toxocariasis. The features observed in these cases are similar to those seen in pars planitis. 22 , 24, 39, 40 Hogan and coworkers 41 reported a case of a child with a diagnosis of uniocu'lar pars planitis, who had typical snowball exudates over the pars plana and in the vitreous. The child died of unrelated causes, and a microscopic examination of the eye was performed. The histopathologic findings showed eosinophils in the· vitreous and a Toxocara larva in the periphery of the retina. Based on these observations, it has been suggested that ocular toxocariasis should be excluded in cases of unilateral pars planitis, particularly in children.

VARIATIONS Intraocular infestation with T. canis is typically seen unilaterally in children with a history of contact with dogs or cats, or geophagia. The course of the disease is usually asymptomatic. Impairment of visual acuity is the most

FIGURE 38-2. Posterior granuloma, macular, in a patient with toxocara chorioretinitis. Exuberant vitritis has been controlled with systemic prednisone. (See color insert.)

CHAPTER 38: OCULAR TOXOCARIASIS

fiGURE 38-3. Peripheral retinitis and retinal detachment in a patient with a peripheral toxocara granuloma. This eye was eventually enucleated .and was the source of the histopathology shown in Figure 38-1. (See color insert.)

Another common manifestation of ocular toxocariasis is chronic endophthalmitis. 14,15 These cases are usually associated with retinal detachment, a low-grade anterior uveitis, posterior synechiae, and a cyclitic membrane between the detached retina and the lens. A hypopyon may develop in severe cases. 42 Papillitis, macular edema, vitreous exudates, and, more rarely, a retrolental mass have been associated findings as well. IS, 19, 42 In children, the most common causes of uveitis involving the posterior pole are Toxoplasma, nematodes, and cytomegalovirus.43 Perkins20 found toxocariasis to be a presumptive diagnosis in 15 of 150 cases (10%) of children with uveitis. A similar incidence has been found in other studies. 43 Additionally, scleritis secondary to Toxocara larva infestation has been reported. 24, 27, 3S, 39 In one study at the Massachusetts Eye and Ear Infirmary, 6 of 130 patients (4.6%) with scleritis had an infectious etiology,44 including a 70-year-old woman with a history of recurrent nodular scleritis. The diagnosis was presumed to be toxocariasis by the ophthalmoscopic findings, and this was subsequently confirmed by biopsy of the scleral nodule, which disclosed a chronic nongranulomatous inflammation with epithelioid cells in the infiltrate, and by antibody titers, which were positive in a 1:64 dilution. Less frequent presentations such as keratitis, optic neuritis, and motile larva are part of the broad spectrum of clinical manifestations seen in this entity.24, 39, 45

COMPLICATIONS Infestation of the eye by Toxocara may result in severely decreased visual acuity as a result of direct retinal injury, by the larva or by secondary effects related to inflammation and scarring. 46 The inflammatory response to the Toxocara larva may be intense enough to produce a connective tissue contraction and reduction of the vitreous volume, followed by traction of this tissue on the retina and choroid, often resulting in detachment of these structures. A cyclitic membrane may be formed extending into the anterior portion of the vitreous and along its anterior surface. Contraction of this membrane may result in detachment of the ciliary body and anterior choroid, with

subsequent impairment of ciliary body function and hypotony. The major causes of decreased visual acuity that have been reported include vitreous traction band, endophthalmitis, macular lesion, retinal detachment, pars planitis, and papillitisY In one study, clinical findings such as detached retina, peripheral fibrous mass extending from the optic disc, macular scarring, and changes of the optic disc were seen in asymptomatic patients with positive Toxocara titers. The association of these findings and seropositivity for Toxocara could be a coincidence; they also could represent the sequelae of ocular toxocariasis in patients who had subclinical inflammation. Amblyopia may also occur as a complication of toxocariasis, particularly when strabismus is present. 4S Toxocariasis was· found to be a common cause of amblyopia in a prospective study in which the etiology of uniocular blindness was analyzed.

DIAGNOSIS

Laboratory Investigations The diagnosis of ocular toxocariasis is based on the clinical findings and their correlation with serologic tests. Currently, the ELISA, which was introduced by Cypress and colleagues49 in 1977, is the most accurate available serologic test. A Toxocara excretory-secretory or exoantigen product is used as an in vitro test. 50 This test has been shown to be highly specific for Toxocara and does not have significant cross-reactivity with other helminthic parasites such as Ascaris. The sensitivity and specificity of the ELISA is approximately 90%. This means that even though 90% of patients with positive results have the disease, 10% of the patients with positive titers do not have ocular toxocariasis. Since cases of retinoblastoma may be included in this 10% of patients with false-positive titers, interpretation of this test has to be correlated with the clinical findings, particularly in areas where Toxocara is prevalent. Pollard and coworkers31 found an optimal cutoff titer greater than 1:8. However, several patients with ELISA titers as low as the 1:2 dilution, in whom enucleation was performed, had a diagnosis of ocular toxocariasis confirmed by biopsy.32, 51, 52 Moreover, a long-term followup of 20 patients with ocular toxocariasis showed that 85% of these patients had a decrease in serum titer, 10% showed an increase, and 5% were stable. 53 Based on these results, the authors recommend not to exclude the diagnosis of toxocariasis because of a low titer, as the patient may have had a higher titer previously. It has been suggested that any serum titer with clinical correlation could be considered highly significant for Toxocara. More important than serum titer is the detection of antibodies in aqueous humor. 54 In a patient with bilateral panuveitis, Toxocara antibodies were detected in the aqueous humor by ELISA assay.55 A Goldmann-Witmer coefficient of 8.63 was calculated for the right eye, and 8.94 for the left. Cytology of the aqueous or vitreous may be used to support the clinical diagnosis of ocular toxocariasis. If there is evidence of eosinophils in the aqueous or vitreous humor, the diagnosis of parasitic infestation, most likely toxocariasis, is suggested. Recently, cases of ocular toxocariasis due to T. cati have been more fre-

CHAPTER 38: OCULAR TOXOCARIASIS

quently reported. In some patients with ocular findings of toxocariasis and negative ELISA titers, specific serologic testing for T. cati was positive. 56

Radiologic Evaluation In addition to the clinical findings and ELISA titers, standardized echography may be useful in helping to establish the diagnosis of ocular toxocariasis. The three most common echographic findings in a group of 11 patients with ocular toxocariasis were (1) a solid, highly reflective peripheral mass (in 91 % of the patients the lesion was found in the temporal periphery), (2) vitreous membranes extending between the posterior pole and the mass, and (3) a traction retinal detachment or fold from the posterior pole to the mass. 57 Although it is useful for detecting the presence of intraocular calcification, computed tomography (CT) cannot absolutely differentiate toxocariasis or other simulating entities from retinoblastoma. In one study, the characteristic findings of toxocariasis on a CT scan have been suggested. 58 Five of 80 pediatric patients with nonrhegmatogenous retinal detachment were diagnosed with ocular toxocariasis. 59 All these patients had pseudomicrophthalmiaresulting from a thickened, inflamed sclera that was thought to be a "typical" finding by the authors. None of the patients had evidence of calcification. Furthermore, calcification can occur in any of the simulating conditions, particularly when there is significant ocular disruption or phthisis. "?

DIFFERENTIAL DIAGNOSIS The differential diagnosis of toxocariasis is not vast, but it includes retinoblastoma, infectious endophthalmitis, retinopathy of prematurity, persistence of hyperplastic primary vitreous (PHPV), toxoplasmosis, Coats' disease, and familial exudative vitreoretinopathy (FEVR). Differentiation between ocular toxocariasis and retinoblastoma has become less difficult with the development of diagnostic techniques such as ELISA, ultrasonography, and CT. However, ocular toxocariasis is still one of the most frequently recognized, nonmalignant lesions that simulate retinoblastoma. 6o Both entities are seen mostly in children, and leukocoria is a common presentation. .Additionally, the clinical presentation of the solitary retinal mass or diffuse endophthalmitis in toxocariasis may simulate an endophytic retinoblastoma or a unilateral, sporadic retinoblastoma. However, organizing vitreoretinal traction and inflammatory signs that are not commonly associated with retinoblastoma characterize the Toxocara lesion. Of 500 patients referred to the ocular oncology service at Wills Eye Hospital, Philadelphia, with a suspected diagnosis of retinoblastoma, only 288 patients (58%) in fact had it. The other 32% comprised diverse entities such as persistent hyperplastic primary vitreous (28%), Coats' disease (16 %), and presumed ocular toxocariasis (16 %) . When the distinction between retinoblastoma and toxocariasis is unclear, the Toxocara ELISA on aspirated aqueous humor and cytologic examination of the same are justified. In a study by Felberg and coworkers,54 five patients with suspected ocular toxocariasis had serum ELISA levels

higher than the 1:4 dilution, and aqueous ELISA levels above 1:276. Antibody was not found in the serum or aqueous humor of patients with retinoblastoma, Coats' disease, uveal malignant melanoma, or central retinal artery obstruction. Finding normal levels of aqueous humor lactate dehydrogenase and phosphoglucose isomerase and the demonstration of eosinophils in vitreous or aqueous aspirates can also facilitate the diagnosis of ocular toxocariasis, and its differentiation from retinoblastoma. Other differentiating features between retinoblastoma (unilateral, sporadic) and toxocariasis include the following: 1. The usual age is 7 to 8 years for ocular toxocariasis but 22 to 24 months for unilateral sporadic retinoblastoma. 2. There is a lack of inflammatory stigmata in retinoblastoma: specifically, no anterior segment scarring, and no secondary cataract, cyclitic membranes, or transvitreal epiretinal membrane formation. 3. Retinoblastoma lesions usually increase in size, whereas those of ocular toxocariasis do not. Some salient differentiating features between toxocariasis and the other differential entities include the following: 1. Infectious endQphthalmitis is distinguished by the history of recent trauma or ocular surgery. Acute signs of external inflammation typical for bacterial endophthalmitis are uncharacteristic in toxocariasis. However, a delayed onset with less virulent bacterial or fungal organisms needs to be differentiated. Vitreous or aqueous sampling for microscopic examination and· microbiologic studies should provide a definitive diagnosis in these cases. Endogenous endophthalmitis usually occurs in the setting of immunodeficiency and positive blood cultures. 2. Differentiation between active toxoplasmosis retinitis and toxocariasis may be difficult, particularly when severe vitritis is present. Serologic studies for toxoplasmosis should provide the diagnostic information. 3. Pediatric conditions such as retinopathy of prematurity, FEVR, PHPV, and Coats' disease usually present neonatally or in early infancy and lack the signs of inflammation of the posterior segment. Retinopathy of prematurity is bilateral, encountered in infants with a history of prematurity and low birth weight, and is characterized by proliferative changes in membrane formation involving the retinal periphery. FEVR is bilateral with characteristic retinal vascular abnormalities and membrane formation with an autosomal dominant inheritance pattern. PHPV is congenital, unilateral, and associated with micro-ophthalmia. The characteristic morphology includes that of a fibrovascular stalk from the disc to the posterior lens surface, forming a retrolental fibrovascular mass causing ciliary body traction. Coats' disease is a unilateral condition occurring almost exclusively in young males. This is characterized by a white, fibrotic subretinal mass in the posterior pole. There are typical vascular telangiectasia and lipid exudation with an absence of epiretinal membrane formation.

CHAPTER 38: OCULAR TOXC'Ct~RI.ASIIS

Medical Medical treatment for patients with ocular toxocariasis has been directed toward the inflammatory response that may produce structural damage and decreased vision. The medications that have been used to achieve this goal are steroids, given locally and systemically, alone or in conjunction with systemic antihelmintic agents. As a p~a~l of management, Dinning and colleagues51 proposed 1~11­ tial treatment with local, periocular, or systemIc sterOIds (prednisolone, 0.5 to 1 mg/kg/ day) or surgery in cases where indicated, with the addition of thiabendazole 50 mg/kg/ day for 7 days, if the previous treatment failed. There are reports of clinical improvement of ocular toxocariasis treated with thiabendazole (25 mg/kg twice a day for 5 days, with a maximum of 3 g/ day), albendazole (800 mg twice a day for 6 days) ,52 and mebendazole (100 to 200 mg twice a day for 5 days). Adequate larvicidal concentrations of thiabendazole given systemically were measured in the aqueous and vitreous hUlnor of a minimally inflamed eye. 53 There are some cases of ocular toxocariasis associated with VLM that have been successfully treated with diethylcarbamazine. Nonspecific medications such as cycloplegic agents are used when the anterior inflammation is present, in order to prevent the development of posterior synechiae and secondary glaucoma. 24

Surgical Surgical procedures such as pars plana vitrectomy, cryopexy, and photocoagulation have been used to treat patients with ocular toxocariasis. 54 Pars plana vitrectomy may be beneficial for patients who have not had a satisfactory response to medical treatment, or for those who have marked vitr~ous fibrosis and tractional complications thereof. 55- 57 Belmont and coworkers 55 obtained a dramatic improvement after pars plana vitrectomy in four patients with Toxocara endophthalmitis; vitrectOIny relieved vitreoretinal traction involving the macula in two of these patients. The employment of pars plana vitrectomy decreased the occurrence of secondary complications due to the progressive inflammation in this study. For this reason, early intervention with this surgical procedure has been recommended. Small and associates 58 achieved reattachment in 83% of 12 eyes with retinal traction detachments caused by toxocariasis, and vision improved in 7 of the 12 eyes. All had had macular detachment preoperatively; traction folds through the macula preoperatively were associated with a poor visual outcome. Hagler and colleagues 59 reported on 17 patients (eyes) undergoing vitreoretinal procedures for ocular toxocariasis, with improved or stable vision in 15. The final acuity was 20/50 in two eyes, 20/60to 20/80 in three, and 20/100 to 20/200 in two; eight others had "stabilized" but poor vision, and two eyes deteriorated. Rodriguez 70 reported on pars plana vitrectomy in 12 eyes affected by chronic ocular toxocariasis endophthalmitis, observing that the anatomic and visual results were better the earlier in the course of the patient's illness the surgery was performed. Six eyes had final visual acuities

of 20/20 to 20/40, one was 20/80, one was 20/200, one was 20/400, and three had light perception only. As a result of the surgery, 66% improved visually; one remained unchanged, and three eyes deteriorated. Five of the eyes required multiple surgeries. Abdel-Latif6'l reported three cases of laser photocoagulation therapy for toxocaral chorioretinitis with "satisfactory" results: "The lesion was reduced to a limited flat scar, and the edema around it subsided in a few weeks, with slight improvement of vision." Resolution of inflammation does not guarantee good visual acuity, as antiamblyopia therapy is essential to achieve good vision in the pediatric population.

PROGNOSIS The final outcome in ocular toxocariasis depends on underlying factors such as the age of the patient, disease duration before diagnosis, structure of the eye involved, degree of inflammation,preexisting amblyopia, and compromise of the macula. The prognosis for improved visual acuity and normal binocular vision is better when the onset of the disease occurs in older patients and the disease is detected early in its course.

CONCLUSIONS Ocular toxocariasis is a common worldwide ocular infection that affects mostly children. It is found in both rural and metropolitan areas. The most common route of infection is the ingestion of soil contaminated with Toxocara larva. In most cases, the course of the disease is mild, but the spectrum of clinical manifestations and severity is broad, and the potential for uniocular blindness due to this entity is well recognized. Consequently, to improve the prognosis, visual acuity screening in daycare centers and in schools may be critical to detect this disease in its early stages. The diagnosis of toxocariasis is essentially clinical, based on the lesion morphology and supportive laboratory data and imaging studies. Differentiation of ocular toxocariasis from retinoblastoma is critical. To avoid unnecessary enucleation of eyes with ocular toxocariasis, it is imperative to establish an adequate correlation between the clinical findings and diagnostic methods including serum ELISA titers and radiologic evaluation by ultrasound and CT scan. It is of particular importance to perform ELISA Toxocara titers on aqueous humor when the clinical diagnosis is not clear or when the serum ELISA is inconclusive. Treatment is directed at complications arising from intraocular inflammation and vitreous membrane traction. Early vitrectomy may be of value both diagnostically and therapeutically. Early therapeutic vitrectomy is recomlnended based on the beneficial results obtained in several patients. If an early vitrectomy is performed, then analysis of ELISA titers and cytology of the vitreous humor should be performed for diagnostic purposes.

References 1. Noble ER, Noble GA: Parasitology. The Biology of Animal Parasites. 5th ed. Philadelphia, Lea & Febiger, 1982. 2. Tabbara KF: Other parasitic infections. In: Tabbara KF, Hyrldiuk

CHAPTER 38: OCULAR TOXOCARIASIS RA, eds: Infections of the Eye. Boston, Little Brown & Co, 1985, pp 697-715. 3. Schmidt GD, Roberts LS: Foundations of Parasitology. St. Louis, Times Mirror/Mosby College Publishing, 1985. 4. Park SS, To KW, Fried AH, et. al: Infectious causes of posterior uveitis. In: Albert DM, Jakobiec FA: Principles and Practice of Ophthalmology. Clinical Practice. Philadelphia, W.B. Saunders, 1994, pp 450-464. 5. Beaver PC, Snyder CH, Carrera GM, et al: Chronic eosinophilia due to visceral larva migrans. Pediatrics 1952;9:7. 6. Schantz PM, Weis PE, Pollard ZF, et al: Risk factors for toxocaral ocular larva migrans: A case control study. Am J Public health 1980;70:1269. 7. Glickman LT, Schantz PM: Epidemiology and pathogenesis of zoonotic toxocariasis. Epidemiol Rev 1981;3:230-250. 8. Parke DW, Shaver RP: Toxocariasis. In: Pepose JS, Holland GN, Wilhelmus KR: Ocular Infection and Immunity. St. Louis, Mosby, 1996, pp 1225-1235. 9. Brown DH: Ocular Toxocara canis: Part II. Clinical review. Pediatr Ophthalmol 1970;7:182. 10. Schimek RA, Perez WA, Carrera GM: Ophthalmic manifestations of visceral larva migrans. Ann Ophthalmol 1979;11:1387. 11. Rasmussen LN, Dirdal M, Birkebaek NH: "Covert toxocariasis" in a child treated with low-dose diethylcarbamazine. Acta Pediatr 1993;82:116. 12. Konate A, Duhamel 0, Basset D, et al: Toxocariasis and functional intestinal disorders. Presentation of 4 cases. Gastroenterol Clin BioI 1996;20:909. 13. Calhoun FP: Intraocular invasion by the larva of the ascaris. Arch OphthalmoI1937;18:963. 14. Wilder HC: Nematode endophthalmitis. Trans Am Acad Ophthalmol Otolaryngol 1950;55:99. 15. Nichols RL: The etiology of visceral larva migrans. I. Diagnostic morphology of infective second stage Toxocara larvae. J Parasitol 1956;42:349. 16. Ashton N: Communications: LarvllJ granulomatosis of the retina due to Toxocara. Br J Ophthalmol 1960;44:129. 17. Irvine WC, Irvine AR: Nematode endophthalmitis-Toxocara canis. Report of a case. Am J Ophthalmol 1959;47:185. 18. Duguid 1M: Communications: Chronic endophthalmitis due to Toxocara. Br J Ophthalmol 1961;45:705. 19. Duguid 1M: Features of ocular infestation by Toxocara. Br J Ophthalmol 1961;45:789. 20. Perkins ES: Pattern of uveitis in children. Br J Ophthalmol 1966;50:169. 21. Ferguson EC, Olson LJ: Toxocara ocular nematodiasis. Int Ophthalmol Clin 1967;7:583. 22. Wilkinson CP, Welch RB: Intraocular Toxocara. Am J Ophthalmol 1971;71:921. 23. O'Connor PR: Visceral larva migrans of the eye. Subretinal tube formation. Arch Ophthalmol 1972;88:526. 24. Shields CL, Shields JA, Barrett J, et al: Vasoproliferative tumors of the ocular fundus. Arch Ophthalmol 1995;113:615. 25. Brown DH: The geography of ocular Toxocara canis. Ann Ophthalmol 1974;6:343. 26. Mok CH: Visceral larva migrans. Clin Pediatr 1968;7:565. 27. Raistrick ER, Hart JCD: Ocular toxocariasis in adults. Br J Ophthalmol 1976;60:365. 28. HartJCD, Rctist:rick ER: Adult toxocariasis: Uniocular retinal lesion in the 20 to 50-year old group. Trans Ophthalmol Soc U K 1977;97:164. 29. Ellis GS, Pakalnis VA, Worley G, et al: Toxocara canis infestation: Clinical and epidemiologic associations with seropositivity in kindergarten children. Ophthalmology 1986;93:1032-1037. 30. Magnaval JF, Michault A, Calon N, et al: Epidemiology of human toxocariasis in la Reunion. Trans R Soc Trop Med Hyg 1994;88:531. 31. Pollard ZF, Jarret WH, Hagler WS, et al: ELISA for diagnosis of ocular toxocariasis. Ophthalmology 1979;86:743. 32. Kielar RA: Toxocara canis endophthalmitis with low ELISA titer. Ann Ophthalmol 1983;15:447. 33. Spencer WH: Vitreous. In: Spencer WH, ed: Ophthalmic Pathology. An Atlas and Textbook, 4tll ed. Philadelphia, WB Saunders, 1996, pp 623-666. 34. Ghaffoor SYA, Smith HV, Lee WR, et al: Experimental ocular toxo. cariasis: A mouse model. Br J Ophthalmol 1984;68:89. 35. Liotet S, Bloch-Michel E, Petithory JC, et al: Biological modifica-

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tions of the vitreous in intraocular parasitosis: Preliminary study. Int Ophthalmol 1992;16:75. Watzke RC, Oaks JA, Folk JC: Toxocara canis infection of the eye: Correlation of clinical observations witll developing pathology in the primate model. Arch Ophthalmol 1984;102:282. Rockey JH, John T, Donnelly lJ, et al: In vitro interaction of eosinophils from ascarid-infected eyes with Ascaris suwn and Toxocara canis larvae. Invest Ophthalmol Vis Sci 1983;24:1346. Gillespie SH, Dinning V\Cf, Voller A, et al: The spectrum of ocular toxocariasis. Eye 1993;7:415. Molk R: Ocular toxocariasis: A review of the literature. Ann Ophthalmol 1983;15:216. Capone A, Aaberg TM: Intermediate uveitis. In: Albert DM, Jakobiec FA: Principles and Practice of Ophthalmology. Clinical Practice. Philadelphia, W.B. Saunders, 1994, pp 423-442. Hogan MJ, Kimura SJ, O'Connor GR: Peripheral retinitis and chronic cyclitis in children. Trans Ophthalmol Soc U K 1966;85:39. Smith PH, Greer CH: Unusual presentation of ocular Toxocara infestation. Br J Ophthalmol 1971;55:317. Giles CL: Uveitis in childhood-part III. Posterior. Ann Ophthalmol 1989;21:23. Hemady R, Sainz de la Maza M, Raizman MB, et al: Six cases of scleritis associated with systemic infection. Am J Ophthalmol 1992;114:55. Sorr EM: Meandering ocular toxocariasis. Retina 1984;4:90. Beiran I, Cochavi 0, Miller B: "Silent" ocular toxocariasis. Eur J Ophthalmol 1998;8:195. Hagler WS, Jarret H, Chang M: Rhegmatogenous retinal detachment following chorioretinal inflammatory disease. Am J Ophthalmol 1978;86:373. Mulvihill A, Bowell R, Lanigan B, et al: Uniocular childhood blindness: A prospe~tive study. J Pediatr Ophthalmol Strabismus 1997;34:111. Cypress RH, Karol MH, ZidianJL, et al: Larva-specific antibodies in patients with visceral larva migrans. J Infect Dis 1977;135:633. Glickman LT, Grieve RB, Lauria SS, et al: Serodiagnosis of ocular toxocariasis: A comparison of two antigens. J din Pathol 1985;38:103. Sharkey JA, McKay PS: Ocular toxocariasis in a patient with repeatedly negative ELISA titer to Toxocara canis. Br J Ophthalmol 1993;77:253. Searl SS, Moazed K, Albert DM, et al: Ocular toxocariasis presenting as leukocoria in a patient with low ELISA titer to Toxocara canis. Ophthalmology 1981;88:1302. Pollard ZF: Long term follow-up in patients with ocular toxocariasis as measured by ELISA titers. Ann Ophthalmol 1987;19:167. Felberg NT, Shields JA, Federman JL: An.tibody to Toxocara canis in the aqueous humor. Arch Ophthalmol 1981;99:1563. Benitez del Castillo JM, Herreros G, Guillen JL: Bilateral ocular toxocariasis demonstrated by aqueous humor enzyme-linked immunosorbent assay. AmJ Ophthalmol 1995;119:514. Sakai R, Kawashima H, Shibui H: Toxocara cali-induced ocular toxocariasis. Arch Ophthalmol 1998;116:1686. Wan WL, Cano MR, Pince Ig, et al: Echographic characteristics of ocular toxocariasis. Ophthalmology 1991;98:28. Edwards MG, Pordell GR: Ocular toxocariasis studied by CT scanning. Radiology 1985;157:685. Haik BG, Saint Louis L, Smith ME, et al: Computed tomography of tlle nonrhegmatogenous retinal detachment in tlle pediatric patient. Ophthalmology 1985;92:1133. Shields JA, Parsons HM, Shields CL: Lesions simulating retinoblastoma. J Pediatr Ophtllahnol Strabismus 1991;28:338. Dinning V\Cf, Gillespie SH, Cooling RJ, et al: Toxocariasis: A practical approach to management ocular disease. Eye 1988;2:580. Dietrich A, Auer H, Titti M, et al: Ocular toxocariasis in Austria. Dtsch Med Wochenschr 1998;123:626. Maguire AM, Zarbin MA, Connor TB, et al: Ocular penetration of tlliabendazole. Arch Ophthalmol 1990;108:1675. Abdel-Latif S: Toxocaral chorioretinitis: Treatment of early cases with photocoagulation. Br J Ophthalmol 1973;57:700. BelmontJB, Irvine A, Benson W, et al: VitTectomy in ocular toxoc,ariasis. Arch Ophthalmol 1982;100:1912. Grand MG, Roper-Hall G: Pars plana vitrectomy for ocular toxocariasis. Retina 1981;1:258. Werner JC, Ross RD, Green WR, et al: Pars plana vitrectomy and

38: OCULAR TOXOCARIASIS subretinal surgery for ocular toxocariasis. Arch Ophthalmol 1999;117:532. 68. Small KW, McCuen BW, de Juan E, Machemer R: Surgical management of retinal traction caused by toxocariasis. Am J Ophthalmol 1989;108:10-14.

69. Hagler WS, Pollard ZF, Jarrett WH, Donnelly EH: Results of surgery for ocular Toxocara canis. Ophthalmology 1981;88:1081-1086. 70. Rodriguez A: Early pars plana vitrectomy in chronic endophthalmitis of toxocariasis. Graefes Arch Clin Exp Ophthalmol 1986;224:218-220.

Virender S. Sangwan

Ascariasis is a helminthic infection of humans caused by the nematode Ascaris lumbricoides. 1 A. lumbricoides is a cosmopolitan parasite and the most prevalent and largest of the human helminths. The normal habitat of the adult worm is the jejunum. The infection is acquired by the ingestion of the embryonated eggs, and the larvae pass through a pulmonary migration phase for maturation. 1

ISTORY Ascaris is possibly the earliest recorded human helminth; it is referred to in texts from Mesopotamia, Greece, Rome, and China. 1 The worm was confused with the earthworm and described as such by the Greeks and the Romans. The genus Ascaris (from the Greek word "askaris," meaning "worm") was first described by Linnaeus in 1758. Goeze described the roundworm of the pig, A. sum, in 1758. Later Davaine (1877), Epstain (1892) and Grassi (1877) showed that Ascaris infection occurs by ingestion of the eggs, which mature into adult worms in the intestines. 2

EPIDEMIOLOGY In endemic areas, the prevaleN'ce of human infestation by Ascaris increases sharply during the first 2 to 3 years of age, remains at a maximum between the ages of 4 to 14 years, and declines in adults. 1 The prevalence of ascariasis worldwide is proportional to human population density, standards of education, level of sanitation and agricultural development, regional geoclimatic conditions, and personal and dietary habits of the people. Ascariasis is most prevalent in crowded rural areas. Of course, the lack of sanitary facilities aids fecal contamination of the soil and spread of infection. Primitive agricultural practices using fresh human feces as fertilizer, especially for the production of vegetables, are responsible for the high prevalence of ascariasis in certain regions of the world. Ascariasis is essentially a backyard and household infection primarily propagated by the seeding of the soil· immediately around the house with eggs present in the droppings of small children, who, in turn, become reinfected from eggs in the soil during play.3, 4 It has been estimated that more than 1.4 billion individuals throughout the world are infected with A. lumbricoides. 4 The majority of the infections occur in Asia, with' advanced countries having the lowest rates of infection. Ascariasis is highly endemic in China and Southeast Asia, with prevalence rates of 41 % to 92%.5 The prevalence in Japan dropped considerably after World War II: 70% to 80% until 1955, 13% in 1962, and 0.04% in 1992. 1 In the Indian subcontinent, ascariasis is highly endemic in Kashmir (70%), Bangladesh (82%), and Central and Southwest India (20% to 49%).1 The overall prevalence of the infection in Mrica varies from 15% to 27%. The prevalence is also high in Latin America and has not changed over the years. 6 In Europe, the prevalence is low

in large cities but can be greater in rural areas, reaching 52% in some areas. 1 Ascariasis is the third lTIOSt common helminth infection (after hookworm and Trichuris trichi7 UTa infections) in the United States. Of the 4 million people infected in the United States, a large percentage are immigrants from developing countries, with infection rates of 20% to 60%.8

CLINICAL CHARACTERISTICS Ascaris infects 25% of the world's population; however, most of these infections are without clinical disease. Clinical disease is mostly restricted to subjects with a heavy worm load. Because heavy infections typically occur in a small percentage of individuals, clinical disease is associated with a small minority of the infections. This minority, however, represents an estimated 1.2 to 2.0 million cases of clinical disease worldwide. It is estimated that around 20,000 deaths occur per year as a consequence of ascariasis. g ,IO

Pulmonary Ascariasis Pulmonary disease caused by Ascaris is due to larvae during their pulmonary migration and maturation. It presents as a self-limiting pneumonia lasting for 2 to 3 weeks and occurs 4 to 16 days after ingestion of the embryonated eggsY' 12 The disease is common in endemic zones associated with Ascaris infection and reinfection, and it is more severe with reinfections. Children are more susceptible to Ascaris pneumonia than adults. Seasonal attacks occur in Saudi Arabia after the onset of spring rains, restarting transmission of Ascaris. 13 The pulmonary disease is caused by larvae in the terminal air spaces and bronchioles, which provoke infiltration with neutrophils, eosinophils, desquamation of epithelium, and exudation of serous fluids, leading to plugging of air spaces and consequent consolidation. The consolidation may affect limited lobules; however, in some cases, it may extend to a single lobe or even multiple lobes. Ascaris pneumonia is common in children, presenting as sudden onset of fever, frequent spasms of cough and wheezing, dyspnea, and substernal distress. In heavy infection, cough is productive, with hemoptysis. Patients may be in status asthmaticus and require admission to an intensive care unit. An urticarial rash or angioneurotic edema may precede or accompany pulmonary manifestations. Abdominal symptoms, such as right quadrant pain and vomiting, may occur. Physical examination often simulates an atypical pneumonia. X-ray examination of the chest usually shows diffuse mottling and prominence of peribronchial regions. Eosinophilia is typically prominent. The filariform larvae of A. lumbricoides can usually be seen on sputum or gastric aspirate examination. Occasionally, there is some biochemical evidence of hepatocellular damage, suggesting larval liver disease.

CHAPTER 39: ASCARIASIS

The adult worm in the upper small bowel usually causes no symptoms and may be discovered through an incidental finding of ascaris eggs on stool examination or when someone presents after passing a worm in stools (or more dramatically through the mouth or nose or any of the body orifices).14 Worms may appear as linear filling defects on routine barium meal examinations of the small bowel. l1 This is the usual story of a large group of people infected with low worm loads. Vague abdominal symptoms in the form of abdominal pain, distention, nausea, and occasional diarrhea are frequent in children with ascariasis in endemic regions; however, their causal relationship with intestinal ascariasis remains unclear.

Peritoneal Ascariasis Ascarides may enter the peritoneal cavity through a gangrenous bowel filled to the bursting point with ascarides or through a perforation caused by typhoid, amebic, or tubercular ulcer. In a small percentage, the worms may be seen wandering in the peritonemn with the context of an intact bowel. In either of these conditions, the outcome usually is fatal peritonitisY If patients survive, wandering peritoneal ascarides disintegrate, and a granulomatous reaction is elicited around the disintegrated worm and ascaris eggs. A chronic granulomatous peritonitis with adhesions simulating tubercular peritonitis occurs. 16

Appendicular Ascariasis In endemic areas, ascarides may eriler the append.ix lumen and reach its tip. 1 Acute appendicular colic and development of a gangrenous appendix tip follow, and the worm reaches the peritoneal cavity adjacent to the appendix. Worms may also. partially exude through the perforation or lie inside the lumen of the appendix. Examination of such appendices after appendectomy reveals no inflammation of the mucosa of appendix. 14

Hepatobiliary and Pancreatic Ascariasis Hepatobiliary and pancreatic ascariasis (HPA) is one of the most common and well-described entities caused by ascaris. 1 Ascarides in the duodenum enter the ampullary orifice and can block it; they cap advance further to the bile duct and hepatic ducts. While in the common duct, the cystic duct can be blocked by worms entering its orifice. Less often, worms can reach the gallbladder or enter the pancreatic duct. In HPA, ascarides reach the duodenum, either because of excessive worm load in the jejunum or abnormal mobility after an intestinal infection caused by viruses, bacteria, or other parasites. Ascarides have a great propensity to explore small openings and, while in the duodenum, enter the ampullary orifice. In fact, duodenoscopic examination in HPA often reveals worms moving actively in and out of the bile duct from the duodenum. Until recently, diagnosis of HPA was made either at laparotomy or at autopsy. The magnitude of the problem of HPA in an endemic area was often underestimated 1 in the reported cases. The worms move actively in and out of the bile duct from the duodenum and usually are not present in the ducts at the time of surgery. In a prospec-

tive study, with the use of endoscopic retrograde cholangiopancreatography (ERCP) early in the disease, ascariasis was found as a cause of biliary or pancreatic diseases in 40 of 109 patients. 17 , 18 Ascariasis was as common a causative factor as gallstones in biliary disease. From June 1983 to November 1989, 500 cases of HPA were reported from one center. 1 Since then, reports of HPA have increased from number of centers in endemic areas. 19- 22 HPA is more common in women than in men, with a mean age of occurrence around 35.0 years (range 4 to 70 years) .23 Children do .suffer from HPA but less often than adults do. This is possibly due to the smaller size of the bile ductal system, making it difficult for the worms to enter. 24 Pregnant women are particularly prone to HPA, and the worm reaches the gallbladder more often than in nonpregnant women. 25 The majority of patients with HPA have had previous surgery on the biliary tree, including cholecystectomy, choledocholithotomy, or sphincteroplasty performed for gallstones. Endoscopic sphincterotomy predispose patients to HPA in endemic areas because of the widened ampullary orifice, which makes it easy for worms to pass into the bile ducts. 26 Worms usually actively move out of the ductal system into the duodenum. Ultrasound examinations reveal that worms usually move out of the ducts within a week. If worms are present in the duct beyond 10 days and have not changed their position, they are usually dead and can form a nidus for bile duct calculi. HPA can cause five distinct clinical presentations 27 : .. .. .. .. ..

Biliary colic Acalculous cholecystitis Acute cholangitis Acute pancreatitis Hepatic abscess

Ocular Ascariasis A few cases of ocular ascariasis have been reported. 27- 30 Most of these cases represent visceral larva migrans caused by Toxocara species rather than by A. lumbricoides. In one report, two photographically donunented cases showed an active ascaridoid larva in the retinal region, but because neither larva was identified microscopically as Ascaris species, it is likely that they belong to the Toxocara species. 27 ,28 In another report, fragments of a larva obtained from the anterior chamber of the eye of an 8-year-old boy from northern Georgia were identified as Ascaris, but the description could not exclude the possibility of a Toxocara larva. 29 Similarly the larva obtained from the eye of a 4-year old European girl in Uganda was carefully examined histologically, but it could only be identified as an ascaridoid larva closely related to those of Toxocaris and Baylisascaris. 30 In 1956, Kaplan and colleagues 31 reported extraction of an intact young adult Ascaris from the nasolacrimal duct of an 18-month-old African girl from Durban. Roche 32 reported a similar case in which an Ascaris worm was f01_1nd in the duct. Asca'ns larvae do not develop in the eye, as was proved by animal experiments with intraocular injection of Ascaris ova. 33

CHAPTER 39: ASCARIASIS

life Cyde Fertilized eggs passed in the feces require 9 to 13 days for incubation and development of the active, first stage larvae. 34 The larvae undergo two molts. The third stage is the infective form (Fig. 39-1). Under favorable circumstances, eggs may remain viable and capable of infection for a period of months to more than 10 years. Boiling kills the Ascaris eggs within minutes. 34 However, eggs are resistant to the usual methods of chemical water purification and can even embryonate in such substances as 2% formalin, potassium dichromate, and 50% solutions of hydrochloric acid, acetic, nitric, or sulfuric acid. When fully embryonated eggs are swallowed, on reaching the duodenum the larvae erupt from their shells and penetrate the wall to reach the liver by the portal venous system. They proceed from hepatic venules through the right side of the heart to the lungs and, after a delay of several days, break into the alveolar spaces. Mter increasing in size and molting to the fourth stage, the larvae transit the respiratory tree, pass the gastric barrier and arrive in the jejunum. They mature there and begin producing eggs within 60 to 65 days after being swallowed. The usual life span of an adult ascaris is approximately 1 year, and a single felnale Inay lay 200,000 eggs in 1 day.34

Immunology A variety of studies have demonstrated that the capacity to expel nematodes from the intestine is immunologically mediated and, particularly, that CD4 + Th cells are critical for worm expulsion. 35 Investigation of cytokine production by Th cells during

4. Infection: lung capillaries to trachea to esophagus to small intestine with maturation and eggs

T. muris infection has shown that in strains which expel their worms, a predominant Th2 response is generated. This is reflected in the characteristic immune changes controlled by Th2 cytokines, which are associated with worm expulsion: mucosal mastocytosis, intestinal eosinophilia, elevated serum IgE levels, and elevated parasitespecific serum IgGI levels. 36 This is similar to observations made in other models of intestinal nematode infection in which the worms are expelled from the intestine (e.g., Nippostrongylus brasiliensis, Trichinella spiralis, and secondary infections by Heligmosomoides polygyrus). 35 In contrast, however, analysis of cytokine production in strains of mouse that did not expel T. muris showed that a dominant Thl response became established. This factor was reflected by elevated levels of parasite-specific IgG2a antibody levels in the serum, a subclass controlled by interferon-l' (IFN-l'). The critical importance of distinct cytokines in controlling worm expulsion and progression to chronic infection was demonstrated by the in vivo administration of cytokine or cytokine receptor-specific neutralizing monoclonal antibodies or recombinant cytokines to T. murisinfected animals. The data from these experiments showed that interleukin 4 (IL-4) was critical in host resistance to T. muris. Neutralization of its activity in vivo changed an animal from one that would expel the parasite into one thafharbored a chronic infection. This was coincident with the suppression of a Th2 response and the induction of a Thl response. IFN-l' was also shown to be critical for the progression to a chronic infection; injection of anti-IFN-l' antibodies into mice that would normally harbor a chronic infection changed their response status, and the animals then expelled their parasites. This was coincident with the depression of the Thl response and elevation of a Th2 response.

1. Entry: eggs containing infective larvae

3. Spread of la'rvae: portal circulation 5. Disease Pneumonitis Liver granulomas & fibrosis Intestinal discomfort Nutritional impairment & obstruction Abnormal migration of --~--+--I adults to bile ducts, appendix, peritoneum, etc.

2. Eggs hatch, larvae invade small intestine

infertile

6. Exit: eggs

FIGURE 39-1. Ascmis lU17lbricoides life cycle. (From Baron S: Medical Microbiology, 3rd ed. New York, Churchill Livingstone, 1991, p 1113.)

CHAPTER 39: ASCARIASIS

The importance of the kinetics of the response· can also be inferred from a series of experiments investigating the cells involved in expulsion of T. muris. 35 In these experiments, severe combined immunodeficiency disease mice were reconstituted with high (1 X 10 7) or low (0.5 X 10 7 ) numbers of IyJ-TIphocytes from normal BALBI c mice. SCID recipients from high cell numbers were able to expel their parasites when infection coincided with the cell transfer. The expulsion of the parasites was associated with a dominant Th2 response. .

Pathology Larval migration often produces important histopathologic changes and symptoms. 34 The worms' passages through the liver rarely give rise to symptoms. If the larvae reach the general circulation, ectopic localization of the larvae in the kidneys, eyes, or central nervous system may rarely give rise to signs and symptoms referable to the parasitized organ. The lung is the site, as a rule, of the greatest damage produced by migrating larvae. Respiratory symptoms develop 26 hours to 5 days after the ingestion of viable eggs. In their passage from the vascular tree to the alveoli, the larvae often produce a bilateral patchy bronchopneumonia known as Ascaris pneumonia (L6ffler's pneumonia), with edema, eosinophilia, and hemorrhage as the predominating histologic features. 34 The intestinal mucosa reveals minute hemorrhages at places of larval penetration. Not all the larvae reach the lungs or the liver because they may die in intestinal mucosa. This results in focal areas of inflammation with infiltration of eosinophils and macrophages. In the hepatic sinusoids, mobile larvae do not elicit an inflammatory response. Dead larvae in the liver, however, simulate a granulomatous reaction. Larval migration may involve organs other than liver and lungs. Migration to the kidney, heart, and brain has been observed.

DIAGNOSIS Gross and microscopic morphology of typical eggs or adult worms in the feces or vomitus are the primary clues to diagnosis. 34 Infertile eggs are not suspended by the zinc sulfate flotation technique, and an occasional case may be missed if this single procedure is used. Ascaris eggs first appear in the feces 60 to 75 days after exposure. The eggs may be fertilized or unfertilized. 1 They have a characteristic size and shape, and can be diagnosed easily on a direct smear. 1 Ascaris pneumonia is confirmed by the radiographic picture of a diffuse, mottled pulmonary infiltrate, together with the identification of third-stage larvae in the sputum. During the stage of pulmonary invasion, high eosinophilia is usually seen. Eosinophilia of 10% or more commonly accompanies ascariasis, but its absence does not rule out the possibility of the jnfection, particularly when active invasion by larvae has ceased. The easiest and most economical method of investigation is a plain film of the abdomen; in the South Mrican series, this test could confirm the presence of worms in the right hypocondrium in most patients. 37 On barium-contrast radiographs, ascarids are occasionally discerned in the jejunum or ileum. 34 When they are

seen in the intestine, the parasite produces a sharply outlined radiolucenscy, within which the barium in the worm's intestinal tract appears as a filamentous radiopacity. Worms in the duodenum can be seen entering the ampulla of Vater, the part of the worm within the biliary tree being invisible; this is known as the ampullary cutoff sign. 38 Ultrasonography and ERCP can help in the diagnosis of HPA. The characteristic sonographic findings of worms in the ducts have been well described. 19 , 39 The worms in the gallbladder have much more characteristic appearances and can be identified with ease. The findings of pancreatic ascariasis on ultrasonography are edematous pancreatitis and the four-line sign indicative of the worm and its intestinal tract. Ultrasonography is a highly sensitive and specific method of detection of worms in the biliary tree. However, ultrasonography cannot diagnose duodenal ascariasis; if ultrasonography was used as a screening method, more than half of the patients with HPA would be missed. 23 ERCP has an advantage as a diagnostic tool in that it permits identification of the worms in the duodenum and those across the papilla. Ascaris in the ducts present as smooth, linear filling defects. ERCP, in addition, has therapeutic potential, facilitating removal of worms from the ducts or the duodenum. 21 ,40 For diagnosis of intraocular disease, a high degree of suspicion is required because it is exceedingly rare. Pars plana vitrectomy may be diagnostic and therapeutic.

TREATMENT Several drugs are available (Table 39-1) and effective for the treatment of ascariasis. PyJ--antel pamoate, mebendazole, and albendazole, however, are drugs of first choice against ascariasis. Parasite immobilization and death of the helminth are slow, and complete clearance of the worm from the gastrointestinal tract may take up to 3 days. Efficacy depends on worm load, strain, pre-existing diarrhea, and gastrointestinal transit time. In the rare case of ocular involvement, topical antiinflammatory therapy may be indicated in addition to systemic treatment.

Pyrantel Pamoate Pyrantel, a cyclic amidine, is a depolarizing neuromuscular blocking agent that results in spastic paralysis of the worm. It also inhibits cholinesterase. It is poorly absorbed, and 50% is excreted in the feces as unchanged drug. Seven percent or less of the dose is found in urine as parent drug and metabolites. It is effective against ascariasis and enterobiasis. The drug is contraindicated

TABLE 39-1. DRUGS USED IN TREATMENT OF ASCARIASIS

DRUGS

DOSE

P)'l'antel pamoate Mebendazole Albendazole Levamisole Piperazine citrate

10 mg/kg single dose PO; maximum 1.0 g 100 mg PO bid X 3 days 400 mg PO (single dose) 120 mg base PO single dose; children 5.0 mg/kg 75 mg/kg qd X 2 days; maximum, 3.5 g

CHAPTER 39: ASCARIASIS

in patients with hepatic disease and during pregnancy. A single dose of 10 mg/kg body weight is taken; purge is advised. Adverse reactions such as anorexia, nausea, vomiting, abdominal cramps, and diarrhea are common. Rarely headache, dizziness, drowsiness, and insomnia may occur. Parasite immobilization and death of the helminth are slow, and complete clearance of the worm from the gastrointestinal tract may take up to 3 days.

Mebendazole Mebendazole, a benzimidazole carbonate, inhibits the formation of the worm's microtubules and irreversibly blocks glucose uptake by the helminth, thereby depleting the endogenous glycogen stored within the parasite, which it requires for survival and reproduction. Mebendazole has no effect on the glucose level in the host. In addition to ascariasis, mebendazole is effective against T. trichiura, Enterobius vermicularis, Ancylostoma duodenale, and Necator americanus. In view of its widespread effectiveness, mebendazole is the drug of choice as a broad-spectrum antihelminthic. Mebendazole is embryotoxic and teratogenic in pregnant rats, and it is not recommended for use in pregnant women. Adverse reactions such as transient abdominal pain and diarrhea, with massive infection and expulsion of worms, have occurred in patients. Neutropenia and abnormal liver function tests occur in 5% of patients with intake of large doses. A dose of 100 mg twice daily orally for 3 days is recommended. No special procedure such as fasting or purge is required. If the patient is not cured 3 weeks !~lfter treatment, a second course is advised.

Albendazole

peristaltic movement of the intestine easily evacuates the paralyzed worms. Piperazine, which has been widely used for more than 25 years for treatment of ascariasis and enterobiasis, is now being withdrawn from the market in developed countries because of sporadic hypersensitive and neurotoxic reactions and because better drugs have been introduced. In developing countries, piperazine is still widely used because it is one of the least expensive drugs available. The daily dose is 75 mg/kg body weight, with a maximum individual dose of 5 g for adults and 2 g for children under 20 kg in weight. The efficacy of a single-dose treatment is 80%, and treatment for 2 consecutive days is effective in more than 90% of ascariasis cases. Patients must not receive concomitant chlorpromazine; convulsions are known to occur, which may occasionally be fatal.

Levamisole Levamisole, a levorotatory s-isomer of tetramisole, is a potent inhibitor of fumarate reductase activity, which is an enzyme essential in the carbohydrate metabolism of Ascaris. Levamisole, which is practically devoid of toxicity for humans, shows nonspecific activation of macrophages and some immunomodulating activities. Used in a single dose of 150 mg for adults and 5 mg/kg in children, it is effective in 96% of patients with ascariasis. None of the antihelminthics used in treatment of adult worms in the intestinal tract have been proved effective in killing the larvae during their migration phase.

COMPLICATIONS Systemic complications related to ascariasis include protein-energy malnutrition, retarded growth, intestinal obstruction, perforation, or volvulus. Although ascariasis is a benign condition, migration of worms to extraintestinal sites can be fatal. Migration occurs in response to antihelminthic drugs, purgatives, intercurrent illness, and often without any cause. The propensity for worms to invade the biliary tree is a result of their preference to migrate through small orifices. It may produce biliary colic, acute cholangitis, acute pancreatitis, and hepatic ascariasis (Hong Kong liver) .34

Albendazole, methyl 5n-propoxythio-2-benzimidazole carbamate, has an exceptionally broad spectrum of antiparasitic activity. It has the advantage of being effective when given as a single dose for the treatment of A. lumbricoides. Therefore, albendazole is ideally suited for mass treatment programs. Periodic treatment with albendazole has been shown to improve the nutritional status of malnourished children with multiple species of intestinal helminths. Albendazole, like other benzimidazoles, inhibits the assembly of tubulin into microtubules and impairs the uptake of glucose, leading to the depletion of glycogen stores in helminths. It also inhibits helminthic-specific fumurate reductase. Albendazole is usually well tolerated when given as a single 400-mg dose for the treatment of intestinal nematodes. Diarrhea, abdominal discomfort, or migration of Ascaris through the nose or mouth occurs occasionally. High-dose prolonged therapy is occasionally complicated by serum transaminase elevation, bone marrow suppression with neutropenia or thrombocytopenia, or less commonly, alopecia. In view of the potential teratogenicity of benzimidazole compounds, albendazole is contraindicated during pregnancy.

Ascariasis is a helminthic infection of global distribution, with more than 1.04 billion persons infected worldwide. The majority of infections. occur in the developing countries of Asia and Latin Atnerica. Of 4 million people infected in the United States, a large percentage are immigrants from developing countries. Ascaris-related clinical disease is restricted to subjects with heavy worm load, and an estimated 1.2 to 2 million such cases, with 20,000 deaths, occurs in endemic areas per year. More often, recurring moderate infection causes stunting of linear growth, causes reduced cognitive function, and aggravates existing malnutrition in children in endemic areas.

Piperazine

References

Piperazine derivatives temporarily paralyze the Ascaris worms by producing neuromuscular blockage through an anticholinergic action at the myoneural junction; the

1. Khroo, MS: Ascariasis. Gastroenterol Clin North Am 1990;25:553-

577. 2. Sun T: Ascariasis. In: Sun T, ed: Pathology and Clinical Features of Parasitic Diseases. New York, Masson, 1980, pp 115-120.

CHAPTER 39: 3. Ascariasis (Edit). Lancet 1989;1:997. 4. Crompton DWT: The prevalence of ascariasis. Parasitol Today 1988;4:162. 5. Thein H: A profile of ascariasis morbidity in Rangoon Children's Hospital, Burma. J Trop Med Hyg 1987;90:165. 6. Botero D: Epidemiology and public health in1portance of intestinal nematode infections in Latin America. Prog Drug Res 1975;19:28. 7. Nesse RE, Bratton RL: Ascariasis, an infection to watch for in immigrants. Postgrad Med 1993;93:171. 8. Intestinal protozoan and helminthic infections: Report of WHO Scientific Group. WHO Technical ReportSeries 666. Geneva, World Health Organization, 1981. 9. Crompton DWT, Nesheim MC, Pawlowski ZS: Ascariasis and Its Public Health Significance. London, Taylor & Francis, 1995. 10. Pawlowski ZS, Davies A: Morbidity and mortality in ascariasis. In: Crompton DWT, Nesheim MC, Pawlowski ZS, eds: Ascariasis and Its Prevention and Control. London, Taylor & Francis, 1989, pp 45-69. 11. Phillis JA, Harrold AJ, Whiteman GV, et al: Pulmonary infiltrates, asthma and eosinophilia due to ascaris sum infestation in man. N EnglJ Med 1972;286:965. 12. Spillman RK: Pulmonary ascariasis in tropical communities. Am J Trop Med Hyg 1975;24:791. 13. Gelpi AP, Mustafa A: Seasonal pneumonitis with eosinophilia: A study of larval ascariasis in Saudi Arabia. Am J Trop Med Hyg 1967;6:646. 14. Paul M: The movements of the adult Ascaris lumbriocoides. Br J Surg 1972;59:437. 15. Efm SEE: Ascaris lumbricoides and intestinal perforation. Br J Surg 1987;74:643. 16. Ochoia B: Surgical complications of ascariasis. World J Surg 1991;15:222. 17. Khuroo MS, Mahajan R, Zargar SA, et al: Prevalence of biliary tract disease in India: A sonographic study in adult population in I\.3.shmil'. Gut 1989;30:201. 18. Khuroo MS, Zargar SA: Biliary ascariasis: A common cause of biliary and pancreatic disease in an endemic area. Gastroenterology 1985;88:418. 19. Desai S, Topin K: Biliary ascariasis: Sonographic findings. Am J Roentgenol 1995;164:767. 20. Maddem GJ, Dennison AR, Blumgart LH: Fatal ascaris pancreatitis: An uncommon problem in the West. Gut 1992;33:402. 21. Saraswat VA, Gupta R, Dhiman RK, et al: Biliary ascariasis: Endoscopic extrication of a living worm from the bile duct. Endoscopy 1993;25:553.

22. Schulman A: Intrahepatic biliary stones: Imaging features and a possible relationship with Ascaris lumbricoides. Clin Radiol 1993;47:325. 23. Khuroo MS, Zargar SA, Mahajan R: Hepatobiliary and pancreatic ascariasis in India. Lancet 1990;335: 1503. 24. Zargar SA, Khuroo MS: Management of biliary ascariasis in children. Ind J Gastroenterol 1990;9:321. 25. Khuroo MS, Zagar SA, Yattoo GN, et al: Sonographicfindings in gallbladder ascariasis. J Clin Ultrasound 1990;20:587. 26. Khuroo MS, Dar J\iIY, Yatto GN, et al: Biliary and pancreatic ascal"iasis: A longterm follow-up. Natl MedJ India 1989;2:4. 27. Price AJ Jr, WadsworthJAC: An intraretinal worm. Arch Ophthalmol 1970;83:768-770. 28. Parson HE: Nematode chorioretinitis: Report of case, witll photographs of viable worm. Arch Ophtllalmol 1953;47:799-800. 29. Calhoun FP: Intraocular invasion by tlle larva of the Ascaris. Arch Ophthalmol 1937;18:963-970. 30. Beaver PC, Bowman DD: Ascaridoid larva (nematoda) from tlle eye of a child in Uganda. AmJ Trop Med Hyg 1984;33:1272-1274. 31. Kaplan CS, Freedman L, Elsdon-Dew R: A worm in the eye: A familiar parasite in an unusual situation. S Mr Med J 1956;30:791792. 32. Roche PJL: Ascaris in the lacrimal duct. Trans R Soc Trop Med Hyg 1971;65:540. 33. Chowdhry AB, Kean BH, Browne HG: Inoculation of helminth eggs into animal eyes. Am J Pathol 1960;36:725-733. 34. Monroe LS: Gastrointestinal parasites. In: Haubrich WS, Schaffner F, eds: Bockus Gastroenterology, 5th ed., Vol 4. Philadelphia, W.B. Saunders, 1995, pp 3113-3196. 35. Grencis RK: T cell and cytokine basis of host variability in response to intestinal nematode infections. Parasitology 1996;112:S31-S37. 36. Else Iq, Grencis RK: Cellular immune response to the nematode parasite Trichuris muris. Differential cytokine production during acute or chronic infection. Immunology 1991;72:508-513. 37. Lloyd DA: Hepatobiliary ascariasis in children. Surg Ann 1982;14:277-297. 38. Lloyd DA: Massive hepatobiliary ascariasis in childhood. Br J Surg 1980;68:468-474. 39. Khuroo MS, Zargar SA, Mahajan R, et al: Sonographic appearances in biliary ascariasis. Gastroenterology 1987;93:267. 40. Khuroo MS, Zagar SA, Yattoo GN, et al: Worm extraction and biliary drainage in hepatobiliary and pancreatic ascariasis. Gastrointest Endosc 1993;39:680.

Martin Filipec

Onchocerciasis is an infectious disease caused by a filarial parasite, Onchocerca volvulus. The disease is transmitted by an insect (fly) of the genus Silllulium. Man is the natural and definitive host of the parasite. The areas of endemic onchocerciasis include equatorial Mrica, some regions of Central and South America, and the Eastern Mediterranean, typically in the vicinity of rivers with fast-flowing water, which are breeding sites of the vector flies. Clinical manifestations include characteristic dermatologic involvement, ocular lesions and lymphatic obstruction due to the presence of microfilariae; and subcutaneous nodules caused by adult worms. Blindness is the major disability in onchocerciasis. Approximately 17.7 million individuals are afflicted by this disease-270,000 are blind and another 500,000 have serious visual impairment.

The first description of onchocerciasis was published by John O'Neill in 1875, who described the presence of microfilariae in the skin of Mricans living along the Gold Coast (Ghana) who suffered from a disease known locally as "craw-craw."l Leuckart, in 1893, described two samples from subcutaneous nodules and n~med the parasite Filaria vovulus. 2 The classification of the Onchocerca parasite was made in 1910 with Leuckart's ''Filaria volvulus" named for the first time, Onchocerca volvulus. 3 PachecoLuna in 1919'1 and Robles in 19195 were the first to associate blindness in A1nerica with onchocerciasis and to describe the inflammatory changes in the anterior segment of the eye. Brumpt described the eye diseasecausing organism and named the parasite Onchocerca caecutiens (blinding).6 It was demonstrated that Onchocerca caecutiens is identical to the previously described Onchocerca volvulus. 3 The first description of intraocular microfilariae was made by Juan Luis Torroella, a Mexican ophthalmologist, in 1931. 7 The first report of blindness due to onchocerciasis in Mrica was published by Hisette in 1932. 8 He also observed the chorioretinallesions to be described later by Bryant. 9 A comprehensive description of the ocular manifestations of onchocerciasis, especially those of onchochorioretinitis, was provided in 1945 by Ridley, a British ophthalmologist serving the British army on the Gold Coast of Mrica. 10 In 1902, notions regarding disease transmission were stimulated by Brumpt's suggestion that flies might be responsible for nodule formation. l1 The entomologic description of the blackfly belonging to the genus Simulium was reported by Roubaud in 1906. 12 However, it was not until 1926 that Blacklock definitely confirmed Simulium damnosum as the vector, with the observation of the development of larval stages of O. volvulus in this blackfly.13 Up until the 1970s, there were few scientists throughout the world studying onchocerciasis. 14 In 1953, the Expert Committee on Onchocerciasis was established by the World Health Organization (WHO). In its first report in

1954, the Committee, attempted to unify terminology and suggested a plan for future research in the field of onchocerciasis and its control. 15 Vector control was shown to be effective in Kenya in 1947 with the use of DDT.16 With new insights as to the pathogenesis and immunology of this disease, new therapeutic modalities have been developed, providing possible strategies for the control of onchocerciasis. The Onchocerciasis Control Program (OCP) began its operations in 1974 in seven countries in West Mrica with extensive larviciding. In 1987, ivermectin, a new, safe, and effective drug suitable for large-scale treatment, became available through a donation by the drug manufacturer Merck and Co., Inc. "for as long as necessary to as many as necessary." Onchocerciasis is second to trachoma, the most common infectious cause of blindness worldwide .17 Ninety-nine percent of all individuals affected by onchocerciasis (and blind because of this disease) live in Mrica. 18 The prevalence of the disease has decreased dramatically during the past 20 years in Mrican countries where the OCP operates. On the other hand, in countries outside the OCP and in America, onchocerciasis remains a major public health problem. The epidemiology of onchocerciasis, the distribution of different patterns of the disease, and the type of ocular pathology are dependent on geographic, environmental, and ecologic factors; the type of parasite; the capacity of the vector to transmit the infection; and individual genetic factors and the types of activity within the community.18 Whenever the blindness rate in the community exceeds 5%, the disease has a deleterious impact, not only on the physical and psychological life of infected individuals, but also on family and community life. The life expectancy of people blinded as the result of onchocerciasis is reduced by approximately 10 to 13 years. The economic life of the whole community deteriorates as entire villages may relocate to areas with a lower risk of infection, but usually with poorer conditions to support subsistence agriculture. 18

Geographic Distribution Onchocerciasis is endemic in 34 countries throughout the world. Twenty-eight of these are located in Mrica and in the Eastern Mediterranean region (Angola, Benin, Burkina Faso, Burundi, Cameroon, Central Mrican Republic, Chad, Congo, Cote d'Ivoire, Equatorial Guinea, Ethiopia, Gabon, Ghana, Guinea, Guinea-Bissau, Liberia, Malawi, Mali, Niger, Nigeria, Senegal, Sierra Leone, Sudan, Togo, Uganda, Tanzania, Yemen, and Zaire) (Fig. 40-1), and six are in Central and South America (Brazil, Colombia, Ecuador, Guatemala, Mexico, and Venezuela) (Fig. 40-2). The last WHO Report, from 1995,18 estiInates that 122.9 million people worldwide are at risk of infection, 17.7 million are infected, and 270,000 are blind; another 500,000 people are severely visually impaired (Table 40-1). These figures are rough estimates, and

CHAPTER 40: ONCHOCERCIASIS

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, I

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I I I I I I I I I

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I

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Endemic onchocerciasis \ Area covered by the OCF\

fiGURE 40-1. Geographic distribution of onchocerciasis in Mrica and Arabian peninsula. (From Report of a WHO Expert Committee on Onchocerciasis Control. WHO Technical Report Series No 852, p 26, WHO, Geneva, 1995.)

Endemic onchocerciasis 1. Oaxaca focus 2. Northern Chiapas focus 3. Southern Chiapas focus 4. Huehuetenango focus 5; Solola-Suchitepiquez focus 6. Escuintla focus 7. Santa Rosa focus 8.. North-central focus 9. North-eastern focus 10. Southern focus 11. Amazonas-Roraima focus 12. Lopez de Micay focus 13. Nariiio focus 14. Esmeraldas focus

....

'"\

... 13

14--"'" Ecuador I

...

-

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\ Brazil

fiGURE 40-2. Geographic distribution of onchocerciasis in the Americas. (From Report of a WHO Expert Committee on Onchocerciasis Control. WHO Technical Report Series No 852, p 27, WHO, Geneva, 1995.)

40: ONCHOCERCIASIS TABLE 40-1. GLOBAL ESTIMATES OF THE POPULATION AT RISK, ONCHOCERCIASIS

AND BLIND BECAUSE OF

REGION

POPULATION AT RISK OF INFECTION (MILLIONS)

POPULATION INFECTED

Mrica OCP area: Original area Extensions non-OCP area: Arabian peninsula Americas Total

17.6* 6.0 94.5 0.1 4.7 122.9

10,032 2,230,000 15,246,800 30,000 140,455 17,657,287

NUMBER BLIND AS A RESULT OF ONCHOCERCIASIS

17,650 31,700 217,850

o

750 267,950

OCP = onchocerciasis control program. *The population given is that which would have been at risk had the OCP not existed. From Report of a WHO Expert Committee on Onchocerciasis Control. Technical Report Series No 852, p 30. WHO, Geneva, 1995.

comparisons with previous reports are difficult. They are almost certainly an underestimate, as there are no accurate data available from many countries.

Endemicity To study endemicity and the impact of onchocerciasis on the population, one must evaluate many factors. 19 The most common indicators used in onchocerciasis epidemiology are the prevalence of infection (percentage of active infection in the population), mean microfilaria density (MFD) in skin biopsy specimens, annual transmission potential (ATP), annual biting rate, prevalence of blindness, specific ocular lesions, ang demographic data. ATP is the total number of infectivej'L3 larvae that would be transmitted in 1 year to an individual exposed at a capture point for 11 hours per day. The annual biting rate is the total number of bites that would be received in 1 year by an individual exposed at a capture point for 11 hours per day. IS According to the prevalence of infection, the level of endemicity in the area can be established. Areas with a prevalence of infection lower than 35% are considered hypoendemic. Areas with a prevalence higher than 60% are considered hyperendemic, and mesoendemic areas exhibit a prevalence of between 35% and 60%.20 Different approaches with varying levels of expense can be used to establish the prevalence of infection in a particular target population. Comparing the use of Small Sample Survey (SSS) on a sample of 390 at-risk persons

FIGURE 40-3. Typical breeding site of Simulium in Upper Ocarno, Venezuela.

and Complete Enumeration Survey (CES) on 1529 people in the same population (using MFD as the target indicator), it was shown that the low-cost SSS gives similar results to the more costly CES.21

Demographic Factors The relatively small number of areas with a high level of endemicity in Central and South America does not correspond to the large density of blackflies in the region. This is probably. a consequence of the low population density. IS The risk for populations from nonendemic areas who migrate to a hyperendemic area is llluch greater than that for individuals living in long-established onchocerciasis areas. 22 The prevalence of onchocerciasis in this population can be as high as 90%, and the number of ocular complications can reach almost the same level.23 The first exposure to transmission may be a risk factor for populations from nonendemic areas. 23

Ecology and Biology of Onchocerciasis Onchocerciasis occurs typically in areas with a hot climate near the equator. Onchocerca volvulus is transmitted by Simulium blackflies, and the disease is limited by the requirements of the blackfly for an appropriate breeding habitat, that is, nonpolluted fast-flowing streams and rivers (0.4 to 0.5 m/sec) with highly oxygenated water and submerged vegetation (e.g., tree trunks) and islands that provide support for the eggs and the development of larvae (Fig. 40-3). A hot climate is necessary for Oncho-

CHAPTER 40: ONCHOCERCIASIS TABLE 40-2. CLINICAL NONOCULAR MANIFESTATIONS OF ONCHOCERCIASIS

SKIN

GENERALIZED

LOCALIZED

Pruritus Papules, macules, urticaria, edema Excoriations, pustules, crusts Scaling ulceration Lichenification ("lizard skin") Atrophy Hyper-, hypopigmentation ("leopard skin")

Acute: people from non-endemic areas Chronic: reactive onchodermatitis ("sowda")

NODULES LYMPHATIC

Lymphadenopathy Lymphedema, elephantiasis "Hanging groin," "hottentot apron"

Adapted from Report of a WHO Expert Committee on Onchocerciasis Conu-ol. Technical Report Series No 852, pp 17-18. WHO, Geneva, 1995.

cerea volvulus to quickly develop into L3 stage larvae within the short lifetime of the blackfly host. The intensity of parasite transmission is related to the proportion of blackfly survival after the infective blood meal, the number of infective stage L3 microfilariae per fly, and the biting rate of the fly vector. 24 , 25 The altitude may also play an important role in the endemicity status of a particular location. For example, southern Venezuelan communities located below 150 meters above sea level are hypo- or mesoendemic, but those above 150 meters are all hyperendemic. This corresponds to the predominant presence in the more elevated regions of Simulium guianense with a high daily biting rate. 26

The most common clinical manifestations of onchocerciasis involve the skin (Table 40-2) and eye (Table 40-3). Less common are the lesions of the lymphatic draining system associated with hanging groin, hottentot apron, hernias, and elephantiasis (see Table 40-2). An. association with other infections and diseases such as lepromatous leprosy,27 filalia Mansonella perstans, 28, 29 epilepsy,30, 31 and dwarfism (Nakalanga syndrOlne) 31 has been re-

TABLE 40-3. CLINICAL OCULAR MANIFESTATIONS OF ONCHOCERCIASIS ANTERIOR SEGMENT

Conjunctiva Hyperemia Limbitis Chemosis Nodules Cornea Live microfilariae, dead microfilariae Punctate keratitis, sclerosing keratitis Anterior chamber, iris Live microfilariae, anterior uveitis Secondary glaucoma Lens Secondary cataract

POSTERIOR SEGMENT

Retina RPE atrophy Intraretinal deposits Cotton-wool spots Hemorrhage Hyperpigmentation Choroid Choriocapillary atrophy Subretinal fibrosis Pigment hyperplasia, cho'rioretinitis Optic nerve Optic neuritis, optic atrophy Visual function Night blindness, visual field loss Visual impairment, blindness

RPE = retinal pigment epithelium. Adapted from Report of a WHO Expert Committee on Onchocerciasis Control. Technical Report Series No 852, pp 17-18. WHO, Geneva, 1995.

ported. A matched case-controlled study did not demonstrate a statistically significant relationship between onchocerciasis and epilepsy. 32

Skin Lesions Onchocercal dermatitis is the most common manifestation of onchocerciasis. Skin changes are now classified as acute papular onchodermatitis (APOD), chronic papular onchodermatitis (CPOD), lichenified onchodermatitis (LOD), atrophy (ATR) , and depigmentation (DPM).33 Many infected persons are asymptomatic. In some individuals, especially those from nonendemic areas, pruritus may be the only symptom of onchocerciasis. Acute papular onchodermatitis develops within 6 months to 2 years after infection and is accompanied by very intense itching (gale filarienne). APOD may be accompanied by erythema and skin edema. Secondary infection of these lesions due to scratching is common. Itching and APOD are typical manifestations of infected individuals from nonendemic areas. APOD may disappear quickly or may spread to become vesicular and pustular. The sites of highest predilection are the shoulders, arms, and trunk (Fig. 40-4); Chronic papular onchodermatitis is characterized by papules, various degrees of itching, and postinflalnlnatory hyperpigmentation (Fig. 40-5). The typical localization of CPOD is on the buttocks, waist area, and shoulders. Involvement of the face ("erispela de la costa") and purplish eruption on the upper body ("Inal morado"), described as typical in Central America, are in fact very rare. Lichenified onchodermatitis is characterized by itching, hyperpigmentation, and hyperkeratosis (lizard skin). LOD is localized preferentially on the limbs and buttocks and is often asymmetric. Atrophy of the skin (presbydermia) , localized mostly on buttocks and limbs, is accompanied by loss of elasticity, excessive wrinkling, and scarring (Fig. 40-6). Depigmentation is typically localized to the pretibial regions when it is described as "leopard skin" (Fig. 40-7). Depigmented areas, together with hyperpigmentation, especially around the hair follicles and normal skin, can be observed. In the Sudan, Yemen, Guatemala, and Ecuador,34 a more severe, localized variety of onchodermatitis, known

CHAPTER 40: ONCHOCERCIASIS

FIGURE 40-4. Acute papular onchodermatitis in an I8-year-old Yanomami girl, Venezuela. (See color insert.)

FIGURE 40-6. Atrophic skin with loss of elasticity and excessive wrinkling in a 34-year-old Yanomami man, Venezuela.

FIGURE 40-5. Chronic papular onchodermatitis (CPOD). (Photo courtesy of E.M. Pedersen.) (See color insert.)

CHAPTER 40: ONCHOCERCIASIS

FIGURE 40-7. Pretibial skin depigmentation (leopard skin). (Photo courtesy of P. Magnussen.)

by the Arabic name "sowda" (from the Arabic for "black"), has been described, usually with extensive involvement of one limb. The skin is itchy, swollen, and dark, with scaling papules and pronounced regional lymphadenopathy. The presence of microfilariae in the skin of "sowda" patients is, in comparison with Mrican onchocerciasis, rare. 35

Nodules (onchocercomata) Onchocercomata are subcutaneous nodules contaInll1.g adult worms. They are painless, round to oval lesions that are either movable or fixed to the periosteum or joint capsule. Their size ranges from a few millimeters to several centilueters in diameter. Although most nodules are visible or at least palpable, some are localized deeply and are not easily detectable. New nodules have a tendency to form in the vicinity of old ones. There is variable localization of the nodules in different endemic locations. In Mrica, the nodules are most common over bony prominences of the pelvis (iliac crest, coccyx, sacrum, and greater trochanter of the femur). Less common is localization on the knees, abdomen, chest wall (Fig. 40-8), and head. In Central America, the nodules tend to be localized above the waist and around the head. Histologically, the nodules contain a firm fibrous capsule that encases the adult worm. An inflammatory infiltrate of varying intensity (polymorphonuclear to epithelioid cells, macrophages, and giant cells)3'1 may form around the worm.

Ocular Lesions Ocular signs and symptoms develop primarily because dead microfilariae are present in the eye. Even a high number of living microfilariae are well tolerated in the eye. Observation of microfilariae in the cornea is possible by slit-lamp examination with high magnification or retroillumination. 36 Dead worms are easily visualized because they are straight and opaque in the cornea. Intraretinal microfilariae can be seen by direct ophthalmoscopy and by three-mirror contact lens examination in which they appear as small reflective opacities with an apple-green tint. 37 Typical subjective complaints of patients with onchocerciasis include photophobia, tearing, foreign body sensation, pain, and decreased visual acuity.

Conjunctiva Limbal edema and hyperemia may be present in patients with keratitis punctata. Heavy pigment accumulation close to the areas of corneal involvement has also been

Pathology of the Lymphatic System Lymph nodes in patients with onchocerciasis may become fibrotic with reduction of germinal centers. Microfilariae, macrophages, plasma cells, eosinophils, and mast cells may be present. 34 Obstruction of lymphatic vessels, with the development of elephantiasis, is not typical for onchocerciasis. Lymphedema can be present in the inguinal or femoral area, producing the phenomenon known as "hanging groin" in males and "hottentot apron" in females.

FIGURE 40-8. Subcutaneous nodule (onchocercoma). (Photo courtesy A. Rothova.)

CHAPTER 40:

observed. 38 Chronic conjunctivitis vvith the presence of microfilariae in the conjunctival biopsy specimens of 15 of 25 patients has been described in the Congo. Small, round, 0.5- to 2-mm-diameter nodules may be present in the bulbar conjunctiva. 39 In one case, a microfilaria was found in such a nodule. 40

Cornea Punctate keratitis is an early manifestation of corneal involvement in younger patients (average age, 24.6 years) Y The appearance of corneal changes on slit-lamp examination is characterized by 0.5- to 1.5-mm "snowflakes" or "fluffy" punctate grayish opacities around dead microfilariae, mainly in the anterior stroma. Up to 50 lesions in one cornea were observed. 42 Punctate keratitis is usually seen after the initiation of microfilaricidal treatment; dead filariae can be observed in the center of the lesion. Opacities are usually transitory with minimal visual impairment. 43 Sclerosing keratitis is associated with longlasting massive onchocercal infection. The average age of patients with sclerosing keratitis is 41.2 years. The highest density of microfilariae and opacities is found in the corneal periphery nasally and temporally, with a lower density centrallyY Prolonged corneal inflammation leads to cicatrization with neovascularization. 42 White corneal opacification usually begins nasally and temporally at the limbus in the interpalpebral fissure (Fig. 40-9), progresses inferiorly (Fig. 40-10), and becomes confluent (Fig. 40-11). When the opacity reaches the optical axis, visual acuity is seriously impaired..

Anterior Uveitis Living microfilariae may be found in the anterior chamber in one quarter of patients with onchocerciasis. 44 ,45 Active anterior uveitis is seen rarely, however, and its severity does not correspond to the number of microfilariae in the anterior chamber. The first sign of anterior uveitis may be the alteration of pupillary reflex to light. Anterior uveitis can vary from chronic, low-grade, nongranulomatous inflammation to severe, turbid, granulomatous uveitis with acute exacerbations accompanied by flare, iris atrophy, anterior and posterior synechiae,

fiGURE 40-9. Incipient sclerosing keratitis: peripheral white corneal opacifications nasally and temporally at the limbus in the interpalpebral fissure of both eyes in a 38-year-old Yanomami man, Ocamo, Venezuela.

fiGURE 40-10. Sclerosing keratitis: opacification of the inferior cornea with pupillary aperture drawn inferiorly and cataract. (Photo courtesy of A. Rothova.) (See color insert.)

and seclusion and occlusion of the pupillae. The pupil may manifest a characteristic pear-shaped distortion with inferior posterior synechiae (see Fig. 40-10) .46, 47

Chorioretinitis Chorioretinal changes in onchocerciasis are usually bilateral and symmetric, and are located temporal to the macula and nasal to the optic nerve. Active inflammation of the retina or choroid is rarely observed. 46 , '18 Onchocercal posterior uveitis is slowly progressive. The mildest retinal change in the course of onchocerciasis is retinal pigment epithelium (RPE) atrophy (Fig. 40-12) ,seen as mottling of fluorescence on fluorescein angiography, sometimes accompanied by atrophy of the choriocapillaris. 46 RPE atrophy can be either diffuse or geographic with distinct borders. 48 Other changes due to chorioretinitis include intraretinal brown and black pigment clumping, intraretinal white and shiny deposits, intraretinal hemorrhages, cotton-wool opacities, and hyperpigmenta-

fiGURE 40-11. Advanced sclerosing keratitis with extended opacification of the cornea. (Photo courtesy A. Rothova.) (See color insert.)

CHAPTER 40: ONCHOCERCIASIS

common being iris atrophy, anterior and posterior synechiae, seclusion of the pupil, secondary glaucOlua, and cataract. 54 Glaucoma is usually related to angle closure as a sequela of anterior uveitis. Open-angle glaucoma in patients with a low intensity of infection also occurs. 54 In general, patients with ocular onchocerciasis have lower intraocular pressure. 56 ,57 In one study, complicated cataract and secondary glaucoma were found to be the causes of visual loss in 28 of 70 patients with uveitis. 58 In another study, a high prevalence of glaucoma was associated with severe eye infection in young males. 56 Complications related to the therapy are common and are described in the following sections.

FIGURE 40-12. Fundus changes in onchocerciasis: optic nerve atTophy, diffuse chorioretinal atrophy, and secondary pigmentary changes, pigment clumping in the macular area. (Photo courtesy A. Rothova.) (See color insert.)

tion. Live intraretinal microfilariae anterior to the RPE were observed in 10 of 30 patients examined by Murphy and colleagues. 37 The development of new chorioretinal lesions and the extension of existing lesions are common with or without treatment. 49- 52

Optic Nerve Disease Optic nerve involvement manifests ~s either primary or secondary optic atrophy. Optic neurftis, characterized by a congested disc, with or without swelling, is not an uncommon finding, occurring either as a direct result of the disease itself, or as part of the Mazzotti reaction precipitated by therapy with diethylcarbamazine. I8 ,46 Optic atrophy may be seen in association with peripapillary hyperpigmentation, scarring, varying degrees of chorioretinal atrophy (see Fig. 40-12), and sheathing of retinal vessels. I8 , 46, '18, 53 The prevalence of optic nerve atrophy varies between 1 % and 9%.18 Retinal and optic nerve pathology is often accompanied by serious constriction of the visual field to 5 to 10 degrees and night blindness. 54. 55

Chronic inflammation of the anterior segment in onchocerciasis is often associated with complications, the most

Transmission Onchocerca Volvulus

Cycle

The female vector ingests microfilariae during a blood meal of an infected human. Microfilariae of Onchocerca volvulus migrate through the fly's midgut to the hemocoel, and further to the thoracic muscles. Following several molts, the microfilariae develop into the infective "L3" larval stage over the next 5 to 8 days and are transmitted through the fly's proboscis to the definitive, human host during the next blood feeding. The transmission of microfilariae in utero in humans was shown in Ghana, where microfilariae were found in skin snips and/ or in the umbilical cords of newborn children. 59

Parasite factors Onchocerca volvulus, together with Wuchereria bancrofti, Brugia malayi, Loa loa, Mansonella perstans, Mansonella streptocerca, and Mansonella ozzardi, belongs to the group of human filarial parasites. The macrofilariae (adult worms) live in the subcutaneous nodules in man. There are usually three females and one male worm per nodule. Females are 30 to 80 cm X 250 to 450 fJvm, and they remain for their entire lifetime in one nodule. The male worms are long, 16 to 42 mm X 125 to 200 fJvm, and they often leave the nodules. The reproductive life of macrofilariae is 9 to 11 years, and their lifespan in total is 13 to 14 years. 60 During their lifetime, females produce millions of microfilariae (Fig. 40-13), which measure 220 to 360 fJvm X 5 to 9 fJvm and have a lifespan of 6 to 24 months. 34

FIGURE 40-13. Onchocerca volvulus microfilaria (hematoxylin). It measures 225 X 5 to 7 !-Lm, no sheath, head is slightly enlarged, anterior nuclei are positioned side by side, no nuclei in the end of the tail which is long and pointed. (Photo courtesy of L. Kolarova.)

40: ONCHOCERCIASIS

Microfilariae migrate from the nodules; invade the eye, skin, and lymphatic tissue; and are the cause of most clinical manifestations of onchocerciasis. Serine proteases and metalloproteases produced (especially by "L3" microfilariae) may facilitate their migration and may pm-ticipate in the tissue destruction. 51 Parasitic nematodes use different strategies to evade the surveillance of the immune system. Nematodes actively produce surface coats that shed antibodies and inflammatory cells. 52 Filarial parasites produce prostaglandins, prostacyclin,. and prostaglandin E 2, thereby inhibiting T-cell activation, lymphokine production, and cytotoxicity, and inducing B-cell unresponsiveness. 53 Biochemical enzyme 5'1 and genetic 55 , 55 studies have demonstrated two different strains of Onchocerca volvulus, rain forest and savanna; the savanna strain is associated with a higher rate of blindness (5% to 10%) in comparison with the rain forest strain (1 % to 2%). A strong correlation between the classification of rain forest and savanna strains and the epidemiologic pattern of blindness was confirmed by the use of strain-specific DNA probes. 57 There are many other Onchocerca strains (e.g., 0. ochengi, O. gutturosa, 0. dukei, and O. armillata) that are transmitted by the same Simulium blackfly vectors that transmit Onchocerca volvulus; these are not pathogenic in man. The definitive hosts of these species are animals (usually cattle). The use of DNA probes makes it possible to distinguish Onchocerca volvulus larvae from those of Onchocerca ochengi and other nonhuman parasites of the same species. In North Camer&on, reduced endemicity in an area with a high transmission of Onchocerca ochengi through the same vector as Onchocerca volvulus was found. 58 This natural inoculation of animal filaria seems to confer cross protection against Onchocerca volvulus in humans. 58

Vector factors Onchocerca volvulus is transmitted by a blackfly of the family Simuliidae, genus Simulium. The main vectors in Mrica and the Arabian peninsula are the Simulium dam,nosum complex and Si1nulium neavei complex. In Central and South America, the most common vectors are the Simulium ochraceum and metallicum complexes. The adult fly is dark and robust, with short legs that are 2 to 3 mm in length. The lifespan of Simuliidae is, on average, 3 weeks, but in some individuals, survival time may be longer than 4 months. 59 Only females transmit the infection during a blood meal. The bite is painful and usually bleeds, and is surrounded by erythema. There is variable survival of the Simulium vector following a blood meal, depending on the microfilarial load and on differential competence in transmission of microfilariae. 70 , 71 A study focusing on the transmission of rain forest and savanna strains of Onchocerca volvulus by distinct groups of vector flies has shown that there is no preferential transmission in West Mrica. 72

Host factors The range of clinical and laboratory manifestations of onchocerciasis varies according to the intensity and type of immune response to the parasite. In general, three groups of individuals exposed to onchocerciasis

can be distinguished: (1) generalized pathology or asymptomatic, living in endemic areas, microfilariae-positive, eye pathology common; (2) asymptomatic, living in endemic areas, microfilariae-negative (endemic normal/putatively immune [EN/PI]); (3) local strong skin involvement (sowda), living in endemic areas, few microfilariae, eye pathology rare. 73 , 74 The association of different HLA class II haplotypes with the different types of immune and clinical response described earlier was recently demonstrated. 75 ,75 Generalized disease is associated with haplotypes DQAl *0101-DQBl *0501 and DQBl *0201; putatively immune individuals (PI) have haplotypes DRB1*1201-DQA1*0501-DQB1*0301-DPA1 *02011DPB1*01011; and localized disease is associated with DPA1*0301-DPBl *0402. The substitution of one amino acid at position 11 of the HLA class II DP alpha 1 chain can be associated either with the disease (methionine) or with the putative immunity (alanine).77 The important functions of DQ molecules in immune regulation and the types of cytokine response are well established and are probably involved in the pathogenesis of onchocerciasis. 78-8o Age older than 14 years in individuals living in endemic areas may be associated with significantly greater risk of infection. 81 High intensity of infection with severe ocular pathology is observed to be more prevalent in males 55 ; this is usually ascribed to the predominance of outdoor activities in this population. In one study in Ecuador, females were shown to be significantly more frequently putatively immune than males,82 a finding corresponding to the lower microfilarial densities and reduced clinical manifestations seen in females in the same area. 83

The pathogenesis of onchocerciasis lesions derives directly from the presence of the foreign parasite in human tissue. The living macro- and microfilariae in the human organism provoke, in general, a very low local and systemic host immune response. They travel through the human tissues incredibly easily.73 The existence of suppressive mechanisms that inhibit the inflammatory response, protecting both the host and the parasite, is in the nature of the phenomenon of parasitism. Most of the pathology that eventually develops is the result of failure of these protective mechanisms due to the host inflammatory response against dying or dead microfilariae. The degree of pathology is directly related to the density of microfilarial infection and the intensity of the inflammatory response. The numbers of microfilariae dying daily in the tissues of infected individuals may range from 10,000 to 500,000, depending on the intensity of infection. 84 The inflammatory response and clinical manifestations depend on the balance between the parasite's ability to evade or suppress host defense mechanisms and the host's ability to regulate its immune response.

Disease The lesions in the eye are primarily caused by living, dying, and dead microfilariae. The exact route of entry of microfilariae into the ocular tissues is not completely clear. They may enter the eye by direct invasion from the

CHAPTER 40: ONCHOCERCIASIS

bulbar conjunctiva'll, 85; the posterior pole can be invaded by migration along the ciliary vessels and nerves 86 ; or they may enter through the retinal and choroidal blood vessels 87 and possibly through the optic nerve via the cerebrospinal fluid. 88 Findings of microfilariae in histologic sections of the sclera suggest the possibility of direct penetration of the parasite. 89 The microfilarial loads in the anterior chamber of the eye correlate significantly with those in the skin. 44 ,90, 91 The presence of microfilariae in skin snips from the outer canthus, in the cornea and the anterior chamber, is closely associated with keratitis punctata, sclerosing keratitis, iritis, and optic nerve atrophy.92,93 There is no such association with chorioretinitis. 93 Twenty or more microfilariae in the anterior chamber are considered to be a risk factor for blinding onchocerciasis. 94 There are few data regarding the pathology in the eye because of the lack of specimens for examination. There is no. or minimal inflammatory reaction around living microfilariae, and they apparently do not cause substantial damage to the ocular tissues. 53 In the cornea, usually after treatment with diethylcarbamazine, acute inflammation gives rise to transitory snowflake opacities-punctate keratitis. The inflammatory reaction around dying and dead microfilariae is accompanied by edema and infiltration by eosinophils. 53 ,57, 95 In sclerosing keratitis, eosinophils, neutrophils, and fibroblasts are observed53, 57; these are associated with limbitis. 53 The tendency of the organism to suppress inflammation is supported by immunohistologic studies ~n the conjunctiva and iris that demonstrate a predominance of CDS + suppressor T cells among the activated cells, with increased major histocompatability complex (MHC) class II expression 96 and increased expression of interleukin-4 (IL-4) mRNA.97 Experimental models of onchocercal keratitis have confirmed the greater potential of the savanna strain to produce corneal inflammation98 and have shown a predominance of CD4 + T cells,99 with the important participation of eosinophilsloo-l02 and IgE in the aqueous humor. lOl , 103 Upregulation of IL-4 and interleukin-5 (IL-5) mRNA production in the cornea indicates the importance of a Th2-type immune response in the development of onchocercal keratitis in the murine modep04 In IL-5 gene knockout mice, however, neutrophils were able to mediate keratitis and caused extensive stromal opacification and damage in the absence of eosinophils. l05 An immune response that mediates the development of experimental keratitis does not develop in IL-4 knockout mice. l06 On the other hand, protective immunity, in the absence of IL-4, develops and remains dependent on IL-5 and eosinophils.l0 7 The pathogenesis of chorioretinal lesions and optic nerve disease is not very clear. It is difficult to distinguish alterations produced by pathogenic molecules elaborated by the parasite from those resulting from the host immune response. 73 The finding of living microfilariae in the vitreous,92 in the retina in vivo,37, 48 and in histologic sections,53,86 together with observations that chorioretinal lesions progress within a few days after treatment with diethylcarbamazine,108, 109 indicates that the direct participation of dying or dead microfilariae and the host inflammatory response play important roles, at least ini-

tially, in the pathogenesis of onchocercal chorioretinitis. A slow progression of pre-existing chorioretinal lesions was also observed after treatment with ivermectin 48 , 1I0 and amocarzine,51 following a substantial reduction of microfilarial loads in the organism. This observation indicates that the density of microfilariae does not influence the progression of chorioretinitis, and that other factors are probably involved in the etiopathogenesis of chorioretinallesions. These observations and the finding of antiretinal autoantibodies in the sera and ocular fluids from onchocerciasis patients led to the idea of the possible involvement of autoimmunity in the perpetuation of ocular inflammation. Autoantibodies against retinal Santigen, Ill, 112 interphotoreceptor retinoid-binding protein (IRBP) ,111 and inner retinal and retinal photoreceptors lI3 were found in the sera and ocular fluids of the patient with onchocerciasis. Immunologic cross-reactivity of recombinant antigen from Onchocerca volvulus with the ocular component of the 40,000 M r in retina, optic nerve, iris, ciliary body, and cornea has been demonstrated, together with the presence of antibodies against this antigen in onchocerciasis patients with posterior segment pathology.1I4, 115 In only two studies was there an association between the presence of autoantibodies and the occurrence of chorioretinitis.II 2, 115 Two other studies showed no difference in onchocerciasis patients with and without chorioretinitis in the specific cellular lymphoproliferative response to S-antigen, IRBP, or recombinant Onchocerca volvulus antigen (Ov39) y6, 117

Systemic Immune Response There is clear evidence that immunity against Onchocerca volvulus exists, and differences in humoral and cellular responses between putatively immune (PI) individuals and microfiladermic (MF) infected individuals in endemic areas have been studied. 73 , 74 Cellular responses to parasite antigens in lymphocyte proliferation tests are usually diminished in MF onchocerciasis patients in comparison to PI individuals.1I8-121 The proliferative response can be restored when exogenous IL-2 is added to the culture. 119 , 122 The evidence shows a different pattern of cytokine production after stimulation of peripheral blood mononuclear cells (PBMCs) with Onchocerca volvulus antigen. A predominant Th2-type response in MF patients and a Thl-type response in PI individuals have been clearly demonstratedy8, 120, 123 Increased IL-IO production by PBMCs of MF patients without stimulation, in comparison with those from PI individuals, may suppress the Thl-type response and promote the development of the disease. 123 In one study, the cytokine production was measured by reverse transcription polymerase chain reaction (RTPCR) with respect to the presence or absence of ocular disease (sclerosing keratitis, uveitis) in MF individuals with both dermal and ocular microfilariae. 124 The expression of IL-4, IL-5, and IL-IO mRNA was significantly higher in persons with ocular disease, but levels of interferon-)' (IFN-)') were the same in both groups.124 Repeated treatment of onchocerciasis patients with ivermectin increases cellular immunity and the production of Thl-type cytokines. 12o The humoral response as measured by production of

CHAPTER 40: ONCHOCERCIASIS

specific IgG and IgG subclasses· in MF individuals is significantly increased in comparison to that in PI persons. 82 , 125-127 Many stage-specific onchocercal antigens are recognized only by sera from PI individuals and sera from mice and chimpanzees immunized by irradiated L3-stage larvae. They are not recognized by sera from infected patients. 128 , 129 Increased levels of total and parasite-specific IgE in onchocerciasis patients were also deIllonstrated. 82 ,121 The production of antibodies against tropomyosin isoform (MOv-14) was demonstrated in infected individuals and may play an important role in host protection. 130 A variety of autoantibodies in onchocerciasis patients have been detected, suggesting a potential role of autoimmunity in the pathogenesis of onchocerciasis. Increased levels of antibodies to calreticulin,131 an antigen identical to the 46-kD Ro/SS-A human autoantigen,132 with high (63%) homology to the ARAL-l antigen of Onchocerca volvulus, were detected in patients with onchocerciasis. The anticalreticulin antibodies were significantly increased in patients with ocular pathology.133 The antibodies to a 2.5-kD antigen identical to human defensins (peptides present in the azurophil granules of neutrophils) have .been detected in patients with "sowda."134 Both nonspecific and antigen-specific circulating immune complexes have been detected in patients with onchocerciasis.135-137 The correlation between immune complex levels was found to be positive for skin disease and negative for ocular disease. 138

DIAGNOSIS

Clinical Diagnosis A thorough dermatologic and ophthalmic exaIllination can be highly indicative of a diagnosis of onchocerciasis. The observation of characteristic clinical manifestations in endemic areas makes the diagnosis relatively easy. In patients from nonendemic areas, the diagnosis of onchocerciasis should be suspected if there is a history of travel to an endemic area and the patient presents with asymmetric pruritus, acute rash, and swelling of a limb. Definitive diagnosis requires the direct demonstration of the parasite by clinical examination and/or by laboratory investigation. Examination of cornea, anterior chamber, and iris on slit lamp; study of the vitreous and retina with a threemirror lens; and the use of direct and indirect ophthalmoscopy are of great importance. The best visualization of live microfilariae in the cornea is attained with high magnification (X 25) and retroillumination of the dilate.d eye. Patients should sit with their heads down on theIr knees for 2 to 5 minutes to allow free microfilariae to circulate in the aqueous humor before slit-lamp examination of the anterior chamber is performed. For detection of optic nerve involvement, a red-dot card screening te~t was developed. The time needed to complete the test IS 1 to 2 minutes; it records nonperception and desaturation of targets with a sensitivity of 54% and a specificity of 96%.139 Examination of the visual field by means ofperimetry may also be of value.

Parasitologic Diagnostic DETECTION OF MICROFILARIAE IN THE SKIN

The classic method for direct demonstration of microfilariae is microscopic, with the use of 0.1 ml of buffer or culture media after an overnight incubation of skin snips at room temperature 0'1' 37°C. 140 Two skin snips are prepared by lifting the skin with a needle and making a bloodless cut of the superficial dermis using a corneoscleral trephine or razor blade (Fig. 40-14). Given the geographic differences among skin infection s~~es in Mrica, two skin snips are taken from over each IlIac crest, whereas in Central America, the skin is taken from each deltoid or scapular region. 141 This method enables one to determine the prevalence and intensity of the infection. The sensitivity of this Illethod is not great and varies with infection intensity in the area. 142 For this reason, in areas with a low intensity of infection, six skin snips are taken. 141 This diagnostic method is now not well accepted by patients in the areas in which repeated skin snipping was performed. Also, the relatively low sensitivity in the diagnosis of early, light, or preclinical infection led to the development of alternative methods. 143 A new, more sensitive and painless alternative to skin snips is a PCR assay performed with a superficial skin scratch.144 DETECTION OF MACROFILARIAE IN NODULES

Ultrasonography may be useful in detecting deep nonpalpable nodules that normally escape clinical detection; it also may help in the differential diagnosis of nodules. 145 ,146 Nodule excision with histologic examination of adult worms can help to establish the definitive diagnosis of onchocerciasis. This surgical procedure can be performed under local anesthesia.

Rapid Methods

Diagnosis

These methods are economical, simple, and rapid; they provide tools for evaluating the epidemiologic situation and endemicity within a community. The most common method is an assessment of pretibial skin depigmentation, "leopard skin,"147, 148 or palpable nodules. 149 The evaluation of subcutaneous nodules by verbal assessment was

FIGURE 40-14. Skin snip by corneoscleral trephine.

CHAPTER 40: ONCHOCERCIASIS

shown to have a sensitivity of 93.5% and a specificity of 83.3%.150 Alternatively, a rapid community asseSSlnent for nodule presence may be achieved with a random sample of 30 men. Once three infectious individuals are identified, the prevalence of infection is likely to be greater than 20%.149 These methods 'are not accurate, but they can give a rough estimate of onchocerciasis prevalence.

Immunologic Skin Tests The Mazzotti test is based on the observation of an adverse reaction after the treatment of onchocerciasis with diethylcarbamazine (DEC) .151 This test may provoke serious complications and is no longer used in the routine diagnosis of onchocerciasis. Use of the Mazzotti test is now acceptable only in patients with suspected onchocerciasis when the parasite is not detectable in the skin or in the eye. The adult patient is given a single dose of 50 mg of DEC per os; 1 to 24 hours later, itching, skin rash, and lymphadenitis are observed as a reaction to the death of microfilariae. 18 The use of topical DEC in a cream, the "Mazzotti patch test,"152 was considered unreliable and has been abandoned. Because of its low price and relatively good sensitivity (80%) and specificity (97%) when using 10% DEC in Nivea milk, the possibilities for DEC patch test use are now being reevaluated. 143

Detection

of Antibodies

Radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) may be used to test for the presence of parasite-specific antibodies. These immunodiagnostic tests are being developed as tools for the detection of preclinical and low-level infections in endemic areas under control. The cardinal problems of low-specificity and sensitivity of these tests were partially solved by the detection of specific Onchocerca antigens153-155 and the cloning of 37 diagnostic specific antigens. Recombinant antigens were tested, and three antigens with high sensitivity to detect early infection (OvI6,156 Ov71,157, 158 and Ov11 159 ) were selected to form an "antigen tri-cocktail."160 The data to evaluate the specificity of this potentially very useful test have now been collected. 18 An ELISA assay using a combination of recombinant antigens OC (Onchocerca clone) 3.6 and OC 9.3 was shown to be a very sensitive test for detection of new infection. 161

Onchocerca. 165 This method has been used in the examination of people in endemic areas in Ecuador and Ghana. 166, 167 Positive results have been demonstrated not only in skin snip-positive but also in some skin snipnegative individuals. 0-150 PCR techniques allow one to study the transmission of different Onchocerca strains and species in fly vectors and in infected individuals. 72 , 168 These data are of utmost importance for epidemiologic studies in endemic areas.

DIAGNOSIS In the differential diagnosis of the skin symptoms and signs, the following conditions must be excluded: infection with Mansonella streptocerca, scabies, insect bites, prickly heat, contact dermatitis, sycosis cruris, post-traumatic and postinflammatory depigmentation, leprosy, tertiary yaws, and superficial mycosis. 169 Subcutaneous nodules, although typical, must be differentiated from IJlnph nodes, lipomas, fibromas, dermal cysts, and ganglia. 18, 169 Ultrasound examination of nodules may help in this differential diagnosis. 145 , 146 Asymmetric limb edema, isolated or accompanied by pruritus with acute rash, is typical for visitors from nonendemic areas. Blood eosinophilia above 2000jmln3 may be present. 170 There may be some similarity to the eosinophilic cellulitis seen in Well's sJl1.drome. l71 Elevated serum levels of angiotensin-coDverting enzyme (ACE) have been found in onchocerciasis patients; therefore, the interpretation of ACE activity should be exercised prudently, especially in patients from endemic areas. 172 Ocular corneal pathology should be distinguished from viral keratitis, exposure keratitis, nutritional keratopathy, phthisis bulbi from other causes,18 and peripheral keratitis associated with intermediate uveitis. In one report, anterior uveitis with a worm in the cornea of a female from the United States was found to be caused by a zoonotic worm of Onchocerca genus (probably Onchocerca cervicalis in which the horse is a host) .173 Chorioretinal pathology must be differentiated from other infectious diseases like toxoplasmosis, syphilis, and tuberculosis, which cause similar posterior changes, and from noninfectious ocular diseases such as retinitis pigmentosa. 17'1

DNA Probes

The goals of onchocerciasis treatment are to treat already infected patients in order to prevent debilitating pathologic eye and skin changes, and to break the life cycle of the parasite in order to prevent further transmission of the disease. Two principal strategies exist in the fight against onchocerciasis: (l) treatment by chemotherapy, and (2) control of the blackfly vector. Onchocerciasis can not be eradicated by these means, but a high level of disease control can be reached. 175

DNA probes specific for Onchocerca volvulus have been developed by the differential screen,ing of genomic DNA libraries. These DNA probes have been derived from a single repeated sequence family with a unit length of 150 base pairs, designated as 0-150 and present in approximately 2000 copies in the Onchocerca volvulus genome. 164 A polymerase chain reaction technique has been developed to recognize different strains (0. volvulus and O. ochengi) and different forms (rain forest and savanna) of

In the past, chemotherapy of onchocerciasis was limited to the use of diethylcarbamazine (DEC) 176,177 and suramin. 176 The use of these . two drugs is accompanied by serious systemic adverse effects, like Mazzotti reaction, proteinuria, and an increased serum level of circulating immunocomplexes. 135 Their use can also increase ocular inflammation 109, 135, 178-180 and may be the cause of optic

Detection

of Antigen

For a long time there was no satisfactory technique for direct onchocercal antigen detection. 162 New, sensitive, low-cost diagnostic tests to detect Onchocerca-specific antigens in tears, urine, and dermal fluid have been recently developed. 163

Treatment

CHAPTER 40: ONCHOCERCIASIS

nerve atrophy. 181 DEC is therefore no longer used and suramin is given only with close medical supervision. Since 1987, a new drug, ivermectin, has become the most widely accepted and used drug in the treatment of onchocerciasis. Ivermectin is a 22,23-dihydro derivative of ivermectin Bl, a macrocyclic lactone produced by an actinomycete, Streptomyces avermitilis; it is effective against helminthic parasites and arthropods and was first successfully used in veterinary medicine. 182 The efficacy and safety of ivermectin in the treatment of onchocerciasis in humans have been repeatedly demonstrated. 178 , 183, 184 The antiparasitic action of ivermectin is not completely understood, but its effect on neurotransmission through stimulation of l'-aminobutyric acid-mediated chloride ion conductance may playa role. 182 , 185 The level of resistance to ivermectin has not been described to date. 18 Ivermectin has a very potent microfilaricidal effect, substantially reducing microfilariae counts within a few days. The maximal effect is reached within a few weeks of treatment and is superior to that of DEC.178 Twelve months after a repeated 150-/Jug/kg annual dose of ivermectin treatment for 5 years, reduction of microfilarial loads exceeding 90% have been seen. 186 There is a significantly lower count of microfilariae when the treatment is repeated every 6 months in comparison with an annual treatment schedule at 1 and 2 years after the first treatment, although the difference at 2 years is very small. 187 , 188 An.other study demonstrated a striking difference in mean microfilarial loads between single-dose treatment and a multiple-dose, ~-i'6-month treatment regimen 18 months after the last dose. 189 The loads in the first group were twice as high as those in the second group. The data from this study also suggest that three or more doses of ivermectin given at 6-month intervals significantly slow microfilarial repopulation, probably through a cumulative effect on macrofilariae. 189 Multiple monthly doses of 150 /Jug/kg of ivermectin 190 and 6 doses of 100 /Jug/kg given at 2-week intervals 191 also have some macrofilaricidal effect. At 12 months, 12% of male and 22% of female worms were killed. 190 In a study using 3-month doses, the mortality of female worms at 25th and 34th months was 25.5% and 32.6%, respectively.192 There was a significantly higher proportion of nodules without male wonns, and both the insemination of females and embryogenesis were diminished after the treatment. 190, 191 Ivermectin also has the ability to decrease the level of transmission through a rapid reduction of vector infectiousness by Onchocerca volvulus with individual treatment given as one or two doses of 200 /Jug/kg of body weight at 6- and 7-month intervals, respectively.193, 194 Mass treatment given as two annual doses of 150 /Jug/kg of body weight in a large community of 14,000 people treated in Liberia reduced the number of infected flies (Simulium yahense) with developing Onclwcerca volvulus larvae by 93.4% to 95%.195 Community-based treatment with ivermectin decreases the transmission of infection as demonstrated by a statistically significant decrease (45% to 77%) in the incidence of new infections in untreated children. 196 ,197 Only a few reports have focused on the effectiveness of ivermectin treatment in the prevention of ocular

changes in infected patients and in the improvement of ocular pathology. Most microfilariae disappear from the eyes within a few weeks after the start. of treatment with only mild inflammation of the anterior segment; no increased inflammation or other pathology of the posterior pole has been observed. 187 , 198, 199 A substantial reduction in the prevalence of punctate keratitis and iridocyclitis after 2 to 6 years of repeated treatment with ivermectin has been described. 187,200-202 There is either n0 202 or a lessmarked reduction in the prevalence of sclerosing keratitis. 203 Regression of advanced sclerosing keratitis after repeated multiple-dose treatment was observed,20o as was reduction or stabilization of optic nerve disease,200, 203, 204 but no reduction in the prevalence and progression of chorioretinitis was found. 48 , 200, 201 Ivermectin is at the present time the drug of choice for the treatment of onchocerciasis; it is used in a single oral dose of 150 /Jug/kg of body weight once or twice a year. 205 The dosage schedule used in most large-scale treatment programs is based on a weight-adjusted dose with a target of 150 /Jug/kg. Standard dosage is 3 lUg for 15 to 25 kg, 6 mg for 26 to 44 kg, 9 mg for 45 to 64 kg, and 12 mg for 65 to 85 kg of body weight. The dose range is from 120 to 230 /Jug/kg. Because of the difficulties of weighing patients and halving the tablets in field conditions, leading to inaccurate doses, a simplified schedule for treatment based on patient height, which can be easily measured, has been suggested. 206 The dose based on height was established as 3 mg for 95 to 124 em, 6 mg for 125 to 149 em, and 9 mg for >150 em. During mass treatment in Nigeria using a standard dosing schedule of 150 /Jug/kg, 79.6% of patients were underdosed. 207 This led to a new suggested dosing schedule that doubled the standard dose of 150 /Jug/kg to 300 /Jug/kg.208 Ivermectin should not be given to children younger than 5 years of age or weighing less than 15 kg, during pregnancy, to nursing mothers during the first week of their child's life, or to persons with other serious illnesses. 18 Treatment strategy in expatriates and patients who are visiting or working in endemic areas is not well established. These patients have been successfully treated with the standard dose of 150 /Jug/kg and were retreated after 1 or 6 months, if necessary. Two reports indicate a higher frequency (61 %) of adverse reactions after the first dose of ivermectin in expatriates than in patients living in endemic areas. 208 , 209 Ivermectin is accepted as a safe and powerful drug in individual treatment and also in community-based largescale treatment programs, having no toxic effects in humans up to a total dose of 1.8 lng/kg of body weight. 18 Most adverse reactions are mild and self-limiting and are observed during the first 2 days after treatment. Most of them are similar to Mazzotti reaction but less severe. The most common reactions are itching, rash, edema of the limbs and face, musculoskeletal pain, painful swelling of lymph nodes, headache, dizziness, weakness, fever, and ocular irritation. Adverse reactions occur in approximately 1.3% to 16% of patients after the first treatment, and in less than 0.5% after the second treatment. 183 , 210-213 Severe reactions such as severe syrnptomatic postural hypotension, dizziness, fever, dyspnea, or pain occurred in 0.24% of a population of 50,929 treated persons. 212 The

CHAPTER 40: ONCHOCERCIASIS

most common side effect of mass treatment by ivermectin is the passing of intestinal worms like AscariS. 214 In areas with endemic onchocerciasis and loiasis, the development of severe encephalopathy, sometimes with coma, was seen in 0.11 % of patients treated with ivermectin. 215 Counts of Loa loa microfilariae higher than 8000 microfilariae/ml significantly increase the relative risk of encephalopathy.215, 216 Before mass treatment, an epidemiologic survey assessing the intensity of Loa loa infection should be performed in areas with endemic onchocerciasis and loiasis, as well as close monitoring after the ivermectin treatment.215, 216 No difference in the rate of major congenital malformations or in the developmental status of 203 children born after inadvertent treatment of their mothers with ivermectin was seen in one study.217 Mass treatment with ivermectin may decrease the frequency of spontaneous abortion in hyperendemic areas. 218 Suramin is the only powerful macrofilaricidal drug used for the treatment of onchocerciasis that has good microfilaricidal activity. Because of its high toxicity, it is not used in large-scale treatment programs. The use of suramin is now limited to the treatment of patients leaving an endemic area or patients with uncontrolled onchodermatitis. 18 The total dose of suramin for an adult weighing at least 60 kg should be 4.0 g. If this dose is well tolerated, an additional dose of 1.0 g can be administered. 57 The recommended schedule for treatment with suramin is as follows: ~.3

1st week 2nd week 3rd week 4th week 5th week 6th week

0.2 0.4 0.6 0.8 1.0 1.0

Total dose

4.0 g or 66.7 mg/kg

g g g g g g

or or or or or or

mg/kg 6.7 mg/kg 10.0 mg/kg 13.3 mg/kg 16.7 mg/kg 16.7 mg/kg

This treatment demonstrated a significant reduction of microfilariae in the skin and in the eye, which lasted for 30 months. 219 The most common serious adverse reactions related to suramin treatment are the Mazzotti reaction, anaphylaxis, nephropathy, skin and mucous membrane exfoliation, icterus, and death. 57 There are concerns about the higher occurrence of optic atrophy and chorioretinitis after treatment with suramin with or without DEC. 176, 219 Suramin treatment is administered intravenously during hospitalization. The patient should be monitored for several weeks after completion of the treatment for the late development of an adverse reaction. Before the administration of subsequent doses of suramin, patients need to have a complete physical examination, as well as urine, hematologic, and ophthalmologic, studies. If all precautions are taken, treatment with suramin is effective and relatively safe. 220 Early reports of potent microfilaricidal and macrofilaricidal effects of amocarzine, the piperazinyl derivative of amoscanate, from studies in the Americas 221 were not confirmed by further studies in Mrica. 222 Treatment of three groups of patients with ivermectin and amocarzine, either separately or in combination, demonstrated an inferior microfilaricidal and macrofilaricidal effect of amocarzine. 222 In addition, amocarzine treatment does

not prevent the progression of onchocercal chorioretinopathy.51 Local and systemic treatment with corticosteroids and mydriatics also should be considered, together with specific antibiotic therapy with ivermectin for patients with acute ocular inflammation, keratitis, and uveitis. The possibility of effective local ocular treatment by diethylcarbamazine citrate and levamisole eyedrops was investigated in two studies. 223 , 224 Both drugs have the potential for local killing of microfilariae but, because of practical difficulties, this treatment was not studied further.

Nodulectomy Surgical removal of the source of the microfilariae-adult worms-by nodulectomy would be a logical approach to the treatment of onchocerciasis. The results of vast nodulectomy campaigns in Guatemala and Mexico are, despite some favorable reports, not conclusive. 18 One of the reasons for their poor efficacy is that more than one third of nodules are not palpable and escape examination. A combination of chemotherapy with nodulectomy has been shown to be of some benefit for lesions involving the anterior segment of the eye. 225 Because of improved chemotherapy and the questionable benefit, invasiveness,· and technical difficulties associated with surgical procedures (given the geographic areas where onchocerciasis is usually treated), the use of nodulectomy is limited. Because a high concentration of microfilariae in the skin around the eye and in the anterior segment is associated with the presence of a head nodule, consideration should be given to excision of these nodules. 226

Control Onchocerciasis represents major health and socioeconomic problems in endemic areas. In hyperendemic areas, high rates of blindness, pruritus, and skin disfiguration lead to instability in community life, the migration of whole villages, the disruption of economic and family life, social stigmatization, and marginalization of infected individuals. 18 The ultimate goal, the eradication of onchocerciasis, is not realistic in the near future; only a high level of disease control is possible. 175 The combination of large-scale treatment with ivermectin and vector control by larviciding seems to be the most powerful strategy for the reduction of onchocerciasis transmission. 227 The Onchocerciasis Control Program (OCP) was launched by the World Health Organization in 1974 in seven countries in West Mrica; later, it was extended to eleven because of an invasion by blackflies from countries outside the OCP.228 OCP started its operations by extensive larviciding and, beginning in 1989, the use of largescale treatment with ivermectin. OCP is considered a major success in public health management. 229 It has been estimated that in OCP countries between the years 1974 and 1995, more than 100,000 people were prevented from going blind, 30 million people were protected from ocular and skin lesions, and 10 million children born in this period were not infected and are at no risk of blindness. 18i 230 The introduction of ivermectin and the commitment of its manufacturer, Merck and Company, to a free supply of the drug enabled OCP to

G

CHAPTER 40: ONCHOCERCIASIS

add chemotherapy to its program and to develop new programs: the Mrican Program for Onchocerciasis Control (APOC) in 19 Mrican countries not involved in OCP, and the Onchocerciasis Elimination Program in the Americas (OEPA), based mainly on the sustainable delivery of community-directed treatment with Mectizan (ivermectin). The number of treatments provided by the Mectizan Donation Program in Mrica and the Americas increased from 1.4 million in 1990 to 19.0 million in 1996.18, 230 The elimination of onchocerciasis transmission through vector control is based on the killing of the larvae of the vector (Simulium species) in their breeding sites by aerial application of insecticides to rivers. Rotational use of seven insecticides (biologic-Bacillus thuringiensis; organophosphates-temephos, phoxim, pyraclofos; synthetic pyrethroids-permethrin, etofenprox; and carbamate-carbosulfan) is the most cost-effective approach; it prevents the development of resistant populations and protects the environment. 231 A reduction of fly bites can be accomplished by the wearing of clothing that covers most of the body, the use of insect repellents, and the avoidance of breeding sites, especially during the times of peak fly activity (during the morning and in the evening). Surveillance of the target areas following successful elimination of the parasite reservoir to prevent recrudescence of the transmission is crucial. To evaluate the epidemiologic situation and to predict trends in OCP countries, the computer simulation ~odel ONCHOSIM has been successfully used. 18 For easy determination of the presence of Onchocerca volvulus infection in the blackfly pool, PCR may be used. 232 , 233 One of the major limitations in the treatment of onchocerciasis is the lack of safe and effective macrofilaricidal drugs suitable for large-scale treatment. The development of a suitable vaccine would provide yet another avenue for the prevention and control of onchocerciasis.

NATURAL HISTORY AND PROGNOSIS There is no detailed information concerning the. natural history and evolution of onchocerciasis. From a few studies in which the population in endemic areas was followed over the long term, some conclusions can be drawn. The evolution of ocular onchocerciasis is usually slow and protracted, with the period between initial infection and clinical presentation of ocular pathology spanning many years. The skin microfilarial loads have a tendency to increase with age, and the development of eye pathology is closely related to the intensity of infection. 54,85 The eye disease and blindness are therefore more prevalent in hyperendemic areas; usually only mild ocular involvement is observed in hypoendemic regions. 85 Eye lesions and visual impairment are therefore rare between the ages of 10 and 19 years; they increase .during the third decade and reach their zenith after age 40. 85 In areas in which the annual biting rate is lower than 1000 and the ATP is lower than 100, blinding eye lesions should not develop. In general, anterior segment inflammation is more severe and progressive in disease caused by the savanna strain as compared with the rain forest strain of Onchocerca volvulus. 92 Posterior lesions do not exhibit differences

among patients from rain forest or savanna areas,'18 but optic neuritis is an important cause of blindness among savanna residents. In hyperendemic areas, the mortality among blind individuals was found to be increased fourfold. 234 In another study, 12 of 16 blind individuals died within a period of 9 years. 52

CONCLUSIONS Onchocerciasis is a well-described clinical entity. The wealth of information regarding the pathogenesis and immunobiology of the ocular disease (except posterior segment lesions) has led to the development of sophisticated diagnostic tools, new medications, and effective strategies for the treatment and control of the disease. A major problem in the treatment of onchocerciasis has been the lack of a macrofilaricidal drug. Owing to the major effort of WHO programs and the continual donation of ivermectin by Merck and Company for its treatment, onchocerciasis has ceased to be a major cause of blindness or a major public health problem in OCP countries in West Mrica. Unfortunately, this is not true for countries outside the OCP area; thus, onchocerciasis should not be considered a problem solved. Eradication of the disease by the means now available is impossible, and recrudescence of the disease, even in countries in which control has been achieved, is still possible and requires vigilant surveillance.

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scale ivermectin distribution and vector control on transmission of Onchocerca volvulus in the Niger basin, Guinea. Bull World Health Organ 1995;73:199. De Sole G, Baker R, Dadzie KY, et al: Onchocerciasis distribution and severity in five West Mrican countries. Bull World Health Organ 1991;69:689. Samba EM: The Onchocerciasis Control Programme in West Mrica. Geneva, World Health Organization, 1994. Molyn.eux DH, Davies JB: Onchocerciasis control: Moving toward the millennium. Parasitol Today 1997;13:417. Hougard JM, Yameogo L, Seketeli A, et al: Twenty-two years of blackfly control in the Onchocerciasis Control Programme in West Mrica. Parasitol Today 1997;13:425. Davies JB, Oskam L, Lujan R, et al: Detection of Onchocerca volvulus DNA in pools of wild-caught Simulium ochraceum by use of the polymerase chain reaction. Ann Trop Med Parasitol 1998;92:295. Yameogo L, Toe L, Hougard JM, et al: Pool screen polymerase chain reaction for estimating the prevalence of Onchocerca volvulus infection in Simulium damnosum sensu lato: Results of a field trial in an area subject to successful vector control. Am J Trop Med Hyg 1999;60:124. Prost A, Vaugelade J: La surmortalite des aveugles en zone de savane ouest-africaine. Bull OMS 1981;59:773.

YosufEl-Shabrawi

Loiasis is a chronic parasitic disease caused by the filarial parasite Loa loa. It is characterized by two major features, Calabar swelling (which is localized angioedema) and subconjunctival migration of the filarial worm. 1 Filarial worms such as Loa loa are nematodes (roundworms) that dwell in the subcutaneous tissue or lymphatics. Eight nematode species infect humans; of these, four- Wucheria bancrofti, Brugia malayi, Onchocerca volvulus, and Loa loa-are responsible· for the most serious filarial infections. 2

HISTORY Philipp Pigafetta (1533-1603) translated the oral Mrican report of the Portuguese Eduart Lopez into the Italian language. But contrary to the common theori a that Loa loa was first noted by Pigafetta, there is no reference to the Mrican eye worm in Pigafetta's work. 2b The first verified report of a subconjunctival worm was by Mongin. He removed a subconjunctival worm in an Mrican girl in the West Indies in 1770. The name Loa has first noted by a French navy surgeon, Guyot. He frequently found a conjunctivitis caused by worms in natives of Angola, and he described them as Loa loa. iin 1895, D. Argyll Robertson described the adult worm that he extracted from the eye of a womatl who had resided at Old Calabar in West Mrica. 3 In 1891, Manson found microfilariae in the blood, naming them "microfilaria diurna." He suggested Chrysops dimidiata as the intermediate host, later proven by Leiper in 1913. 3a

EPIDEMIOLOGY Loiasis is endemic to the rain forests of Nigeria, Zaire, northwest An.gola, the Congo, Chad, the Central Mrican Republic, Gabon, the Cameroon Republic, and southwest Sudan. 4 Up to 13 million people are estimated to be infected. In hyperendemic areas, exposure may approach up to 100%. If Loa loa is carried to other parts of the world, as by Mricans to America, or European colonists returning home, the worm dies out. The reason is the localization of its intermediate host, the female bloodsucking mangrove flies Chrysops silacea and C. dimidiata, to the rain forests of Mrica. These vectors are day-biting flies that are attracted by people moving through open spaces in tlle jungle. They usually settle on the ankles, exciting little or no pain, and draw large quantities of blood. These flies are infected by ingesting human blood contaminated with parasitic microfilaria. 4 In Calabar, 3.5% of wild flies that are caught carry Loa loa. Monkeys, especially the drill (Mandrillus leucophaeus) , harbor a form of Loa, but the microfilariae of this form are nocturnally periodic and the vectors are the night-biting Chrysops langi and Chrysops centurionis. Although the two strains have been hybridrized experimentally, it is unlikely that monkeys act as reservoir hosts, because the nocturnal vector species of Chrysops do not usually bite humans.

In the fly, the microfilaria (primarily 250 to 300 /-Lm long by 6 to 8 /-Lm wide)5 penetrate the intestinal wall and become infectious larvae intracellularly. Within 3 days after ingestion, the larva becomes broad and torpedo shaped; on the fourth and fifth days, the squat form lengthens to 0.8 to 1 mm; on the sixth day, the corkscrewlike appearance is replaced by gentle curves. The development is complete after 10 days, when the microfilariae reach a size of 2 mm by 0.03 mm. Then the larvae congregate in the head of the fly in large numbers. Every time an infected fly feeds, larvae emerge and are deposited on the human skin, from which they disappear rapidly by burrowing into the skin. In the mammalian host, the worms migrate along the interfascial planes, where they develop into adults. In about 4 to 6 months, after mating, the gravid females release microfilariae, which enter the host's circulatory system. Mter transmission to another fly, a new life cycle is initiated. The microfilariae of Loa loa circulate in the blood of humans with a diurnal periodicity whose peak occurs around noon. 4

MORPHOLOGY Loa loa is a filiform, cylindrical, whitish, semitransparent worm with numerous round and smooth translucent protuberances and a blunt tail. Males measure 3 to 3.4 cm in length and 0.35 to 0.43 mm in width; females are bigger (5 to 7 cm by 0.5 mm). The cuticle is covered with small bosses, which is helpful in histologically distinguishing Loa loa from other filarial parasites. 4 The microfilarial loa is similar in size and structure to microfilarial bancrofti. In fresh blood, it may be impossible to distinguish them. In dried stained films, Loa loa assumes an angular attitude, the tail end giving a corkscrew appearance. Microfilarial loa takes up methylene blue (diluted 1:5000) in 10 minutes, as opposed to microfilarial bancrofti, which is much slower to do SO.4

Systemic The most common pathology associated with Loa loa in humans is Calabar swelling,1, 2 named after the region in Mrica where it was first described. Other reported systemic complications include nephropathy, 6 cardiomyopathy,2 arthritis, lymphangitis, peripheral neuropathy,7 and encephalopathy.5, s, 9 Sites of Calabar swelling1, 2 are localized areas of erythema and angioedema, often 5 to 10 cm or more in size. They often occur on extremities, typically around joints such as the wrist of knee, and last for about 1 to 3 days before spontaneous regression. If the inflammatory reaction extends to nearby joints or peripheral nerves, corresponding symptoms may emerge. These swellings appear to be caused by hyperemic reactions to adult worms. Calabar swellings are usually found

CHAPTER 41: LOIASIS

in expatriates and can be totally absent in patients native of microfilaremia sometimes makes the diagnosis diffito areas with high incidences of Loa loa infections.10, 11 cult. They may in some instances occur only during treatment with diethylcarbamazine (DEC). In addition to Calabar Ocular Manifestations swellings, multiple papillomatous erythemas may occur as The characteristics of ocular involvement by Loa loa are soon as 1 to 4 weeks after infection.10, 12 These represent listed in Table 41-1. subcutaneous moving larvae. The nephropathy,5,6 generally presenting with proteinOrbit uria, appears to be immune-complex mediated. Renal Lids When the worms appear in the subcutaneous tissues of biopsies show signs of chronic glomerulonephritis or the lids and orbit, they may induce intense irritation membranous glomerulonephropathy. Following DEC and edema. These swellings may be of considerable size, treatment, the proteinuria may increase transiently. Encephalopatht' 8, 9 occurred only rarely before treat- reaching from the lid margins to the brows, and they ment with DEC became available, but it has become may disappear as rapidly as they appear, when the worm burrows into deeper tissues. These sojourns of the worm, a feared and increasingly observed complication. The leaving the subcutaneous tissues of the lids for the conpathogenesis is not yet clear, but two possibilities have junctiva, disappearing into the orbit, flitting over the been proposed: (1) an allergic reaction to dying microfibridge of the nose to the lids of the other eye or down laria in association with apre-existing subacute encephaliacross the cheek, cause intense irritation to the patient. tis, and (2) a Herxheimer's reaction to released neuroAs a general rule, heat entices the parasite to the surface, tropic endotoxin. The symptoms may range from whereas cold drives it into deeper tissues. 13 , 14 psychoneurotic complaints such as insomnia, irritability, depression, and headache, to coma and death after treatment with DEC in patients with high concentrations of Conjunctiva microfilaremia (over 500 microfilariae per 20 mm 3).1 Mi- This worm has also been named Mrican eye worm. Subcrofilariae are often found in the cerebrospinal fluid. 5 conjunctival migration of the filariae is the most common Pathologic findings in these patients are (1) a generalized ocular involvement16-28 and often the only clinical sign in acute cerebral edema, thought to originate as an allergic a patient with loiasis. Their presence under the conjuncreaction to the parasite or parasitic "debris" after DEC tiva usually leads to itching, pain, foreign body sensation, treatment, or (2) a chronic subacute encephalitis charac- irritation, and a mild hyperemia of the conjunctiva. These terized by a necrotizing granulomato'tls reactions to de- signs may persist until the worm burrows into deeper generating microfilariae found not only associated with tissues or is paralyzed by the instillation of cocaine, bringthe cerebral vessels htit also extending to the paren- ing instant relief. 13 An acute periorbital angioedema and chyma. Retinal hemorrhages frequently accompany the conjunctival nodules may evolve as the result of the presence of a dead worm. 13 Rarely, the nematode may be encephalitis. Cardiomyopathi' 5 is related to loiasis more circum- encysted in the subconjunctival tissues. 15 stantially. Epidemiologic correlations have been found between the distribution of loiasis and endomyocardial fibrosis. Patients present with characteristic cardiac abnor- TABLE 41-1. CHARACTERISTICS OF OCULAR malities, such as fibrosis of the endocardium in one or INVOLV~MENT BY LOA LOA both ventricles that affects the apex and the inflow tracts. Conjunctiva and lids In addition, high levels of peripheral blood eosinophilia Presence of adult worm and elevated levels of antifilarial titers are found in these Mild hyperemia patients. Although the relationship between the endoPeriorbital angioedema myocardial fibrosis and loiasis is not yet clear, it may be Conjunctival nodules less the filariae themselves and more the eosinophilia Anterior segment Presence of adult worm that leads to the cardiac damage, because the cardiac Edema of the iris and ciliary body lesions found resemble those found in Loffler's fibroblasFibrous membrane in the chamber angle tic parietal endocarditis, an entity characterized by a disCells and flare in the anterior chamber order of eosinophil production known as hypereosinophiLens Cataract lie syndrome. 5 It has become apparent that there are significant differences in clinical manifestations of infections between visitors to endemic regions and natives. 11 In the native population, loiasis is often an asymptomatic infection despite high levels of microfilaremia. Infections may be recognized only after subconjunctival migration of adult worms or manifestations of Calabar swellings. Nephropathy, encephalopathy, and cardiomyopathy are rare. In temporary residents or visitors, allergic symptoms predominate. Calabar swelling tends to be more frequent, microfilaremia is rare, and eosinophilia and increased levels of antifilarial antibodies are characteristic. The lack

Choroid Chronic perivascular inflammatory infiltrate Presence of microfilaria Retina Retinal edema Exudative retinal detachment Subretinal fluid with the presence of microfilaria Large superficial hemorrhagic sheets Disseminated yellowish exudates Retinal vessels Obstructed arterioles Microaneurysms occluded by microfilaria Chronic perivascular inflammatory infiltrate Occlusion of the central retinal artery

CHAPTER 41:

nn'lI'iOfY"d'lifY'

Segment

Intracameral migration of Loa loa is very rare. 29-3I The worms, if still alive, are usually seen by the patients as moving shadows. Atropine may restrict the movements and kill the worm, but pilocarpine apparently irritates it and makes it burrow deeper into the tissues.I3, 20 The presence of a live worm may in some instances initially cause surprisingly little inflammation. I3 , 29, 31 Mter the worm dies, an eye that has tolerated the living filaria well for a long period may suddenly become inflamed,I3, 31 showing considerable inflammatory response, with signs of extensive iridocyclitis, which is usually associated with some degree of keratitis, a cloudy aqueous, vitreous opacification, and raised intraocular pressure. I3 Apart from these inflammatory signs, however, symptoms may be very mild unless the worms burrow into the ciliary body, in which case the pain may be excrutiatingY

Posterior Segment Reports of posterior segment involvement by Loa loa are very limited. As documented by Osuntokun and Olurin 3I and by Toussaint and Danis,32 the presence of nematodes in the posterior segment is usually associated with massive retinal destruction. In most circumstances, extensive hemorrhagic lesions have been reported, associated with either retinal detachment, retinal neovascularization with vitreous hemorrhage, a subretinal exudate,31 or the presence of multiple yellowish exudates throughout the retina and the presence of occluded arterioles. 32 Under these circumstances, free microfilariaet may be found in the retina and lumina of retinal and choroidal vessels on histologic evaluation. In addition to an inflalnmatory response, acute retinal ischemia may result from occlusion of the central artery by microfilariae. 33 , 34 Toussaint and Danis 32 described a 38-year-old man who later died of filarial meningoencephalitis. The patient was referred to the hospital because of bilateral reduction of vision with photophobia, increased size of the parotid gland, disseminated petechiae over his whole body, and a mobile worm in the left upper lid. At this stage, the patient was somnolent. Funduscopic examination revealed multiple superficial hemorrhagic lesions, partially covered with a yellowish exudate throughout the retina. In addition, several occluded arterioles were present. The histologic examination showed extensive hemorrhagic sheets, serous exudates, and free microfilariae in the retina. The luminae of several retinal and choroidal vessels were distended by microfilariae and surrounded by chronic inflammatory cells. Osuntokun and Olurin 3I described two patients with an intraocular Loa loa. The first patient, a 22-year-old Nigerian woman, reported to the hospital with a 6-month history of pain, itching, and a sensation of a worm in her right eye. There was no light perception, the cornea was hazy, and, in the anterior chamber, a vigorously moving worm was seen. Mter enucleation of the eye, a total retinal detachment with gelatinous exudate was seen, with the features of a male Loa loa in the anterior chamber. The second patient, a I5-year-old Nigerian girl, was referred to the hospital because of pain and feelings of a worm in her right eye for 5 months. Minimal flare and cells were present in the anterior chamber. The patient

was scheduled for surgical removal of the worm 1 week later but did not return until 3 months later, when she complained of further pain. The worm was no longer mobile and was embedded in a thick fibrinous membrane. Because of the development of violent inflammation after removal of the worm, the eye had to be enucleated.

DIAGNOSIS A definitive diagnosis of loiasis requires the detection of either microfilariae in the peripheral blood, urine, or other body fluid, or the isolation of an adult worm. In practice, the diagnosis must often be based on a characteristic history, clinical presentation, blood eosinophilia, and elevated levels of antifilarial antibodies, particularly in travelers to the endemic regions, who are usually amicrofilaric. Other clinical findings include hypergammaglobulinemia, elevated levels of serum IgE, and elevated leukocytes. 1, 2

Detection of Microfilaria in

Specimen Specimens should be collected before treatment IS 11lltlated. Since the parasitemia varies with the filarial species, a travel history should be obtained to maximize the best collection time fot the species of filaria suspected. The best collection time for Loa loa is midday (between 10 AM and 2 PM).

Type

of Sample

Venous blood samples provide sufficient material for performing a variety of tests. Earlobe or finger-prick blood may be taken for direct wet, thin, and thick blood smears. At least two thick smears and two thin smears should be prepared as soon as possible after collection. For increased sensitivity, concentration techniques can be used. These include centrifugation of the blood sample lysed in 2% formalin (Knott's technique), or filtration through a 3-f-1m Nucleopore membrane. Smears can be stained with Giemsa or hematoxylin and eosin. Filaria may even be detected in the urine or other body fluids of a patient with a high level of microfilaremia or soon after DEC treatment has been initiated. Pronounced eosinophilia is seen in association with the liberation of microfilariae from the female worm, with corresponding clinical correlates of Calabar swelling and pruritus, thought to be an IgE-mediated allergic response. Typically, the eosinophil count can be from 20,000 to 50,000jmm 3 •

Microscopy Loa loa microfilaria are sheathed with a relatively dense nuclear column. The tail tapers and is frequently coiled, and the nuclei extend to the end of the tai1. 4

Molecular Diagnosis Earlier methods using species-specific radiolabeled probes to target DNA35 have been replaced by more sensitive and specific polymerase chain reaction-based assays.36,37

CHAPTER 41: LOIASIS

Antibody Detection Diagnosis by the detection of antibodies is of lilnited value because of substantial cross reactivity between filaria and other helminths. Furthermore, a positive serologic test does not distinguish between past and current infections. For indirect serum immunofluorescence antibody tests 1, 22 or enzyme-linked immunosorbent assays (ELISA) ,38 the antigen usually used is from the canine heartworm Dirofilaria immitis. Attempts to use a Loa loaspecific antigen have been proven sensitive but not adequately specific. 39, 40

Antigen Detection Using an ilnmunoassay (e.g., ELISA)41 for circulating Loa loa antigens is a useful approach, especially in cases of low microfilaremia,· but its results have to be considered with care because of its high cross reactivity.

TREATMENT

Surgical Removal

the Worm

Adult worms may be removed from under the conjunctiva by first anesthetizing them with either atropine or 10% cocaine. Pilocarpine should not be used, because it is known to irritate the worm, which may then disappear into deeper tissues. 13 , 20 The worm should first be firmly immobilized using a forceps and then removed after incising the conjunctiva.

Diethylcarbamazine DEC has been the therapeutic mainstay for the last 40 years and has proven effective against both the microfilaria and the adult worm. The exact mechanism of action is still not clear. It is thought that DEC leads to a hyperpolarization of the muscle cells of the parasite, inhibiting movement, and that it induces morphologic alterations on the surface layers of the filarial membrane, exposing previously hidden antigenic determinants and stimulating a host inflammatory response. 42-44 The inflammatory response following DEC treatment may take the form of a Mazzotti reaction with dermatologic and neurologic manifestations. Encephalitis, rarely observed before the introduction of DEC in 1947, has been seen increasingly as a complication of therapy that may lead to death or severe neuropsychiatric sequelae. Persons with microfilaremia (above 500 organisms per 20 mm3 blood) are at highest risk, and a single dose of DEC can precipitate the reaction. 5 Therefore, concomitant treatment with corticosteroids and antihistamines is highly recommended to reduce the risk of allergic reactions caused by the destruction of microfilariae. The current therapy consists of administering 6 to 8 mg of DEC per kilogram of body weight in three divided doses per day over a 3-week period. 12 Therapy can be initiated with 50 mg three times daily and each dose thereafter is increased by 50 mg until a dose of 6 to 8 mg/kg body weight has been reached. Gradually increasing the dose seems to diminish the adverse side effects caused by the drug. Depending on the microfilaria counts, up to three courses of DEC treatment may be required. 12 In the case of high microfilaremia (500 mi-

crofilariae per 20 mm 3 blood), lower starting doses as small as 0.5 mg/kg/ day are recommended with additional corticosteroids (40 to 60 mg/day). If the antifilarial treatment does not have any adverse side effects, the prednisone can be rapidly tapered and the DEC dose gradually increased to 6 to 8 mg/kg/ day. Care should be taken to ascertain whether the patient also has onchocerciasis, as DEC can cause severe cutaneous reactions in such patients. 1

Ivermectin Ivermectin is a safer drug than DEC and is used in a single dose. Adverse neurologic side effects as seen with DEC have not been described with ivermectin. It has been shown to reduce microfilaremia, but it does not seem to be effective against adult worms. 45 , 46 Ivermectin should be given at a dose of 200 to 400 j-Lg/kg body weight. Pretreatment with ivermectin, before the use of DEC, to reduce the chance of neurologic complications seems to be a possible way of treating patients with heavy microfilaremia.

Albendazole Albendazole, 200 mg twice daily for 3 weeks, is effective only against adult worms. 47 Because of its minimal effect against microfilariae, allergic side effects are very unlikely. The effect of albendazole, based on a continuous slow reduction of microfilaremia, correlates well with the average survival of microfilaria (6 to 14 months) .

Mebendazole Mebendazole, in dosages of 100 to 500 mg 3 times a day over 28 days, has been shown to reduce microfilaremia over 4 to 6 weeks without complications, but it is not known whether it is active against adult worms. 1

PREVENTION CHEMOPROPHYLAXIS Prevention depends on avoiding places where biting flies are numerous, wearing protective clothing, and using insect repellents. DEC can be used as a chemoprophylactic agent given either at a dose of 300 mg once weekly or 200 mg twice daily over three consecutive days once a month. 48

References 1. Duke BOL: Loiasis. In: Strickland GT, ed: Hunter's Tropical Medicine, 7th ed. Philadelphia, W.B. Saunders, 1992, pp 727-772. 2. Nutman TB, Weller PF: Harrison's Principles ofInternal Medicine, 14th ed. New York, McGraw-Hill, 1998, p 1215. 2a. Belding D: Te,xtbook of Parasitology, 3rd ed. New York, AppletonCentury-Crofts, 1965, p 542. 2b. Gruntzig J: The first description of Loa loa infestation of the eye by Pigafetta: A historical error. Klin Monatsbl Augenheilkd 1976;169:383-386. 3. Lymie S, Bruckner G, Bruckner DA: Diagnostic Medical Parasitology, 3rd ed. Washington, DC, ASM Press, 1997, pp 275-291. 3a. Manson-Bahr: Proc R Soc Med 1939;31:1623. 4. Wilcocks, Manson-Bahr: Manson's Tropical Diseases, 17th ed. Baltimore, Williams and Wilkins, 1972, pp 1051-1054. 5. Ottesen AE, Warren KS, Mahmoud AAF: Tropical and Geographical Medicine, 2nd ed. New York, McGraw-Hill Information Service, 1990, pp 403-405. 6. Pillay VKG, Kirch E, Kurtzman NA: Glomerulonephropathy associated with filarial loiasis. JAMA 1973;225:179.

CHAPTER 41: 7. Schofield FD: Two cases of loiasis with peripheral nerve involvement. Trans R Soc Trop MedHyg 1955;49:588-589. 8. VanBogaert L, Dubois A, Janssen PG: Encephalitis in Loa loa filariasis.] Neurol Neurosurg Psychiatry 1955;18:103. 9. Carme B, Boulesteix], Boutes H, Puruhence MG: Five cases of encephalitis during treatment of loiasis with diethycarbamazine. Am ] Trop Med Hyg 1991;44:684-690. 10. Canne B, Mamboueni]P, Copin N, Noireau F: Clinical and biological study of Loa loa filariasis in Congolese. Am ] Trop Med Hyg 1989;41:331-337. 11. Klion AD, Massougbodji A, Sadeler BC, et al: Loiasis in endemic and nonendemic populations: Immunologically mediated differences in clinical presentation.] Infect Dis 1991;163:1318-1325. 12. Greene BM: Loiasis. In: Gorbach SL, Bratlett NR, Blacklow, eds: Infectious Diseases. Philadelphia: W.B. Saunders, 1992, pp 20122013. 13. Duke-Elder WS. Systems of Ophthalmology, 2nd ed. London, Henry Kimpton, 1968, pp 401-405. 14. Fleck BW, MacDonald M: Periocular Loa loa in eastern Scotland: A report of two cases.] R ColI Surg Edinb 1987;32:163-165. 15. Carme B, Botaka E, Lehenaff YM: Dead Loa loa filaria in a subconjunctival site. Apropos of a case.] Fr Ophthalmol 1988;11:865-867. 16. Reisman], Krolman GM, Hogg GR: COl'Uunctival Loa loa. Can] Ophthalmol 1974;9:379-380. 17. ]ohnsons G], Axsmith K, Desser SS: The elusive Loa loa. A case report of ocular filariasis in Canada. Can] OphthalmoI1973;8:492496. 18. Sacks HN, Williams DN, Eifrig DE: Loiasis. Report of a case and review of the literature. Arch Intern Med 1976;136:914-915. 19. Wiesinger EC, Winkler S, Egger S, et al: Mrikanischer Augenwurm als Erstmanifestation einer Loiasis. Dtsch Med Wochenschr 1995;120:1156-1160. 20. Sachs HG, Heep M, Gaberl VP: Chirugische Wurmentfernung bei Loa-Loa Ophthalmie. Klin Monatsbl Augenheilkd 1998;213:367369. 21. Patel CK, Churchill D, Teimory M, Tabendeh H: Unexplained foreign body sensation: Thinking"lof loiasis in at risk patients prevents significant morbidity. Eye 1993;7:714-715. 22. Radda TM, Picher 0, Egerer I, Gnad HD: Serum immunofluorescence examination in Loa ophtlulmia. Klin Monatsbl Augenheilkd 1981;178:147-148. 23. Grupp A: A case of Loa-loa filariasis. Klin Monatsbl Augenheilkd 1975;167:70-76. 24. Vey EK: Filaria-Loa-Ioa: Case report. Ann OphthalmoI1975;7:389392. 25. Lee BY, McMillan R: Loa loa: Ocular filariasis in an Mrican student in Missouri. Ann Ophthalmol 1984;16:456-458. 26. Clausen M, Roider ], Fuhrmann C, Laqua H: Stabbing pain, conjunctival changes, foreign body sensation and unilateral red eye. Subconjunctival macrofilariasis in systemic Loa loa filariasis. Ophthalmology 1998;95:56-57. 27. Farrer WE, Wittner M, Tanowitz HB: Mrican eye worm (Loa loa) in a tourist. Ann Ophthalmol 1981;13:1177-1179.

28. Fenton P: Loa loa: The African eye worm. Arch Ophthalmol 1966;76:866-867. . 29. Canne B, Kaya-Gandaziami G, Pintart D: Localization of the filaria Loa loa in the anterior chamber of tlle eye. Apropos of a case. Acta Trop 1984;41:265-269. 30. Satyavani M, Rao KN: Live male adult Loa loa in the anterior chamber of the eye-A case report. Indian] Pathol Microbiol 1993;36:154-157. 31. Osuntokun 0, Olurin 0: Filarial worm (Loa loa) in tlle anterior chamber. Report of two cases. Br] Ophthalmol 1975;59:166-167. 32. Toussaint D, Danis P:. Retinopathy in generalized loa-loa filariasis. A clinicopathological study. Arch Opthalmol 1965;74:470-476. 33. Corrigan M, Hill D: Retinal artery occlusion in loiasis. BrJ Ophthalmol 1968;52:477-480. 34. Langlois M: Filarios loa. Thrombose de l'artere centrale de la retine et syndrome cerebellux. Rev Neurol 1962;107:381. 35. Chandrashekar R: Recent advances in diagnosis of filarial infections. Indian] Exp BioI 1997;35:18-26. 36. Toure FS, Kassambra L, Williams T, et al: Human occult loiasis: Improvement in diagnostic sensitivity by the use of a nested polymerase chain reaction. Am] Trop Med Hyg 1998;59:144-149. 37. Singh B: Molecular metllOds for diagnosis and epidemiological studies of parasitic infections. Int] Parasitol 1997;27:1135-1145. 38. Churchill DR, Morris C, Fakoya A, et al: Clinical and laboratory features in patients with loiasis (Loa loa filariasis) in the UK] Infect 1996;33:103-109. 39. Ogunba E: Serological investigations with Loa loa antigens. ] .Helminthol 1972;46:241-250. 40. Ottesen EA, Weller PF, Lunde MN, Hussein R: Endemic filariasis on a Pacific island. II. Immunologic aspects: Immunoglobulin, complement and specific antifilarial IgG, IgM and IgE antibodies. Am] Trop Med Hyg 1983;31:953-961. 41. ]aoko WG: Loa loa antigen detection by ELISA: A new approach to diagnosis. EastMr Med] 1995;72:176-179. 42. Haque A, Capron A, Ouaissi A, et al: Immune unresponsiveness and its possible relation to filarial disease. Contrib Microbiol Immunol 1983;7:9-21. 43. Mackenzie CD, Kron MA: Diethycarbamazine: A review of its action in onchocerciasis, lymphatic filariasis and inflammation. Trop Dis Bull 1985;82:Rl. 44. Yazdanbakhsh M, Duym L, Am"den L, Partono F: Serum iriterleukin6 levels and adverse reactions to diethycarbamazine in lymphatic filariasis. ] Infect Dis 1992;166:453-454. 45. Chippaux ]P, Ernould ]C, Gardon], et al: Ivennectin treatment of loiasis. Trans R Soc Trop Med Hyg 1992;86:289. 46. Hovette P, Debonne ]M, Touze ]E, et al: Efficacy of ivermectin treatment of Loa loa filariasis patients without microfilaremia. Ann Trop Med Parasitol 1994;88:93-94. 47. Klion AD, Massoughbodji A, Horton], et al: Albendazole in human loiasis. Results of double blind, placebo controlled trial. J Infect Dis 1993;168:202-206. 48. Nutman TB, Miller Iill, Mulligan M, et al: Diethycarbamazine prophylaxis for human loiasis. Results of a double blind study. N Engl ] Med 1988;319:752-756.

Lawrence A. Raymond and Adam

Cysticercosis is the most common ocular tapeworm infection. It occurs especially in underdeveloped areas where hygiene is poor. Cysticercosis is usually caused by Cysticercus cellulosae, the larval form of the pork tapeworm, Taenia solium. Occasionally, cysticercosis in humans is caused by the larvae of the beef tapeworm, Taenia saginata. Humans become infected usually by drinking contaminated water or eating food containing the eggs of Taenia solium. If untreated, intraocular cysticercosis usually results in blindness and atrophy of the eye (Fig. 42-1). The best means of cure is surgical removal of the larva, although destruction of the larva can be obtained with diathermy, photocoagulation, or cryogenic applications. Porcine cysticercosis has been described since antiquity. Cysticercus observed in the anterior chamber of the human eye was first reported by Sommerring in 1830; the first extraction was by Schott in 1836. 1 Cysticercosis of the posterior segment of the eye was first described by Coccius in 1853. 2 von Graefe was the first surgeon to remove the larva from the vitreous cavity in 1858. 3 Since 1945, most reports of ocular cysticercosis deal with its treatment. Three of the lar~est series of cases of ocular cysticercosis were from Brazil and Mexico. Junior 4 collected 111 cases, Sa.ntos and colleagues 19 cases,5,5 and Cardenas and colleagues 30 cases. 7 These will be reviewed in detail in the sections Treatment and Prognosis. Most other reports since 1945 have been small series of one to three cases. Hutton and colleaguesS reported the first successful removal of an intravitreal cysticercus by pars plana vitrectomy in 1976. Postoperative visual acuity was 20/20, but the reported follow~up period was very brief. Later communication with Hutton revealed that there was no further ocular inflammation in his patient after several years. 9 In 1975, Rodriquez lO of Bogota, Columbia, reported at the Inten1ational Photocoagulation Congress the successful photocoagulation of a small (less than 8 mm), early posterior subretinal cysticercus. Pavan n brought modern vitrectomy instrumentation to a remote area in Peru aboard the Oribus airplane and successfully removed a live submacular cysticercus through a retinotomy in the temporal macula in 1986. This technique avoided making a posterior sclerotomy, which is frequently associated with difficulty in exposure, vitreous hemorrhage, subretinal hemorrhage, uncontrolled vitreous loss, migration of,the mobile larva into the vitreous during the surgery, and postoperative anterior segment necrosis after disinsertion of several recti luuscles.2, 11 Cysticercosis, the most common ocular tapewonu infection, has a worldwide distribution. Infestation by the pork

Kaufman

tapeworm is common in South and Central America, Mexico, the Philippines, India, Eastern Europe, Southeast Asia, and Russia, but it is rare in Great Britain and the United States. 5, 12, 13 Cysticercosis is rare in Jews and Muslims, since these cultures do not generally eat pork. Tapeworm infestation (intestinal taeniasis) is uncommon among religious traditions that eschew pork. 14 However, cysticercosis has no ethnic predilections, being related luore frequently to sanitation and poverty than to the ingestion of contaminated pork. Ocular involvement in cysticercosis occurs in 12.8%14 to 46% 1 of infected patients. Bilateral ocular involvementl , 4,15 and multifocal uniocular involvement l , 4, 9,15-17 are very rare. Ocular cysticercosis seems to be a disorder of the young, often occurring between the ages of 10 and 30 years. There is no sex predilection. 14, IS In Poland, Melanowski described an increase (56 cases reported) of ocular cysticercus during World War II.2 Sixteen years after World War II, there were no cases reported. Improved hygiene was considered the basis for this improvement. 2 Junior, in 1949, reported III cases of ocular cysticercosis from only one hospital in Brazi1. 4 Santos and colleagues5 reported 19 cases of ocular cysticercosis frOlu 1975 to 1978 at one hospital in Mexico. These combined cases outnumber the total of all other cases documented in the recent world literature. The high prevalences in Mexico and Brazil suggest that the patients derive from rural areas and areas with poor sanitation and hygiene. 1 Ocular cysticercosis has not been a comluon problem in the Western world since legislation was enacted governing the feeding of human garbage to pigs, disposal of human waste, purification of drinking water, and the enforcement of adequate standards of meat preparation and inspection. 5, 12 With increased international travel to areas where cysticercus is prevalent and endeluic, and where inadvertant ingestion of contaminated water and food may occur, this disease may become more frequent in the Western world. 5

CLIN Cysticercosis may affect any portion of the visual pathways from the orbit to the visual cortex; posterior segment involvement seems the most common. 19 , 20 The symptoms depend on the location of the ocular involveluent. Patients with cysticercosis of the eyelid may have a painless, stationary or slowly enlarging mass. 21 Patients with subconjunctival involvement may be asymptomatic, present with a recurrent conjunctivitis unresponsive to topical antibiotics,14 or develop a painless or painful swelling of the conjunctiva. IS, 22 Orbital cysticercosis may present as a gradually increasing, painless, nonaxial proptosis. 14 Patients with intraocular cysticercosis may be asymptomatic or present with poor vision, progressive worsening of vision, a single floater, a moving sensation, black spots,

CHAPTER 42:

FIGURE 42-1. Cysticercus is pearly white in vitreous. (From Aracena T, Roca F: Macular and peripheral subretinal cysticercosis. Ann Ophthalmol 1981;13:1265.)

ocular discomfort, photophobia, or a red eye. 8 , 9,16,20,23 Patients with macular subretinal cysticercosis may describe a sudden central visual loss or a paracentral shadow and moving sensationY Patients with optic nerve involvement may have gradually incr~,asing painless diminution of vision, seizures, or symptoms'"related to increased intracranial pressure. 14 Epileptifonu seizures may occur in cerebral cysticercosis. 24- 26 Review of symptoms may reveal a history of epilepsy or previous removal of a tapeworm. About one in 10 patients in Mexico who require brain surgery for the relief of epileptiform seizures is found to have cerebral cysticercosis. 25 The duration of ocular symptoms before surgical removal varies. Commonly, the patient may have symptoms for a few weeks to months. Intravitreal or subretinal cysticercus without surgical removal of the larva usually leads to blindness within 3 to 5 years. 4 , 9, 18 Visual acuity may be 20/30 in peripheral subretinal cysticercus, or hand motions in submacular cysticercus. 19 , 27 The anterior segment examination is variable-evaluation may reveal a quiet eye without conjunctival injection, circumlimbal flush in a patient with two intravitreal cysticerci, or a minimally injected eye with numerous large keratic precipitates and an intense anterior-chamber cellular reaction. A hypopyon may be a presenting sign in intravitreal cysticercosis. The lenses are often clear with an intravitreal cysticercus. 2 , 9,16,18,28 Biomicroscopic examination in intravitreal cysticercosis reveals a variable degree of inflammatory cells in the vitreous body. The vitreous cellular infiltration may be more pronounced during earlier stages of the disorder. 16, 18 With administration of steroid to sub-Tenon's depot and/or orally, the vitreous reaction decreases and a globular translucent cyst in the vitreous becOlues visible. 16, 18 With prolonged retention of the live intravitreous cysticercus over a 6-month period, a sluoldering 1 + vitritis and iritis may be observed. 16

While the cysticercus is alive within the eye, it often induces a mild to moderate ihflammatory reaction in the anterior chamber and/or vitreous. An intense inflammatory response occurs when the parasite dies. Destruction of a cysticercus 8 mm or larger by diathermy, photocoagulation, or irradiation, without its removal from the eye, usually results in blindness and phthisis, probably resulting from the release of chemical toxins from the parasite and subsequent intraocular inflammation. 4 , 8, 29 Biomicroscopic examination in a case with live submacular cysticercus may reveal minimal or no anterior chamber inflammatory reaction; only the vitreous adjacent to the macula may show inflammatory cells. 19 , 28 Edema and hemorrhages in the retina at the posterior pole, subretinal exudate in the macula, retinal vessel sheathing, serous or exudative retinal detachment, retinal pigment epithelial disturbances, and hyperemia and blurring of the optic disc may accompany submacular cysticerCUS. 2 ,23 If the submacular cysticercus emerges into the vitreous leaving a macular break, a chorioretinal scar luay develop around the break. 19 , 28 In one series of 30 patients in Mexico with intraocular cysticercosis, a high prevalence of retinal detachment (53%) was found in 16 patientsat the time of diagnosis. 7 Sometimes a subretinal cysticercus away from the macula or in the peripheral fundus may be accompanied by a focal active necrotizing chorioretinitis 16 or an overlying serous detachment. 3o The clinical appearance of the parasite in the vitreous or subretinal space is characteristic. It is a globular or spherical, translucent or white cyst with a head, or scolex, that undulates with evagination or invagination in response to the examining light (see Fig. 42-1). The cyst varies in size from about one-fifth to six disc diameters 2o , 23, 30 An area of retinal pigment epithelial atrophy is presumed to be the entry site of the cysticercus into the subretinal space. 20

Human cysticercosis is caused by the ingestion of the pork tapeworm, T. solium, when contaminated vegetables, fruit, or water is consumed. In this setting, the eggs behave as if they were within the intermediate host-that is, they hatch in the upper intestines in humans. The resulting embryos penetrate the gut, invading lymphatics and the blood stream, and traveling to various organs, including the subcutaneous tissue, brain, heart, and eye. In these various organ tissues, the larvae, known also as larval cysts, grow. Autoinfection can also occur from fecaloral contamination, with the patient being the definitive host of the adult tapeworm, which releases eggs into the feces. The cycle starts again from the eggs. Sometimes, the patient acquires the parasite by ingestion of undercooked pork containing the larval cysts. In this case, the larval cyst develops in the intestines as the adult tapeworm. Thus, it is possible for the patient to harbor both the larval cyst and the adult tapeworm forms of T. solium. 13 In humans, cysticercosis affects the eye more COlUmonly than any other organ. The cysticercus is capable of invading every ocular tissue. Seventy-two percent of reported cases of ocular cysticercosis involve both retina and vitreous. The parasite has been found more often in

CHAPTER 42: CYSTICERCOSIS

the subretinal space (35%) than in the vitreous body (22%).1,19 The anterior segment, including ciliary body, iris, and anterior chamber, is a less common site (5%). The lens is rarely a resting site for the parasite, as found by von Graefe in one of 90 cases reported in 1866. 1 A secondary cataract may occur, related to the ocular inflammation associated with the parasite. In the eye, the embryo develops into a larva, known as a bladder worm or cysticercus. A larva may reach 15 to 18 mm in size over 3 to 4 years. 6 With the larva inside the subretinal space, an exudative retinal detachment may develop. The larva may perforate the retina, causing a retinal break; sometimes the break is self-sealing. Other times the retinal break leads to a rhegmatogenous retinal detachment. The larva can migrate through a retinal break into the vitreous body. If the parasite resides in the macula, macular scarring is likely. 5 If the larval cyst is untreated, it usually grows until inflammation destroys the eye. Histologically, the necrotic cysticercus is surrounded by a zonal granulomatous inflammatory reaction with an abscess that contains eosinophils. 31 ,32 Death of the larva is associated with marked immunologic stimulation 5 , 6 and severe endophthalmitis. 5 ,31 The pathogenesis of the common and severe manifestations of ocular infection in untreated intravitreal cysticercosis, leading often to blindness and atrophy of the eye, appears poorly understood. Santos and colleagues 33 developed an experimental animal model using rabbits and Taenia crassiceps cysticerci. Grou"Q I rabbits were inoculated with a single living cysticercus in the vitreous. Group II rabbits received an intramuscular dose of steroid prior to parasite injection. An intense inflammatory reaction occurred in group I rabbits; group II rabbits had minimal inflammatory changes. Histopathologic studies revealed a severe histiocytic infiltrate with generalized retinal damage in group I and mild inflammatory infiltrate in group II. The ocular lesions in group I rabbits resembled those found in human ocular cysticercosis. These findings suggest that ocular damage in intravitreal cysticercosis might be directly related to inflammatory changes produced by the presence of larval cysticerci.

DIAGNOSIS The diagnosis of cysticercosis is based on a careful ocular, medical, and epidemiologic history, a review of systems, an ocular examination demonstrating the characteristic larva and associated inflammation (Table 42-1), and a microscopic and histologic examination of the cysticercus. The clinical presence of the motile anterior chamber, intravitreous, or subretinal cysticercus is pathognomonic. Characteristic for the larva of T. solium is the translucent, undulating, white cyst with a white head, or scolex. The invaginated scolex appears as a central, dense, white spot and is mobile under bright light ,within the cystic body (see Fig. 42-1). At other times, the scolex is visible with its hooklets and suckers protruding from the cyst. When exposed to the light of the indirect ophthalmoscope, the scolex returns rapidly to the cyst. 20 ,27 Clinically, the scolex may measure approximately 500 by 700 microns in diameterY The cyst may measure between 0.3 and 9 mm. 20 , 23, 30 Ultimately, the diagnosis is established by pathologic

TABLE 42-1. OCULAR CYSTICERCOSIS: DIAGNOSTIC FEATURES Patient characteristics Demographics: Worldwide distribution, but especially in South and Central America, Mexico, India, Eastern Europe and Russia; rare in Jews and Muslims Age: 10 to 30 years History of ingestion of undercooked, contaminated pork (e.g., scrapple), contaminated vegetables, or water Ocular symptoms Blurred vision Ocular discomfort Photophobia Floaters Painful swelling of cOl~unctiva Painless stationary or enlarging mass of eyelid (orbital pseudotumor) White mass (leukocoria) Ocular examination Anterior segment Variable, from no iritis or mild iritis to intense iritis with hypopyon Clear lens Posterior Segment Variable vitritis, from mild to intense Variable posterior vitreous separation Cystic larva or larvae Retinal break, rhegmatogenous retinal detachment; exudative retinal detachment; chorioretinal scar or atrophy; epimacular membrane Optic atrophy, optic disc edema, anterior optic neuritis Other diagnostic features Epileptiform seizures Slight fever Cysticercus or cysticerci in almost any area within or around the eye

examination with hematoxylin and eosin staining of the surgically removed specimen. Sometimes, a portion of the parasite cannot be identified because of necrosis or its fragmentation. 30 Unlike the larva of the pork tapeworm T. solium, the larva of the beef tapeworm has no hooklets. 34 ,35

fluorescein Angiography Fluorescein angiography (FA) can be helpful in delineating a clear limit or border for a vessel-spared swelling or cyst of the retina, strengthening the presumption of a larva in the subretinal space. 28 FA may show leakage from retinal vessels near the subretinal larva or on the optic disc. 23 In the early transit phase of FA, the subretinal cysticercus is hypofluorescent. The FA stains the parasite in the recirculation phase. 3o

Ultrasonography A-scan ultrasonography of subretinal cysticercosis reveals a high-amplitude echo corresponding to the inner cyst wall and overlying retina, which encloses a low-medium amplitude cystic cavity. B-scan ultrasonography reveals a convex curvilinear echo corresponding to the inner cyst wall and the overlying retina and surrounding a smaller round density representing the scolex. 30

Computerized Cerebrospinal

Tomography Testing

The potentially life-threatening nature of extraocular cysticercosis is reflected by the 40% mortality of patients

CHAPTER 42: CYSTICERCOSIS

with central nervous system involvement. 36 Once the infection is diagnosed, it is important to search for parasites in the central nervous system. Computerized axial tomography (CAT) may reveal intracerebral calcification or hydrocephalus. 36 Testing the cerebrospinal fluid and serum for T. solium and Echinococcus granulosus antigens may be helpful.

Other Diagnostic Tests In cysticercosis, anterior chamber paracentesis may reveal a large number of eosinophils. 34 Eosinophilia may be present. 37 If the patient is a definitive host with the adult tapeworm in the gastrointestinal tract, stool examination may reveal the eggs of T. solium. 37 Serologically, the cysticercosis diagnosis can be made by the precipitin reaction, complement fixation, or indirect hemagglutination. 20 ,37 Radiographs of the calves and thighs may demonstrate the calcifications of cysticercosis. 24 Anticysticercus antibodies have been detected by enzyme-linked imlTIUnOSOrbent assay (ELISA) in approximately 80% of cases with neurocysticercosis and 57% of patients with ocular cysticercosis 7,38 If at presentation the vitreous is opaque and poorly visualized, investigation to exclude various infections and noninfectious causes of uveitis is important. The tests include ultrasonography of the eye, complete blood count with differential, eosinophil count, erythrocyte sedimentation rate, serum angiotensin-converting enzyme, lysozyme, serologic tests for syphilis, skin testing with purified protein derivative for tuberculosis, and chest radiograph.

DIFFERENTIAL DIAGNOSIS The diagnosis of intraocular cysticercosis depends on the clarity of the ocular media to view the larva and adequate dilated examination of the eye. The differential diagnosis of intraocular cysticercosis includes conditions that present with a white intraocular spherical mass and cloudy media. When associated with a hazy cornea, cysticercosis may simulate a dislocated lens in the anterior chamber. 39 Preoperative use of steroids cleared the cornea in the case described by Kapoor and colleagues,39 allowing visibility of the typical undulating lTIOVements in the anterior .chamber of a free-floating cysticercus, which was extracted. When associated with a hazy vitreous with an intense cellular reaction, cysticercosis may mimic a focal active necrotizing chorioretinitis or retinochoroiditis, such as in toxoplasmosis1 6, 31, 40 Buyck and colleagues'll reported on 23 children presenting with a retrolental white mass or leukocoria. The underlying disorders were often already much advanced. Six children had retinoblastoma, six had Coats' disease, five had retinopathy of prematurity, four had persistent hyperplastic primary vitreous, one had intraocular cysticercosis, and one had retinal detachment. In differentiating these disorders, study of the vessels in the white mass was the most helpful tedlnique. Ophthalmoscopy, especially with the surgical binocular microscope, resolved the differential diagnosis of each patient with leukocoria even before additional investigation was performed (e.g., ultrasonography or computed tomography [CT] of the skull and orbits as performed for retinoblastoma).

In retinoblastoma, the observation of the vasculature of the retinal tumor is often possible. In Coats' disease, the typical lamp bulb-like vessels are pathognomonic. In persistent hyperplastic primary vitreous, a radial pattern behind the lens is often observed. A retinal tumor in the fellow eye helps to confirm retinoblastoma rather thau Coats' disease, which is typically unilateral. Cysticercosis would be very unlikely in a premature infant and should not be confused with the typical findings of retinopathy of prematurity.41 Another disorder to be considered in the differential diagnosis of retinal or subretinal cysticercosis includes diffuse unilateral subacute neuroretinitis (DUSN), caused by a motile nematode larva in the retina or subretinal space. 42-44 While both conditions may have unilateral visual loss, vitritis, and a larva moving in response to the examination light, the larva of DUSN is larger and differs in morphology from cysticercus. One of several larvae of DUSN, measuring between 1000 and 2000 microns in length, makes visible subretinal tracks, not observed clinically in cysticercosis. 42-44 The growth of the larva of cysticercosis over several months leads to a large cystic structure. 14 When located in the subretinal space, cysticercosis may be misdiagnosed as a serous detachment of the retinal pigment epithelium or retina, or as a choroidal tumor. 40

TREATMENT Untreated intravitreal or subretinal cysticercus usually leads to blindness and atrophy or phthisis of the eye within 3 to 5 years. 1, 4, 8, 32 Although the live parasite may be tolerated,20 an intense inflammatory reaction often occurs resulting in destruction of the globe. A few studies advocate photocoagulation of small subretinal cysticerci (less than 8 mm) ,5, 10, 19 but most authors report poor results when the dead parasite is allowed to remain in the eye. l, 4Junior, reflecting on his experience with III cases in one hospital in Brazil, wrote, "To leave the parasite in the eye is to condemn the eye to blindness or total 10ss."4 The management of cysticercosis has taken several forms, depending on the anatomic location of the cyst. Antihelmintic drugs, such as praziquantel and albendazole, have been used in the medical treatment of active neurocysticercosis with viable intraparenchymal parasitic cysts and extraocular cysticercosis. 45 ,46 In a randomized, controlled clinical trial of oral albendazole (15 mg/kg once daily for. 1 month) cOlTIpared to a placebo in 24 ultrasonographically diagnosed and ELISA-positive cases of extraocular or orbital cysticerci, marked clinical ilUprovement was seen in all cases in the treatment group at 4 weeks, with collapse of the cyst at 6 weeks (75%) and complete disappearance at 3 months (100%). No clinical or ultrasonographic change was noted in the control group.46 In a pilot study of oral albendazole (30 mg/kg for 15 days with a low-dose steroid [5 to 10 mg daily]), 20 of 21 patients with orbital myocysticercosis diagnosed by ultrasonography, supported by CT or lTIagnetic resonance imaging, had complete resolution of the cyst. Before treatment, the cysts measured 6.2 to 13.4 mm (mean, 11.4 mm). There was no placebo control groupY Praziquantel and albendazole are usually not effective

CHAPTER 42: CYSTICERCOSIS

in intraocular cysticercosis. 45 , 48, 49 The best means of cure is early surgical removal of the larva, although larval destruction by diathermy, cryo treatment, or photocoagulation has sometimes been successful. 5, 10,50

the Junior described a case in which the parasite Inigrated from the subhyaloid space to the anterior chamber, and the scolex attached itself firmly to the posterior cornea. The parasite was extracted with forceps. 1, 4

Larva in the Lens In 1866, von Graefe reported extraction of a cataract, which was complicated by marked iritis. He found in the lens a cysticercus 6 mm in diameter. 1

Larva in the Vitreous For the intravitreal cysticercus, pars plana or open-sky vitrectomy has frequently proven successful. 5, 8, 9, 11, 16, 19, 20, 30 The pars plana approach, which utilizes three ports for infusion, endoillumination, and cutting suction techniques, when compared to open-sky vitrectomy, seems to give superior visibility of the larva, unhampered by glare or light scatter· from the anterior surface of the vitreous gel, and it less often requires lensectomy.9 Pavan 11 observed that the scolex jammed in the tip of the 20-gauge tapered needle, preventing aspiration of the larva. If the larva had become disengaged from the needle tip and lodged in the peripheral vitreous skiq, it might have been difficult to retrieve. Fortunately, he released the larva in the vitreous cavity, reapplied a higher suction, and withdrew the extrusion needle with the larva attached to its tip. Alternatively, a larger-gauge extrusion needle may be employed, such as an 18-gauge angiocatheter, as is sometimes used in silicone oil removal, which would allow complete aspiration of the entire cysticercus into the collection bottle. 51 During removal of the live intravitreal cysticercus, Santos and colleagues5 and Topilow and colleagues 20 have noted that, although the body of the cyst is usually soft, the head or scolex is hard and sometimes requires a second application to engage or aspirate it from the vitreous cavity. A limited vitrectomy is recommended around the mobile intravitreal parasite to facilitate its capture in the vitreous cavity before performing a subtotal vitrectomy to remove any toxic products released from the cyst. A periocular steroid injection at the conclusion of surgery and then postoperative topical steroid and mydriatics are often required to control the mild subsequent vitritis.

Larva in the Subretinal Space The classic external approach with a sclerotomy was the initial method of removal of a subretinal cysticercus. 2, 4, 20, 23,28 The technique required accurate localization as with a retinal break or subretinal metallic foreign body, but during surgery the larva was frequently mobile in the subretinal space or migrated into the vitreous, leading to inadequate localization and failure to remove the parasite. 28 ,30 For the more posteriorly situated larva, extensive periocular surgery might be required to achieve adequate exposure and access. A lateral canthotomY'and temporary

disinsertion of one or more rectus muscles have frequently been necessary.2 Complications of an external approach with a sclerotomy include vitreous hemorrhage,23 retinal incarceration and vitreous 10ss,4 choroidal hemorrhage, 19, 52 failure to remove the larva,5 anterior segment ischemia after telnporary disinsertion of several rectus muscles,2 retinal detachment,5,52 and bacterial endophthalmitis. 5, 27, 52 Steinmetz and colleagues 30 reported pars plana vitrectomy and retinotomy in the successful removal of a subretinal cysticercus. After removal of the posterior vitreous, a retinotomy was created by endodiathermy over the larva. The suction cutter was inserted through the retinotomy, and the cyst was removed from the subretinal space. Internal drainage of subretinal fluid was followed by endolaser treatment to surround the retinotomy. A gas-fluid exchange was performed, using the long-acting gas 12% perfluoropropane, for tamponade.

Larva in

Submacular

oJIlUi'a.... 'Il;;

Removal of a submacular cysticercus has been achieved by pars plana vitrectomy with retinotomy, followed by gas-fluid exchange and endolaser treatment around the retinotomy, and then postoperative face-down positioning until the air bubble was absorbed. l1

Larva Attached to the Optic Disc

Zinn and colleagues9 removed two intravitreous cysticerci from the surface of the optic disc during pars plana vitrectomy. Fibrous or glial-type strands, rather than the suckers or rostella, appeared to be the source of the attachment of the larvae to the surface of the optic disc.

As previously mentioned, an external approach with a sclerotomy is fraught with many potential complications. Pars plana vitrectomy with retinotomy for surgical removal of subretinal cysticercus minimizes the risk of nonremoval of the larval cyst and improves the visibility of the parasite during surgery. Removal of the posterior hyaloid in cases of subretinal and intravitreal cysticercosis is recommended to prevent the contraction of the vitreous cortex that often leads to a postoperative retinal detachmen t. 53

In most cases of untreated intraocular cysticercosis, the parasite will eventually die after 2 to 4 years. The accompanying release of toxins induces an inflammatory reaction that likely will lead to loss of vision and severe intraocular damage. 19, 52 Yet, early removal of the larva from the anterior chamber may allow good vision. 1, 54 Santos and colleagues5,6 treated 19 eyes with intraocular cysticercosis and achieved a successful result in 68 % of these patients using various techniques including vitrectomy or sclerotomy to extract the larva from the vitreous or subretinal space or photocoagulation to destroy a small subretinal larva (less than 8 mm in diameter) . Cardenas and colleagues7 treated 30 eyes with intraocular cysticercus by vitrectomy, sclerotomy, or laser photocoagulation, finding useful vision (20/20 to 20/100) in only 19% and vision of 20/200 or worse in 81 %. In their

c

CHAPTER 42:

series, there was a.high prevalence of retinal detachment (53 %) at the time of diagnosis, of subretinal cysticerci in or near the macula (80%), and of dead larvae within 9 of the 12 subretinal cysticerci (75%). A less desirable visual result could be expected with these problems. Human cysticercosis is a parasitIC infection of the tapeworm T solium. Infection depends on many factors, chiefly hygiene, meat inspection, water treatment, and local or cultural habits. Humans are infected usually by ingesting T solium eggs from contaminated soil, food, or water. For patients in or from endemic areas, it is important to have a high index of suspicion for the diagnosis of cysticercosis. Seizures, subacute proptosis, ocular motility disorders, uveitis, retinal detachment, or optic di~c edema may be presenting signs of cysticercosis. Early surgical removal of the larva in the posterior segment by pars plana vitrectomy is advocated, because intraocular parasite death results in marked inflammation and damage to the eye.

References 1. Duke-Elder S, Perkins ES: Diseases of the Uveal Tract. In: DukeElder S, ed: System of Ophthalmology, vol 9. St. Louis, CV Mosby, 1966, P 478. 2. Segal P, Mrzyglod S, Smolarz-Dudarewicz J: Subretinal cysticercosis in the macular region. AmJ Ophthalmol 1964;57:655. 3. von Graefe A: Cysticercus im Glaskorper durch die Cornea extrahirt. Albrecht von Graefes Arch Ophthalmol 1858;4:171. 4. Junior L: Ocular cysticercosis. AmJ Ophthalmol 1949;32:523. 5. Santos R, Dalma A, Ortiz E, et al~, Management of subretinal and vitreous cysticercosis-Role of photocoagulation and surgery. Ophthalmology 1979;86:1501. 6. Ganley JP: Disnlssion of presentation by Santos R, Dalma A, Ortiz E, et al: Management of subretinal and vitreous cysticercosis-Role of photocoagulation and surgery. Ophthalmology 1979;86:1505. 7. Cardenas F, Quiroz H, Plancarte A, et al: Taenia solium ocular cysticercosis-Findings in 30 cases. AIm Ophthalmol 1992;24:25. 8. Hutton WL, Vaiser A, Snyder WE: Pars plana vitrectomy for removal of intravitreous cysticercus. Am J Ophthalmol 1976;81:571. 9. Zinn KM, Guillory SL, Friedman AH: Removal of intravitreous cysticerci from the surface of the optic nervehead-A pars plana approach. Arch Ophthalmol 1980;98:714. 10. Rodriquez A: Light coagulation in early posterior subretinal cysticercosis. Presented at the International Photocoagulation Congress, September 28-0ctober 1, 1975. 11. Pavan PR: Submacular cysticercosis. In: Bovino JA, ed: Macular Surgery. Norwalk, Appleton and Lange, 1994, p 165. 12. Franken S: Intraocular cysticercus. Ophthalmologica (Basel) 1975;171:7. 13. King CH: Cestodes (Tapeworms). In: Mandell G, BennettJE, Dolin R, eds: Principles and Practice of Infectious Diseases, vol 2. New York, Churchill-Livingstone, 1995, p 2544. 14. Malik SRK, Gupta AK, Choudhry S: Ocular cysticercosis. Am J Ophthalmol 1968;66:1168. 15. Kapoor S, Kapoor MS: Ocular cysticercosis. J Pediatr Ophthalmol Strabismus 1978;15:170. 16. Messner KH, Kammerer WS: Intraocular cysticercosis. Arch Ophthalmol 1979;97:1103. 17. Wood TR, Binder PS: Intravitreal and intracameral cysticercosis. Ann Ophthalmol 1979;11:1033. 18. Sen DK, Mohan H: Ocular cysticercosis in India. J Pediatr Ophthalmol Strabismus 1978;15:96. 19. Kruger-Leite E, Jalkh AE, Quiroz H, et al: Intraocular cysticercosis. AmJ Ophthalmol 1985;99:252. 20. Topilow HW, Yimoyines DJ, Freeman HM, et al: Bilateral multifocal intraocular cysticercosis. Ophthalmology 1981;88:1166. 21. Perry HD, Font RL: Cysticercosis of the eyelid. Arch Ophthalmol 1978;96:1255. 22. Sen DK, Thomas A: Cysticercus cellulosae causing subconjunctival abscess. Am J Ophthalmol 1969;68:714.

23. Bartholomew RS: Subretinal cysticercosis. Am J Ophthalmol 1975;79:670. 24. Dixon HBF, Hargreaves WH: Cysticercosis (Taenia soliurn)-A further ten years' clinical study, covering 284 cases. Q J Med 1944;13:107. 25. Robbins SL: Textbook of Pathology with Clinical Applications. Philadelphia, W.B. Saunders, 1957, p 381. 26. Stepien L: Cerebral cysticercosis in Poland-Clinical symptoms and operative results in 132 cases. J Neurosurg 1962;19:505. 27. Luger MHA, Stilma JS, Ringens PJ, et al: In-toto removal of a subretinal Cysticercus cellulosae by pars plana vitrectomy. BrJ Ophthalmol 1991;75:561. 28. Aracena T, Roca F: Macular and peripheral subretinal cysticercosis. Ann Ophthalmol 1981;13:1265. 29. Arciniegas A, Gutierrez F: Our experience in the removal of intravitreal and subretinal cysticerci. Ann Ophthalmol 1988;20:75. 30. Steinmetz RL, Masket S, Sidikaro Y: The successful reInoval of a subretinal cysticercus by pars plana vitrectomy. Retina 1989;9:276. 31. Hogan MJ, Zimmerman LE: Ophthalmic Pathology-All Atlas and Textbook, 2nd ed. Philadelphia, W.E. Saunders, 1962, pp 25, 488, 566,644. 32. Yanoff M, Fine BS: Ocular Pathology-A Text and Atlas, 2nd ed. Philadelphia, Harper and Row, 1982, pp 109, 114, 116. 33. Santos A, Paczka JA, Jimenez-Sierra JM, et al: Experimental intravitreous cysticercosis. Graefes Arch Clin Exp Ophthalmol 1996;234;515. 34. Manshot WA: Intraocular cysticercus. Arch Ophthalmol 1968;80:772. 35. Neva FA, Brown HW: The Cestoda, or tapeworms. In: Basic Clinical Parasitology, 6th ed. Norwalk, Appleton and Lange, 1994, p 181. 36. Topilow HW: Cysticercosis. In: Fraunfelder FT, Roy FH, eds: Current Ocular Therapy, 4th ed. Philadelphia, W.B. Saunders, 1995, p 121. 37. Duke-Elder S: Di:>eases of tlle Outer Eye (Part 1). In Duke-Elder S, ed: System of Ophthalmology, vol 8. St. Louis, CV Mosby, 1965, P 425. 38. Plancarte A, Espinoza B, Flisser A: Immuno-diagnosis of human neurocysticercosis by enzyme-linked immunosorbent assay. Childs Nerv Syst 1987;3:203. 39. Kapoor S, Sood GC, Aurora AL, et al: Ocular cysticercosis-Report of a free floating cysticercus in the anterior chamber. Acta Ophthal~ mol 1977;55:927. 40. Gass JD: Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment, 4tll ed, vols 1, 2. St. Louis, Mosby-Year Book, 1997, pp 156, 618. 41. Buyck A, Casteels I, Dralands L, et al: Retrolental white mass. Bull Soc Belge Ophtalmol 1991;241:61. 42. Raymond LA, Gutierrez Y, Strong LE, et al: Living retinal nematode (filarial-like) destroyed with photocoagulation. Ophthalmology 1978;85:944. 43. Kazacos KR, Vestre WA, Kazacos EA, Raymond LA: Diffuse unilateral subacute neuroretinitis syndrome: Probable cause. Arch Ophthalmol 1984;102:967. 44. Kazacos KR, Raymond LA, Kazacos EA, .et al: The raccoon ascarid-A probable cause of human ocular larva migrans. Ophthalmology 1985;92: 1735. 45. Liu LX, Weller PF: Antiparasitic drugs. N EnglJ Med 1996;334:1178. 46. Sihota R, Honavar SG: Oral albendazole in the management of extraocular cysticercosis. Br J Ophthalmol 1994;78:621. 47. Puri P, Grover AK: Medical management of orbital myocysticercosis: A pilot study. Eye 1998;12:795. 48. Kestelyn P, Taelman H: Effect of praziquantel on intraocular cysticercosis-A case report. Br J Ophthalmol 1985;69:788. 49. Santos R, Chavarria M, Aquirre AE: Failure of medical treatment in two cases of intraocular cysticercosis. AmJ OphthalmoI1984;97:249. 50. Michels RG: Indications and results (parasitic endophthalmitis). In: Michel RG: Vitreous Surgery. St. Louis, CV Mosby, 1981, pp 352353. 51. Wilson CE: Video of removal of intravitreal cysticercus. Presented at Cincinnati Society of Ophthalmology, Cincinnati, OH, March 10, 1998. 52. Gupta A, Gupta R, Pandav SS, et al: Successful surgical removal of encapsulated subretinal cysticercus. Retina 1998;18:563. 53. Quiroz-Mercado H, Santos A: Surgical removal of subretinal cysticercus. Arch Ophthalmol 1998;116:261. 54. Schmidt U, Klauss V, Stefani FH: Unilateral iritis by cysticercallarva in the anterior chamber. Ophthalmologica 1990;200:210.

Neal

Barney

The term diffuse unilateral subacute neuroretinitis (DUSN) was first used by Gass in the February issue of the Journal of the Royal Society of Medicine in 1978. 1 He described 29 patients seen with consistent features that included unilateral, insidious loss of vision, usually severe in nature; vitritis; focal and diffuse pigment epithelial (PE) disturbance; retinal vessel narrowing; optic atrophy; retinal circulation time; and subnormal electroretinogram (ERG) findings. This definition was reiterated in the May 1978 issue of Ophthalmology.2 Unique in these series of patients were the observations of the earliest findings of the syndrome. Bascom Palmer Eye Institute had previously noted 13 patients as having unilateral wipe-out syndrome. 3 Gass now added his observations of some early changes in certain patients who subsequently developed the appearance of unilateral wipe-out syndrome.

HISTORY DUSN is now believed to be caused by a small number of different Nematode larvae. Kuhn~,4 in 1892, described a motile worm near the macula that proved to be a Nematode on excision. Nayar5 observed a 2.5-cm worm, likely an adult, that moved from the subretinal space, through the vitreous into the anterior chamber, from where it was extracted. A nematode, resembling onchocerca, was reported protruding through the subretinal space into the vitreous by Barrada. 6 Nematode infestation as a cause of retinal granuloma was first reported in the pathologic review of Wilder. 7 Ashton 8 reported four cases of nematodiasis as a cause of retinal granuloma in children. Parsons 9 found a small, white, motile mass in a patient with severe macular destruction in 1952. Ashton reported four cases of nematodiasis as a cause of retinal granulomas, all in children. 8 It was not until 1968 that Rubin demonstrated findings similar to macular degeneration or healing central serous retinopathy could be attributed to a Nematode infection. lO Price corroborated these findings but in a patient with a demonstrable motile worm in the left eyeY His patient had a previous history of chorioretinitis in the macula of the right eye that is reported as steroid responsive. A worm was never seen in the right eye, only the left. Ten years elapsed before the observations of Gass that connected early changes to the eventual appearance of the unilateral wipe-out syndrome and referral to the syndrome as DUSN. He suggests, at the beginning of his article, a viral etiology, but in an addendum, he indicates the finding of a motile wonn in 2 of 12 additional patients. 1

Nematode infection in children has long been a concern in the differential diagnosis of intraocular tumors of

childhood. Granuloma formation can give a mass effect that could appear as retinoblastoma. The earliest reports by Gass and Ra)'lnond contain patients from areas in which nematodiasis is common in animals such as the raccoon. A near-exhaustive search of the literature reveals that 53 cases have been reported in the United States. 3,8-15 De Souza,16 of Brazil, was the first to report two patients outside the United States. He further reported the surgical management of a third case from BrazilP Subsequently, a total of eight patients have been reported in the following countries: Canada, France, Germany, Scotland, and Switzerland. 18- 22 The age range in the largest series by Gassis reported as 5 to 22 years with a mean of 12.5 years. 1 The age range in the other reported patients is 4 to 84 years. 8- 11 , 13-15 In reviewing published papers other than the large Gass series, 17 patients were age 4 through 17 and 22 patients were age 18 through 84. 8- 11 ,14,15 The large Gass series contains 10 women and 21 men. 1 Race is difficult to determine from the individual cases. The large Gass series classifies 20 patients as white and five patients as black. 1 The right eye was affected in 13 patients in the large series, and the left eye was affected in 12 patients. 1 The remaining cases totaled 22 right eyes involved and 16 patients with the left eye involved.8-11, 14, 15

It is now well accepted that the clinical characteristics are manifest in early and late stages. Gass 23 first described the unilateral wipe-out syndrome in patients between 1963 and 1977. His observations in 1978 then led him to conclude that early findings and subsequent progression of DUSN would lead to the clinical appearance of the unilateral wipe-out syndrome. 1 Typically, patients are young and in good health, with no antecedent illness and no significant past ocular history. In the early stage, sYJ.llptomatic decrease in visual acuity is reported by the patient in two thirds of cases. Decreased vision in the early stages is discovered during routine examination about one third of the time. Central or paracentral scotoma is the principal complaint of . sYJ.llptomatic patients in the early stage. 1, 2 About one fourth of sYJ.llptomatic patients with early-stage disease have mild redness and visual obscurations,24 and a single patient gave a I-day history of a shifting parafoveal scotoma. 10 One patient gave a 3-week history of transient mild irritation. Photophobia or severe pain is rarely reported. Three quarters of patients presenting in the late stages have profound vision loss when the condition is first detected. One patient presented with a 2-month history of decreased vision and intermittent micropsia preceded by an II-year history of nyctalopia. Visual acuity is profoundly decreased in the majority

CHAPTER 43: DIFFUSE UNILATERAL SUBACUTE NEURORETINITIS

of patients who present in the early stages. In a series of 18 patients, 15 of whom presented within 1 month of the onset of decrease of vision, 10 patients had vision worse than 20/200. 12 An afferent pupillary defect is found in nearly every patient regardless of stage of disease. Visual field testing typically reveals a central scotoma with variable peripheral changes in either early or late stages. Visual acuity is the late stage is profoundly decreased, with 80% or more showing vision of 20/200 or worse. At present, the most characteristic ocular finding in the early stage is a motile subretinal worm. Gass' series of 25 patients in February of 1978 notes this as an addendum. 1 In his May 1978 series of 36 patients, he notes the presence of a worm in two patients. 2 Many subsequent case reports use the presence of a motile subretinal worm as a defining characteristic of the early stage of the disease. Perhaps more important than the worm, which is very difficult to observe, are the other characteristic early findings noted in Gass' two large series. The eye is typically white externally. The cornea is clear, with only a few patients presenting with anterior chamber cells, flare, and keratic precipitates. Hypopyon is rare. The lens is normally clear. Vitritis is present in all patients and may obscure some details of the fundus. The optic nerve has a blurred margin in just over half of the patients with early-stage disease. The retina has multiple, focal, graywhite to gray-yellow lesions in the deep or outer retinal layer. These vary in size from 1200 to 1500 /-Lm and are found in the peripapillary region and juxtamacular region (Fig. 43-1). It is unusual for lesi;ons to be found in the foveal region. When a motile worm is seen, it seldom overlies a retinal lesion. Occasionally, there is a small serous retinal detachment overlying these lesions. The lesions themselves are evanescent and have the possibility of different outcomes. The lesion may resolve with no pigment epithelial disturbance or residual finding. More commonly, there is mild change in color of the underlying pigment epithelium or focal depigmentation. Rarely, the pigment in the area of the lesion will migrate into the retina near the vessels. The pigment epithelium not affected directly with a lesion often shows a diffuse mot-

fiGURE 43-1. Early-stage DUSN: vitritis, disc margin swelling, and multiple yellow-white lesions at the level of the retinal pigment epithelium (RPE) and outer retina. (Courtesy of Donald Gass, M.D.) (See color insert.)

fiGURE 43-2. Late-stage DUSN: Vessel attenuation and chorioretinal scars. (Courtesy of Donald Gass, M.D.) (See color insert.)

tling. Mild retinal arteriole narrowing occurs in one half of eyes in the early stages. Few comments are found about the anterior segment findings in the late stage other tllan the lack of cataract development. The presence of optic atrophy and severe retinal arteriole narrowing seems to define the late stage best (Fig. 43-2). Although vitritis may be present, it is found in less than half of patients with late-stage disease. Retinal arteriole sheathing is found in most patients with late-stage disease. Retinal arteriole narrowing may vary by quadrant. The retinal pigment epithelial changes were both focal and diffuse, and were most prominent in the peripapillary and peripheral retina. Focal, atrophic, pigment, and epithelial mottling is also found. Choroidal neovascular membrane is infrequent, but when it is present, it is usually in the periphery. Again, the central macula seems to be spared of most changes seen in the late stages.

The first description of pathologic changes secondary to nematode larva infestation of the eye were presented as findings of granulomas in whole globes. 7 Chorioretinitis as a result of nematode larva was first reported by Parsons in 1952,9 and then Rubin in 1968. 10 Gass proposes a viral etiology in the body of his first article. 1 As an addendum in this article, he describes twelve additional patients with the same findings, two of which have a motile worm, thought to be toxocariasis. In May of 1978 Gass includes these twelve patients in his series and suggests tllat more than one etiologic agent can produce DUSN. Since 1978, a heightened awareness of the syndrome, particularly its early stages, almost requires the observation of a motile worm. Attention subsequently focuses on the clinical description of worm size, motility, and species. Three phyla of wormlike animals exist: Annelida (segmented worms), Nemahelminthes (Nematoda or roundworms) and Platyhelminthes (flat worms). There are an estimated 80,000 species of Nematodes that are parasites of vertebrates. Most Nematodes have only one host, the definitive host, and pass through simple or complex life cycles both within and outside of the host. Transmission to a new

CHAPTER 43: DIFFUSE UNILATERAL SUBACUTE NEURORETINITIS

host is by ingestion of larva or mature infectious egg, or by transcutaneous passage of the larva. With rare exceptions, Nematodes typically do not multiply in the human host. Gass described the size of the worm in his initial two cases as 25 to 50 f-Lm in width and 500 f-Lm in length, and tapered at both ends. This is similar to the size reported by Parsons, 9 Rubin,IO and Price 11 and was believed to be compatible with but not diagnostic of Toxocara canis. 2 A review of cases of DUSN in 1983 suggested two endemic areas of the United States, each with a different size worm causing the ocular disease. 12 Four hundred to one thousand microns in length seemed to be the size of the most commonly reported worms in the southern states. 12 The northern states of Kentucky, Illinois, Minnesota, and Nebraska had reports containing worm length of 1500 to . 2000 f-Lm. Interestingly, there is a greater likelihood of the longer worm leaving a tract of coarse clumping of pigment epithelium in the wake of its travels. 12 The shorter worm predisposes to leave focal, chorioretinal atrophic scars. In this series, they suggest that the clinical presentation is not consistent with other reports of Toxocara canis. Kazacos proposed the raccoon-associated Baylisascaris genus as the cause of DUSN, particularly the species procyonis. 25 He proposes that the marked zoonotic potential of this larva to cause visceral and ocular larva migraines in a wide variety of mammals and birds makes it an ideal candidate to be a cause of DUSN. Fatal central nervous system disease of two children substantiates the potential for human infection. :t;xperimentally, the larva may be seen in the retina within 3 to 7 days of infection. Additionally, the Baylisascaris larvae may grow while they are within the eye and would account for the range of lengths of larvae seen, such as those that are 400 to 2000 f-L m .15 , 25, 26 Significant morphometric, serologic, and epidemiologic support for Baylisacaris as the causative agent was published in a case by Goldberg. 24 Two Brazilian patients were reported to have DUSN, each caused by a worm of 400 to 500 f-Lm in length. 16 The 1500micron-long worm presenting in a German patient was thought to be consistent with Baylisascaris species. 20 Finally, the Trematode, Ala'ria mesocercaria, is suggested as causative of two patients with DUSN by the measure of 500-micron length, but a ISO-micron width, which is considerably wider than previously published studies. The focal pigment epithelial changes seen are easily explained by the location or the travel pattern of the worm. It is speculated that focal chorioretinal white spots are an immune response to a secretion or excretion from the worm. 2 The diffuse pigment epithelial changes are somewhat more difficult to explain except as a toxic reaction. This might be sufficient to account for the outer retinal findings but ERG findings, arterial narrowing, and optic disc pallor are not as easily ascribable to the pigment epithelial changes. Indeed, in one eye with profound vision loss, there were no significant histopathologic correlates. 2 Worms, regardless of species, have been observed in the eye for up to 3 years.

At present, the diagnosis is made when the clinical characteristics of DUSN are found in conjunction with an

intraocular worm. Certainly, the diagnosis luay be strongly entertained without the presence of a worm if there is a classic, late-stage appearance. Serologic testing has been variable. Gass found negative Toxocara serology in many reported patients. 12 On further inspection, these serology reports need to be evaluated in light of the most likely species and timeliness of the testing. Kazacos points out that three of five of Gass' patients with small worms had positive results on an enzyme-linked immunosorbent assay (ELISA) for Toxocara when it was performed when the worm was visible. 26 Fluorescein angiography findings vary with the stage of disease. In the early stage, there is hypofluorescence of the focal white lesions followed by staining. Mild leakage is commonly seen at the optic disc. Cystoid macular edema is reported but uncommon. Occasionally, there is evidence of peripheral retinal vascular leakage. The late stage of DUSN has delayed appearance of fluorescein in the retinal vessels. Pigmented epithelial alterations cause diffuse, widespread hyperfluorescence. Focal window defects correlate with areas of chorioretinal scar with a loss of pigment epithelium. Electrodiagnostic testing has been performed on numerous patients. Electroretinographic changes include a mild to moderate decrease in rod and cone function, with the B wave more affected than the A wave. Despite the involvement of the pigment epithelium, there is an abnormal electro-oculogram (EOG) in only about one half of patients. Kelsey believes that the finding of abnormal ERG and normal EOG in some patients strongly implicates the neuroepithelium as diseased in this entity.27 The differential diagnosis of the early, multifocal, peripheral lesions includes sarcoid and other entities that cause focal chorioretinitis: toxoplasmosis, histoplasmosis, or multifocal choroiditis and panuveitis. Because the early stage of the disease may produce significant vision loss with apparent direct involvement of the macula, it differs from acute posterior multifocal placoid pigment epitheliopathy (AMPPE) or serpiginous choroiditis. These entities would typically have decreased vision associated with involvement of the macula. The lesions of DUSN usually do not involve the macula. The late stage of DUSN is characterized by optic atrophy, vessel narrowing, and focal and diffuse pigment epithelial abnormalities. These findings may cause confusion with post-traumatic chorioretinopathy, occlusive vascular disease, sarcoid, or a toxic retinopathy.

Treatment modalities vary with the decade in which the report is made. Parsons9 used various forms of medication without success. He next planned localized transscleral diathermy under direct visualization, but the worm again moved into the periphery. Photocoagulation is first mentioned as a possible treatment, but it was not carried out by PriceY It is imperative that clear goals be established for any therapeutic attempt with clear temporal windows for judging efficacy. Obviously, the patient with late-stage DUSN, no visible worm, and poor vision is unlikely to benefit from any form of treatment. Early-stage disease

43: DIFFUSE UNILATERAL SUBACUTE NEURORETINITIS

with moderate vision loss and confirmation of a visible worm would be parameters suggestive of treatment. Rubin first employed anthelminthic therapy and corticosteroids. 10 The indications for therapy were a visible worm, 2-day progressive loss of vision from 20/60 to 20/ 200, and worsening central scotoma. Thiabendazole, 2 g by mouth, for 5 days was started concurrently with prednisone, 40 mg by mouth, for 3 weeks. Chlorpromazine, used to counteract anticipated nausea from thiabendazole use, was discontinued secondary to postural hypotension. Vision returned to 20/60 with some decrease in the size of the scotoma. The worm disappeared from the fundus within 24 to 48 hours after treatment. Concurrent with the disappearance was the development of Inacular edema and a linear hemorrhage inferior to the macula. RaYlnond gives the first report of photocoagulation of a worm in October of 1978. 15 Indications for treatment were the presence of a motile worm· and a decline in vision to 20/100. Six weeks after sYlllptoms developed, xenon photocoagulation was administered to the worm and adjacent tissues. At the time of treatment, the worm was at the 11:30 position approximately 2.5 disc diameters from the center of the fovea. Vision returned to 20/80. A second patient had argon laser photocoagulation to a worm and maintained 20/20 vision. Several authors have successfully used photocoagulation to eradicate these wonns. 12, 16,20,28-31 In February 1978, Gass 1 suggests the use of corticosteroids in the early stages. He suggested monitoring improvement of the visual field to judge efficacy. In May 1978, it was clear tha; the presence of a motile worm should direct one's choice of therapy. Many authors suggest photocoagulation of a worm identified in the periphery. 2 In this series of 36 patients, two were found to have motile worms. Corticosteroid treatment was initiated with 80 mg of prednisone in both of these 14-year-old boys within 1 month of the onset of sYlllptOlns; each patient received a 3- or 4-day course of thiabendazole as 1.5 mg by mouth per day. There was no improvement in vision in either patient. The steroid was tapered to low levels. Gass, regarding thiabendazole treatment in five other patients, found it ineffective as measured by continued motility in three of the five patients. 12 There is no comment regarding the two other patient outcomes. He noted diethylcarbamazine was also ineffective. In each patient in whom anthelmintics failed, photocoagulation or local excision stopped further worm movement. In 1991, Gass 13 published four cases in which no worm was found and thiabendazole was successfully used. In three of four cases, vitritis was reduced and in two cases, the active lesions resolved without further recurrence. In these two cases, however, one last lesion developed with a resultant chorioretinal scar. This was presumed to be the site of the worm. Transvitreal worm removal has been reported. 17 At present, treatment of a visible worm with photocoagulation seems to offer the best chance for halting worm motility and resolution of the active gray-white lesions.

The unilateral nature of this disease is somewhat fortunate given the typically poor visual outcome. Approxi-

mately 80% of patients in the late stages will have vision of 20/200 or worse. An afferent pupillary defect is seen in most patients, and visual field changes are remarkable for paracentral scotomas. There are no reported complications from photocoagulation of the worm. Particularly, there is no evidence that photocoagulation of the worm causes an exuberant inflammatory reaction. Anthelminthic treatment carries with it the risk of toxicity such as nausea, anorexia, dizziness, fatigue, tinnitus, hypotension, and pruritus. Although it is not truly a complication, the risk of resistance is theoretically possible.

PROGNOSIS DUSN is a unilateral disease with a poor prognosis for vision. Early reports indicate that the disease is present usually for months before diagnosis and treatment. Despite increased awareness and early detection of a worm, in many recent patients, there appears to be significant vision loss.

1. Diffuse unilateral neuroretinitis is a multifocal retinochoroiditis. 2. It is reported primarily in North America, but cases have been reported from Europe and South America. It occurs in the first through third decade. 3. A larva of a nematode is implicated as the causative agent 4. Usually, the early stage and certainly the late stage have significant findings suggestive of the disease. 5. Photocoagulation appears to be the treatment of choice.

References 1. Gass JD, Scelfo R: Diffuse unilateral subacute neuroretinitis. J R Soc Med 1978;71:95. ' 2. Gass JD, Gilbert WRJr, Guerry R, et al: Diffuse unilateral subacute neuroretinitis. Ophthalmology 1978;85:521. 3. Gass JD: Subretinal migration of a nematode in a patient with diffuse unilateral subacute neuroretinitis. Arch Ophthalmol 1996;114:1526. 4. Kuhnt H: Extraction eines neuen Entozoon aus dem Glask6per des Menschen. Arch Augenheilk 1892;24:205. 5. Nayar KK, Pillai AK: A case of filariasis oculi. Br J Ophthalmol 1932;16:549. . 6. Barrada MA: Filaria in macula. Bull Ophthalmol Soc Egypt 1934;29:63. 7. Wilder HC: Nematode endophthalmitis. Trans Am Acad Ophthalmol Oto 1950; 99-108. 8. Ashton N: Larval granulomatosis of retina due to toxocara. Br J Ophthalmol 1960;44:129. 9. Parsons HE: Nematode chorioretinitis: Report of a case with photographs of viable worm. Arch Ophthalmol 1952;47:799. 10. Rubin ML, Karufman HE, Tierney JP, et al.: An intraretinal nematode (a case report). Trans Am Acad Ophthalmol 1968;72:855. 11. Price JA, Wadsworth JA: An intraretinal worm. Report of a case of macular retinopathy caused by invasion of the retina by a worm. Arch Ophthalmol 1970;83: 68. 12. Gass JD, Braunstein RA: Further observations concerning the diffuse unilateral subacute neuroretinitis syndrome. Arch Ophthalmol 1983;101:1689. 13. Gass JD, Callanan DG, Bowman CB: Successful oral therapy for diffuse unilateral subacute neuroretinitis. Trans Am Ophthalmol Soc 1991;89:97. 14. Deleted.

CHAPTER 43: DIFFUSE UNILATERAL SUBACUTE NEURORETINITIS 15. Raymond LA, Gutierrez Y, Strong LE, et al: Living retinal nematode (filarial-like) destroyed with photocoagulation. Ophthalmology 1978;85:944. 16. de Souza EC, da Cunha SL, Gass ]D: Diffuse unilateral subacute neuroretinitis in South America. Arch Ophthalmol 1992;110:1261. 17. de Souza EC, Nakashima Y: Diffuse unilateral subacute neuroretinitis. Report of transvitreal surgical removal of a subretinal nematode. Ophthalmology 1995;102:1183. 18. Bernasconi OR, Piguet B: [Unilateral diffuse subacute neuroretinitis]. Klin Monatsbl Augenheilkd 1997;210:327. 19. Kinnear FB, Hay], Dutton GN, et al: Presumed ocular larva migrans presenting with features of diffuse unilateral subacute neuroretinitis. [Letter.] Br] Ophthalmol 1995;79:1140. 20. Kuchle M, Knorr HL, Medenblik-Frysch S, et al: Diffuse unilateral subacute neuroretinitis syndrome in a German most likely caused by the raccoon roundworm, Baylisascaris procyonis. Graefes Arch Clin Exp Ophthalmol 1993;231:48. 21. Salvanet-Bouccara A, Troussier H: [Diffuse unilateral subacute neuroretinitis. Apropos of a case].] Fr Ophtalmol 1987;10:667. 22. Yuen VB, Chang TS, Hooper PL: Diffuse unilateral subacute neuroretinitis syl1.drome in Canada. [Letter.] Arch Ophthalmol 1996; 114:1279.

23. Gass ]DM, ed: Stereoscopic Atlas of Macular Diseases, ed 2. St. Louis, CV Mosby, 1977, pp 226-227. 24. Goldberg M.A, Kazacos KR, Boyce WM, et al: Diffuse unilateral subacute neuroretinitis. Morphometric, serologic, and epidemiologic support for Baylisascaris as a causative agent [see comments]. Ophthalmology 1993;100:1695. 25. Kazacos KR, Vestre WA, Kazacos EA, et al: Diffuse unilateral subacute neuroretinitis syndrome: Probable cause. [Letter.] Arch Ophthalmol 1984;102:967. 26. Kazacos KR, Raymond LA, Kazacos EA, et al: The raccoon ascarid. A probable cause of human ocular larva mig-rans. Ophthalmology 1985;92:1735. 27. Kelsey]H: Diffuse unilateral subacute neuroretinitis. [Letter.]] R Soc Med 1978;71:303. 28. Carney MD, Combs ]L: Diffuse unilateral subacute neuroretinitis. Br] Ophthalmol 1991; 75: 633. 29. Casella AM, Farah ME, Belfort R]r: Antihelminthic drugs in diffuse unilateral subacute neuroretinitis. Anl] Ophthalmol 1998;125:109. 30. Matsumoto BT, Adelberg DA, Del Priore LV: Transretinal membrane formation in diffuse unilateral subacute neuroretinitis. Retina 1995;15:146. 31. Sivalingam A, Goldberg RE, Augsburger], et al: Diffuse unilateral subacute neuroretinitis. Arch Ophthalmol 1991;109:1028.

Mehran A. Afshari·and Nasrin Afthari

Schistosomiasis or bilharziasis is a parasitic disease of the circulatory system that affects over 200 million people in about 75 countries. I - 3 The disease may cause significant morbidity and mortality in humans. Fortunately, ocular involvement in schistosomiasis is rare. Most of the reported cases of ocular schistosomiasis have granuloma of the conjunctiva. 3, 4 However, adult schistosoma worms have also been found in the anterior chamber and in a branch of the superior ophthalmic vein. 5 , 6 Schistosomal choroiditis may occasionally be seen in patients who have hepatosplenic involvement. 7,8 Other presentations of ocular schistosomiasis include nongranulomatous uveitis, retinal vasculitis, inflammation of the retinal pigment epithelium, dacryoadenitis, orbital pseudotmTIor, cataract, and optic nerve· atrophy. 9-16

HISTORY

Schistosomiasis is a disease with ancient roots. 3 Calcified Schistosoma eggs have been found in an Egyptian mummy from 1200 Be. 1,17 In 1851, a German doctor, Theodore Bilharz, discovered the worm responsible for schistosomiasis and named it Distomum haematobium (later Schistosoma haematobiwn).1 Bilharz's nalTIe became synonymous with the human disease (bi'harziasis). The first effective treatment, tartar emetic, was used by McDonough in 1918. 1 The first reported case of ophthalmic schistosomiasis was by Sobhy Bey (1928) from Egypt. 18 The patient was an 8-year-old boy with swelling of his tarsal conjunctiva and limbus. Until 1972, only 13 cases of ocular schistosomiasis were reported in the literatureY At present, less than 100 cases of ocular schistosomiasis have been reported. About 10% of the world population (500 to 600 million people) are exposed to schistosomiasis, and over 200 million people in 75 countries are infected. 1, 2, 19 The disease is endemic in Mrica, South America, and Asia. 2 Schistosomiasis is usually seen in areas with fresh water temperature averaging between 25° and 30°C (between 36 degrees north and 34 degrees south latitude).1 S. haematobium is found in Mrica and Southwest Asia, S. japonicum is present only in the Far East, and S. 1nansoni is found in the Americas, Mrica, and Southwest Asia. 20 Unfortunately, because of increased exposure to contaminated water, the number of cases is increasing. 17 In the United States, more than 400,000 people are infected. 2,20, 21 Most of these patients are immigrants from the endemic areas (Puerto Rico, Brazil, the Middle East, and the Far East). Because the intermediate host does not exist in the United States, the infection cannot be transmitted in this country.2

PARASITOLOGY

CYCLE

The three major schistosoma species that infect humans are S. haematobium, S. japonicum, and S. mansoni. Less

prevalent species include S. intercalatum and S. mekongi.17, 19 All of these species share the same basic life cycle. 19 The lTIOSt important difference is the location of the adult worms. HUlTIanS are the principal definitive hosts for S. mansoni and S. haematobium; but S. japonicU1n has a variety of reservoir hosts in addition to humans, including dogs, cats, pigs, cattle, deer, and water buffalo. Humans are infected through contact with water contaminated with the infective stage of the parasite, which is called cercariae. 19, 22 Mter contact with human skin or the lTIUCOUS membranes, the microorganisms maintain their position by using their suckers. 20 With the help of secretions from penetration glands, cercariae penetrate the intact skin.19, 20 Penetration occurs within seconds to 10 lTIinutes after contact by Schistosoma. 2o Mter entering the human body, the organisms transform into schistosOlTIules or developing schistosomes that have a wormlike appearance. 20 These larva migrate to the lungs and finally to the portal vein, probably through an intravascular route. 19, 20 Schistosomules rapidly mature in the intrahepatic portal vein. The male and female schistosomes pair in the portal vein and then move to the venules of the bladder, ureter, and mesentery based on species of Schistosoma. 19 , 20 ' Mature S. haematobium, worms are found in the venous plexus of the bladder and ureter. S. mansoni live in the inferior mesenteric veins, and S. japonicum worms are in the superior mesenteric veins. 22 Adult worms are about 1 to 2 cm long and are found in pairs. 2o ,23 Female worms are carried by the male worms in a groove formed by lateral edges of the male worms. 22 The adult worms migrate in blood vessels without causing local inflammatory response. Fortunately, adult worms do not multiply in the human body, and immunosuppressive medications do not cause an increase in the number of worms. 19 Eggs burrow their way through the blood vessels and into the tissues of the walls of the intestine and bladder, and eventually reach the lumen of the urinary tract or bowel, and then are carried to the outside environment by urine or stool. If the eggs are deposited in fresh water, motile miracidia emerge which infect freshwater snails. These snails, of the genera Biomphalaria, Bulinus, and Oncomelania, are the intermediate hosts. Inside the snails, parasites divide asexually and are released into the water. At this stage, parasites are able to infect humans. 22

CLINICAL MANifESTATIONS Most of the infected individuals are asymptomatic. The clinical manifestations of each type of schistosomiasis depend on the intensity of the infection (i.e., parasitic load) and variation in the host response. 23 Skin penetration by cercaria mayor may not cause a pruritic maculopapular rash. 2,23 _'l..UlI.."';;;;

Schistosomiasis (Katayama fever)

Acute schistosomiasis may be seen after infection with S. 1nansoni and S. japonicum but is rare in S. haem,atobium

CHAPTER 44: SCHISTOSOMIASIS

infections. Patients report intense transient itching, fever, chills, headache, hives, angioedema, weakness, myalgia, anorexia, weight loss, nonproductive cough, abdominal pain, and diarrhea. 19 , 20 Generalized lymphadenopathy, hepatomegaly with tenderness, and splenomegaly are common. Lid edema, urticaria, and purpura may be present. 20 Eosinophilia is almost always present, which may be as high as 90%.20 Leukocytosis and hyperglobulinemia are also common. 19 Symptoms gradually improve within a few weeks to a few months. The specific diagnosis can be made by testing blood for the antibodies to the adult schistosome gut antigens, by finding the eggs in the stool or urine, or by a rectal biopsy.19 )

Chronic Schistosomiasis Most of these patients have a low to moderate worm load, and a large number of them are asymptomatic. 23 The patients with chronic infection caused by S. mansoni, S. japonicum, or S. mekongi may complain of abdominal pain, diarrhea, or dysentery. Blood loss frOlTI the gastrointestinal tract may lead to anemia. The eggs may remain in portal circulation, leading to blockage of presinusoidal portal blood flow, resulting in portal hypertension. The earliest clinical sign is hepatomegaly. Later splenomegaly, and hematemesis from esophageal varices may be seen. At the terminal phase, jaundice, ascites, and liver failure develop.2 In chronic infection with S. haematobium, the worms are located in the veins of the bladder or ureter. Patients complain of micturition freque~cy, hematuria and dysuria. 2, 22 Urinalysis shows red blood cells, Schistosoma eggs, and occasionalleukocytes. 22 The granulomatous reaction to the eggs may lead to obstructive uropathy and irregularities of the urinary bladder wall. Hydroureters, hydronephrosis, and filling defects of the bladder may be seen in imaging studies. In terminal stages, chronic renal failure or bladder cancer may be seen. 2

Cardiopulmonary Schistosomiasis Embolization of schistosomal eggs to the lungs is seen frequently at autopsy. In some patients, the eggs cause a significant granulomatous reaction, which leads to pulmonary hypertension and cor pulmonale. 20

Central Nervous System Schistosomiasis Brain and spinal cord involvement is rare in schistosomiasis. S. japonicum may cause cerebral lesions like granuloma or encephalitis, whereas S. haematobium and S. mansoni may result in granulomas of the spinal cord. 20

Ectopic Schistosomiasis

are not definitely known. The following hypotheses have been postulated. 3-6,8 . 1. Cercariae may penetrate the skin and mucous membrane of various parts of the body, and then develop in nearby local veins. Abboud studied the penetration of cercariae of S. mansoni into ocular structures (including eyelids, conjunctiva, sclera, and cornea) of experimental animals. 4 Subconjunctival injection of cercariae and instillation of cercariae on the skin, cornea, and conjunctiva did not cause ocular lesions, but it did produce generalized schistosomiasis. Therefore, the theory supporting the local route of infection through the eye has fallen out of favor. 4 2. Eggs may reach unusual sites through a patent foramenovale. 3. Eggs may be deposited by theschistosomes in the gastrointestinal and genitourinary veins and then be filtered through the liver and lung capillary plexus. 4. The worms may migrate and circulate against the· blood stream. The presence of worms in a branch of the superior ophthalmic vein supports this theory. 5. Eggs that are free in the portal system may enter the caval system through the enlarged anatomical portocaval collaterals. In portal hyperten~ion, which is common in schistosomiasis, these collaterals are unusually large. Ocular lesions are caused by S. haematobium, and S. mansoni. S. haematobium is responsible for most of the ocular lesions. Allergic ocular involvement and lid edema may be seen at the time of infestation. 20 , 24

Conjunctival Lesions The most commonly reported ocular lesion is egg granuloma in the conjunctiva. 5, 16, 25 Conjunctival infection was first reported in Egypt by Sobhey Bey in 1928. 18 These lesions are primarily seen in male patients and are usually unilateraI,15 Conjunctival lesions are small, soft, slTIooth, and pinkish yellow in color. 15 All of the first nine reported cases occurred in children (seven boys and two girls) from 5 to 12 years of age. 5 Histopathologic examination of most of the cases reveal the presence of schistosomal ova in the granuloma. Badir reported a case in which the worms were observed in situ under the conjunctiva of a 12-year-old boy.5 The patient had a lesion of the palpebral conjunctiva of the upper eyelid near the medial canthus. The lesion was excised, and a pathologic examination revealed an inflammatory granuloma beneath the epithelium containing a large number of schistosomal eggs. Additionally, in this specimen, a male and a female schistosome were identified in a dilated orbital vein (a branch of the superior ophthalmic vein).5

Ectopic lesions in schistosomiasis are not common. Schistosomiasis may involve the uterus, ovary, testis, prostate, spermatic cord, epididymis, pancreas, gall bladder, omenOrbital Schistosomiasis tum, stomach, kidney, adrenal gland, globe, and orbit. 3 Jakobiec et al. reported an II-year-old boy with a mass in Ocular schistosomiasis is discussed in detail in the next his lacrimal gland a year after trauma to his brow (Fig. section. 44-1). Pathologic examination showed widespread destruction of the lacrimal gland by a granulomatous lesion. Ocular Schistosomiasis Throughout the granuloma, eggs of S. haematobium were Mechanism present. 9 Mortada reported a case of schistosomiasis preThe exact route and mechanism by which the schisto- sented as orbital pseudotumor with eosinophilia. Howsomes can reach ectopic sites such as the globe and orbit ever, neither ova nor worms were found in the biopsy.26

CHAPTER 44: SCHISTOSOMIASIS

FIGURE 44-2. S. mansoniworm in the anterior chamber. (From Newton JC, Kanchanaranya C, Previte LR: Intraocular Schistosoma mansoni. Am J Ophthalmol 1968;65:774.)

FIGURE 44-1. Schistosomal dacryoadenitis. (From Jakobiec FA, Gess L, Zimmerman LE: Granulomatous dacryoadenitis caused by Schistosoma haematomum. Arch Ophthalmol 1977;95:279.)

Intraocular Schistosomiasis Schistosoma may cause uveitis, 11, 27 choroiditis, chorioretinitis,7, 8, 27 inflammation of retinal pigment epithelium,10 maculitis,11 retinal vasculitis, retinal vascular occlusion, retinal hemorrhage,4 hyphema,6 optic nerve swelling,lO or optic nerve atrophy.13 Injection of cercariae of S. mansoni into the anterior chamber of experimental animals resulted in aqueous flare, keratic precipitates, and hypopyon. 4 Stein and Char developed an experimental uveitis mode1in rabbits using intraocular injection ofS 17wnsoni eggs. 28 Intraocular inflammation became clinically apparent after five days, and on histologic examination, an eosinophilic infiltrate of the vitreous and choroid were seen. The chorioretinitis caused disruption of the photoreceptor layer. Mter a month, granuloma developed around the eggs that was similar to schistosomal granuloma in other parts of the body.28

lesions were yellowish white translucent nodules varying in size and were located in the choroid (Figs. 44-4 and 44-5). An important characteristic of these nodules is their variation in size. The size may correlate with the number of eggs present and with the various phases of their development. 8 In all five cases, the anterior chamber was quiet, but in one patient, there were a small number of cells in the vitreous. These nodules did not interfere with vision if there was no macular nodule. 7 Pittella studied the eyes of two deceased patients with hepatosplenic schistosomiasis. 8 In one patient, three granulomas were found in the choroid. Each granuloma was characterized by S. mansoni ova in the choroid, with a slight projection to the retina, surrounded by epithelioid cells in palisade formation, lymphocytes, plaslllocytes, and eosinophils (Fig. 44-6).8

Intraocular Worm A case of S. mansoni worm in the anterior chamber has been reported in New York City (Figs. 44-2 and 44-3).6 The patient was a 19-year-old Hispanic man who presented with hyphema. Mter absorption of the hyphema, it was noted that a white mobile tubular structure was present in the anterior chamber. The worm was removed surgically, and 3 months later, vision returned to 20/20. 28

Choroiditis In a study of 50 patients with hepatosplenicschistosomiasis, five patients were found to have choroiditis. 7 The

FIGURE 44-3. Gonioscopic view of intraocular S. mansoni. (From Newton JC, Kanchanaranya C, Previte LR: Intraocular Schistosoma mansoni. AmJ Ophthalmol 1968;65:774.)

CHAPTER 44: SCHISTOSOMIASIS

FIGURE 44-4. Medium-sized schistosomal nodules in the posterior pole. (From Orefice F, Simal CJR, PittellaJEH: Schistosomotic choroiditis. 1. Funduscopic changes and differential diagnosis. Br J Ophthalmol 1985;69:294.)

Inflammation Epithelium

of the

Retinal Pigment 'V'

Dickinson reported a 17-year-old man with visual acuity of 20/200, afferent pupillary defect, and iridocyclitis. lo On funduscopy, optic disc swelling and multiple creamy lesions resembling acute multifocal placoid pigment epitheliopathy were seen. Stool examination revealed S. mansoni ova. Six weeks after treatment with praziquantel, the patient's vision returned to normal, the disc swelling resolved, and fundus lesions evolved into chorioretinal scars. lO

FIGURE 44-6. Schistosomal granuloma in the choroid. (From Pittella JEH and Orefice F: Schistosomatic choroiditis. II. Report of the first case. Br J Ophthalmol 1985;69:300.)

Optic Nerve Involvement Unilateral optic nerve atrophy and optic nerve swelling may be seen in patients with ocular schistosomiasis.10, 13 Creed reported a case of optic atrophy in a patient with a history of schistosomiasis.1 3 CT scan showed an optic nerve lesion that could be a granuloma encasing an egg.

FIGURE 44-5. Fluorescein angiogram showing hyperfluorescent schistosomal nodules. (From Orefice F, Simal CJR, Pittella JEH: Schistosomatic choroiditis. 1. Funduscopic changes and differential diagnosis. Br J Ophthalmol 1985;69:294.)

CHAPTER 44: SCHISTOSOMIASIS

However, there is no histologically proven case of optic nerve involvement in schistosomiasis.

TREATMENT

Systemic The drug of choice for the treatment of schistosomiasis is praziquantel, which is effective against all types of schistosome species. 2, 19, 22 For patients with S. hae1natobium and S. mansoni infections, Praziquantel is prescribed as two oral doses of 20 mg/kg body weight. 2 For treatment of S. japonicum, praziquantel is administered as 20 mg/kg body weight in three doses given at four hour intervals. 2, 20

Ocular Treatment with praziquantel is usually sLuficient except for complicated cases. 24 Topical steroids may be needed to decrease the symptoms of conjunctival schistosomiasis. Excision of periocular nodules is both diagnostic and therapeutic. Uveitis cases may be treated with a combination of systemic antiparasite medications and topical steroids. If a worm is present inside the globe or orbital veins, it can be removed by surgery.24

PROGNOSIS Schistosomal conjunctival granuloma has a good prognosis. However, .the prognosis of intraocular schistosomiasis depends on the tissue involved and the extent of involvement.

CONCLUSIONS Although schistosomiasis is a common systemic disease, its ocular involvement is rare. The most common presentation of ocular schistosomiasis is granuloma of the conjunctiva. However, schistosomiasis may cause uveitis, retinal vasculitis, inflammation of the retinal pigment epithelium, choroiditis, dacryoadenitis, orbital pseudotumol', cataract, and optic nerve atrophy. Praziquantel is the drug of choice for the treatment of schistosomiasis.

References 1. Strickland GT, Abdel-Wahab MF: Schistosomiasis. In: Strickland GT, ed: Hunter's Tropical Medicine, 7th ed. Philadelphia, WB Saunders, 1991, p 781. 2. Mahmoud AAF: Trematodes (schistosomiasis) and other flukes. In: Mandell GL, Bennett ]E, Dolin R, eds: Principles and Practice of Infectious Diseases, 4th edition. New York, Churchill Livingstone, 1995, p 2538. 3. Fatt-hi A, Kamel I: Ectopic bilharziasis. ] Laryngol Otol 1980; 94:1179.

4. Abboud A, Hanna LS, Ragab HAA: Experimental ocular schistosomiasis. Br] Ophthalmol 1971;55:106. . 5. Badir G: Schistosomiasis of the conjunctiva. Br ] Ophthalmol 1946;30:215. 6. Newton ]C, Kanchanaranya C, Previte LR: Intraocular Schistosoma mansoni. Am] Ophthalmol 1968;65:774. 7. Orefice F, Simal CJR, Pittella ]EH: Schistosomotic choroiditis. 1. Funduscopic changes and differential diagnosis. Br] Ophthalmol 1985;69:294. 8. Pittella]EH, Orefice F: Schistosomotic choroiditis. II. Report of the first case. Br] Ophthalmol 1985;69:300. 9. ]akobiec FA, Gess L, Zimmerman LE: Granulomatous dacryoadenitis caused by Schistosoma haematobium. Arch Ophthalmol 1977;95:279. 10. Dickinson A], Rosenthal AR, Nicholson KG: Inflammation of the retinal pigment epithelium: A unique presentation of ocular schistosomiasis. Br] Ophthalmol 1990;74:440. 11. Hollwich F, Dieckhues B, ]unemann G, et al: Bilharziose des Auges. Klin Mbl Augenheilk 1972;161:430. 12. Tabbara KF, Shoukrey N: Schistosomiasis. In: Gold DH, Weingeist TA, eds: The Eye in Systemic Disease. Philadelphia,]B Lippincott, 1990, p 184. 13. Creed TD: Unilateral optic atrophy presumed secondary to schistosomiasis of the optic nerve.] Am Optom Assoc 1993;64:440. 14. Tabarra KF, Hyndiuk RA, eds: Infections of the Eye, 2nd edition. Boston, Little Brown and Co, 1995, p 191. 15. Duke-Elder SS: System of Ophthalmology. St. Louis, c.v. Mosby, 1976. 16. Kean BH, Sun T, Ellswortl1 RM, eds: Color Atlas/Text of Ophtl1almic Parasitology. New York, Igaku-shoin, 1991. 17. Mahmoud AAF, Wahab MFA: Schistosomiasis. In: Warren KS, Mahmoud AAF, eds: Tropical and Geographical Medicine, 2nd edition. New York, McGraw-Hill,1990, pp 458-473. 18. Sobhy Bey M: La Bilharziose palpebroconjonctivale. d'Ocul, Tome CLXV 1928;165:675. 19. Nash TE: Schistosomiasis and other trematode infections. In: Fauci AS, Braunwald E, Isselbacher Ig, et aI, eds: Harrison's Principles of Internal Medicine, 14th ed. New York, McGraw-Hill, 1998, p 1217. 20. Kline MW, Sullivan TJ: Schistosomiasis. In: Feigin RD, Cherry]D, eds: Textbook of Pediatric Infectious Diseases, 3rd ed. Vol II. Philadelphia, W.B. Saunders, 1992, p 2112. 21. Warren KS: Helminthic diseases endemic in the United States. Am ] Trop Med Hyg 1974;23:723. . 22. King CH: Schistosomes. In: Behrman RE, Kliegman RM, Arvin AM, eds: Textbook of Pediatrics, 15th ed. Philadelphia, W.B. Saunders, 1996, p 1001. 23. Cheever AW: Schistosomiasis. In: Hoeplich PD, Colin Jordan M, Ronald AR, eds: Infectious Diseases, 5th ed. Philadelphia, ].B. Lippincott Company, 1994, p 864. 24. Fraunfelder FW, Fraunfelder FT: Schistosomiasis. In: Fraunfelder FT, Hampton Roy F, Grove], eds: Current Ocular Therapy, 4th ed. Philadelphia, W.B. Saunders, 1995, p 134. 25. Abdalla Cairo MI: Schistosomal granulomatosis of the conjunctiva. The Eye, Ear, Nose and Throat Monthly 1967;46:452. 26. Mortada A: Orbital pseudo tumors and parasitic infections. Bull Ophtl1almol Soc Egypt 1968;61:393. 27. Andrade CDE: Oftalmologica Tropical. Rio de Janeiro, Rodrigues, 1940. 28. Stein PC, Char DH: Intraocular granuloma: A Schistosoma mansoni model of ocular inflammation. Invest Ophthalmol Vis Sci 1982;23:479.

E. Mitchel Opremcak

Ophthalmomyiasis is an insect-mediated ocular disorder caused by botfly larvae (order Diptera). Botfly maggots may infest the ocular surface causing ophthalmomyiasis externa or may invade the eye, resulting in a clinical disease termed ophthalmomyiasis interna.

HISTORY Maggot infestation of necrotic tissue in animals and humans has been a naturally occurring event throughout history. Larvae from the Calliphoridae family of flies are still used to debride and clean medically resistant cases of wound necrosis and severe osteomyelitis. 1, 2 Ocular disease, caused by maggots, was first reported in Austria in 1900. 3 The larva of Hypoderma bovis was identified after surgical removal from the eye of a child. Unfortunately, the child died from the complications of chloroform anesthesia. Most of the early reports were in children in the German medical literature and reported a poor visual outcome, often as a result of a purulent chorioretinitis. 4 In 1933, DeBoe published a case of "Dipterous larvae passing from the optic nerve into the vitreous chamber" in the English literature. 5 Anderson reported a case and provided the first review of the li.erature on ophthalmomyiasis interna in 1934. 6 Since then, several cases have been reported describing the various clinical presentations and evolving treatment strategies, including the use of ophthalmic lasers and vitreoretinal surgical techniques. 2,7-9

Ophthalmomyiasis is an insect-mediated ocular disease caused by the larval stage of several families of flies in the order Diptera. 3, la, 11 Certain families in this order are obligate parasites and require living tissue to complete their life cycle. The most common cause of ophthalmomyiasis externa is the sheep nasal botfly (Oestrus OViS).12-14 As an obligate parasite, this species requires sheep as the host to complete their developlnental cycle. An adult botfly will spray immature larvae into a flock, where they are inhaled into the nasal cavity by the sheep.4 Once on the mucous Inembranes, the larvae migrate to the sinuses and develop into mature larvae before leaving the host by falling out the nose. Accidental human infestation has occurred worldwide, in areas endemic to the sheep botfly and in geographic proximity to flocks of sheep. It is postulated that the airborne, immature larvae attach to mucous membranes and conjunctiva of hlllnan hosts, resulting in ophthalmomyiasis externa. 15 Rarely, Oestrus ovis larvae penetrate the eye to cause ophthalmomyiasis interna. 2 In contrast, H. bovis is an obligate parasite, requiring cattle as the natural host to complete its life cycle. 16- 18 This species of botfly lay eggs directly on the skin of a cow, where they hatch. The immature larvae penetrate the skin and migrate through the tissues. Eventually, the

mature larvae emerge through the skin again to fall on the ground to pupate. Most of the reported cases of ophthalmomyiasis interna are thought to be caused by this organism. The route of infestation in humans may be via direct deposition of eggs in the conjunctival culde-sac, with subsequent penetration of hatched immature larvae into the eye. Alternatively, the maggot may gain access to the eye after migrating through the human host for several months. 9, 18 The mature larva then gains access to the eye by penetrating the sclera, through the optic nerve, or via ciliary vessels. Ophthalmomyiasis interna is often noted in temperate regions that have a significant population of both the host cattle and H. bovis botfly.9 Other families of flies in the order Diptera have been reported to cause ophthalmomyiasis. Rabbits and rodents are host to Cuterebra sp. and larvae from these flies have been reported to cause human disease in North America. 19 Certain flies are facultative parasites (Calliphora sp.) and may also cause ophthalmomyiasis. Most cases of orbital myiasis have been associated with the Calliphoridae family of botfly.3, 20, 21 These flies require decaying organic material for the developmental cycle of the ova, larvae, and adult fly. Opportunistic human infestation by these flies occurs in areas with substandard public health conditions and poor personal hygiene. 9

CLINICAL Ophthalmomyiasis externa is characteristically a unilateral disease of the ocular surface. Patients may complain of tearing, eyelid twitching, ocular irritation, and rednessY Visual acuity is typically good but may be slightly impaired. On ocular examination, motile larvae can be seen on the cornea, or in the conjunctival cul-de-sac. 22 Secondary keratitis, conjunctival hyperemia, hemorrhages, and a follicular conjunctivitis can be noted on biomicroscopic examination. Patients with ophthalmomyiasis interna may be asymptomatic or, early in the course of the disease, may present with unilateral decrease in visual acuity. 6, 23 In the later stages with the death of the maggot, secondary ocular inflammation may result in pain, photophobia, and redness. 24 On biomicroscopic and fundus examination, the observation of a single, motile, white to translucent larva is pathognomonic (Fig. 45-1). The organism is segmented and tapered at both ends. In some instances, the maggot has been reported to move away from the examination light. Larvae have been observed in the anterior chamber, lens, vitreous, and the subretinal space. They can migrate from the anterior chamber to the vitreous cavity and may leave the eye entirely, leaving behind the characteristic subretinal tracks. 16 , 19, 23 In one reported case, a maggot was observed to migrate from the optic nerve head into the vitreous cavity.5 When under the sensory retina, migration of the maggot results in characteristic, linear scars or "railroad tracks" at the level of the retinal pigment

CHAPTER 45: OPHTHAlMOMYIASIS

migration and location of the organism within the eye. When alive, the mature larva can cause trauma to the delicate intraocular tissues and structures. The subretinal tracks represent such mechanic injury to the RPE. Datu.. age to the optic nerve, secondary macular hemorrhage, and retinal detachment have been reported complications of larval migration through the eye and retina. 17 Uveitis can occur with the death of the larvaY, 17, 25, 26 In one case in which the maggot was removed surgically, the vitreous contained lymphocytes, eosinophils, plasma cells, and epithelioid cells. 2

DIAGNOSIS FIGURE 45-1. Composite "collage" fundus photograph demonstrating the etiologic agent of ophthalmomyiasis, the botfly maggot. (From Gass JD: Stereoscopic Atlas of Macular Disease, 3rd ed. St. Louis, CV Mosby, 1987. Courtesy of Constance Fitzgerald, MD, with permission from ]. Donald Gass, MD, and Mosby Publishers.) (See color insert.)

epithelium (RPE) .23 (Fig. 45-2) Death of the maggot may result in mild to severe intraocular inflammation. Chorioretinitis, purulent panuveitis, vitreous hemorrhages, and retinal detachment has been reported with the death of a larva in cases of ophthalmomyiasis internaP In most cases, however, death of the larva within the eye has not been associated with significant uveitis. 9

PATHOGENESIS Ocular surface disease in ophthalmomyiasis externa is due primarily to mechanical injury caused by the maggot and its mouth hooks and intersegmental spines. 9 Corneal edema, and conjunctival hyperemia and a follicular conjunctivitis are common reactions to the larval infestation and movement. Small conjunctival hemorrhages as a result of tissue damage from the oral hooks and the thorax spines may be observed. The ocular manifestations and clinical presentation of ophthalmomyiasis interna depends on the route of

FIGURE 45-2. Fundus photograph of a patient with longstanding ophthalmomyiasis, demonstrating the extensive RPE loss in "track" fashion, evidence of tlle very extensive amount of migration and travel of the maggot. (From Gass JD: Stereoscopic Atlas of Macular Disease, 3rd ed. St. Louis, CV Mosby, 1987. Courtesy of]. Donald Gass, MD, witll permission from Mosby Publishers.) (See color insert.)

The diagnosis is made on clinical grounds, by observing the maggot on the ocular surface or within the eye. On fundus examination, the presence of subretinal, crossing, linear tracks are suggestive but not diagnostic for this condition. Although they are characteristic of ophthalmomyiasis, linear scars in the retina have been observed in other helminthic diseases and may be similar in appearance to the linear equatorial streaks in histoplasmosis, angioid streaks, and traumatic choroidal ruptures. Fluorescein angiography may help show the extent of injury to the RPE and macula. 23 The larva can be specifically identified in cases in which it is surgically removed from the eye. On removal, the maggot should be ,'fixed in formalin and processed for microscopic examination. 9 Characteristic surface structures on the maggot allow classification of the organism to family, genus, and species. 19

Treatment for ophthalmomyiasis externa consists of removing the larva from the ocular surfaceY Topical and regional anesthetics provide both comfort and facilitate the removal process by immobilizing the maggots. 27 Therapeutic strategies vary for patients with ophthalmomyiasis interna, depending on the location of the maggot and whether the organism is alive or deadY In some case reports, dead larva have been observed within the eye and appear to be well tolerated, with patient retention of good vision and no inflammation. s,9 In patients with a dead maggot in the eye and no uveitis, the eye and the larva may be observed without therapy. Such tolerance, however, for a relatively complex organism within the eye would be unexpected. A dead botfly maggot would have multiple unique proteins capable of inciting uveitis unless their antigens are denatured or removed. In most cases, when the maggot is alive, attempts have been made either to kill the organism via laser photocoagulation or surgically to reluove it from the eye. Argon laser photocoagulation has been used to kill the larva with some success. S,25 In one report, using settings at 10 burns of a 200-J.1m spot size, at 400 lUW, and a 0.1second duration, laser photocoagulation was successful in killing the maggot without significant intraocular inflammation. S It is possible that the photocoagulation denatured the larval antigens and, by that, prevented an inflammatory response. In another patient, photocoagulation was accompanied by a severe, postlaser uveitis. 25 Topical, regional and oral corticosteroids may be used to treat uveitis associated with the death of the larva. In

CHAPTER 45: OPHTHALMOMYIASIS

several cases, the larvae was extracted surgically from the eye. 2 ,7 Both vitrectomy and subretinal sutgical techniques have been employed to remove intraocular maggots. Most of these cases resulted in improved visual acuity following removal of the parasite. Complications of ophthalmomyiasis are prilnarily due to mechanical injury accompanying maggot migration, intraocular inflammation associated with the death of the organism, and trauma from surgical removal. 2, 7, 9, 25 Retinal tears and detachment have been reported in cases of ophthalmomyiasis interna. These problems can be addressed by standard vitreoretinal surgical techniques. Ocular inflammation may occur with the death of the maggot following laser photocoagulation and can be treated with corticosteroid regimens. Vitreoretinal surgical techniques can be complicated by retinal detachment, cataract, hemorrhage, and endophthalmitis. In most cases, these surgical risks are acceptable when compared with the potential injury caused by random, intraocular larval migration and death of the organism.

PROGNOSIS The prognosis for ophthalmomyiasis externa is good. Removal of the maggots results in return of ocular comfort and resolution of the conjunctival irritation. The visual prognosis for ophthalmomyiasis interna depends on the migration route of the maggot and on whether the death of the larva incites infl~mmation. A poor visual prognosis can be expected if tne path of the maggot involves critical structures such as the optic nerve or the macula. Retinal detachment may be repaired but may be associated with poor central vision if the macula is involved. Laser photocoagulation and death of the maggot may result in uveitis, which can be treated with corticosteroids. Surgical removal of the organism from the vitreous cavity or the subretinal space eliminates this risk and may preserve vision in selected cases.

CONCLUSIONS Ophthalmomyiasis is a rare, unilateral ocular disease caused by the larvae of the botfly. Several families in the order Diptera can infest human hosts and cause mild ocular surface disorder or a more serious ophthalmomyiasis interna. Surgical removal of the organism may effect a better visual prognosis and reduce the chances of uveitis. Vision may be impaired as a result of mechanical injury to the optic nerve or macula.

References 1. Bunkis J, Gherini S, Walton RL: Maggot therapy revisited. West J Med 1985;142:554.

2. Rapoza PA, Michels RG, Semeraro RJ, et al: Vitrectomy for excision of intraocular larva (Hypoderma species). Retina 1986;6:99. 3. Kersten RC, Showkrey NM, Tabbara KF: Orbital myiasis. Ophthalmol 1986;93:128. 4. Hoffman BL, Goldsmid JM: Ophthalmomyiasis caused by Oestrus avis L. (Diptera:Oestridae) in Rhodesia. S MrMed J 1970;10:644. 5. DeBoe MP: Dipterous larva passing from the optic nerve into the vitreous chamber. Arch Ophthalmol 1933;10:824. 6. Anderson WE: Ophthalmomyiasis interna: Case report and review of the literature. Trans Am Acad Ophthalmol Otolarygol 1934;39:218. 7. Custis PH, Pakalnis VA, Klintworth GK, et al: Posterior internal ophthalmomyiasis: Identification of a surgically removed Cuterebra larva by scanning electron microscopy. Ophthalmology 1983;90:1583. 8. Fitzgerald CR, Rubin ML: Intraocular parasite destroyed by photocoagulation. Arch Ophthalmol 1074;91:162. 9. Glasgow BJ: Ophthalmomyiasis. In: Pepose JS, Holland GN, Wilhelmus KR, eds: Ocular Infection and Immunity. St Louis, CV Mosby, 1995, P 1505. 10. Beaver PC, Jung RC, Cupp EW: Clinical Parasitology, 9th ed. Philadelphia, Lea & Febiger, 1984, p 680. 11. Kean BH, Sun T, Ellsworth RM: Ophthalmomyiasis. In: Kean BH, Sun T, Ellsworth RM, eds: Color Atlas/Text of Ophthalmic Parasitology. New York, Igaku-Shoin, 1991, p 105. 12. Cameron JA, Shoukrey NM, Al-Garni AA: Conjunctival ophtl1almomyiasis caused by tl1e sheep nasal botfly (Oestrus avis). AmJ Ophthalmol 1991;112:331. 13. Harvey JT: Sheep botfly: Ophthalmomyiasis externa. CanJ Ophtl1almol 1986;21:92. 14. Reingold~, RobbinJB, Leipa D, et al: Oestrus ovis ophthalmomyiasis externa. Amj,Ophtl1almol 1984;97:7. 15. de Vries LAM, van Bijsterveld OP: Ophthalmooestriasis conjuntivitivae. Ophthalmologica 1986;192:193. 16. Mason GI: Bilateral ophthalmomyiasis interna. Am J Ophthalmol 1981;91:65. 17. Edwards KM, Meredith TA, Hagler WS, et al: Ophthalmomyiasis interna causing visual loss. Am J Ophthalmol 1984;97:605. 18. Vine A, Schatz H: Bilateral posterior interior ophthalmomyiasis. Ann Ophthalmol 1981;13:1041. 19. Mathur SP, Makhija JM: Invasion of the orbit by maggots. Br J Ophthalmol 1967;51:406. 20. Glasgow BJ, Maggiano JM: Cutm'bra ophthalmomyiasis. Am j Ophtlnlmol 1995;119:512. 21. Wood TR, Slight JR: Bilateral orbital ophthalmomyiasis. Report of a case. Arch Ophtl1almol 1970;84:692. 22. Laborde RP, Kaufman HE, Beyer WE: Intracorneal ophthalmomyiasis. Arch Ophthalmol 1988;106:880. 23. Gass JDM, Lewis RA: Subretinal tracks in ophthalmomyiasis. Arch Ophtl1almol 1976;94:1500. 24. Slusher MM, Holland WD, Weaver RG, et al: Ophthalmomyiasis interena posterior: Subretinal tracks and intraocular larvae. Arch Ophtl1almol 1979;97:885. 25. Forman AR, Cruess AF, Benson WE: Ophthalmomyiasis treated by argon laser photocoagulation. Retina 1984;4:163. 26. Hess C: Severe purulent chorioretinitis with destruction of the retina due to a cause not known up to the present time. Arch Augenh 1913;74:227. 27. Medownick M, Finkelstein E, Lazarus M, et al: Human external ophthalmomyiasis caused by tl1e horse botfly larva (gastrerophilus sp.). Aust N ZJ Ophthalmol1985;13:387.

I Stefanos Baltatzis

Ophthalmia nodosa is defined as severe ocular inflammatory reaction precipitated by hairs of certain insect or vegetable material that has come into contact with the eye. The term "nodosa" is derived frOln the granulomatous nodule formed on the conjunctiva and. in the iris in response to caterpillar hairs or sensory setae.

Thus, a definite history of caterpillar contact is not necessary for the diagnosis of the condition. In fact, none of the 103individuals described by Bishop and Morton 9 (1967) gave a history of direct caterpillar contact.

CLINICAL

The clinical manifestations of ophthalmia nodosa vary greatly and are classified according to Candera and associates 10 as follows: ISTORY Type 1. An acute, anaphylactoid reaction consisting of The dermal reaction to sharp and irritant caterpillar setae conjunctival chemosis and inflammation combined with (Lepidoptera) was known to the Greeks and the Romans, epiphora and foreign body sensation beginning immediand was commented upon by Dioscorides and Pliny. 1 ately and lasting for weeks. The loose tissues of the eyelid Schon (1861) was the first who described the disease are primarily involved, producing a marked periorbital that was later called "pseudotuberculosis" by Wagenwan 2 edema and allergic dermatitis. Shama and colleaguesl l (1890) and renamed ophthalmia nodosa by Saemich 3 have described an acute toxic or allergic reaction to (1904). Gunderson 4 extensively reviewed the disease in caterpillar hairs with periorbital edema. Histamine pres1945. ent in the caterpillar hairs has been implicated in this reaction. To date, studies have failed to identifY all of the EPIDEMIOLOGY precipitating toxins. The cause of ophthalmia nodosa is region specific, ocType 2. Chronic mechanical keratoconjunctivitis curring primarily as a result of needles of plants, such as caused by hairs lodged in the bulbar or palpebral conthe common burdock, which is found in all the contigu- junctiva. The symptoms appear from minutes to days after ous 48 states of the United States, or urticarial hairs of the hairs reach the eye. The cornea may show linear some caterpillars. According to Watson and associates, 5 scratches adjacent to the hair (Fig. 46-2). only six varieties of caterpillars are known to cause ophType 3. Formation of one or more gray-yellow conjuncthalmia nodosa. Also, hairy spiders commonly called tar- tival nodules (granulomas). Setae may be subconjunctival antula can cause ophthalmia nodosa, especially in areas or intracorneal, producing nebulae around them with or where keeping such spiders as pets is fashionable. without synechiae. The patient may be entirely asymptoMaerothylaeia rubi and Aretia eaja are the caterpillar matic at this stage. species found only. in British Isles, whereas Traumetopoea Type 4. Intense iritis secondary to hair penetration pityoeampa(pine processionary), Thaumetopoea jordana, into the anterior chamber (Fig. 46-3). The iritis tends to Isia Isabella, and Dedrolimnus pini may be found in other be severe and is often associated with iris nodules and countries. Two other species have also been associated even with hypopyon. In rare cases, hairs penetrate the with ophthalmia nodosa, namely, Thaumetopoea pinivora, lens and cause an intralenticular foreign body reaction. Type 5. Vitreoretinal involvement (l0% to 20%),12 another pine processionary, and Thaumetopoea proceswhich may occur relatively early or may develop years sionary L, an oak processionary. 5 Hairy spiders of the family Therapsosidae (commonly after the contact with the hairs (Fig. 46-4). The hairs called tarantulas) (Fig. 46-1A and B) possess specialized gain access to the vitreous and subretinal space either hairs on the dorsal surface of the abdomen at a density by entering the anterior chamber and then penetrating of approximately 10,000/mm,2 and 0.10 mIn in length. 6 , 7 through the iris or lens, or by migrating transclerally When threatened, the spider rapidly vibrates its hind legs from a conjunctival focus. Chorioretinal tracks tend to be across the dorsal (l.bdomen, which is densely covered with pigmented, with a white, inflamed leading edge. barbed hairs. This reaction sprays a cloud of hairs in tb Rare cases of overt endophthalmitis have been rethe path of the . perceived threatening predator. Cooke ported,13 but milder forms of vitritis with or without cysand coworkers6-8 classified projectile tarantula hairs into toid macular edema or papillitis are more common. four types. Species native to South and Central America, Patients may develop some or all of these features. the Caribbean, and Mexico possess the relatively large Although it is possible for each of the five types of reacand sturdy type III hairs, which are known to produce a tion to develop sequentially, a patient Inay manifest only prolonged ai1.d intense urticaria in human tissue. Contact one type even without having a history of contact with with caterpillar setae occur by direct contact with caterpil- caterpillars. Some cases may be due to wind-blown hairs lars, by contact with the larval cocoon into which setae or to forgotten contact with a caterpillar in childhood. may be shed and interwoven, by contact with adult Lepi- The type and severity of the ocular reaction and the doptera which may carry larval setae on their bodies after ultimate prognosis probably depend on the number of emerging from the cocoon, by direct reaction to the adult hairs or the amount of foreign material that comes into setae themselves, or by wind-borne spread of setae. contact with or gains entry into the eye.

46: OPHTHALMIA NODOSA

FIGURE 46-1. A, Tarantula; ventral surface of the spider, showing tagma, opisthosoma, and prosoma. B, Additional, more magnified view of the ventral surface of the tarantula spider showing the fans chelicera. Images courtesy of Antoine Morin and Jon Houseman, from the Biodidac website, URL: http://biodidac.bio.uottawa.ca/.

FIGURE 46-2. A, Slit-lamp photograph of a patient with ophthalmia nodosa, with keratitis secondary to a tarantula hair. B, Ophthalmia nodosa with both keratitis and uveitis. (Courtesy of Dr. E. Mitchel Opremcak.) (See color insert.)

FIGURE 46-3. Ophthalmia nodosa with hypopyon uveitis. (Courtesy of Dr. E. Mitchel Opremcak.) (See color insert.)

FIGURE 46-4. Ophthalmia nodosa, with intraocular penetration of tarantula hair, "vith production of posterior uveitis and the formation of vitreal infiltrates, both in the form of snowballs and in the form of a snowman (central figure). (Courtesy of Dr. E. Mitchel Opremcak.) (See color insert.)

CHAPTER. 46: OPHTHALMIA NODOSA

The pathologic damage caused by setae is a function of their direct toxicity and locomotion. Caterpillar hair toxicity is dependent on the concentration of toxins in the venom gland, which is connected to the hair shaft. The intraocular inflammation is presumably due to both the presence of foreign material and in part to the effect of the urticating toxin. 14 Chemical analysis of the urticating toxin shows a small fraction of water-soluble protein with esterase, protease, and phospholipase activity.15 The material can also give rise to IgG antibodies in rabbits. 16 In 1986, Lamy and colleagues 17 identified the urticating protein of the pine processionary caterpillar as thaumeatopoein; there is a similar protein in other urticating caterpillars. Althongh ophthalmia nodosa has been known for more than a century, the mechanism of caterpillar hair migration into the eye remains controversial. Gunderson and coworkers 12 have suggested that because the setae have no propulsive power of their own, movements of the globe with versions, respirations, and pulse, together with the constant iris movement, propel the spines forward. It can be seen from electron microscopy that the orientation of the spines is vital to facilitation of this forward only movement. Asher18 proposed that the cellular infiltration around the damaged base of the hair pushes the undamaged tip of the hair toward the direction of least resistance. Whereas the soft conjunctival and episcleral tissues permit the formation of a protruding nodule, the stiffer cornea and scl~a do not. As a result, the hair is propelled forward in its same interlamellar space unless the sharp tip happens to enter a neighboring interlamellar space, in which case it will continue to move parallel to the lamellae. Histopathologically, the granulomatous reaction consists of histiocytes, epithelioid cells, and macrophages surrounding the foreign material. Occasionally, eosinophils have been observed in the lesion, 2 and in· severe cases, there is a perivascular infiltration of chronic inflamlnatory cells in the retina extending into the scleral channels and the episcleral tissues. In 1983, Haluska and associates 19 described an experimental model of ophthalmia nodosa in albino rabbits and they found that the lesion produced in the cornea of the animals was silnilar to that found in the human cornea. Cross sections of the caterpillar cilia were observed within the cornea surrounded by inflammatory nodules composed of epithelioid and giant cells and mononuclear inflammatory cells. In some sections, giant cells were seen within the center of the fragmented cilia.

The diagnosis is usually missed; because most physicians are completely unfamiliar with the disease and pay no particular attention to the disorder. Inspection of the stained cornea under magnification reveals a distinctive pattern of minute linear scratches of the corneal epithelium, which serve to indicate the presence and the location of the cause, in a patient with type II ophthalmia nodosum. These scratches are predomi-

nantly vertical, but one may see oblique and horizontal abrasions as well. Biomicroscopic examination of the everted lid reveals the protruding tip or a minute projecting spicule of caterpillar hair as a dark spot close to the lid margin, surrounded by a small zone of hyperemia, which may be obscured by a tenacious deposit of mucus. In type 4 and 5 cases, the patient usually presents with an irritable eye, ciliary injection, flare, and cells in the anterior chamber or in the vitreous. Setae can be identified within the corneal stroma embedded in focal exudates; other setae can be found lodged in the iris and adjacent trabecular band. Fundus examination, which is limited by photophobia, reveals yellow patches of retinochoroiditis with or without vitritis, usually situated at the temporal macular area with the inciting hair lodged at a corresponding point in the vitreous cortex.

The treatment of reactions to caterpillar hairs or setae depends on the type of ocular involvement. 2o Type 1 (toxic) reactions should be treated with irrigation and mechanical removal of the visible hairs, followed by administration of antibiotic and steroid drops. Type 2 reactions (mechanical chronic keratoconjunctivitis) necessitate a meticulous search for minute, often occult fragments of hairs, the relnoval of which gives immediate relief. Progression to type 3 reactions (conjunctival, nodules, granulomas, and corneal penetration) is treated with surgical removal of the conjunctival nodule as soon as possible in the hope of preventing intraocular migration of the hairs. Intracorneal hairs can either be removed at the slit lamp, using special forceps, or be observed if the hairs are few and deeply seated. This may be a difficult decision to make. Should there be any evidence of a tendency for movement, which could result in intraocular migration of the hairs, surgical intervention is clearly indicated. One may consider lamellar or penetrating keratoplasty if the hairs are numerous and located in such a way as to allow their excision within the confines of the trephination. Type 4 reactions due to penetration into the anterior chamber can be treated with topical steroids. Anterior chamber hairs or iris nodules should be removed, the latter through an iridectomy. Type 5 reactions (vitritis, vitreoretinal involvement) should be treated with local and systemic steroids, with vitrectomy reserved for resistant cases. Recently, successful treatment of vitreous reaction by argon laser photocoagulation 21 of the offending hairs has been described. This is based on experimental evidence showing that in vitro either neodymium:yttrium-aluminum-garnet (YAG) laser or argon laser can disrupt the hairs, most importantly by destroying the tip and the reserve barb of the hairs. Raspillar and colleagues have advocated the use of barrier photocoagulation as a strategy to prevent migration of the hair into the macula. 22

s

CHAPTER 46: OPHTHALMIA NODOSA

Allergic dermatitis, nodular conjunctivitis,catarrhal conjunctivitis and marginal keratitis, nummular keratitis, destructive uveitis, nodular iritis (granulomatous response), intralenticular foreign body, severe vitritis and papillitis, subretinal migration of the hairs, and rarely, endophthalmitis and phthisis bulbi necessitating enucleation13 are among the reported complications of the fulminating type of ophthalmia nodosa.

PROGNOSIS Although there have been cases reported in the literature in which caterpillar hairs have caused severe damage to the eye,13 in general, the long-term prognosis of the disease appears to be relatively good, even in the case of intraocular migration of hairs. The uveitis caused by intraocular migration in the majority of cases is responsive to standard steroid management, usually resolving within a few weeks.

Caterpillar hairs and the Alnerican burdock (Arctium minus; cocklebur) vegetable needles are responsible for a wide variety of ocular inflammatory reactions, ranging from simple conjunctival, corneal, and anterior chamber involvement to severe vitreous and retinal inflammation. The treatment depends on the type of location and severity of ocular involvement. Simple lavage or mechanical removal will suffice for hairs remaining as external foreign bodies. Once they have migrated into the conjunctiva, surgical excision of the foreign bodies is required. Intracorneal hair may necessitate surgical excision. But if the hairs are deep, simple observation is justified, with further surgical action in cases of progressive migration. Once the hairs enter the anterior chamber, topical steroids usually control the rather intense resultant uveitis. Iris nodules may be excised if they are few in number. Intravitreal hairs may cause vitritis and chorioretinitis, requiring systemic and/or periocular steroid therapy, or even therapeutic vitrectomy.

1. Picarelli ZP, Valle JR: In: Buccherl W, Deulofeu V, Buckely EE, eds: Venomous An.imals and Their Venoms. New York, Academic Press, 1981. 2. Wagenmann A: Veber Pseudotuberculose Entzundung der Coruunctiva und Iris durch Raupenhaare. Arch Ophthalmol 1890;36:126134. 3. Saemisch T: Ophthalmia Nodosa, Graefe-Saemisch Handbuch der gesamten Augenheilkunde, 2nd ed, Vol 5, Pt 1. Leipzig, W. Engelman, 1904, pp 548-564. 4. Gunderson T, Heath P, Carron LK: Ophthalmia nodosa. Trans Am Ophthalmol Soc 1945;48:151-167. 5. Watson PG, David S: Ophthalmia nodosa. Br J Ophthalmol 1966;50:209. 6. Berman E: Un cas d' ophtalmia nodosa. Clinique Ophtalmologique 1928. These. Universite de Lausanne. 7. Cooke JAL, Roth YD, Miller FH: The urticating hairs of the theraphosid spider. Am Museum Noviates 1972, No 2498, p 1. 8. Cooke JAL, Miller FH, Grover RW, Duffy JL: Urticaria caused by tarantula hairs. AmJ Trop Med Hyg 1973;22:130. 9. Bishop lW, Morton MR: Caterpillar-hair keratoconjunctivitis. Am J Ophthalmol 1967;64:778-779. 10. Candera W, Pachtman MA, FountainJA, Wilson FM: Ocular lesions caused by caterpillar hairs (ophthalmia nodosa). CanJ Ophthalmol 1984;19:40-44. 11. Shama SK, Etkind PH, Odell TM, et al: Gypsy-moth-caterpillar dermatitis. N EnglJ Med 1982;306:1300-1301. 12. Gunderson T, Heath P, Garron LK: Ophthalmia nodosa. Trans Am J Ophthalmol Soc 1945;48:151-167. 13. Steele C, Lucas DR, Ridgway AEA: Endophthalmitis due to caterpillar setae. Br J Ophthalmol 1984;68:284-288. 14. Tyzzer EE: The pathology of the browntail moth dermatitis. J Med Res 1907;16:43-64. 15. Dejong MCJM, Bleumink E: Investigative studies of the dermatitis caused by the larva of the browntail moth III. Chemical analysis of skin-reactive substances. Arch Dermatol Res 1977;259:247-262. 16. Dejong MCJM, Bleumink E IV: Further characterization of skinreactive substances. Arch Dermatol Res 1977;259:263-281. 17. Lamy M, Pasturead NH, Novak F, et al: Thaumeatopoein: An urticating protein from the hairs and integument of pine processionary caterpillar. Toxicon 1986;24:347-356. 18. Ascher KW: Mechanism of locomotion observed on caterpillar hairs. AmJ Ophthalmol1966;65:354-355. 19. Haluska FG, Puliafito CA, Henriquez A, Albert DM: Experimental gypsy moth (LY17lantria dispar) ophthalmia nodosa. Arch Ophthalmol 1983;101 :799-801. 20. Fraser SG, Dowd TC, Basanquet RC: Intraocular caterpillar setae. Eye 1994;8:596-598. 21. Marti-Huguet T, Pl~ol 0, Cabiro L, et al: [Endophthalmos caused by intravitreal caterpillar hairs. Treatment by direct photocoagulation with argon laser.] J Fr Ophtalmol 1987;10:559-564. 22. Raspiller A, Lepori JC, George JL: Coriorerinopathie par migration des poils de chenilles. Bull Med Soc Fr Ophtalmol1984;95:153-156.

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Isabelle Cochereau and Thanh Hoang-Xuan

CHANGING PATTERNS OF UVEITIS IN HIV INFECTION The acquired immunodeficiency syndrome (AIDS) was first recognized in 1981, and human immunodeficiency virus (HIV) was identified as the etiologic agent in 1984. Opportunistic infections are now better diagnosed and their pathogenesis is better known. Progress in the management of HIV-infected patients has led to changes in the profile of the disease. HIV is a retrovirus that infects CD4 + T lymphocytes, which are pivotal effectors of cell-mediated immunity. HIV integrates the host cell genome, where it induces the synthesis of new virions. The release of the new virions kills the infected cell (Fig. 47-1). The decline in CD4 + T-Iymphocyte numbers leads to severe immunodeficiency, permitting the development of opportunistic infections and malignancies. In response to each opportunistic infection, multiplication of the remaining CD4 + T lymphocytes increases the number of circulating virions in a vicious circle. This is why the prevention of opportunistic infections is so important for slowing the progression of HIV disease. Antiretroviral drugs interfere with various steps of HIV replication (see Fig. 47-1). Reverse-transcriptase inhibitors prevent the transformation of viral RNA into DNA, thereby preventing it from integrating the host cell genome. Protease inhibitors (PIs) prevent the assembly of new viral proteins. The recent advent of highly active antiretroviral therapy (HAART) , including at least one PI, has led to a dramatic improvement in the prognosis of HIV infection. HAART induces a marked fall in the frequency of opportunistic infections and malignancies, and a corresponding increase in life expectancy. 1 PIs restore immunity, as reflected by a clinical improvement, an increase in CD4+ T-cell counts,2 and the decline in HIV viral load. Several PIs are available (Table 47-1) and can be combined in various regimens. However, resistance to PIs is developing, and it is impossible to predict how effective existing drugs will be in a few years' time. HIV is transmitted by sexual contact (both homosexual and heterosexual), by blood (e.g., contaminated material for intravenous injection, blood products), and from mother to child. In industrialized countries, the main groups at risk are homosexuals with multiple partners, and intravenous drug users, but heterosexual t:ransmission is on the increase. In developing countries, most cases of infection are the result of heterosexual contacts, contaminated blood or materials, and mother to child transmission. The absolute cumulative number of cases is highest in Mrica, followed by the Americas, Asia, and Europe. Treatment and prevention are optimal in the industrialized countries, whereas they are often totally lacking in the developing countries. The World Health Organiza-

tion (WHO) estimates that about 40 million people will be infected worldwide by the year 2000. 3 The diagnosis of HIV infection is based on the presence of specific antibodies against HIV antigens. Two tests are available: enzyme-linked immunosorbent assay (ELISA) is routinely used for screening, and western blot is used to confirm a positive ELISA. Antibodies usually appear 3 to 6 weeks after primary exposure to HIV, but in some cases they can emerge several months later. The degree of immunodeficiency is assessed in terms of the CD4 + T-cell count. Most opportunistic infections occur when this count falls below 200 cells/ /-LI, and the most severe complications occur at counts below 50 cells/ /-Ll. Syphilis and candidiasis can occur at any CD4 + T-cell count, whereas tuberculosis occurs at around 300 cells/ /-LI, cryptococcal meningitis and toxoplasmosis at around 100 cells/ /-LI, cytomegalovirus (CMV) retinitis, varicellazoster virus (VZV) retinitis, disseminated Pneumocystis carinii pneumonia (PCP), cryptococcosis, and histoplasmosis occur at below 50 cells/ /-Ll. Quantification of plasma HIV RNA (the viral load) reflects the level of HIV replication. The main target of antiretroviral therapies is to drive viral load below the current detection limit. Both CD4 + T-cell counts and viral load are used to adjust antiretroviral therapy and to begin prophylaxis. The ocular manifestations of HIV infection are many and varied, involving the ocular adnexa, eyeballs, and nerves. Although the most frequent ocular manifestation of AIDS is HIV retinopathy, the main retinal opportunistic infection is CMV retinitis.4-6 Herpes zoster ophthalmicus, lymphoma, and certain drugs can also cause uveitis. In industrialized countries, the pattern of ocular involvement in HIV infection has changed over the years. 7 At the beginning of the pandemic, when no treatment was available, CMV retinitis was a sign of approaching death, with a survival time of only a few weeks. Later, the advent of the anti-CMV drugs ganciclovir and foscarnet improved the survival time, especially when luaintenance therapy was given routinely. The introduction of the first anti-HIV drugs, followed by routine use of primary prophylaxis for the most common opportunistic infections, led to an increase in life expectancy. However, as more and more patients started to survive for long periods despite severe immunodeficiency, CMV retinitis became increasingly frequent and increasingly resistant to therapy. The frequency of ocular manifestations of HIV infection has further changed since the beginning of the HAART era. Retinitis, especially that induced by CMV, is less frequent. Conversely, inflammatory reactions in the anterior chamber or vitreous are on the increase as a result of immune resconstitution. 8 ,9 Patients with healed CMV retinitis can develop vitritis and cystoid macular

CHAPTER 47: HUMAN IMMUNODEfiCIENCY VIRUS-ASSOCIATED UVEITIS

Steps

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FIGURE 41-1. Main steps of HIV infection of the cell.

edema, which alter their visual function despite the fact that the CMV infection itself is controlled. The management of such inflammation in patients recovering from immunodeficiency is a major clinical challenge.

TABLE 47-1. ANTIRETROVIRAL AGENTS CURRENTLY AVAILABLE fOR THE TREATMENT Of HIV INfECTION Reverse transcriptase inhibitors Nucleosides Zidovudine (AZT) Didanosine (ddI) Zalcitabine (ddC) Lamivudine (3TC) Stavudine (d4T) Abacavir Non-nucleoside reverse transcriptase inhibitors Neviparine Delavirdine Efavirenz Protease inhibitors Saquinavir Ritonavir Indinavir Nelfinavir Amprenavir Lopinavir

As each cause of retinitis is discussed in detail in other sections, only the specificities of AIDS-associated retinitis will be dealt with here. In HIV infection, ophthalmic involvement often is a sign of a disseminated opportunistic disease. Etiologic diagnosis is crucial, as it can identify a life-threatening infection and enable systemic therapy to be started. The management of these patients requires close collaboration with internists. Ocular involvement usually requires special monitoring and therapy to preserve visual function. As ocular lesions can be directly observed by fundus examination and photography, they can be used as an indicator of the course of the infection. Indeed, they have been used as a major end point in therapeutic trials, especially those testing systemic anti-CMV drugs.

and the Eye HIV has been isolated from the cornea, vitreous, and retina. No clinical manifestations seem to be related to its presence in the cornea or vitreous. However, the presence of HIV in the endothelium of the retinal vasculature induces HIV retinopathy, which is the most common form of retinal involvement in HIV-infected patients.

CHAPTER 41: HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED UVEITIS

FIGURE 47-2. HIV microangiopathy. (See color insert.)

HIV retinopathy is mainly characterized by cotton-wool spots and scattered intraretinal hemorrhage (Fig. 47-2), both of which are asymptomatic unless they are located in the macular area. Cotton-wool spots have been reported to occur in up to two thirds of patients. 4 , 6 They are not specific and are the same as those seen in diabetes mellitus: They consist of fluffy patches in the posterior pole, of different ages, often located along the vessels. Histopathologic examination discloses swollen nerve fibers, which result from disrupted axonal transport caused by ischemia. The etiology of this ischemia is probably multifactorial, including HIV infection of the endothelium of the retinal microvasculature, and deposition of circulating immune complexes. Intraretinal hemorrhages are superficial in the posterior pole and deep in the periphery. HIV retinopathy can occur at any stage of the disease, but its frequency increases with the degree of immunodeficiency.6, 10, II Isolated perivascular sheathing has been described in the absence of opportunistic retinal infections, mainly in Mrican patients (especially children) .12,13 The etiology of this perivasculitis is unclear. Although rare, anterior or posterior uveitis can be related to HIV infection. Systemic antiretroviral drugs such as zidovudine have been reported to be effective on uveitis resistant to corticosteroids 14 and on uveitis associated with small multifocal retinal infiltrates located in the midperiphery or anterior retina. 15

CMV retinitis generally occurs when the CD4 + T-cell count falls below 50//-11. The risk of CMV retinitis correlates well with the degree of immunodeficiencyY' 18 CMV retinitis is more frequent in HIV-infected patients than in HIV-seronegative immunosuppressed patients, probably because the risk factors for HIV infection (sexual contacts and needle sharing) are also risk factors for CMV infection. CMV retinitis is frequently aSyIuptomatic in HIV-infected patients with severe immunodeficiency, as no cells are present in the anterior chamber or in the vitreous, and as the retinitis has a tendency to affect tlle periphery before targeting the macula and optic disc. Patients may complain, however, of flashes, floaters, or cloudy vision. Some may even notice loss of peripheral visual field or central vision. The diagnosis of CMV retinitis is based on clinical examination in patients with CD4 + T-cell counts below 50//-11 and those with a suspected systemic opportunistic infection. The typical course of CMV retinitis is relentless centrifugal extension from the initial lesion toward the entire retina. 19 Typically, the central area of the lesion is healed and atrophic; the borders are edematous, white, and hemorrhagic; and new small patches are scattered throughout the adjacent retina. These patches then coalesce, inducing the advancement of the borders. Without treatment, CMV retinitis destroys the entire retina of patients with severely immunodeficient AIDS. There are two different clinical appearances of CMV retinitis: the fulminant form, with extensive necrosis and hemorrhage, often located on a vessel in the posterior pole (Fig. 47-3), and the indolent form, with granular borders and no hemorrhage, often located far from a vessel in the periphery (Fig. 47-4). Several anti-CMV drugs can halt the progression of the retinitis but, being only virustatic, they do not clear CMV from the eye. Maintenance therapy is thus required to prevent relapses of CMV retinitis, for as long as the immunodeficiency persists. The drugs currently available are ganciclovir, foscarnet, cidofovir, and fomivirsen (Table 47-2). Systemic administration is best, as CMV infection is a systemic disease. However, intravitreous therapy can be of

Opportunistic: Chorioretinal Infections

eMv Retinitis CMV retinitis is by far the most frequent retinal opportunistic infection in HIV-infected patients. It is the only opportunistic eye infection that is a diagnostic criterion for AIDS. 16 Its real frequency is difficult to determine because of recruitment biases in the different published series, but it has changed with the evolution of HIV disease. Early in the pandemic, only a few patients who reached the later stages of immunodeficiency developed CMV retinitis. Later, with increasing life expectancy, the frequency increased. Since the advent of HAART, the incidence of CMV retinitis has been cut by a factor of 6Y

FIGURE 47..,3. Fulminant CMV retiIiitis. (See color insert.)

CHAPTER 47: HUMAN IMMUNODEfiCIENCY VIRUS-ASSOCIATED UVEITIS

fiGURE 47-4. Indolent CMV retinitis.

value because the retina is the most frequent clinical target of CMV (80%). Local therapy can halt the progression of CMV retinitis, and it is less demanding for the patient relative to systemic therapy. During local therapy alone, contralateral or extraocular CMV infection occurs in 50% and 31 % of patients, respectively, at 6 months. 2o Combination with oral ganciclOvir may be recommended to prevent further dissemination of CMV during local therapy.21 Ganciclovir and foscarnet were the first anti-CMV drugs. Mter the induction phase (two.J' infusions a day), both drugs induce healing of the lesions within 2 to 4

TABLE 47-2. ANTI-CMV DRUGS CURRENTLY AVAILABLE fOR THE TREATMENT Of CMV RETINITIS Systemic therapy Intravenous ganciclovir Induction Maintenance Intravenous foscarnet Induction Maintenance Intravenous cidofovir Induction Maintenance Oral ganciclovir Intravitreal therapy Ganciclovir Induction Maintenance Foscarnet Induction Maintenance Cidofovir Fomivirsen NaIve patients Induction Maintenance Non-naIve patients Induction Maintenance Ganciclovir intravitreal device Surgical implantation Change if relapse (~ 8 months CMV, cytomegalovirus.

5 mg/kg bid. 5 mg/kg once a day 90 mg/kg bid. 90 mg/kg once a day 5 mg/kg once a week for 2 weeks 5 mg/kg every 2 weeks 1 g tid as maintenance therapy only 2000 f.1g per injection 2 injections per week 1 injection per week 2400 f.1g per injection 2 injections per week 1 injection per week 1 injection of 15 f.1g every 6 weeks 165 f.1g per injection 3 injections in 3 weeks 1 injection every 2 weeks 330 f.1g per injection 2 injections in 4 weeks 1 injection every 4 weeks

in immunodepressed patients)

weeks. Without maintenance therapy, relapses occurred within 3 weeks. 22 With maintenance therapy (one infusion a day), relapses occur within a mean of 2 months. 23-26 A prospective comparative study of intravenous ganciclovir and foscarnet showed similar times to relapse, 59 and 56 days respectively.27 However, the patients on foscarnet had a longer survival time, probably in part because of an anti-HIV effect of foscarnet. However, in practice, ganciclovir is the first-line choice because of its better tolerability and simpler administration. Combinations of ganciclovir and foscarnet have been used to overcome resistance to each drug (given at the full dosage to obtain a synergistic effect) or to avoid severe side effects (halfdoses of each drug). Oral ganciclovir is effective as maintenance therapy.28,29 The time to relapse is a little shorter than with intravenous ganciclovir, but most patients prefer the oral route despite the large number of tablets to be taken daily. Intravenous cidofovir has the advantage of being given only once a week during induction therapy, and once every second week during maintenance therapy. On this regimen, the mean time to relapse is 123 days.3o The main side effects of cidofovir are renal impairment and anterior uveitis. Initial studies employing a human monoclonal antiCMV antibody (MSL-109) in patients being treated with standard antiviral regimens demonstrated a delay in progression of CMV retinitis. 3l Since the advent of HAART, maintenance therapy is discontinued in patients who have a restored immunity.32-36 Systemic plimary prophylaxis of CMV retinitis with oral ganciclovir halves the relapse rate. 37 The dosages are 1000 mg tid for patients with CD4+ T-cell counts below 50/ /Jul, or up to 100/ /Jul in those with a history of AIDSdefining opportunistic infection. Valganciclovir, a ganciclovir prodrug, is being assessed in oral induction therapy of CMV retinitis. Local therapy was initially developed because of the side effects of systemic administration. Ganciclovir has been widely used and has proved to be effective and safe. 38-41 Initially administered at a dose of 200 /Jug in 0.05 ml per injection, it is now injected into the vitreous at a dose of 2000 /Jug.42 Intravitreal foscarnet at a dose of 2.4 mg per il~ection has shown some efficacy43 but is probably less potent than intravitreous ganciclovir. Intravitreous injections are still indicated for patients with active CMV retinitis who are starting HAART regimens. An intraocular ganciclovir implant is the most effective therapy against CMV retinitis, with a time to relapse of 223 days.2o However, implantation requires surgery, which can precipitate retinal detachment. In case of relapse, the device must be replaced. Intravitreal devices are now mainly used for CMV retinitis resistant to other therapies or in a case of noncompliance with daily treatment. 44-46 Intravitreal cidofovir was initially promising, with a mean time to relapse of 53 days after a single injection of 20 /Jug,47 but its low therapeutic index has restricted its development.48 Intravitreal fomivirsen, an antisense drug, is effective on CMV retinitis,49 but its side effects may restrict its use to last-resort therapy.

CHAPTER 47: HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED UVEITIS

The choice of therapy depends on systemic· manifestations and individual tolerability. One therapy can be switched to another at any time if necessary. Note that the fall in the incidence of CMV retinitis has slowed down the clinical evaluation of new drugs. Retinal detachment is a serious complication of CMV retinitis. It occurs in patients with active or healed retinitis, and the risk increases with the area of necrotic retinitis and its extension toward the periphery. Retinal detachment usually necessitates vitrectomy with silicone oiLSo-52 Before the HAART era, the silicone oil was left in the eye; but with the increasing life expectancy of HIV-infected patients the silicone oil should be replaced by gas tamponade after extensive laser barrier therapy.52 In "maculaon," small, localized retinal detachment, laser photocoagulation delimitation may be successful for a while, but most cases of retinal detachment will break through the laser barrier within weeks to months. 52 Since the advent of HAART, inflammation of the vitreous has become frequent, affecting up to 60%53,54 of eyes in which CMV retinitis remains healed. The vitritis often predominates in the anterior vitreous, with gray flakes responsible for floaters. 55 Anterior inflammation with gray keratic precipitates can occur.56 Chronic cystoid luacular edema can eventually lead to visual deterioration.57-59 The treatment of these new complications is not clearly defined. Topical anti-inflammatory therapy and oral acetazolamide are ineffective. Systemic steroids have some effect, but they have the disadvantage of increasing the immunodeficiency, with a risl~ of CMV retinitis recurrence. Tapering is often associated with a relapse of the inflammatory manifestations. Systemic steroids can also increase metabolic disorders such as diabetes mellitus and lipid disturbances, especially in patients on HAART. In patients with unilateral uveitis, injections under Tenon's capsule, are of value despite the risks of elevated intraocular pressure and substantial systemic diffusion leading to systemic side effects.

Ocular Toxoplasmosis In the United States, ocular toxoplasmosis is estimated to occur in 1% to 2% of patients,6 and it is more frequent in Europe and the developing countries where the baseline seroprevalence is higher. Ocular toxoplasmosis generally occurs in patients with CD4 + T-cell counts below 150/ /-Ll. It can be either acquired or the result of reactivation of a latent infection. 6o , 61 In AIDS patients, it can be associated with cerebral toxoplasmosis in up to 40% of patients. It manifests as classical unifocal or multifocal retinitis (Fig. 47-5), or as diffuse necrotizing retinitis in patients with severe immunodeficiency.62 An assay for parasitemia can be positive. In contrast to the situation in CMV retinitis, concomitant inflammation of the anterior chamber· with posterior synechiae and vitritis are not unusual. Antitoxoplasmic ilumunoglobulin assay in anterior chambersamples is not of value in AIDS patients because of. the· major disturbances of immunoglobulin synthesis associated with the disease. Polymerase chain reaction may assist with the diagnosis. The therapy of ocular toxoplasmosis in. HIV-infected patients consists of pyrimethamine plus sulfadiazine or clindamycin. During the induction phase the toxoplasmic

FIGURE 47-5. Ocular toxoplasmosis.

lesions heal within 7 weeks. On maintenance therapy (at half the induction dose), relapses are less frequent than in CMV retinitis, at around 20% after 2 years. 61 The incidence of ocular toxoplasmosis fell drastically after the introduction of primary prophylaxis with oral trimethoprim-sulfamethoxazole; with a further decrease after the advent of HAART.

VZV Retinitis VZV retinitis is rare, occurring in less than 1% of AIDS patients,6 but it is a severe retinal infection with a poor prognosis. The most devastating form, called progressive outer retinal necrosis (PORN), is usually reported in patients with profound immunodeficiency (CD4 + T-cell count below 50/ /-LI). PORN is characterized by m ultifocal deep retinal lesions scattered throughout the fundus. In approximately one third of patients, these outer retinal lesions present in the macular area, with rapid progression to confluence, sometimes giving the appearance of a cherry-red spot (Fig. 47-6). The areas of necrosis are white, and the vessels appear orange by contrast, giving a characteristic "cracked mud" appearance (Fig. 47-7). The advancing borders are preceded by multiple small lesions in the adjacent retina. No inflammation of the anterior chamber or vitreous is noted. The other form is seen in patients with CD4 + T-cell

FIGURE 47-6. VZV retinitis: cherry-red spot macula. (See color insert.)

47: HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED UVEITIS

tomatic, plaquelike, yellow-white, round or multilobular foci of the posterior pole (Fig. 47-8), which enhance slowly.67, 68 No inflalnmation of the vitreous or anterior chamber is noted. P. carinii choroidopathy recedes slowly on systemic trimethoprim-sulfamethoxazole or pentamidine. P. carinii choroidopathy has been reported in patients receiving aerosolized pentamidine as primary or secondary prevention of P. carinii pneumonia, a form of prophylaxis localized to the lungs, thereby allowing the development of extrapulmonary infection. 69 There have been few recent reports of this entity with the institution of more widespread systemic prophylaxis for P. carinii.

Tuberculosis fiGURE 47-7. VZV retinitis: cracked mud appearance. (See color insert.)

counts above 50/1-11. It resembles the acute retinal necrosis syndrome described in immunocompetent patients. The necrosis starts from the periphery and extends rapidly toward the posterior pole. 63-65 Inflammation of the anterior chamber is noted, along with vitritis. These two forms are probably two aspects of the same disease occurring at different stages of immunodeficiency. In both varieties, the uniformly poor prognosis is related to the rapidity of lesion extension despite therapy, and the frequency (70%) of retinal detachment, ~ptic nerve involvement, and bilateralization of the retinitis, with 67% of patients in the largest published series to date having a final visual acuity of no light perception. 66 Although some cases of VZV retinitis have responded favorably to acyclovir, the current approach in AIDS patients is to treat very aggressively with intravenous foscarnet combined with intravitreous ganciclovir to obtain kinetic and antiviral syn.ergy.65

The choroidal lesions found in disseminated tuberculosis are asymptomatic. They do not induce reactions in the anterior chamber or vitreous. They reflect disseminated tuberculosis and occur in patients with severe immunodeficiency.70-72 They manifest as either one or a few conspicuous orange lesions with enough relief to raise the vessels (Fig. 47-9), or as miliary lesions scattered through the fundus. Appropriate therapy leads to slow healing.

Cryptococcosis The most common ocular manifestation of cryptococcosis is papilledema (Fig. 47-10) with peripapillary hemorrhages related to cryptococcal meningitis. 73 ,74 Some cases of cryptococcal involvement of the choroid have been described in patients with disseminated cryptococcosis. The ocular manifestations of cryptococcosis respond to appropriate systemic therapy with intravenous amphotericin B or an imidazole. However, optic nerve involvement can sometimes lead to optic atrophy, even if the meningitis is well controlled by anticryptococcal therapy.

Other Opportunistic Infections

In contrast with Pneul1wcystis carinii pneumonia, which occurs in patients with CD4+ T-cell counts of 200/1-11, P. carinii choroidopathy is seen in patients with CD4 + Tcell counts below 50/1-11 (see Chap. 37). It is a sign of disseminated P. carinii infection. It manifests as asymp-

Histoplasma capsulatum retinitis has been described in highly immunodepressed patients with systemic disseminated infection. 75 Mycobacterium avium-intracellulare has been found in autopsy studies of patients with disseminated infection, in association with P. carinii infection.76, 77 A case of Sporothrix schenckii endophthalmitis has been reported in an HIV-positive individual with disseminated cutaneous sporotrichosis. 78

fiGURE 47-8. Pneumocystosis. (See color insert.)

fiGURE 47-9. Ocular tuberculosis. (See color insert.)

Pneumocystosis

CHAPTER 47: HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED UVEITIS

FIGURE 47-10. Papilledema in cryptococcal meningitis.

Other Chorioretinal Infections Syphilis Syphilis occurs at any degree of immunodeficiency but often when CD4+ T-cell counts are above 200/IJ,,1. This is not an opportunistic infection but is often seen in AIDS patients with multiple sexual partners. The course of syphilis in HIV-infected patients is accelerated, and neurosyphilis is more severe than in HIV-seronegative patients. Ocular syphilis manifests as retinitis with vasculitis, involvement of the optic nerve, vitritis, and inflammation of the anterior chamber, with S'bmetimes a hypopyon. 79-82 The diagnosis is based on positive Venereal Disease Research Laboratory (VDRL) , Treponema pallidum hemagglutination assay (TPHA) , and fluorescent treponemal antibody (FTA)-absorbed tests. Therapy consists of intravenous penicillin for 15 days.

Candidiasis Although oroesophageal candidiasis is frequent in AIDS, ocular candidiasis is rare and is not considered an opportunistic infection. It mainly occurs in intravenous drug users after use of contaminated injection equipment. CD4 + T-cell counts are variable and may often be quite high, as the patients are still active intravenous drug users. The clinical manifestations and management of such patients is the same as that of HIV-seronegative patients.

FIGURE 47-11. Herpes zoster ophthalmicus.

CD4+ T-cell counts are above 200/f-L1. In HIV-infected patients, herpes zoster ophthalmicus is extensive (Fig. 47-11) and relapsing, and it requires intravenous acyclovir therapy. Although keratitis is the lUOSt common form of ocular involvement, anterior uveitis is frequent85 , 86 and must be aggressively treated with topical steroids and cycloplegic and monitored for the development of secondary complications. HIV-infected patients with a history of herpes zO'ster may be at risk of VZV retinitis.

DRUG-RELATED UVEITIS In the context of HIV infection, rifabutin was the first medication reported to induce drug-related uveitis. 87 ,88 Rifabutin is given as curative or preventive treatment for disseminated M. avium-intracellulare-complex infection, usually for patients with severe immunodeficiency. Rifabutin-related uveitis is total, including severe inflammation of the vitreous and anterior chamber, and occasionally a hypopyon. 89 , 90 No retinal lesions are noted. In severe cases, it can manifest as endophthalmitis (Fig. 47-12). With topical steroid therapy and discontinuation of rifabutin, the uveitis disappears within a few days; The pathogenesis of rifabutin-related uveitis is unclear, but a local immunoallergic reaction to rifabutin, and M. aviumintracellulare antigen-antibody conflicts have been postu-

Lymphoma Retinal l)'luphoma is a very rare complication of AIDS and is often misdiagnosed. It manifests as retinitis and vitritis resistant to various antibiotics. The diagnosis is based on ocular ultrasonography, oculo-orbital and cerebral magnetic resonance imaging, the presence of malignant cells, and elevated interleukin-l0 levels in cerebrospinal fluid or the vitreous', and possibly on retinal biopsy.83,84 The prognosis is poor despite radiotherapy and chemotherapy, because of the frequent cerebral involvement.

ZOSTER Herpes zoster ophthalmicus is frequent in HIV-infected patients. It occurs at an early stage of the disease, when

FIGURE 47-12.

Rifabutin~related uveitis.

CHAPTER 47: HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED UVEITIS

FIGURE 47-13. Cidofovir-related uveitis.

lated. The occurrence of rifabutin-related uveitis is promoted by concomitant use of fluconazole or clarithromycin, which both increase the serum concentration of rifabutin by inhibiting the cytochrome P450 system. Cidofovir, an anti-CMV nucleoside analogue, can induce anterior uveitis, whether administered intravitreally or intravenously. The frequencies have been reported to be 26% to 32% after intravitreal administration91, 92 and 26% to 44% after intravenous administration. 93 The uveitis is accompanied by low intraocular pressure, and sometimes by posterior synechiae (Fig. 47-~3) or vitritis. These manifestations may be related to a direct toxic effect of cidofovir on the ciliary body.93 Uveitis generally responds favorably to local steroid therapy but can relapse if cidofovir is continued. Studies of large series are needed to determine the respective roles of PIs, microbial pathogens, immunity and coadministered drugs in the onset of drug-induced uveitis in HIV-infected patients,

SUMMARY The profile of HIV disease has recently changed with the advent of HAART, which induces a significant restoration of the ilnmunity. Opportunistic infections such as CMV retinitis are less frequent. Ocular inflammatory reactions can develop, especially in CMV-infected eyes. The future of HIV infection depends on the importance of resistance to HAART, and to the availability of new effective antiHIV compounds.

References 1. Palella F], Delaney KM, Moorman AC, et al: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl] Med 1998;338:853-860. 2. Autran B, Carcelain G, Li TS, et al: Positive effects of combined antiret:roviral therapy on CD4 T-cell homeostasis and function in advanced HIV disease. Science 1997;277:112-116. 3. World Health Organization: AIDS-Global data: The current global situation of the HIV/ AIDS pandemic. Wkly Epidemiol Rec 1993;68:9-11. 4. Holland GN, Pepose ]S, Pettit TH, et al: Acquired immune deficiency syndrome: Ocular manifestations. Ophthalmology 1983; 90:859-873. 5. Jabs DA, Green WR, Fox R, et al: Ocular manifestations of acquired immune deficiency syndrome. Ophthalmology 1989;96:1092-1099. 6. Jabs DA: Ocular manifestations of HIV infection. Trans Am Ophthalmol Soc 1995;93:623-683.

7. Jabs DA, Bardett]G: AIDS in ophthalmology: A period of transition. Am] Ophthalmol 1997;124:227-233. . 8. NussenblattRB, Lane HC: Human immunodeficiency virus disease: Changing patterns of intraocular inflammation. Am] Ophthalmol 1998;125:374-382. 9. Holland GN: Pieces of a puzzle: Toward a better understanding of intraocular inflammation associated with human immunodeficiency virus disease. Am] Ophthalmol 1998;125:383-385. 10. Freeman WR, Chen A, Henderly DE, et al: Prevalence and significance of acquired immunodeficiency syndrome-related retinal microvasculopathy. Am] Ophthalmol 1989;107:229-235. 11. Kuppermann BD, Petty ]G, Richman DD, et al: Correlation between CD4 + counts and prevalence of cytomegalovirus retinitis and human immunodeficiency virus-related noninfectious retinal vasculopathy in patients with acquired immunodeficiency syndrome. Am ] Ophthalmol 1993;115:575-582. 12. Kestelyn P, Van de Perre P, Rouvroy D, et al: A prospective study of the ophthalmologic findings in dle acquired immune deficiency syndrome in Mrica. Am] Ophthalmol 1985;100:230-238. 13. Kestelyn P, Lepage P, Perre PVD: Perivasculitis of the retinal vessels as an important sign in children widl AIDS-related complex. Am] OphdlalmoI1985;100:614-615. 14. Rosberger DF, Heinemann MH, Friedberg DN, et al: Uveitis associated with human immunodeficiency virus infection. Am] Ophthalmol 1998;125:301-305. 15. Levinson RD, Vann R, Davis ]L, et al: Chronic multifocal retinal infiltrates in patients infected with human immunodeficiency virus. Am] Ophthalmol 1998;125:312-324. 16. Centers for Disease Control: 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep 1992;41:1-19. 17. Doan S, Cochereau I, Guvenisik N, et al: Cytomegalovirus retinitis in HIV-infected patients widl and without highly active antiretroviral therapy. Am] Ophthalmol 1999;128:250-251. 18. Pertel P, Hirschtick R, Phair], et al: Risk of developing cytomegalovirus retinitis in persons infected with the human immunodeficiency virus.] Acquir Immune Defic Syndr 1992;5:1069-1074. 19. Holland GN, Shuler ]D: Progression rates of cytomegalovirus retinopathy in ganciclovir-treated and untreated patients. Arch Ophthalmol 1992;110:1435-1442. 20. Martin DF, Parks D], Mellow]D, et al: Treatment of cytomegalovirus retinitis widl an intraocular sustained-release ganciclovir implant. Arch Ophthalmol 1994;112:1531-1539. 21. Martin DF, Kuppermenn BD, Wolitz RA, et al: Oral ganciclovir with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group. N Engl] Med 1999;340:1063-1070. 22. Palestine AG, Polis MA, De Smet MD, et al: A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 1991;115:665-673. 23. Holland GN, Sidikaro Y, Kreiger AE, et al: Treatment of cytomegalovirus retinopathy with ganciclovir. Ophthalmology 1987;94:815-823. 24. Jabs DA, Newman C, de Bustros S, et al: Treatment of cytomegalovirus retinitis with ganciclovir. Ophthalmology 1987;94:824-830. 25. Jacobson MA, O'DonnelllJ, Brodie HR, et al: Randomized prospective trial of CMV maintenance therapy for cytomegalovirus retinitis. ] Med Virol 1988;25:339-349. 26. Jacobson MA, O'DonnelllJ, Mills]: Foscarnet treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Antimicrob Agents Chemother 1989;33:736-741. 27. Studies of Ocular Complications of AIDS Research Group: Mortality in patients widl the acquired immunodeficiency syndrome treated widl either foscarnet or ganciclovir for cytomegalovirus retinitis. N Engl] Med 1992;326:213-220. 28. The Oral Ganciclovir European and Australian Cooperative Study Group: Intravenous versus oral ganciclovir: European/Australian comparative study of efficacy and safety in the prevention of cytomegalovirus retinitis recurrence in patients with AIDS. AIDS 1995;9:471-477. 29. Squires KE: Oral ganciclovir for cytomegalovirus retinitis in patients with AIDS: Results of two randomized studies. AIDS 1996;10(Suppl 4) :S13-S18. 30. Poplin M,Pollard R, Tierney M, et al: Combination therapy of cytomegalovirus (CMV) retinitis with a human monoclonal antiCMV antibody (SDZ MSL-109) and either ganciclovir (DHPG) or

CHAPTER 47: HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED UVEITIS

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68. 69.

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73.

74.

75.

76.

77.

immune recovery vitI-itis in cytomegalovirus retinitis patients following institution of successful highly antiretI-oviral therapy. J Infect Dis 1999;179:697-700. Zegans ME, Walton RC, Holland GN, .et al: Transient vitreous inflammatory reactions associated with combination antiretroviral therapy in patients with AIDS and cytomegalovirus retinitis. Am J Ophthalmol 1998;125:292-300. Walter KA, Coulter VL, Palay DA, et al: Corneal endothelial deposits in patients with cytomegalovirus retinitis. Am J Ophthalmol 1996;121:391-396. Newsome R, Casswell T, O'Moore E, et al: Cystoid macular edema in patients with AIDS and cytomegalovirus retinitis on highly antiretroviral therapy. Br J Ophthalmol 1998;82:456-457. Silverstein BE, Smith JH, Sykes SO, et al: Cystoid macular edema associated· With cytomegalovirus retinitis in patients with theacquired immunodeficiency syndrome. Am J Ophthalmol 1998; 125:411-415. Cassoux N, Lumbroso L, Bodaghi B, et al: Cystoid macular edema and cytomegalovirus retinitis in patients with HIV disease treated with highly active antiretroviral therapy. Br J Ophthalmol 1999;83:47-49. Holland GN, EngstI-om RE, Glasgow BJ, et al: Ocular toxoplasmosis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 1988;106:653-667. Cochereau-Massin I, LeHoang P, Lautier-Frau M, et al: Ocular toxoplasmosis in human immunodeficiency virus-infected patients. Am J Ophthalmol 1992;114:130-135. Parke DW, Font RL: Diffuse toxoplasmic retinochoroiditis in a patient with AIDS. Arch Ophthalmol 1986;104:571-575. Forster DJ, Dugel PU, Frangieh GT, et al: Rapidly progressive outer retinal necrosis in the acquired immunodeficiency sYIldrome. Am J Ophthalmol1990;110:341-348. Margolis TP, Lowder CY, Holland GN, et al: Varicella-zoster virus retinitis in patients with the acquired immunodeficiency syndrome. AmJ Ophthalmol 1991;112:119-131. Kuppermann BD, Quiceno JI, Wiley C, et al: Clinical and histopathological study of varicella zona virus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 1994;118:589-600. Engstrom RE, Holland GN, Margolis TP, et al: The progressive outer retinal necrosis syndrome. Ophthalmology 1995;101:14881502. Rao AN, Zimmerman PL, Boyer D, et al: A clinical, histopathologic, and electron microscopic study of Pneumocystis carinii choroiditis. AmJ Ophthalmol1989;107:218-228. Shami MJ, Freeman W, Friedberg D, et al: A multicenter study of Pneumocystis choroidopathy. AmJ Ophthalmol1991;112:15-22. Dugel PU, Rao NA, Forster DJ, et al.: Pneumocystis carinii choroiditis after long-term aerosolized pentamidine therapy. Am J Ophthalmol 1990;110:113-117. Muccioli C, Belfort R: Presumed ocular and central nervous system tuberculosis in a patient with the acquired immunodeficiency syndrome. AmJ Ophthalmol1996;212:217-219. Recillas-Gispert C, Ortega-Larrocea G, Arellanes-Garda L, et al: Chorioretinitis secondary to Mycobacterium tuber'culosis in acquired immune deficiency syndrome. Retina 1997;17:437-439. Campinchi-Tardy F, Dm-wiche A, Bergmann JF, et al: Tubercules de Bouchut et SIDA. A propos de 3 cas. J Fr Ophtalmol 1994;17:548554. Kestelyn P, Taelman H, BogaertsJ, et al: Ophthalmic manifestations of infections with Cryptococcus neofonnans in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 1993; 116:721-727. Cohen DB, Glasgow BJ: Bilateral optic nerve cryptococcosis in sudden blindness in patients with acquired immune deficiency syndrome. Ophthalmology 1993;100:1689-1694. Specht CS, Mitchell KT, Bauman AE, et al: Ocular histoplasmosis with retinitis in a patient with acquired immune deficiency syndrome. Ophthalmology 1991;98:1356-1359. Whitcup SM, Fenton RlVI, Pluda JM, et al: Pneunwcystis carinii and lvlycobacterium, avium-intmcellulare infection of the choroid. Retina 1992;12:331-335. Morinelli EN, Dugel PU, Riffenburgh R, et al: Infectious multifocal choroiditis in patients with acquired immune deficiency syndrome. Ophthalmology 1993;100:1014-1021.

CHAPTER 41: HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED UVEITIS 78. Kurosawa A, Pollock S, Collins M, et £11: SjJorothrix schenckii endophthalmitis in a patient with human immunodeficiency virus infection. Arch Ophthalmol 1988;106:376-380. 79. Bouisse V, Cochereau-Massin I, Jobin D, et £11: Syphilitic uveitis and human immunodeficiency virus infection. ] Fr Ophtalmol 1991;14:605-609. 80. McLeish VVM, Pulido ]S, Holland S, et £11: The ocular manifestations of syphilis in the human immunodeficiency virus type I-infected host. Ophthalmology 1990;97:196-203. 81. Shalaby IA, Dunn ]P, Semba RD, et £11: SyphilitiC: uveitis in human immunodeficiency virus-infected patients. Arch Ophthalmol 1997;115:469-473. 82. Kuo IC, Kapusta MA, Rao NA: Vitritis as the primary manifestation of ocular syphilis in patients with HIV infection. Am] Ophthalmol 1998;125:306-311. 83. Stanton CA, Sloan DB, Slusher MM, et £11: Acquired immunodeficiency syn.drome-related primary intraocular lymphoma. Arch Ophthalmol 1992;110:1614-1617. 84. Rivero ME, Kupperrnann BD, Wiley CA, et £11: Acquired immunodeficiency syn.drome-related intraocular B-cell lymphoma. Arch Ophthalmol 1999;117:616-622. 85. Sandor EV, Millman A, Croxson TS, et £11: Herpes zoster ophthalmicus in patients at risk for the acquired immune deficiency syndrome (AIDS). Am] Ophthalmol 1986;101:153-155. 86. Margolis TP, Milner MK, Shama A, et £11: Herpes zoster ophthalmicus in patients with human immunodeficiency virus infection. Am] Ophthalmol 1998;125:285-291.

87. Shafran SD, Singer ], Zarowny DP, et £11: A comparison of two regimens for. the treatment of l\!IycobacteriLim avium complex bacteriema in AIDS: Rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin: Canadian HIV Trials Network Protocol 010 Study Group. N Engl ] Med 1996;335:377-383. 88. Shafran SD, Singer], Zarowny DP, et £11: Determinants of rifabutinassociated uveitis in patients treated with rifabutin, clarithromycin, and ethambutol for Mycobacterium avium complex bacteriema: A multivariate analysis. Canadian HIV Trials Network Protocol 010 Study Group.] Infect Dis 1998;177:252-255. 89. Saran BR, Maguire AM, Nichols C, et £11: Hypopyon uveitis in patients with acquired immunodeficiency syn.drome treated for systemic Mycobacterium aviwn complex infection with rifabutin. Arch Ophthalmol 1994;112:1159-1165. 90. Jacobs DS, Piliero P], Kuperwaser MG, et £11: Acute uveitis associated with rifabutin use in patients with human immunodeficiency virus infection. Am] Ophthalmol1994;118:716-722. 91. Chavez de 1£1 Paz E, Arevalo ]F, Kirsch LS, et £11: Anterior nongranulomatous uveitis after int:ravitreal HPMPC (cidofovir) for the treatment of cytomegalovirus retinitis. Analysis and prevention. Ophthalmology 1997;104:539-544. 92. Akler ME, Johnson DW, Burman ~, et £11: An.terior uveitis and hypotony after intravenous cidofovir for the treatment of cytomegalovirus retinitis. Ophthalmology 1998;105:651-657. 93. Davis ]L, Tasldntuna I, Freeman WR, et £11: !litis and hypotony after treatment with intravenous cidofovir for cytomegalovirus retinitis. Arch Ophthalmol 1997;115:733-737.

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Nadia Khalida Waheed and C. Stephen Foster

SYSTEM LYMPHOMA

Definition Intraocular-central nervous system (CNS) lymphoma is a rare and lethal malignancy, most commonly a diffuse, large cell l)'lnphoma of B cells, although, rarely, it may also be of T-cell origin. 1 Several types of lymphomas can involve the eyes. These include systemic non-Hodgkin's lymphoma or systemic Hodgkin's disease, both of which can metastasize to the eye. However, intraocular Hodgkin's disease is exceptionally rare, with only a handful of reported cases, and histologic documentation in less than five eyes. 2-6 The most import~nt of the lymphomas is non-Hodgkin's lYITIphoma of the eye and the CNS (or intraocular-CNS) lymphoma, also called primary CNS lYITIphoma, with more than 150 cases reported.

History Intraocular-CNS lYITIphoma, previously termed reticulum cell sarcoma or microgliomatosis, was first described by Givner in 1955. 7 In the earlier series, definitive diagnosis of intraocular-CNS lymphoma was based on histopathologic examination of enucleated eyes, or brain biopsy and studies at autopsy.8 In 1975, Klingele and Hogan published the first report of the use of a vitreous biopsy specimen for the diagnosis of intraocular-CNS lymphoma. 9 This has since become a widely performed procedure for the diagnosis of this condition. 7, 8,10,11

Epidemiology Although it is a rare malignancy, the incidence of intraocular-CNS lymphoma has trebled over the last decade, an increase not correlated with a correspondingly large increase in known predisposing factors. 12 This malignancy most commonly occurs in middle to late adulthood, with a median age of 50 to 60 years 12 , 13; however, cases have been reported in children,14, 15 and the youngest reported patient was 15 years 01d. 16 The sex distribution is not clear. Although an earlier study reported no sexual predilection, some recent studies report a higher incidence in women,11, 17-19 and one reports a higher incidence in men. 12 Immune suppression seems to be a risk factor in the development of intraocular-CNS lymphoma. This condition has been associated with acquired immunodeficiency

s)'l1drome (AIDS)20 and immune suppression following transplant surgery,21 and with congenital immunodeficiencies (e.g., Wiskott-Aldrich syndrome and severe combined immunodeficiency).

Clinical Characteristics Intraocular-CNS lYITIphoma arises from the eye or the brain, the spinal cord, or the leptomeninges, and then spreads throughout the CNS.13, 22, 23 Systemic spread outside the CNS and eye is rare, occurring in only about 10% of autopsied cases. 24 , 25 Ocular manifestations antedate clinically evident CNS involvement in 50% to 80% of the cases reported in the ophthalmic literature,17, 26 although this may represent an overestimation because of a selection bias for patients with ocular involvement. Overall, around 20% of patients with primary CNS lymphoma exhibit ocular involvement at the time of diagnosis. 23 Most of the symptoms of intraocular-CNS lymphoma are related to the posterior segment-blurred vision and/ . or floaters are the commonest.24, 27 In the early stages of the disease, floaters may actually be the only symptom, without even a decrease in visual acuity. Anterior segment sYITIptoms such as redness and pain are very rare. The initial presentation may be unilateral, although ultimate bilateral involvement is the rule. 23 , 28, 29 Examination reveals no or very mild external signs of inflammation. On slit-lamp examination, there is often mild anterior segment inflammation, with aqueous cells and flare and keratoprecipitates on the corneal endothelium. 13 , 16, 21, 22, 30 The vitreous typically contains large clumps or sheets of cells, and a fundus examination shows multifocal, large, yellow, sub-retinal pigment epithelium (RPE) infiltrates with overlying solid pigment epithelium detachment8, 17, 24, 25, 31 visualized through a hazy vitreous (Fig. 48-1A to D). Ocular findings may be in excess of those expected from clinical vision testing. Reported atypical presentations include hemorrhagic retinal vasculitis resembling a viral retinitis,28, 32 and a normal-appearing fundus with subretinal lesions noted only by fluorescein angiography. Vitreous opacification may make the retina difficult to visualize. Because intraocular-CNS lymphoma is more likely to involve the deep brain structures than the cerebral cortex, seizures and motor s)'lnptoms, although they do occur, are less common than in patients with other kinds of brain tumors. It has been reported that since the frontal

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES

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FIGURE 48-1. A to D, Intraocular-CNS lymphoma. Note the dense vitritis (A), and the presence of retinal infiltrates that should raise the suspicion of intraocular-CNS lymphoma. (See color insert.)

lobe is the most commonly involved region of the. brain, changes in personality and the level of alertness are commOl) at the time of presentation. 27 CNS findings such as headaches, confusion, sensory deficits, focal weakness, diplopia, right-left confusion, poor memory, imbalance, motor weakness, and difficulty with gait have been reported. 19 ,33 A history of seizures in a patient with no prior history of seizure disorder is also a strong indication of CNS involvement. Thus, careful CNS history taking and a thorough neurologic examination are vitally important, as they may indicate CNS involvement. Systemic non-Hodgkin lymphoma presents with obvious systemic symptoms (fever, weight loss, lymphadenopathy) before ocular involvement. VVhen ocular involvement does occur, hypopyon in an uninflamed eye,29 hyphema, and choroidal infiltrates have been reported. 34 This is in contrast to intraocular-CNS lymphoma, which usually presents as subretinal infiltrates and thus may be confused with melanoma of the choroid. Similarly, Hodgkin's disease almost invariably presents with systemic symptoms before the eye is involved. Bilateral anterior and posterior uveitis with no retinal change l1 ; uveitis with peripheral white, flat retinal deposits resembling miliary tuberculosis9; and anterior uveitis alone 1o have been reported in patients with ocular involvement in Hodgkin's disease. Lymphoid hyperplasia of the uvea is another disorder that must be distinguished from intraocular-CNS lymphoma. This disorder is characterized by a well-differentiated, small lymphocytic infiltration of the uveal tract. It

presents usually unilaterally as anterior uveitis, iris heterochromia, vitritis, and choroidal infiltrates,35, 36 and it is often considered a low-grade lymphoid neoplasm; it usually responds to treatment with corticosteroids, although sometimes moderate doses of radiotherapy are needed; it has a favorable long-term prognosis. 36, 37 Hoang-Xuan and associates have recently described a "new" masquerade syndrome in a patient presenting with histology-proven anterior and posterior scleritis and choroidal white dots, unresponsive to systemic high-dose steroids and cyclophosphamide therapy. This patient was found to have mucosal-associated lymphoid tissue lymphoma on a repeat conjunctival biopsy.38

Pathology, Immunology, and Pathogenesis Most intraocular-CNS lymphomas are diffuse, large cell lymphomas of B-cell origin,39 with a few reported cases of T-cell origin. 1 Gross specimens show large gray patches of subretinal and retinal infiltration above a thickened choroid. Collections of lymphoma cells are found between Bruch's membrane and the RPE, with reactive (mainly T) lymphocytes in the retina and choroid, surrounding the B cells. Cytopathology specimens obtained from the vitreous of patients with intraocular lymphoma show mainly reactive T cells, histiocytes, necrotic debris, and fibrinous material, and few frankly neoplastic (B) cells. The malignant lymphoma cells are anaplastic (i.e., they have a high nuclear-to-cytoplasmic ratio), and they have lobulated nu-

CHAPTER 48:

clei with multiple small nucleoli, coarse chromatin, and mitotic figures (see Fig. 48-1). Immunohistochemistry marks them positive for B-cell markers (CDI0, CDI9, CD20, CD21, CD22) and for monoclonal K and A. chains. In contrast, histiocytes have large vesicular or watery nuclei with small nucleoli and minimal clmnping of the nuclear chromatin. Macrophages have much more opaque cytoplasm and somewhat eccentric nuclei, and they may contain ingested debris, including melanin granules. 19 Cytokines play an important role in conditions involving immunologic cells, and intraocular-CNS lymphoma is no exception. Interleukin-4 (IL-4) and IL-I0 are potent growth and differentiation factors for B lymphocytes, and IL-I0 induces B cells to secrete large quantities of immunoglobulin G (IgG) , IgA, and IgM.40 IL-I0 is also a negative regulator for IL-12-induced inflammation and has been seen primarily as a cytokine-synthesis inhibitorY IL-6, a multifunctional cytokine, plays a central role in inflammatory defense mechanisms and has been found in the aqueous and vitreous of patients with non-neoplastic uveitis. The same is true of IL-12 levels, which correlate to the degree of inflammation. 42 IL-I0 has been reported to be associated with the presence of malignant lymphoid neoplasms. 43 ,44 The role of IL-I0 levels in the diagnosis of intraocular-CNS lymphoma is discussed in the section on diagnosis. At the genetic level, translocation of the BCL2 gene, a proto-oncogene located on chromosome 18, is believed to be the fundamental event ill''fmany hematologic malignancies, including non-Hodgkin lymphoma,45 where a t(14;18) translocation brings the BCL2 gene into juxtaposition with the Ig heavy-chain promoter located on chromosome 14,46 resulting in overexpression of the BCL2 gene. Several investigators have also detected this immunoglobulin heavy-chain rearrangement by polymerase chain reaction (PCR) in ocular specimens of patients with intraocular-CNS lymphoma. 44 , 47, 48

Diagnosis The three cornerstones of diagnosis in intraocular-CNS lymphoma are a thorough CNS evaluation (including a history and neurologic examination as well as magnetic resonance imaging [MRI]), CNS cytology, and a diagnostic vitrectomy. The differential diagnoses of sarcoid and, less commonly, tuberculosis, which may present in a similar way, must be excluded with appropriate investigations. A high index of suspicion for intraocular-CNS lymphoma is necessary to avoid missing or delaying the diagnosis, especially in middle-aged or older patients presenting with chronic vitritis. 39 Findings of intense ocular inflammation (in the absence of significant pain, photophobia, or conjunctival hyperemia), and sub-RPE infiltrates, sheets and clumps of vitreous cells, and steroid resistance (after a possible initial period of steroid responsiveness), should raise suspicion for intraocular-CNS lymphoma. The reported average interval of 21 months between the onset of ocular symptoms and definitive diagnosis ll has been shown to be reduced considerably, with most patients diagnosed between 20 and 52 weeks, if one maintains a high index of suspicion based on clinical findings. 19

.·.M~..;lI""-f~Um;;;n.A'"'.IY'm;;;

SYNDROMES: MALIGNANCIES

Any recent-onset CNS sYJ-nptoms or findings on a neurologic examination raise the suspicion of CNS spread. An MRI is warranted, however, in all patients suspected of having CNS lymphoma, even if the history and exalnination are negative. On a computed tomography (CT) scan or with MRI, the appearance of an intraocular-CNS lymphoma is characteristic, with the tumor being supratentorial and multicentric in 50% of cases. 49 Unlike brain metastasis and malignant gliomas, which show ring enhancement on administration of contrast, these lesions characteristically have dense and diffuse enhancement with distinct borders. A lumbar puncture must be performed on all patients suspected of having intraocular-CNS lymphoma, regardless of the results of the neurologic evaluation. Ten milliliters of cerebrospinal fluid (CSF) is appropriate for cytology. A repeat lumbar puncture may be required for diagnosis. Lymphoma cells are extremely fragile, and to optimize results, specimens should be transported to the laboratory immediately. Lumbar puncture can be negative in a patient with intraocular-CNS lymphoma, since CNS disease may lag ocular disease by months to yearsY Even in the presence of CNS involvement, lumbar puncture can give false-negative results as a result of mishandling of the specimens or steroid therapy; steroids may be cytolytic in intraocular-CNS lymphoma and may even cause intraocular-CNS lymphoma lesions to decrease in size. Vitreous biopsy of an eye with more severe vitritis or reduced vision is used to assess ocular involvement and is carried out even if the lumbar puncture results are negative. This is the gold standard for assessing ocular involvement in the disease. A standard three-port pars plana vitrectomy (PPV) is performed; before instituting the infusion, 1 ml of undiluted vitreous is obtained by a syringe and delivered immediately to the cytology laboratory.21, 26 The specimens are fixed by mixing one part of 10% neutral-buffered formalin with one part of specimen for approximately 12 hours. A 5-ml fixed specimen is then spun at 1000 rpm for 5 minutes in a cytospin chamber to concentrate the cells onto glass slides. These are then dried and stained with a modified Papanicolaou's staining technique for cytopathologic analysis. Histochemical staining using monoclonal antibodies against the B- and T-cell markers and against K and A. light chains is also done, and the slides are interpreted by a cytopathologist. . Total vitrectomy is then performed with infusion. Tissue culture medium enriched with 10% fetal calf serum can be added to the collection chamber of the vitrectomy machine to improve cell viability. This diluted specimen is then submitted for modified Papanicolaou's staining, histochemical staining, flow cytometry, and IL analysis. Problems encountered are similar to those of lumbar puncture specimens: the fragility of the lymphoma cells (which may be damaged by improper handling), steroid therapy (which most of these individuals were on for vitritis prior to the vitrectomy), and the high ratio of reactive cells to malignant cells. The diagnosis can easily be missed by pathologists who have had little experience with this condition. False negatives can be minimized by immediate delivery of the specimens and by the availability of an experienced cytopathologist. Even so, multiple

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES

vitreous samples may be needed to make a definitive diagnosis. 25 ,50 Ancillary diagnostic modalities include the measurement of IL levels. High IL-10 levels and an elevated ratio of IL-10 to IL-6 in vitreous specimens have been associated with intraocular-CNS lymphoma, according to some reports. 5l ,52 However, a study at our center shows that IL10 can be detected even in vitreous specimens of patients with non.:.neoplastic uveitis and that, conversely, IL-10 levels are not always elevated in patients with intraocularCNS lymphoma. 53 Thus IL-10 levels are suggestive but not diagnostic of lymphoma, with vitreous biopsy cytopathology still being the only definitive means of diagnosing ocular involvement in intraocular-CNS lymphoma. Several investigators have identified the t(l4;18) locus by PCR in ocular specimens of patients with intraocularCNS lYlnphoma,47,48 and successful amplification in both frozen and formaldehyde-fixed and paraffin-embedded samples have been reported using this method. 54 ,55 Thus this promising new method may provide an additional diagnostic clue when traditional methods fail to provide an unequivocal answer.

Treatment The optimal treatment of intraocular-CNS lymphoma is still controversial. In the case of documented CNS involvement, combined radio- and chemotherapy is recommended. Whole brain radiation with 50 gray (Gy) and an additional 10-Gy boost to the tumpr side is recommended.18, 28 However, despite high radiosensitivity, whole brain radiation alone leads to a high relapse rate, with most patients dying within 1 to 5 years of diagnosis. 28 A marked improvement in survival of patients is reported when cranial radiation is combined with intrathecal methotrexate (MTX) as systemic chemotherapy.55 Intrathecal MTX is needed because the CNS levels of intravenous (IV) chemotherapy may be short-lived 57 and variable, despite the fact that high-dose cytosine arabinoside can lead to therapeutic levels in CSF.32 MTX may also be delivered by an Omaya reservoir,27 and intravitreal MTX has been employed in some patients with intraocular-CNS lymphoma with promising results. 58 Radiation therapy has proved to be effective for ocular findings in patients with detectable involvement only in the eye and no detectable CNS involvement. A dose of 30 Gy is given, typically to both eyes, since bilateral involvement is. the rule. 18, 25, 28 In these patients, there is controversy about whether to limit treatment to the eye or to prophylactically irradiate the CNS as well. Although one group of investigators has reported long-term (24 and 109 months) disease-free survival with ocular radiation only,25 many researchers recommend prophylactic CNS radiation in addition to orbital radiation inpatients with isolated ocular involvement, since these patients often have subclinical CNS involvement by the time ocular manifestations arise. 25 ,59 Rouwen and colleagues 59 advise a combination of chemotherapy for CNS disease and radiotherapy for ocular disease even if CNS involvement cannot be documented· by MRI and lumbar puncture, since penetration of the blood-brain barrier by chemotherapeutic agents is doubtful.

Prognosis of this condition is poor, despite a generally good initial response. The 5-year survival is less than 5% and median survival varies in different series from 13 to 26 months. 12 , 17, 25 Char and colleagues, however, suggest that the median survival in these patients improves if a combination of intrathecal chemotherapy and radiotherapy of the CNS and orbit is employed. 25

Complications Cranial radiotherapy produces significant CNS toxicity in long-term survivors, which is exacerbated by chemotherapy,13, 50 especially MTX. However, administration of chemotherapy before radiotherapy may reduce the risk of leukoencephalopathy and late toxicity. 50, 51 Some investigators recommend using systemic and intrathecal chemotherapy for intraocular-CNS lymphoma,52 with radiotherapy used only for recurrent disease. This tends to minimize the toxicity associated with combination chemotherapy and radiotherapy usage. Survival rates may improve with a combination of intrathecal chemotherapy and radiotherapy to the orbits and whole brain. 25

Conclusion Intraocular-CNS lymphoma is an insidious and aggressive malignancy that presents masquerading as intraocular inflammation. A high index of suspicion, a thorough CNS evaluation, and cytologic examination of vitreous samples are the cornerstones of diagnosis. Management is controversial, but earlier diagnosis and new treatment modalities provide some hope for patients with this condition.

Definition Leukemias are malignant neoplasms of the hematopoietic stem cells, characterized by diffuse replacement of the bone marrow by neoplastic cells. 53 Traditionally, leukemias are classified on the basis of the cell type involved and on the maturity of the leukemic cells into acute lymphocytic (ALL), acute myelocytic (AML) , chronic lymphocytic (CLL) , and chronic myelocytic (myelogenous) (CML) leukemias. The acute leukemias are characterized by the presence of very immature cells called blasts and a rapidly fatal course in untreated patients; chronic leukemias are associated, at least initially, with well-differentiated leukocytes, and with a relatively indolent course. The acute leukemias typically exhibit the characteristics of an abrupt, "stormy" onset, with symptoms related to depression of normal bone marrow function, organ infiltration, and CNS manifestations. The alteration in normal marrow function and the ability to infiltrate tissues, especially common in ALL, is responsible for many of the ocular manifestations. The chronic leukemias, although a more diverse group of disorders, do, to some extent, share the same properties. Leukemic ophthalmopathy was apparently first established as a clinical entity in the late 19th century by Liebreich in his paper on leukemic retinopathy and central retinal artery embolism. 54 In the early 1900s, leukemic invasion of the optic nerve was considered a preterminal curiosity; however, with

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES

treatments of leukemia, there was a resurgence of interest in the eye as a site where leukemic cells may escape the effects of systemic treatment and later proliferate to cause relapse.

Epidemiology Estimates of ocular involvement in leukemia vary: Pathologic studies show a higher incidence than clinical ones and many findings are transient, waxing and waning with time and treatment. Ridgeway and associates,65 for example, report abnormalities on ocular examination in 9% of children suffering from acute leukemias, whereas DukeElder66 estimates that up to 90% of patients with leukemia demonstrate some ocular abnonnality at some point in the disease course. However, it is generally accepted that the eye is involved far lTIore often in acute than in chronic leukemias. For example, Kincaid and Green,67 in a review of pathology specimens, report ocular involvement in 82% of cases of acute and in 75% of chronic leukemic eyes, and this difference is noted in most other studies as well.

Clinical Presentation and Diagnosis As effective chemotherapy programs have led to longer survival times for leukemic patients, sites of extramedullary leukemic infiltration have been examined more closely because they may act as reservoirs for proliferation of leukemic cells and eventual systemic relapse. These sites have been considered "pharmacologic sanctuaries," relatively unaffected by systemi~ chemotherapy and requiring separate radiotherapy. 68-71 Although the CNS is one of the most frequent sites of relapse after initial induction of remission,72 it is now generally accepted that the eye, like the CNS, is a pharmacologic sanctuary, requiring radiation for elimination of tumor cells. 65 ,73 Ocular involvement in leukemia occurs either because of infiltration of leukemic cells or because of various hemorrhagic phenomena, and practically any part of the eye can be involved. The ocular abnormalities are described next, according to the part of the eye involved. Recognizing leukemic involvement of the eye is important because it may present the first manifest signs of extramedullary relapse, and prompt identification and

initiation of treatment can be life saving, especially acute leukemias.

HI

Retina Leukemic retinopathy is observed in both the acute and chronic forms of leukemia, but it is common in the acute form. It is characterized by tortuous, dilated retinal veins, which may have an irregular "boxcar" or "sausage" appearance. 74 Perivascular sheathing is often present and is thought to represent infiltration of leukemic cells. 75 Hard exudates and cotton-wool spots are also a prominent feature; the cotton-wool spots have been suggested to be either nerve fiber layer infarcts or localized collections of leukemic cells. 76 The most striking feature of leukelnic involvement of the retina, however, is the presence of retinal hemorrhages, most commonly located in the posterior pole (Fig. 48-2A, B). These hemorrhages may be at any level of the retina, including extension into the subretinal or vitreous spaces. 75 Most commonly they are intraretinal, either round or flame shaped. These intraretinal hemorrhages may appear as the classic white-centered Roth's spots, with the white centers representing cellular debris, capillary emboli, or accumulations of leukemic cells. 76 , 77 Hemorrhages in the subhyaloid space are boat shaped and may break into the vitreous, thus obscuring visualization of the poste~ior pole. Subretinal hemorrhages are rare. Kuwabara and Aiell0 78 first described nodular retinal infiltrates, looking much like miliary nodules, associated with local necrosis and hemorrhage in a patient with chronic myelogenous leukemia, and Schachat and colleagues 79 described similar leukemic infiltrates in up to 3% of newly diagnosed ALL and AML cases. These infiltrates have been found to occur in association with elevated leukocyte counts with a high proportion of blast cells 80 and have been associated with fulminant disease and early demise. Peripheral retinal microaneurysms are a feature of chronic leukemias, especially chronic myelogenous leukemia. 81 Prolonged leukocytosis seems to be necessary for the development of peripheral retinal microaneurysms, and this may be caused by increased lateral pressure on

FIGURE 48-2. A and B, Fundus photographs in a patient with leukemia. Flame-shaped nerve fiber layer hemorrhages and large subhyaloid hemorrhages can be seen. (See color insert.)

CHAPTER48: MASQUERADE SYNDROMES: MALIGNANCIES

the walls of vessels as a consequence of increased viscosity. Retinal neovascularization, similar to the sea-fan configuration seen in sickle cell anemia, is a rare complication that has alSo been found in patients with chronic myelogenous leukemia; it is associated with peripheral vascular occlusion and capillary dropout. This has been related to higher white blood cell counts and, in one case, with increased number of circulating platelets. 82-84

Uveal Tract CHOROID

The choroid is commonly infiltrated with leukemic cells, although this may go undetected clinically. In fact, histopathologically, the choroid may be the most commonly affected part of the eye,57,75 with the most striking changes observed in acute leukemias, especially ALL.75 When visible clinically, these leukemic choroidal infiltrates may manifest as bilateral serous detachment of the retina,57 or as single large choroidal masses and overlying serous retinal detachment in adults with chronic myelogenous leukemia. 85 This choroidal involvement can also induce secondary changes in the RPE including atrophy, hypertrophy, and hyperplasia, and occasionally giving rise to a leopard spot pattern. 57 This may occur because of either primary invasion or compressive involvement of the choriocapillaries by neoplastic cells. 85 Fluorescein angiographic changes in patients with choroidal infiltration and overlying serous retinal detachment of the retina show a multitude of RPE leakage poinrs in the early phase of the angiogram, described as a milky-way pattern. 85 With time, these leakage points become more diffuse, and dye leaks into the subretinal space. IRIS AND ANTERIOR SEGMENT

Anterior segment involvement in leukemias is unusual but has received increasing attention as a site of extramedullary relapse. Most cases of anterior segment involvement have had acute lymphoblastic leukemia, although cases with CLL and AML have also been reported. 87-89 Patients characteristically present with unilateral or bilateral symptoms of acute iridocyclitis with conjunctival injection, iritis, hypopyon, pseudohypopyon, or spontaneous hyphema. 55, 88, 90-93 The pseudohypopyon has, in some case reports, been defined as "shaggy, irregular, free-floating material" that fails to settle inferiorly and has a characteristic creamy-white color. 94 It consists of leukemic cells that have infiltrated into the anterior chamber and may initially respond to topical or periocular steroids, although the infiltrate recurs. Diffuse or nodular iris involvement may occur. Diffuse involvement presents as discoloration with a whitish gray film and heterochromia iridis. Nodular involvement is seen as illdefined densities extending usually to the pupillary margin. 95 Glaucoma may occur with these findings as a result of leukemic infiltration of the trabecular meshwork, or as angle-closure glaucoma following choroidal infiltration and hemorrhage. 94 ,96-98 Diagnosis is established by anterior chamber paracentesis with cytologic examination of the aqueous humor. 94 Low-dose, local anterior segment irradiation is the treatment of choice. 94,95 Although most patients have had meningeal or hema-

tologic relapse at the time of iris infiltration, cases have been reported in which involvement of the iris may be the first, or even the only site of relapse; again, the anterior segment has been postulated as a "pharmacologic sanctuary" for leukemic cells. Bremner and Wright,99 for example, report a case with the typical symptoms of iridocyclitis and a hypopyon, with typical "glutinous" leukemic cells in the crypt of the iris as the only site of leukemic relapse, in which symptoms resolved with local corticosteroid therapy, only to recur. Gruenewald and associates 100 and Ninane and colleagues 101 also report cases with the anterior segment as the first site of relapse. Tabbara and Beckstead94 report the case of a 3-month-old infant with bilateral eye redness and anterior chamber pseudohypopyon as the first detected sign of acute promonocytic leukemia. VITREOUS

Leukemic involvement of vitreous may present with a vitreous hemorrhage in the presence of retinal changes. Infiltration of the vitreous with leukemic cells without hemorrhage is uncommon, most likely reflecting the barrier function of the intact internal limiting membrane. 78 However, such cases have been reported, both in pathologic studies 57 and in case reports. Reese and Guy mention vitreous opacities in one of their cases,102 and Swartz and Schumann 103 report the case of a patient with ALL, treated with several cycles of chemotherapy, who then presented with unilateral, progressive, painless loss of vision found to be caused by dense cellular infiltration of the vitreous, with clumping of cells and vitreous fibrils into opaque sheets as the only sign of leukemic involvement of the CNS. This patient did not receive CNS prophylactic radiation, but relapse in the eye can occur even after such radiation has been given, as seen in the case described by Bremner and Wright. 99 Diagnosis is made by a PPV with cytologic examination of the vitreous. Infections are a distinct possibility in patients with leukemia because of the leukemic state itself and the treatment received, and so endophthalmitis may have to be excluded by a Gram stain and culture of the vitrectomy specimen for bacteria and fungi. In addition, opportunistic infections commonly seen in patients with AIDS, such as cytomegalovirus retinitis, other acute necrotizing herpetic infections, and toxoplasmosis, may appear in patients with leukemia who are immunosuppressed.

Optic Nerve Leukemic optic nerve infiltration occurs primarily in children with acute leukemias and especially ALL.73 This is a particularly worrisome finding; like vitreous involvement, it implies CNS disease. Involvement of the optic ne~ve can be pre1aminar, with primarily invasion of the optic nerve head, or retrolaminar. Prelaminar invasion is associated with a fluffy, edematous appearance to the nerve head with moderate edema and hemorrhage. The visual acuity may be altered only minimally, or it may be significantly impaired if edema and hemorrhage extend into the macular area. 73 Retrolaminar invasion, on the other hand, is associated with a profound decrease in vision and moderate to pronounced disc elevation and some edema and hemorrhage. This must be distinguished from

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES

papilledema due to increased intracranial pressure, and this is done by a lumbar puncture. Differentiation is important because infiltration of either type of leukemic optic neuropathy responds dramatically to radiation therapy, whereas papilledema does not. In fact, with retrolaminar infiltration, urgent institution of radiation therapy is necessary to restore vision and to prevent permanent visual loss. Since the recognition of the CNSas a pharmacologic sanctuary, and the eye as an extension of this pharmacologically privileged site,68, 70, 104 it is now widely accepted that the posterior pole of the eye should be included in radiation therapy for the prophylaxis of CNS leukemic involvement.65 Thus the frequency of optic nerve head involvement in leukemias is decreasing with the use of prophylactic posterior pole radiation and more aggressive systemic and intrathecal chemotherapy.73

Orbital and Lid Involvement Approximately 11 % of children with unilateral proptosis have some form of acute leukemia,105 and leukemia accounts for 2% to 6% of orbital tumors of childhood. 106 Orbital involvement of the eyes occurs as a result of either tissue infiltration by leukemic cells or hemorrhage. Thus, patients may have infiltration of the lid, orbit, or lacrimal gland, proptosis, diplopia, motility disturbances, ecchymosis, lid hemorrhage, or retrobulbar hemorrhage, which may extend forward into the subconjunctival space. In an undiagnosed patient, biopsy may be required for diagnosis of leukemia, and in tlqe immunocompromised leukemic patient with proptosis (especially one on chemotherapy), infection must be excluded. 107 Orbitalleukemia may also present with infiltration of any other orbital structure including the lacrimal gland, the rectus muscles, the dermis, and the lacrimal draining system. 68 , 108 Granulocytic sarcoma, or chloroma, a variant of myelogenous leukemia, classically presents with tumor masses in the orbit. These may be unilateral or bilateral, and they have a greenish appearance on gross pathologic examination because of the presence of the enzyme myeloperoxidase. 109 A chloroma may manifest at any time in the course of myelogenous leukemia, sometimes preceding hematologic signs. In myeloproliferative disorders, it may be a harbinger of a blast crisis and transformation into AML.ll0 Thus, in the presence of granulocytic sarcoma, the ophthalmologist must be alerted to the imminent appearance of AML. These tumors have a poor prognosis, with a survival of between 1 and 30 months after onset of ocular signs and symptoms. l1l , 112

Other Unusual Manifestations Leukemia can present with infiltration and hemorrhage into practically any part of the eye, and thus a number of uncommon manifestations have been reported in the literature, including corneal ring ulcer in AML,113 Sjogren's syndrome with lacrimal gland enlargement in CLL,114 and anterior segment ischemia115 in CML.

Pathogenesis Various studies have attempted to relate the pathologic findings in the eyes of leukemic patients with the overall systemic changes. Although most authors have been un-

able to relate the retinal findings of leukemia to. hematologic status,80, 116 Culler 117 reports a correlation between low red cell and platelet counts and retinal hemorrhages, and the relationship between low platelet counts and hemorrhages is confirmed by two more recent prospective studies. 118 ,119 Kincaid and Green67 have suggested that the relationship between retinal findings and the blood count may be inconclusive because the blood profile in these patients varies during the disease course, and the appearance of the retinal findings may be delayed, correlating better with the blood cell counts of approximately a month earlier.

Treatment and Prognosis The treatment and prognosis for signs and symptoms in leukemia were described in preceding sections. As longterm survival and even cure of leukemia become a possibility, increasing attention is being paid to the ocular manifestations, both as a sign of extramedullary disease relapse, and in terms of vision preservation to enhance quality of life. Although, even with irradiation and intrathecal MTX, visual outcome is not always good, new studies evaluating the ocular morbidity of acute leukemias have shown surprisingly good results in both AML and ALL patients,120, 121 as prophylactic and treatment approaches for extramedullary leukemia continue to be refined, based 011' the type of leukemia, previous treatments, marrow relapse, and CSF profile.122-124 Development of the concept of certain extramedullary sites, including the CNS and the eye, as pharmacologic sanctuaries has been a significant step in decreasing ocular as well as systemic morbidity.65, 80, 125, 126 The most striking example of this is ALL, which now has a 90% remission rate and a 50% cure rate. 125 , 126

MALIGNANT

Definition Malignant melanoma of the eye is a malignant melanocytic stromal proliferation of the choroid, the ciliary body, or the iris. Malignant melanoma of the choroid and ciliary body is the most common primary intraocular malignancy.

History Melanoma was considered to be the most C01nmon malignancy of the eye up to the 1960s, when it was thought to have an incidence around 20 times greater than that of metastatic tumors. 127 However, with increased survival of cancer patients and with the proliferation of medical literature, it came to be recognized that malignant melanomas, although the most common primary eye malignancy, are in fact, much less common than metastatic tumors of the eye.

Epidemiology Melanomas are the most prevalent primary eye malignancies, with posterior melanomas occurring at a higher frequency than iris melanomas. Iris lesions account for only 3.3% to 12.5% of all surgically excised melanomas128-132; they occur at an average age of between 40 and 50 years 128, 132-136 and with equal incidence in men and

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES

women. 128-130, 132, 135, 136 They occur more in whites and in patients with light irides than in Asians and blacks. 128 , 134, 137 :Most iridic melanomas (and also nevi) arise from the inferior portion of the iris, more often peripherally and temporally.128, 134, 136 Choroidal melanomas occur at an average age that is about 10 years above that for iris melanomas. They are eight times more common in whites than blacks l38 , 139 and six times more common in whites than in some Asian populations.140, 141

Clinical Characteristics In a high proportion of patients, iris melanomas arise from pre-existing lesions that suddenly undergo active growth. 129 , 130, 132, 142 They present in three patterns-ring, tapioca, and diffuse melanomas. Diffuse melanomas present with unilateral acquired heterochromia and secondary glaucoma. Although they have the highest likelihood of Inetastasizing, they also have an excellent prognosis. 132 , 142-144 Ring melanomas involve more than two thirds of the angle circumferentially, and they are associated with secondary glaucoma. Many are diagnosed incorrectly because of failure to recognize an infiltrating pigmented lesion as a cause of refractory glaucoma. Tapioca melanomas 145 are lightly pigmented or nonpigmented multifocal nodules that project into the anterior chamber. These lesions are sometimes associated with glaucoma. They were initially thought of as benign, but now it is recognized that some can be categorized histologically as melanomas,142 and metastatic disease has bet:n reported. 146 Clinical differentiation between malignant and benign lesions is based on clinical features. A lesion is considered malignant if it is 3 mm or greater in diameter and 1 mm or greater in thickness and has three of the following five features l47 , 148: secondary glaucoma, secondary cataract, photographic documentation of growth, ectropion irides, and prominent vascularity. Notable tumor growth and intense vascularity have been cited as being the most reliable signs for the diagnosis of Inelanoma of the iris. 149 However, these traditionally accepted concepts are now being challenged, and a recent study by Jakobiec and Silbert shows no correlation between the type of lesion and the presence of ectropion uvea, splinting or distortion of the pupil, vascularity, involvement of the chamber angle, glaucoma, or touching of the cornea. 142 This study concludes that progressive growth or involvement of the ciliary body in a ring configuration with progressive glaucoma is more commonly associated with benign tumors; nevertheless, a lesion with these features must still be scrutinized very c1osely.142 Tumors with ciliary body involvement (Fig. 48-3A-D) are also associated with a higher incidence of malignancy (although neither episcleral dilatation nor sector cataract reflected malignancy or ciliary body involvement) .142 Some studies also show that medial location and presence of pigment dispersion onto the iris or angle structures are the only features associated with tumor growth. 150 According to other studies, however, iris melanomas are more likely to be inferiorly and temporally 10cated;128, 134, 136 some authors believe that a superiorly located lesion is unlikely to be amelanoma151 1:>ut may be metastatic or a ciliary body tumor. Because of clinical findings such as pigment dispersion in the anterior cham-

ber and pigment on the anterior surface of the lens, this condition can masquerade as uveitis. Choroidal melanomas present with symptOlns of visual loss, photopsias, and visual field defects, although they may be asymptomatic. Unusual presentations, including severe pain, suggest a diagnosis other than that of choroidal melanoma; but pain may occur in melanOlnas associated with inflammation, massive extraocular extension, or neovascular glaucoma. An ocular history of an old nevus, or systemic nonocular malignancies may be helpful in establishing a diagnosis, but one must also remember that 6% to 10% of melanoma patients have another primary neoplasm. 152 , 153 Examination is of vital importance in the diagnosis, as it has been reported that indirect ophthalmoscopy leads to a correct diagnosis of melanoma in greater than 95% of cases. 154 Visual fields are not helpful in ruling out benign lesions,147, 155 as melanomas have no characteristic visual field changes. Scleral transillumination is blocked by melanomas but not by choroidal effusions. Melanomas appear classically as pigmented, dome- or collar buttonshaped tumors with associated exudative retinal detachment that may involve the macula and thus decrease vision (see Fig. 48-3E). Although only a minority of choroidal melanomas have the collar-button configuration, breaks in Bruch's membrane are rarely seen with any other type of lesion. Other signs include a deposition of lipofuscin at the level of the RPE, seen as an orange pigment; a tumor with an elevated, globular shape; exudative retinal detachment with a large tumor; and tumor pigmentation (although nearly one fourth of tumors are nonpigmented). Some large melanomas, especially those involving the ciliary body, may have prominent scleral vessels called sentinel vessels (see Fig. 48-3C). Uncommon presentations include diffuse melanoma (less than 5 mm thick, covering more than 25% of the uveal tract), 156 which has a higher rate of extraocular spread. Melanomas may also present with significant anterior uveitis, especially with iridial melanomas, or posterior inflammation with choroidal and ciliary melanomas; these cases may be very similar to the presentation of sarcoid, tuberculous uveitis, or posterior scleritis, and the choroidal mass may be misdiagnosed as a granuloma. 145 Fraser and Font,1.57 for example, in a series of 450 eyes with melanomas of the choroid and ciliary body, report that 22 (4.9%) had ocular inflammation: episcleritis (7 patients), anterior or posterior uveitis (14 patients), and panophthalmitis or endophthalmitis. Haddab and associates 158 report the case of a 22-year-old man with a decreased visual acuity and signs of cells and flare in the anterior chamber; keratoprecipitates, posterior synechiae, and round yellowish nodules on the iris; and elevated intraocular pressure and cataract, who was initially treated for anterior uveitis for at least 2 months before a diagnosis of ciliary body melanoma was made. Similarly, Furdova and associates 159 report the case of a 23-year-old woman with an ultimate diagnosis of malignant melanoma penetrating the optic nerve, diagnosed as intermediate uveitis and treated for a prolonged period as an outpatient, and later with a PPV, until malignant cells were found in her anterior chamber 4 months after the PPY. Thus, Inelanomas must be kept in mind in the case of such

CHAPTER 48: MASQUERADE SYINIJIRC)MIES:

OYU""U.. O'I...: lID"1II_O"'I!\l"",ilB;;;.;Jl

FIGURE 48-3. A and B, Ciliary body melanoma: Note the mass protruding d01'vnward in the photograph at the 12 o'clock position. C, The dilated 'sentinel' scleral blood vessel can be seen in the area over the tumor. Patients with unilateral, especially sectoral, cOl-uunctivitis should always have a dilated examination to rule out an intraocular tumor. D, Cataract in a patient with ciliary body melanoma. E, Malignant melanoma. The large, elevated dome shape of the tumor seen in this picture is characteristic. Tumors may also show breaks in Bruch's membrane, giving a collar-button appearance. Although most tumors are pigmented, nearly 25% can be nonpigmented. (See color insert.)

presentations, especially if the patient does not respond to treatment. Certain atypical findings may lead to a diagnosis other than melanoma: The presence of significant hemorrhage is seen in choroidal melanomas only when the tumor has broken through Bruch's membrane, or with large tumors; a mass lesion less than 4 mm with hemorrhage should bring to mind other possibilities (e.g., ruptured macro aneurysms, disciform lesions, and localized choroidal detachment). Multiple choroidal tumors are suggestive of metastasis or lymphoid lesions; black pigmentation is suggestive of RPE hypertrophy, hyperplasia, or melanocytoma; a pink-orange color is typical of choroidal hemangioma, hemorrhage, or osteoma; absence of pigmentation, although present in one fourth of melanomas, must

prompt one to rule out choroidal hemangiomas and metastasis. Pigmented choroidal lesions between 1.5 and 3 Inm in thickness have been termed intermediate elevated pigmented choroidal tumors and may have signs of chronicity. These lesions, however, must be carefully observed for signs of growth by sequential examinations, photography, and ultrasonography, and for the presence of growth, exudative retinal detachment, and lipofuscin, which increase the likelihood of malignancy.

Pathology Sunlight exposure is thought to be important in the pathogenesis of iridial melanomas,16o thus its predilection

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES

for light irides and Caucasians. These lesions are also thought to develop from preexisting benign nevi. 142 , 161 The histopathologic classification of iris and choroidal melanomas was originally described by Callender. 162 Uveal melanomas are assigned into the following groups based on their histopathologic features: spindle A, spindle B, fascicular, mixed, epithelioid and necrotic. Now melanomas with a spindle A histology are regarded as benign spindle cell nevi. 162 , 163 This classification system has been shown to have prognostic value for ciliochoroidal melanomas, as mortality increases linearly from the spindle A cytology to the aggressive epithelioid cytology.130, 164-166 However, since iridic lesions have been found to behave in a much more benign fashion than melanomas of the choroid and ciliary body, iridic melanomas have been classified into a nine-part histopathologic classification by ]akobiec and Silbert 142 ; these investigators argue that, based on the clinical behavior of iris melanomas, a majority of these lesions are inherently benign. However, other investigators dispute this, saying that although luelanocytic iris tumors have an excellent prognosis, this is primarily because of their conspicuous location and their smaller size at diagnosis,167 and therefore they should not be considered distinct from posterior melanomas.

Diagnosis Iris Melanomas Excluding primary ciliary body mel~nomas with iris extension is vital because of the completely different management and prognosis of these two conditions. This is done by indirect ophthalmoscopy with scleral depression, scleral transillumination, and gonioscopy. Ultrasonography is done if primary ciliary body melanoma cannot be excluded. Benign lesions simulating malignant melanoma of the iris must also be excluded. One study, for example, found that only 24% of lesions referred as presumed iris melanoma had been correctly diagnosed,148 and the major misdiagnosed lesions in that series were primary cysts (38%) and nevi (31 %). Photographic documentation of any stromal melanocytic tumor of the iris is required; photographic evidence of progressive growth or a diffuse ring configuration point toward malignant melanoma. Similarly, glaucoma points toward a malignant lesion, as does the tendency of the lesion to spread beyond the pupillary neuroectodermal margin of the iris and, for example, to deposit on the lens or cause retrocorneal nodules. Fluorescein angiographic patterns may also help differentiate between a benign and a malignant lesion.168-17°Benign nevi have a filigree vascular network pattern (early filling, late leaking), or they may be angiographically silent, while malignant tumors have irregular and indistinct vascular channels that fill later (i.e., in mpre than 30 seconds). Although these features are useful, they probably should not be used as a definitive or decision-making investigation in determining malignancy.l7l Several other tests have been suggested but not found to be useful.147, 149

Choroidal Melanomas Choroidal melanoma is diagnosed on the basis of indirect ophthalmoscopy, scleral transillumination, and ultraso-

nography. For lesions more than 3 mm thick, combined A and B scan ultrasonography has a more than 95% accuracy in the diagnosis of choroidal melanomas. 154 The three characteristic features on B scan are an acoustically silent zone within the melanoma, choroidal excavation, and shadowing in the orbit. A scan features include medium to low vitreal echoes, with smooth attenuation and vascular pulsations within the tumor. Ultrasonography of a nevus, in contrast, shows a flat lesion with choroidal discontinuity on the B scan and medium to high internal reflectivity on the A scan. Intermediate elevated pigmented choroidal lesions (between 1.5 and 3 mm in height), although difficult to diagnose on ultrasonography, nevertheless may exhibit enlargement on sequential ultrasound exams. Ancillary investigations include fluorescein angiography, CT, MRI, indocyanine green angiography, and radioactive phosphorus uptake. Fluorescein angiography is of limited value. 154 Larger melanomas may show an intrinsic tumor "double circulation" with extensive leakage, late staining, and multiple pin-point leaks or "hot spots" at the level of the RPE,155, 172 but these signs are by no means very sensitive or specific. Fluorescein angiography, however, can be useful in differentiating heluorrhagic lesions (e.g., ruptured macroaneurysms, disciform lesions, and localized choroidal detadlluent). High-resolution CT173, 174 is actually less accurate than ultrasonography; MRI, nuclear MRI (NMRI) , and Doppler studies still have an uncertain role. Indocyanine green angiography may be useful in the diagnosis of choroidal melanomas, hemangiomas, and uveal metastasis. 175 A radioactive phosphorus uptake test has a low sensitivity and specificity,16O-165, 176-181 and fine-needle aspiration biopsy (FNAB) is neither generally required nor a good diagnostic measure for determining cell type or differentiating melanoma from nevi or other spindle cell tumors, and it carries with it the additional possible risk of seeding of-the needle tract.

Treatment Because iris melanomas have a generally good prognosis, observation with photos every 3, 6, or 12 months, depending on clinical features, may be all that is warranted. 142, 147, 149 Surgical intervention is indicated, with complete excision usually by sector iridectomy, if the tumor growth is pronounced and/ or refractory secondary glaucoma occurs, or the tumor grows over the pupillary margin and affects vision. 147, 150 Some investigators advise iridocyclectomy for peripheral lesions that either involve the chamber angle or are associated with glaucoma,147, 149 with the potential visual consequences and even mortality with delayed tumor removal dictating this course. However, since up to 50% of patients undergoing iridocyclectomy retain no useful vision, some investigators have recommended ultrasound-guided needle biopsy for cytologic diagnosis before iridocyclectomy.142, 150 Because it has been recognized that the prognosis of iris melanomas is good, however, there is a trend toward conservative manageluent of iris lesions with local excision (iridocyclectomy), with follow-up every few months for spindle B histology, and enucleation is advised only if epithelioid cells are discovered on biopsy, except in the monocular

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES

patient. 152 Another surgical modality for which smaller melanomas of the ciliary body or anterior choroids may be amenable is partial lamellar sclerouvectomy. The management of choroidal tumors is based on their size. A major advance in the treatment of choroidal tumors is that of external beam radiation. Pioneering work on this modality done by Gragoudas and associates of the Massachusetts Eye and Ear Infirmary, among. others, has shown encouraging results in some laboratory and animal studies. 182 ,183 Advantages of this technique are that a maximum density of ionization can be focused onto a localized volume, and thus large-sized tumors and tumors adjacent to critical structures can be treated. This modality is being used in certain centers in the United States and other countries; the major disadvantages are limited availability and cost. Concerns about its use in humans have also been raised, with a study showing the use of radiation prior to enucleation actually adversely affecting survival,184 hypothesized to be the result of preexisting metastases. At present; therefore, the most common modality for treating medium-sized choroidal melanomas is radiotherapy, employing either radioactive iodine (P25) or ruthenium (Ru l06 ) plaques to the sclera over the base of the tumor. Transpupillary thermotherapy is an emerging modality for the treatment of small- to medium-sized tumors, pioneered by Shields and associates. 176, 177 Large tumors require enucleation except in the elderly, unfit, or monocular patients. For medium-sized tumors, distinguishing between benign and malignant lesions becomes important. Gener~l health, age, and vision in the opposite eye also have to be considered; a course of observation for growth may be justifiable in smaller tumors in older patients. In small tumors, differentiatingnevus from melanoma is important, and the ratio of height to base diameter is critical; pigmentation and secondary retinal detachlnents also playa role. Drusenoid appearance indicates chronicity and thus may point toward a benign, slow-growing tumor. In most patients, a period of observation is adequate. Medical evaluation in patients undergoing enucleation is important not only for assessing the general health of the patient but also in looking for second malignancies and to rule out metastases.

Complications Complications of partial resection of iris melanomas are metastatic spread, usually through the surgical wound from glaucoma filtration procedures,185-190 and after surgical and accidental trauma. The complications associated with enucleation include infection, bleeding, and extrusion or migration of the implant, as well as the psychological consequences of loss of one eye. This is especially severe for the asymptomatic patient. Similarly, the complications of radiation have been discussed elsewhere in this chapter. Interestingly, because of the observation that few patients have metastases from uveal melanoma noted at the time of initial presentation and before enucleation, some investigators have hypothesized that enucleation may potentiate the spread of metastases.191-19'1 Most surgeons have emphasized the use of techniques to minimize the possible spread due to enucleation, such as the "no

touch" technique 191 and maintaining normal intraocular pressure during surgery.192, 193

Prognosis Most melanocytic iris tumors behave in a benign fashion (unlike choroid and ciliary body melanomas 166, 195) and do not metastasize. Although the controversy as to whether iris lesions are inherently benign or not continues, most iris melanomas have a good prognosis unless metastatic spread134 , 185 or extraocular extension has occurred. 188 In malignant melanoma of the iris and ciliary body, overall mortality has been reported at 35% in 5 years and 50% in 10 years,196 with the prognosis depending on size (largest tumor diameter in contact with sclera), pigmentation, cell type, scleral extension, mitotic activity, location of anterior margin of the tumor and optic nerve extension,152 age at enucleation, height of tumor, and the integrity of Bruch's membrane. 153 The same studies identify a cutoff size of 10 mm as the most important marker, a size of 10 mm or less having a better prognosis than a size of more than 10 mm. The five leading predictors of survival in these studies were largest diameter of the tumor, epithelioid cells per high-power field, invasion to line of transection, location of anterior margin of the tumor, and degree of pigmentation.

Condusions Iris melanomas and choroidal ciliary melanomas represent two very different malignancies of the melanocytic stromal cells, which can masquerade as intraocular inflammation. Iris melanomas have a typically indolent course, whereas choroidal ciliary melanomas must be distinguished from other similar conditions, as the management and prognosis depend to a very large extent on accurate diagnosis.

Definition A retinoblastoma is a malignancy arising from the photoreceptor precursor cells of the retina. 197, 198 It is the commonest ocular tumor of childhood.

History The first report of retinoblastoma in medical or ophthalmic literature comes from the mid 18th century, when the case of a 3-year-old girl with bilateral ocular tumors was described. William Hey, in 1805, introduced the term fungus haematodes to describe retinoblastomas and other highly vascular, fungating tumors, but it was Wardrop, who, in his Observations on Fungus Haematodes or Soft Cancer, first brought together the scattered reports and descriptions of this tumor, identified its retinal origin, and distinguished it from "soft cancers" in general, on the basis of its occurring primarily in children. 199 Virchow20o coined the tenn retinal glioma, which persisted in the literature until it was recognized that the tumor arose from the neuroepithelial cells of the retina, when Verhoff, of the Massachusetts Eye and Ear Infirmary, named the tumor retinoblastoma. Retinoblastomas have been studied extensively as a part of molecular

CHAPTER 48: MASQUERADE SYNDROMES:

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genetics, and they have been vital to our understanding of how genes cause cancer.

Epidemiology The incidence of retinoblastoma is 1 in 20,000 infants and children. The vast majority of retinoblastomas present in children under 3 years of age-the tumor rarely presents in children over 5 years. 201 Around 40% of retinoblastomas are familial-that is, the mutation in the retinoblastoma gene is a germ-line Inutation that is transInitted from the parents, and· 60% are sporadic; however, not all familial cases have a positive fanlily history. Seventy percent of these tumors are unilateral and 30% bilateral, with familial cases typically presenting bilaterally. The familial cases are generally diagnosed earlier, many by screening examinations in infancy; bilateral cases are diagnosed at an average age of 15 months and unilateral cases at 24 months. 202

Clinical Characteristics The two most common modes of presentation are leukokoria and strabismus,203, 204 highlighting the need for a dilated fundus examination in all patients with strabisInus. A less common presentation is as intraocular inflammation 205 ; other uncommon presentations include secondary glaucoma, proptosis, and a pinealoblastoma. Because distant metastases tend to occur late, most patients present with local signs before distant Inetastasis. Intraocular inflammation may be true inflamlnation (i.e., an inflammatory response to necrosis of the tumor) or only simulated inflammation as tumor cells enter the anterior chamber and simulate anterior uveitis. Retinoblastoma can easily be confused with granulomatous uveitis of almost any cause, including tuberculous and syphilitic. 206 , 207 Weizenblatt207 reports a case of an 8-year-old boy, initially presenting with unilateral decreased vision, ciliary injection, balled and strand-like vitreous opacities, and a gray focus in the fundus, but with no retinal mass. The patient was initially diagnosed and managed as having uveitis, but on recurrence of symptoms, he was considered to have endophthalmitis and was evaluated for possible tuberculous, syphilitic, brucellaI', tularemic, and toxoplasmic etiologies. The diagnosis of retinoblastOlna was made only after the patient's death more than a year later. Ellsworth 205 reports a case of left esotropia at birth and a typical picture of granulomatous uveitis with vitreous haze that made examination of the fundus impossible, which later proved to be a retinoblastoma with massive involvement of the choroid. And Stafford and colleagues report a case series in which nearly 40% of patients with retinoblastoma had been initially misdiagnosed with uveitis. 208 Because delay in the diagnosis of this tumor is associated with spread and a high mortality, it is essential to consider and exclude retinoblastoma in any major disease in the eye of a child that precludes a view of the fundus. Among the uncommon presentations, secondary angle-closure glaucoma occurs as a result of mass effect closing the anterior angle. Proptosis, caused by growth of the tumor into the orbit, is a rare presentation in developed countries, but it is extremely common, and may

indeed be the most COlnmon, in developing countries. 209 Patients may also present with pinealoblastoma,210, 211 a retinoblastoma in the pineal body, although these generally occur at a stage when patients have already been diagnosed with retinoblastoma.

Pathophysiology, Pathology, Immunology The genetics of retinoblastoma have been of great interest to molecular biologists studying cancer. Human cells are known to carry two copies of the retinoblastoma gene (Rb) , a cancer suppressor or proto-oncogene, located on chromosome 13q14. According to Kn.udson's two-hit hypothesis, which has since been substantiated by considerable experimental evidence, both normal alleles of the Rb locus must be inactivated for retinoblastoma to develop. In familial cases, children are born with one normal and one defective copy of the Rb gene. The second copy is lost through some form of somatic mutation (point mutation, interstitial deletion of 13q14, or even cOlnplete loss of chromosome 13). Loss of both copies gives rise to retinoblastoma. Since the first Inutation is a germ-line mutation inherited from an affected parent, it is present in all cells of the body, whereas the second mutation (the second hit) occurs in a retinal precursor cell whose progeny then give rise to the retinoblastoma; this mutation is thus present only in cells of the tumor itself. In sporadic cases, both normal Rb genes are lost by somatic mutation in one of the retinoblasts. Thus the mutations are present only in the progeny of this retinoblast, which then form the tumor. Patients with familial retinoblastoma, who have a mutant copy of the gene in all cells of the body, are also at a greatly increased risk of developing osteosarcoma and some other soft tissue sarcomas. Interestingly, inactivation of the Rb locus has been observed in several other tumors, including adenocarcinoma of the breast, small cell carcinoma of the lung, and bladder cancer. Because of the familial nature of retinoblastoma, risk assessment becomes important for falnily members. This will be discussed later. Spread of the retinoblastoma may be direct (into the orbital tissues from the globe), via the optic nerve into the CSF, and hematogenously to the bone marrow. Distant metastases occur late in the course of the disease (Fig. 48-4).

Diagnosis Because a retinoblastoma is the most common intraocular malignancy of childhood, any patient with the presenting signs of leukokoria, strabismus, or uveitis must have this condition ruled out. The differential diagnosis of leukokoria includes persistent hyperplastic primary vitremIS, posterior cataract, retrolental fibroplasia, retinoblastoma, coloboma of choroid or optic disc, and uveitis. 212 As mentioned, around 40% of misdiagnosed cases of retinoblastOlna may initially be diagnosed as uveitis. 208 Other rare intraocular tumors of childhood (e.g., medul10epitheliOlna, and possibly optic gliomas) may also be diagnosed as retinoblastoma. These can generally be excluded by a thorough clinical history and examination,

s

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES

FIGURE 48-4. Flexner-Wintersteiner rosettes, which are characteristic of retinoblastoma. (Courtesy of Thadeus P. Dqja, MD.) (See color insert.)

although some patients may present a difficult diagnostic problem. In pediatric patients suspected of this malignancy or presenting with uveitis, a family history is vital, followed by a complete eye examination, including a visual acuity and dilated fundus examination. The fundus examination is usually carried out under general anesthesia, with careful documentation of the size al'id location of the tmllor on a large fundus drawing, which is essential for followup and planning radiation. Bone marrow aspiration and biopsy, and a lumbar puncture for cytocentrifuge examination, may also be performed under the same anesthesia, although the usefulness of such methods has recently been questioned. 213 Ancillary measures include CT of the orbit and head 214 which may lead to a diagnosis of pinealoblastoma215 but is of limited value in evaluating optic nerve involvement, because spread to the optic nerve is infiltrative and does not generally enlarge the nerve. It may, however, distinguish between an invading tumor and one merely impinging on the nerve. Occasionally, retinoblastoma calcifications may be visible on the CT scan and may help distinguish retinoblastoma from non-neoplastic conditions. 216 , 217 A bone scan may identify a bone metastasis, although it is not used regularly in aspllptomatic patients. 21s Reports show that MRI may help estimate differentiation in retinoblastomas. 219 Lactate dehydrogenase (LDH) levels in the aqueous humor may also be very helpful in a difficult differential diagnosis. 220 Elevated total LDH levels in the aqueous humor are very sensitive and fairly specific for retinoblastoma, although they must be interpreted with caution in patients with glaucoma or large numbers of histiocytes and neutrophils in the eye, and they may also be elevated in conditions such as Coats' disease. LDH isoenzYITIe patterns in the aqueous humor, and the ratio of aqueous humor to serum LDH are of doubtful value and probably not useful in establishing the diagnosis of retinoblastoma.221-234 Blood specimens must be obtained from the patient, parents, and siblings for DNA analysis for risk assessment.

Blood samples from affected individuals are used to identify the germ-line mutation in the Rb gene. Searching for this mutation in the parents and siblings of the patient helps assess the risk of retinoblastoma in the siblings and future siblings of,'the patient. In nonfamilial cases, the germ-line mutations are not present. However, even in familial cases it is sometimes not possible to identify the germ-line mutation by direct methods, and restriction fragment length polYITIorphisms (RFLP) or other DNA polymorphism analysis of two or more family members affected by the disease may be necessary. If the patient is the only individual affected by the disease, these RFLPs cannot be used, but risk is predicted by a study of whether the disease was unifocal or multifocal (which includes bilateral retinoblastoma, multifocal retinoblastoma, unifocal retinoblastoma with a related primary in the CNS, and unifocal retinoblastoma with a subsequent osteosarcoma) and a genetic analysis of cells obtained from the tumor. The risk of developing retinoblastoma in offspring and siblings of the patient is then calculated and forms the basis on which these at-risk individuals are followed, if necessary, with examination under anesthesia.

Treatment Ellsworth, in 1969, observed that in the treatment of retinoblastoma, "life is gambled for sight, "205 and this holds true even today with the targets for treatment being the complete control of malignancy and the preservation of useful vision. The most commonly used treatment in patients with good prognostic factors (Reese-Ellsworth criteria la, Ib, lIa, and lIb; Table 48-1) 205 is external beam radiation. Because of the numerous side effects of radiation on the normal tissue of the eye, a balance must be achieved between providing sufficiently high and extensive radiation for a realistic chance of eradicating the cancer, and minimizing the radiation exposure of normal tissue. External beam radiation therapy (EBRT), either through a Weiss 226 approach of a two-field plan (a classic split-field, an ipsilateral temporal field, and a more lightly weighted

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES TABLE 48-1. THE REESE-ELLSWORTH CRITERIA Ia b Ila b IlIa b IVa b Va b

Solitary tumor less than 4 dd or behind the equator Multiple tumors, none larger than 4 dd, all at or behind the equator Solitary tumor 4-10 dd, at or behind the equator Multiple tumors, 4-10 dd, at or behind the equator Any lesion anterior to the equator Solitary tumor larger than 10 dd behind the equator Multiple tumors, some larger than 10 dd Any lesion extending anteriorly to the ora serrata Massive tumor involving over half the retina Vitreous seeding

dd, disc diameter. From Ellsworth RM: The practical management of retinoblastoma. Trans Am Ophthalmol Soc 1969;67:463-534, with permission.

anterior field), or through Schipper's227, 228 or Harnett's229 contact lens treatment (with a temporal split-field photon approach), provides more exten~ive radiation; cobalt plaque approaches lead to more limited radiation exposure but are unsuitable for patients with significant vitreous seeding, two or more tumors, large (>10 mm) tumors, or tumors near or on the macula, since the potential for new tumor development or incomplete radiation of existing tumor exists. Follow-up of patients undergoing radiotherapy is important to observe and document regression of disease. This inCludes examination of the patient toward the end of radiotherapy, and a repeat examination under anesthesia at 6 weeks after radiotherapy, with documentation on large retinal drawings at each visit. Successful local control following radiotherapy is defined as a failure of the tumor to enlarge. However, there are a number of different patterns of response that the tumor can show: Type 1: Conversion of tumor to a lumpy, calcified mass-the "cottage cheese" appearance Type 2: Change from solid, pink, or opaque and vascular, to translucent, gray, and less vascular, the "fish-flesh" appearance Type 3: A combination of types 1 and 2 Type 4: Total loss of tumor, retina, and choroid, leaving bare sclera230 Larger tumors show types 1 or 3 and smaller ones types 2 or 3 patterns. Very small tumors may show a type 4 pattern. Larger tumors, however, tend not to change, or to shrink only slowly over time. As mentioned, failure to increase in size represents local success of radiotherapy. The second modality of treatment is enucleation. Enucleation should be considered in all eyes where there is no chance of preserving useful vision. 205 Indications include unfavorable Reese-Ellsworth (see Table 48_1)205 criteria, including tumors anterior to the ora serrata, especiallywith anterior segment invasion, total retinal detachment, and a posterior segment full of tumor. Relative indications include invasion of optic nerve by tumor 231 (it may be helpful to obtain a CT scan to decide whether the tumor is invading or merely impinging on the nerve), viable-looking vitreous seeds that are poorly responsive to radiation (as it is difficult to assess the viability of vitreous seeds by examination alone, attempts

to treat the eye with radiation may be made if the outcome of treatment with radiotherapy seems otherwise favorable in terms of visual rehabilitation). Following enucleation, pathologic examination of the obtained specimen is conducted to identify spread into the orbit or globe, which may require combined radiation and chemotherapy, or very rarely an exenteration. 232 Tumor cells are obtained and used for DNA analysis to help identify the mutations causing the tumor. At the time of enucleation, a long segment of the optic nerve should be obtained in an effort to ensure removal of any optic nerve invaded by tumor, and the nerve should be examined for evidence of tumor invasion. Photocoagulation and cryotherapy are other modalities of treatment. These are used primarily when the tumors are small, few in number, and remote from the disc and macula. 230 , 233, 234 They are used as second-line treatment for recurrences after EBRT, with photocoagulation used for more posterior and cryotherapy for more anteriorly located tumors. However, these techniques are not very successful when viable tumor masses have broken from the main tumor mass during EBRT, settled along the vitreous base, and continued to grow. Control in both these modalities (in contrast to control in radiotherapy) is defined as complete disappearance of the tumor, with formation of a flat scar. 235 This might take a few weeks to evolve, and both cryopexy and photocoagulation can be repeated if a response does not occur with the initial treatment. Photocoagulation involves using a laser to put a double row of burns around each tumor. Cryotherapy, performed trans-sclerally, involves three to four freeze-thaw cycles. Photoactive dyes have been used in conjunction with laser or electromagnetic energy in treatment, although clinical experience with this is still limited. The technique involves absorption of photoactive dyes by the tumor mass and therefore increased vulnerability to treatment with laser, 236 ultraviolet light, or visible light. 237 Long-term follow-up of patients is planned after the initial therapy. Examination under anesthesia is carried out every 3 months for 4 years, every 6 months for another 2 years, and then annually for an additional 2 years, when most children are old enough to tolerate annual peripheral retinal examinations without anesthesia. Regular ophthalmic screening appropriate for age is also conducted. These children must also be screened for secondary nonocular tumors associated with retinoblastoma. Siblings in whom the risk of the hereditary retinoblastoma gene cannot be excluded must also be followed up regularly. This usually takes the form of examinations under anesthesia every 3 months up to 4 years of age, and less frequently thereafter. The frequency of examinations can be altered in those with low risk (1 % to 5%), and eye examinations without anesthesia may be used in those with extremely low risk «0.1 %).

Prognosis Overall, in countries where adequate medical care facilities for early detection and treatment of this disease are available, the prognosis of retinoblastoma is good.238-242 More than 85% of children in developed countries have

CHAPTER 48: MASQUERADE SYN[JIRC)MIES: MALIGNANCIES

long-term survival following retinoblastoma. 202 , 243 In developing countries where such facilities are not readily available, the survival rate is poor. 209 Several prognostic indicators for retinoblastoma have been studied. The Reese-Ellsworth criteria (see Table 481), the present criteria of suitability for radiation using tumor control and vision preservation as end points, divide the tumor into different prognostic categories. Studies also show that local spread into the orbital tissues and the optic nerve 202 ,232, 244 decreases survival, although local spread is usually still quite controllable; survival of patients with optic nerve spread depends also on the extent of posterior involvement of the nerve. Massive choroidal involvement may also have some prognostic significance. 245 Although retrobulbar spread and spread outside the orbit was· traditionally considered fatal, the use of combined chemotherapy has resulted in long-term survival and apparent cure in some patients with bone marrow spread.239-242 Pinealoblastomas, on the other hand, have a very poor prognosis, being uniformly fatal. 210, 211 However, even if the retinoblastoma is survived, individuals with the 13q14 locus abnormalities in the germcell line (i.e., in hereditary retinoblastoma) have an increased risk of other malignancies, the commonest being osteosarcoma, followed by malignant melanoma. Other malignancies with a higher risk in these patients include soft tissue sarcomas, skin cancers, leukemias, lymphomas, and brain tumors-2% to 5% of these children develop tumors of the pineal region.246,~~52 Because about 67% of these tumors are in the radiation field,246 they have traditionally been considered radiation induced. However, these tumors also occur in patients who have not received radiation therapy,246 and it has been shown that although the irradiated group initiate second tumor development approximately 5 years earlier than the nonirradiated group, the frequency of second tumor development is approximately equal with or without radiation, and furthermore that the ultimate total risk of tumors in patients with hereditary retinoblastoma is extremely high regardless of radiation therapy.242 The extent of mortality from the second tumors is controversial, with various series reporting ranges from 59% of bilateral retinoblastoma patients dead by 35 years after diagnosis, to others with only 4% after 30 years. 2'18-251 This disparity may be the result of selection biases in the patient population.

Complications Radiotherapy can potentially be associated with a large variety of complications. These include cataract formation, retinal vasculitis, changes in irradiated tissue, and possibly, second malignancies. Cataract formation is ilnportant because, in a child, this almost always leads to amblyopia. 253 Temporal fields seem to protect against cataract formation,201 but the newer lateral field approaches, where there is an intersection of the lens and the anterior field edge, lead to increased cataract production. 254 However, the technique developed by Weiss and colleagues,226 Inentioned previously, minimizes the risk when properly conducted. Retinal vasculitis is another, dose-dependent, and potentially visually devastating consequence of radiation. It

is the commonest initial cause of vision loss in children treated with two or more full courses of EBRT to the entire retina. 201 Plaque approaches can also cause vascular damage, hemorrhage, and subsequent vitreous opacity.216,217 Effects of radiation on growing tissues include hypoplasia of temporal bone, above a threshold level of 2000 to 3500 cGy. These changes, however, if symmetrical, are not cosmetically disfiguring. This complication is markedly decreased in plaque therapy. Similarly, failure of eruption of molar teeth has been reported. Second tumor formation, as discussed previously, has classically been attributed to radiotherapy, but there is evidence that the risk of second tumors in patients with hereditary retinoblastoma is extremely high regardless of radiation use. These tumors are believed to occur when changes at both the 13q14 loci eliminate production of the tumor suppressor gene; these tumors also follow a two-hit pattern, with the first hit in extraocular tissues being the germ-line mutation, and the second hit being caused by some other mutagen, which could be radiation. Both alleles being inactivated in a nonocular tissue gives rise to a tumor of that tissue. The role of radiation in this complication may possibly be addressed in the future by more effective neoadjuvant chemotherapy followed by more local approaches including radiation. 238 , 242 However, the only hope for the elimination of such tumors lies in gene therapy that can reverse effects of the germline mutation.

Conclusion Retinoblastoma is a childhood malignancy that can masquerade as uveitis. Diagnosis is important because the tumor is curable if treated early and must be ruled out in all children with uveitis. Not only is it important to treat the index case but also to determine the familial nature of the disease and to counsel and follow-up relatives.

METASTASIS

Definition Metastatic disease is the commonest malignancy affecting the eye,255 and its incidence is growing as patients with systemic malignancies survive longer. Metastases to the eye were first reported by Horner in 1864,256 and they were initially believed to be uncommon. 257 , 258 But in the late 1900s, it came to be recognized that metastatic malignancies were more common than previously thought, with incidences among various groups of cancer patients ranging from 4.7% to 27%.257-259

Epidemiology Although ocular metastasis is rare for most cancers, its incidence is increasing as the survival time for cancers increases and as metastatic manifestations become more common and surveillance for them becomes more vigilant. Choroidal metastasis in patients dying of systemic malignancies range from 5% to 27%; this broad reported range probably reflects the variety of patients seen in any particular setting. In breast cancer patients with no ocular symptoms, for example, the incidence is 9.2%, whereas it

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES

is 27% in those with symptoms,260 and autopsy studies report even higher incidences (37% in patients dying of breast cancer,255 9.3% in patients dying of all types of cancers 261 ), probably reflecting the addition of cases with subclinical ocular metastasis. The most common primary cancers for ocular metastasis are the breast,262-266 the lungs,127, 263, 264, 267 and "unknown," in that order. However, breast cancer metastasizes to the eye late in its course, so that it is usually clinically evident elsewhere, either in the breast itself, or as lung or disseminated metastases 260 before ocular sYluptoms arise. The malignancies with the highest incidence of ocular presentation preceding extraocular detection are lung and renal cell carcinoma. The incidence of lung cancer metastatic to the eye is increasing as the incidence of this cancer increases, and lung metastases are now the commonest malignancies of the iris. 268 , 269 Metastases from cancers of the kidney and prostate and cutaneous melanoma are not uncoluluon. 127, 262, 263, 267, 270 Metastases from adenocystic cancer;Merkel's male breast cancer, and choriocarcinoma have also been reported.271-277 Clinical series on the incidence of ocular luetastases from different primary malignancies· tend to select for the less aggressive malignancies (e.g., breast), when the metastases have· had time to grow and manifest as ocular sYJ-llptoms, whereas autopsy studies have comparatively higher frequencies of the more aggressive malignancies, when death occurs before the ocular disease becomes clinically manifest. Interestingly, some malignancies are also associated with a higher incidence of primary choroidal cancers: The relationship between breast cancer and primary choroidal n1.elanoma has been well documented. 278 This, then, indicates the need to differentiate primary choroidal cancers from metastases in a patient with a systemic malignancy. The most frequent sites for ocular metastasis are the posterior choroid,263, 264 the· orbit, the iris, and the ciliary body,255, 264, 279 in that order. Metastases to the retina are rare and occur in less than 1 % of cases. 263 , 267

Clinical Characteristics The patient may be aSYJ-llptomatic. When symptoms are present, posterior segment sYJ-llptoms such as decreased visual acuity, floaters, and field defects are the ones most often reported. 263 Metamorphopsia, diplopia, red eye, ptosis, anisocoria, and exophthalmos are other presenting signs. 263 Pain may also occur, and this along with unexplained retinal detachment, glaucoma, neovascularization, and uveitis should alert the clinician to the possibility of metastatic cancer. 267 On examination, visual acuity is frequently decreased, but it may improve through refraction. 260 Slit-lamp examination and dilated funduscopic examination may disclose serous retinal detachment263 , 264 with a flat elevation of the retina and choroid. Choroidal metastases typically have an irregular outline, are yellow-gray to pink-white in color with edematous and detached overlying retina, are generally several disc diameters in size, and luay have overlying clumps of pigment. They are frequently multiple and bilatera12 60 (Fig. 48-5). Disc edema may also be present. Other possible findings include vitreous heluor-

FIGURE 48-5. Metastases to the choroid. Note the multiple lesions and irregular outline. Choroidal metastases are typically multiple, have an irregular outline, are yellow-gray to pink-white in color with edematous and detached overlying retina, are generally several disc diameters in size, and may have overlying clumps of pigment. (See color insert.)

rhage, increased intraocular pressure, and anterior and posterior uveitis. Posterior uveitis in metastatic malignant masquerade has been reported to present as clumps of pigmented or nonpigmented cells on vitreous strands, which may partially obscure the view of the retina and which are discovered to be refractory to steroid treatment. An anterior segment presentation is less common, but patients may have sYJ-llptoms of blurred vision, red eye, photophobia, pain, and (occasionally) spontaneous hyphema. Patients are reported to have iritis or anterior uveitis (in nearly half), secondary glaucoma28o (in around two thirds), and a mass lesion of the iris (60%),279 which is most commonly an inferiorly situated gray-white or pink nodule, although infiltrative lesions may also be present. Typical presentations include mild nongranulomatous anterior uveitis with associated increase in intraocular pressure, refractory to steroid treatment, or recur'"' rent after the treatment is stopped. 281 Anterior segment presentations are typically associated with tumor location in the anterior segment of the eye,262 and gonioscopy is an obviously important diagnostic step in such cases. Despite careful examination, however, no visible lesion may be detected in the eye. Denslow and Kielar, for example, reported a case in which no obvious lesions were identified in the eye, nor could a primary malignancy be found, although bone metastasis occurred later in the course of the disease. 281

Pathophysiology, Pathology, and Immunology Spread of tumors to the eye is via the hematogenous route, most commonly through the pulmonary circulation and then via the carotids into the ciliary arteries, and thence to the choroid. This explains the high incidence of lung metastasis (up to 85%) in people with metastatic ocular malignancy.127 The origin of the left common carotid artery directly from the aorta has been suggested as an explanation for the preponderance of

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES

lesions in left eyes reported by some 255 , 259, 262, 264, 265, 267, 282-285 but not others, and the distribution of ciliary arteries is sometimes used to explain why these lesions are more frequent at the posterior pole and temporally, where there is a greater density of these blood vessels. Some tumor cells may, however, bypass the lungs and reach the eye via Batson's vertebral plexus of veins, or they may simply be too small to be filtered out by the pulmonary blood vessels. This has been suggested as an explanation for the absence of lung metastasis of the primary cancer in about 15% of cases.

misdiagnosis), whereas metastatic tumors can give a wide variety of signals.292-294 MRI is also clearly helpful for the evaluation of the brain for metastatic lesions. 293 For iris lesions, anterior chamber tap and cytology have been suggested for diagnosis in difficult cases. 286 , 295 Cytologic features of the cells obtained by this method may help distinguish between metastatic and melanotic nodules and also provide clues about the origin of the primary tumor in the case of iris metastases with an occult primary. Direct ciliary body lesion biopsy has also been reported and found to be diagnostic in a case of carcinoid tumor metastatic to the iris. 296

Diagnosis

At the same time, if metastases are suspected in the absence of a known primary, the patient is also evaluated for the primary tumor. Elevated carcinoembryonic antigen (CEA) levels also suggest metastases when a primary tumor has not been identified,281, 297 but CEA is a nonspecific marker of malignancy. CEA and galnma-glutamyltranspeptidase levels may be used adjunctively to distinguish metastasis from amelanotic melanomas. 298

The major differential diagnosis in these patients is that of primary uveal melanoma. The distinction is ilnportant as the two conditions are managed differently and carry very different prognoses. Other major differential diagnoses of choroidal metastases are rhegmatogenous retinal detachment and choroidal granulomas. Differentiation of metastatic ocular malignancy from primary uveal melanoma is based on the characteristic clinical findings of flat, infiltrative choroidal lesions with large overlying retinal detachments in metastatic disease, which may be multifocal and biiateraP60 There is a history of malignancy in many cases, and this is clearly very helpful in the clinical differentiation process. Diffuse choroidal infiltration and vitreous seeding with no obvious choroidal mass has also been described in malignant skin Inelanoma metastatic to the eye. 286 ,287 Prilnary uveal melanomas, by contrast, are characteristically described as bulky growths with a collar-button appearance, as they rupture through the Bruch's membrane and are associated with small retinal detachments, although this is not always the case. They are generally unilateral, single lesions and have only a weak association with other malignancies (e.g., breast cancer). Serial funduscopic examinations usually show a more rapid growth in the case of Inetastasis. Amelanotic uveal melanomas may present a difficult differential diagnostic challenge and, while additional studies may provide clues, the clinical examination including indirect ophthalmoscopy usually provides the most reliable means of distinguishing these tumors from choroidal metastases. 154 The iris, in metastatic disease, may show prominent vascularity. Choroidal metastases exhibit early blockage of the choroidal blood flow on fluorescein angiography, with late staining of and leakage· from these vessels. Fluorescein angiography of iris metastases shows extensive leakage of the iris vessels. 288 Ultrasonography shows prominent acoustic brightness with moderate to high internal reflectivity, compared to the characteristic findings of choroidal melanomas on ultrasonography, described previously in this chapter. In the case of effusions and detachments, the metastatic lesions can be difficult to see, and therefore ultrasonography can be extremely valuable in helping to establish the diagnosis. 280 MRI can also be useful in differentiating metastases from uveal melanomas.289-291 Uveal melanomas have been described as having a characteristic MRI appearance with a high signal intensity resulting from short T1 relaxation times, (although this is not always the case and clinical correlation of the MRI findings is always essential to avoid

Treatment By far the most common treatment in patients with ocular metastatic disease is radiotherapy. The patients have metastatic (and therefore often end-stage) disease, so radiation is used for palliation and to improve vision and quality of life; most stLldies report around a 90% success rate with radiation in achieving stabilization of vision and improved quality of life. 260 , 299-305 Radiation is also used when the lesions are causing retinal detachment, or when they are rapidly enlarging despite the fact that the patient is on systemic chemotherapy.260 Enucleation is indicated when metastases are suspected but primary uveal melanoma cannot be excluded (although this is rare and eye-saving measures such as needle biopsy of choroidal lesions has been reported 3(6 ); in the case of low-grade malignancies and solitary metastasis to the eye, when excision of the primary malignancy and the solitary metastasis may effect a cure 264 ,307, 308 (this may occur with carcinoid tumors or, occasionally, with renal cell carcinomas 3(9 ); and for a blind and intractably painful eye when enucleation may improve the quality oflife. Rarely, in anterior uveal disease, local excision is useful as an eye-preserving measure. When vision is not being threatened, systemic therapy and observation are usually sufficient.277, 310

Complications Complications of radiotherapy include madarosis, radiation-induced cataract, keratoconjunctivitis, and radiation retinopathy. These were discussed in some detail in the earlier section on retinoblastoma. However, many patients do not survive long enough to experience the full force of these side effects.

Prognosis The prognosis for patients with metastatic ocular disease is poor (overall survival of 6 to 12 months 262 ), as Inetastasis represents disseminated cancer but differs for various primary tumors and with location within the eye. Longterm survival of patients with solitary carcinoid tumor metastatic to the eye has been reported. 307, 308, 311 Breast cancer tends to metastasize late in its course, whereas

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES

lung cancer metastasizes early. Cutaneous melanOlnas also tend to metastasize to the eye later, and in association with widespread metastasis,286, 287, 311-313 and therefore they have one of the worst prognoses.

Conclusion Metastatic malignancy to the eye can masquerade as uveitis, and the uveitic masquerade may be the first presenting sign of an occult malignancy. Thus metastases must be considered, especially in the older patient presenting with uveitis refractory to or recurring after steroid therapy. Although the prognosis is poor, as metastatic disease is generally associated with advanced, pre-terminal primary cancers, the importance of malting this diagnosis'lies in the fact that, with early recognition, a considerable amount can be done to improve the quality of life in these patients.

PARANEOPlASTIC SYNDROMES

Definition In patients with cancer, symptom complexes that cannot be readily explained, either by local or distant spread of the tumor or by elaboration of hormones indigenous to the tissue from which the malignancy arose, are called paraneoplastic syndromes. A number of different malignancies produce paraneoplastic syndromes with involvement of neuronal tissue-the cerebellum, the anterior horn cells, and the sensory root ganglia to name just a few-and in many of these, the pathogenic factor is the presence of antibodies to CNS antigens. Similarly, paraneoplastic neuronal degeneration of the retinal photoreceptor cells causing both rod and cone dysfunction, and associated with antibodies to certain retinal elements, has been described as cancer-associated retinopathy (CAR). Melanoma-associated retinopathy (MAR) syndrome is another visual paraneoplastic condition. MAR is very similar to CAR, but it is associated with metastases from cutaneous melanomas and with certain distinguishing clinical features. Bilateral diffuse uveal melanocytic proliferation is a recently described paraneoplastic entity characterized by a bilateral, diffuse proliferation of melanocytic cells throughout the uvea in association with a systemic malignant neoplasm.

History CAR was first described by Sawyer and associates in 1976314 in a case series of three patients with small cell carcinoma of tlie lung. These three older patients had vision loss with symptoms before the diagnosis of cancer, early visual field defects of ringlike scotomas, and retinal arteriolar narrowing. Histopathologic examination in these cases revealed widespread, severe degeneration of the outer retinal layers and mild melanophagic activity. In 1982, Kornguth and associates315 published the first report demonstrating antiretinal ganglion cell antibodies in patients with small cell carcinoma of the lung. In 1987, Thirkill and associates 316 reported the isolation of the 23kD CAR retinal antigen, and in 1992 they identified it as the photoreceptor componentrecoverin. 317 Since then, it has been recognized that malignancies other than pulmonary small cell carcinoma, and retinal proteins other than recoverin can be associated with the CAR syndrome.

Epidemiology CAR seems to be equally common in men and women; in a summary of 28 patients with CAR,318 16 were men and 12 were women. The patients are generally older adults, the same summary reporting an age range between 37 and 76 years, with 22 of 28 patients being 60 years or older. Many patients with CAR are slllokers, and this is consistent with the preponderance of patients having pulmonary small cell cancer. Thirkill and colleagues,319 for example, in a series of 10 patients, identify all as heavy smokers. The most common malignancy associated with CAR is small cell cancer of the lung, seen in about 60% of the cases; however, non-small cell pulmonary cancer, endometrial carcinoma, breast adenocarcinoma, cervical small cell carcinoma, embryonal rhabdomyosarcoma, and melanoma318 have also been reported to be associated with CAR.

Clinical Characteristics Characteristically, patients present with fairly rapid, unexplained vision loss occurring over several weeks to months and often associated with photopsias, night blindness, positive transient visual phenomena, and visual field disturbances. The vision loss frequently precedes the diagno~ sis of a systemic malignancy, tliUS making diagnosis of CAR less apparent. The time reported between onset of visual symptoms and the diagnosis of cancer varies from a few weeks to several months. 316, 318, 320 Gehrs and Tied.. man, for example, report an interval of 18 months in one of their patients. 32o Vision loss is often asymmetric; the presenting visual acuity may range from 20/20 to light perception. 319 Some people report frank nyctalopia, whereas others report glare and photosensitivity, possibly reflecting differences in the relative involvement of rods or cones. Color vision loss may be present at the time of presentation or may develop over the course of tlie disease. Transient, painless visual obscurations, including dimming of central vision and loss of peripheral vision, may last from seconds to minutes. Bizarre visual phenomena, such as halos, "floating tissue paper"314 in the eye, "swarms of bees" over the central vision,314 and "shimmering curtains" have been reported. Visual field changes characteristically show initial midperipheral scotomas that eventually lead to classic ring scotomas 321 with central sparing,319 although there are many variations on this pattern, and central defects may also occur. Arcuate defects, because they result from damage to the outer retina, do not respect the horizontal meridian. 318 These changes may be asymmetrical between the two eyes,319 and diagnosis of the condition can easily be missed if visual-field testing is not done. The slit-lamp examination is usually norma1.3 21 However, there are several reports of patients having vitritis in association with this condition. Thirkill and associates, for example, report vitreous cells in seven of a series of eight patients. 319 Although the vitreous reaction is very often mild, this case series included patients with heavy debris, 2 + cells, and peripheral vitreous clumps of cells. Ohkawa and associates 322 report a case with mild bilateral iridocyclitis and vitritis with retinopatliy characterized by a mot-

s

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES

tled RPE pattern, narrowed arterioles, and several spots of hyperpigmentation. In the CAR syndrome, the fundus can appear remarkably normal in the early stages of the disease, although subtle arteriolar narrowing is characteristic 321 and disc pallor mayor may not be present. 321 Although mottling of the RPE has been described, the appearance of the fundus may be completely normal,319 thus making diagnosis of the disease even more difficult.

Pathology Histopathologic study of the eyes in these cases reveals widespread, severe degeneration of the outer retinal layers, and mild melanophagocytic activity. There is "severe disintegration of the photoreceptors, marked loss of nuclei from the outer nuclear layer, and macrophages containing phagocytosed granules from the RPE," with almost complete preservation of the other layers of the retina. 314 There may be variation on this basic pattern, with sparing of cones being reported on the histopathologic examination of the eyes of patients with primarily rod dysfunction clinically and on electroretinography (ERG). Clearly, then, it seems that specific cells in the retina are being targeted in this condition. The most well-accepted mechanism for the pathogenesis of the CAR syndrome involves autoimmunity to components of the retinal photoreceptors. The most wellrecognized antigen to which an autoimmune reaction is produced in CAR, especially in association with small cell carcinoma of the lung, is the 234.D antigen recoverin, which is a component of the photoreceptor cells. Experimental evidence suggests that there is aberrant expression of recoverin in pulmonary small cell carcinoma, which results in sensitization to this photoreceptor component. 323 Retinal proteins other than the 23-kD antigen have also been implicated in CAR, including 40-kD, 45kD, and 60-kD proteins, none of which have been cloned to provide the exact protein sequence of the retinal antigen involved. 324

Diagnosis The diagnosis can be difficult, especially when the ocular presentation occurs before the systemic neoplastic process has been discovered. Jacobson and associates321 have described a characteristic triad of photosensitivity, ring scotomas, and attenuation of retinal arteriolar caliber. These, together with the other features described, especially when they occur in the older patient and when abnormalities on the examination of the eye are inconsistent with the degree of symptomatic disability of the patient, should raise the suspicion of CAR. The ERG pattern can be extremely sensitive in making the diagnosis of CAR, showing reduced amplitudes or being totally flat in these patients; progression of the disease may be associated with progressive reductions in ERG amplitudes. 319 On the other hand, visual acuity may be normal in the presence of a flat ERG, indicating severe retinal dysfunction with relative macular sparing. The relative rod and cone dysfunction in CAR varies from patient to patient: Patients with clinical problems associated with rod dysfunction (e.g., nyctalopia, prolonged dark adaptation, and peripheral or ring scotomas) show

an abnormal scotopic ERG, whereas those with clinical features suggestive of cone dysfunction (e.g., glare and photosensitivity, decreased acuity, and dyschromatopsia) show a typically abnormal cone ERG.319 Immunohistochemical testing is also required in these patients, to identify the presence of the antiretinal antibodies. In any patients suspected of having CAR, and with no known malignancy, a search for the systemic malignancy must also be undertaken. Before making the diagnosis of CAR, metastatic involvement of the eye, optic nerve compression, and chemotherapy-induced toxicity need to be excluded. MAR differs from CAR in that it usually occurs in individuals who have an established diagnosis of cutaneous melanoma, and it is usually found to be associated with metastases. Although cases have been reported in which MAR occurred in the absence of any obvious metastasis after extensive evaluation,325 caution is advised in declaring such patients metastases free, since an occult metastasis may well become apparent later. MAR patients are typically men, presenting with shimmering, flickering, or pulsating photopsias, with progressive visual loss over months. Progression of symptoms, although reported, appears to be uncommon. The primary manifestation in MAR is a central visual field defect, with relative sparing of the peripheral visual fields, and ERGs show a characteristic pattern (similar to congenital stationary night blindness) with a markedly reduced bwave in the presence of a normal dark-adapted a-wave. 326 Such a pattern localizes the pathology to the inner retinal plexes rather than the photoreceptors. Indeed, MAR is not associated with recoverin hypersensitivity, and since it commonly develops long after the primary cancer is discovered, it is thought to involve a different mechanism. Studies have shown the presence of immunoglobulins that react selectively with the bipolar ,cells of the retina. 327 Identification of MAR is important, as it could be the first sign of metastases in a patient with a seemingly stable or cured condition. Bilateral diffuse uveal melanocytic proliferation is another condition that frequently presents with visual symptoms prior to the diagnosis of the, systemic malignancy. Dilated episcleral vessels, early maturation of cataracts, and moderate vitritis have been described as typical ocular features, with proliferation of choroidal nevus-like lesions, and the presence of round, yellow-orange lesions at the level of the RPE, associated with serous macular detachment. Fluorescein angiography shows numerous window defects of the RPE at the posterior pole. Histopathologic examination shows choroidal thickening with proliferation of benign-looking, spindle-shaped melanocytes. This condition should be suspected 'in patients with multiple, bilateral uveal nevi, with serous retinal detachment, vitritis, and cataracts. Diagnosis is important as it could lead to the early detection and therefore improved prognosis of a malignancy.

Treatment Several treatment modalities have been tried with inconsistent results. Treatment is based on the premise that CAR is an autoimmune condition, and therefore immunosuppressive therapies are the mainstay of treatment.

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES

Prednisone, plasmapheresis, and intravenous immunoglobulin have been used, with the antiretinal antibody titers used to monitor treatment. 327 It has been suggested that if antibody titers do not fall to baseline with a particular immunosuppressive agent, changing to other immunosuppressive measures may be necessary. The treatment for patients with the MAR syndrome IS similar to that of CAR.

Prognosis The visual prognosis of paraneoplastic retinopathies, both CAR and MAR, is generally poor, with different treatment modalities showing inconsistent results. Patients may show no response even on plasmapheresis, presumably because once retinal structures have been irreversibly damaged, immunosuppressive therapy will not reverse the change. However, there have been reports of both CAR and MAR patients who have improved with treatment,327 and of CAR patients who failed a trial of prednisone and plasmapheresis but responded dramatically to intravenous immunoglobulin. 328

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249. Del' Kinderen DJ, KotenJW, Wolterbeck R, et al: Nonocular cancer in hereditary retinoblastoma survivors and relatives. Ophthalmic Pediatr Genet 1987;8:23-25. 250. Draper GJ, Sanders BM, Kingston JE: Second primary neoplasms in patients with retinoblastoma. BrJ OphthalmoI1986;53:661-671. 251. Lueder GT,Judisch GF, O'Gorman TW: Second monocular tumors in survivors of hereditary retinoblastoma. Arch Ophthalmol 1986;104:372-373. 252. Schifter S, Vendelgo L, Jensen OM, Kaae S: Ewing's tumor following bilateral retinoblastoma. Cancer 1983;51:1746-1749. 253. Traboulski EI, Zimmerman L, Manz HJ: Cutaneous malignant melanoma in survivors of hereditable retinoblastoma. Arch Ophthalmol 1988;106:1059-1061. 254. Pesin SR, Shields JA: Seven cases of tlilateral retinoblastoma. Am J Ophthalmol 1989;107:121-126. 255. Bloch RS, Gartner S: The incidence of ocular metastatic carcinoma. Arch Ophthalmol 1971;85:673. 256. Horner F: Carcinoma del' Dura Mater Exophthaimus. Klin Monatsbl Augenheilkd 1864;2:186. 257. Duke-Elder S, ed: System of Ophthalmology, vol 9. Disease of the Uveal Tract. St Louis, CV Mosby, 1966, p 917. 258. Godtfredsen E: On the frequency of secondary carcinoma of the choroid. Acta Ophthalmol 1944;22:394. 259. Albert DM, Rubenstein RA, Scheie HG: Tumor metastases to the eye. Part 1. Incidence in 213 patients with generalized malignancy. AmJ Ophthalmol 1967;63:723. 260. Mewis L, Young SE: Breast carcinoma metastatic to the choroid: Analysis of 67 patients. Ophthalmology 1982;89:147. 261. Nelson CC, Hertzberg BS, Klintworth GK: A histopathologic study of 716 eyes in patients with cancer at the time of death. Am ] OphthalmoI1983;95:788. 262. Ferry AP, Font RL: Carcinoma metastatic to the eye and orbit. 1. A clinicopathologic study of 227 cases. Arch Ophthalmol 1974;92:276. 263. Freedman ML, Folk JC: Metastatic tumors to the eye and orbit: Patient survival and clinical characteristics. Arch Ophthalmol 1987;105:121. 264. Stephens RF, Shields JA: Diagnosis and management of cancer metastatic to the uvea: A study of 70 cases. Ophthalmology 1979;86:1336. 265. Hart WM: Metastatic carcinoma to the eye and orbit. Int Ophthalmol Clin 1962;2:465. 266. Reese AG: Tumors of the Eye, 2nd ed. New York, Hoeber, 1963. 267. Castro PA, Albert DM, Wang "'Cf, Ni C: Tumors metastatic to the eye and adnexa. Int Ophthalmol Clin 1982;22:189. 268. Sanders TE: Metastatic carcinoma of the iris. Am J Ophthalmol 1938;21:646. 269. Green WR: The uveal tract. In: Spencer WH, ed: Ophthalmic Pathology: An Atlas and Textbook, 3rd ed, vol 3. Philadelphia, W.B. Saunders, 1985, pp 1352-2140. 270. Boldt HC, Nerrad JA: Orbital metastases from prostate carcinoma. Arch Ophthalmol 1988;106:1403. 271. Guttmann SM, WeissJS, Albert DM: Choroidal metastases of adenocystic carcinoma of the salivary gland. Br J Ophthalmol 1986;70:100. 272. Small KW, Rosenwasser GO, Alexander EA III, et al: Presumed choroidal metastasis of Merkel cell carcinoma. Ann Ophthalmol 1990;22:187. 273. Mooy CM, de Jong PTVM, Verbeek AM: Choroidal metastases of oesophageal squamous cell carcinoma. Int Ophthalmol 1990; 14:63. 274. Scilletta B, Racalbuto A, Russello D, et al: Carcinoma of the male breast and ocular metastases. Ital J Surg Sci 1989;19:93. 275. Schlaen ND, Naves AE: Orbital and choroidal metastases from carcinoma of the male breast. Arch Ophthalmol 1986;104:1344. 276. Kurosawa A, Sawaguchi S: Iris metastasis from squamous cell carcinoma of the uterine cervix. Arch Ophthalmol 1987;105:618. 277. Barondes MJ, Hamilton AM, Hungerford J, et al: Treatment of choroidal metastasis from choriocarcinoma. Arch Ophthalmol 1989;107:796. 278. Henkind P, Roth MS: Breast carcinoma and concurrent uveal melanoma. AmJ Ophthalmol 1971;71:198. 279. Ferry AP, Font RL: Carcinoma metastatic to the eye and orbit. II. A clinicopathological study of 26 patients with carcinoma metastatic to the anterior segment of the eye. Arch Ophthalmol 1975;93:472.

CHAPTER 48: MASQUERADE SYNDROMES: MALIGNANCIES 280. Sneed SR, Byrne SF, Mieler WF, et al: Choroidal detachment associated with malignant choroidal tumors. Ophthalmology 1991;98:963. 281. Denslow GT, Kielar RA: Metastatic adenocarcinoma to the anterior uvea and increased carcinoembryonic antigen levels. Am J Ophthalmol 1978;85:363. 282. Jensen OA: Metastatic tumors to the eye and orbit. A histopathological analysis of a Danish series. ActaPathol Microbiol Scand 1970;212:201. 283. Albert DM, Rubenstein RA, Scheie HG: Tumor metastasis to the eye. Part II. Clinical study in infants and children. Am J Ophthalmol 1967;63:727. 284. Goldberg RA, Rootman J, Cline RA: Tumors metastatic to the orbit: A changing picture. Surv Ophthalmol 1990;35:1. 285. Hutchison DS, Smith TR: Ocular and orbital metastatic carcinoma. Ann Ophthalmol 1979;11:869. 286. Char DH, Schwartz A, Miller TR, et al: Ocular metastases from systemic melanoma. AmJ Ophthalmol 1980;90:702. 287. Fishman ML, Tomaszewski MM, Kuwabara T: Malignant melanoma of the skin metastatic to the eye. Arch Ophthalmol 1976;94:1309. 288. Freeman TR, Friedman AH: Metastatic carcinoma of the iris. Am J OphthalmoI1975;80:947. 289. Peyman GA, Matee MF: Uveal melanoma and similar lesions: The role of magnetic resonance imaging and computed tomography. Radiat Clin North Am 1987;25:471. 290. Peyster RG, Shapiro MD, Haik BG: Orbital metastases: Role of magnetic resonance imaging and computed tomography. Radiat Clin North Am 1987;25:647. 291. Raymond WR N, Char DH, Norman D: Magnetic resonance imaging evaluation of uveal tumors. AmJ OphthalmoI1991;111:633. 292. Mafee MF, Peyman GA, Peace JH, et al: Magnetic resonance imaging in the evaluation and differentiation of uveal melanoma. Ophthalmology 1987;94:341. 293. Haik BG, Saint Louis L, Smith ME, et al: Magnetic resonance imaging in choroidal tumors. Ann Ophthalmol 1987;19:218. 294. Liu KR, Peyman GA, Mafee M~ et al: False positive magnetic resonance imaging of a choroidal nevus simulating a choroidal melanoma. Int Ophthalmol 1989;13:265. 295. Scholz R, Green WR, Baranano EC, et al: Metastatic carcinoma of the iris. Diagnosis by aqueous paracentesis and response to irradiation and chemotherapy. Ophthalmology 1983;90:1524. 296. Bardenstein DS, Char DH, Jones C, et al: Metastatic ciliary body carcinoid tumor. Arch Ophthalmol 1990;108:1590. 297. Denslow GT, Kielar RA: Metastatic adenocarcinoma to the anterior uvea and elevated CEA levels. Cancer 1978;42:1504. 298. Michelson JB, Felberg NT, Shields JA: Evaluation of metastatic cancer to the eye. Carcinoembryonic antigen and gamma glutamyl transpeptidase. Arch Ophthalmol 1977;95:692. 299. Bradly LW, Shields JA, Augsberger lJ, et al: Malignant tumors of the eye. In: Mansfield CM, ed: Therapeutic Radiology, 2nd ed. New York, Elsevier, 1989. 300. Maor M, Chan RC, Young SE: Radiotherapy of choroidal metastases. Breast cancer as primary site. Cancer 1977;40:2081. 301. Dobrowsky W: Treatment of choroidal metastases. Br J Radiat 1988;61:140. 302. Minatel E, Forber L, Trovo MG, et al: The efficacy of radiotherapy in the treatment of intraocular metastases. Rays (Roma) 1988; 13:95. 303. Orenstein M, Anderson D, Stein J: Choroidal metastases. Cancer 1972;29:1101. 304. Reddy S, Saxena VS, Hendrickson F, et al: Malignant metastatic disease of the eye: Management of an uncommon complication. Cancer 1981;47:810.

305. Brady LW, Shields JA, Augsburger lJ, et al: Malignant intraocular tumors. Cancer 1982;49:578. . 306. Augsburger lJ: Fine needle aspiration of suspected metastatic cancers to the posterior uvea. Trans Am Ophthalmol Soc 1988;86:499. 307. Bell RlVI, BullockJD, Albert DM: Solitary choroidal metastasis from bronchial carcinoid. BrJ Ophthalmol 1975;59:155. 308. Rodrigues MM, Shields JA: Iris metastasis from a bronchial carcinoid tumor. Arch Ophthalmol 1978;96:77. 309. Kindermann "VR, Shields JA, Eiferman RA, et al: Metastatic renal cell carcinoma to the eye and adnexa. A report of three cases and review of the literature. Ophthalmology 1981;88:1347. 310. SierockiJS, Norman CC, Schafrank M, et al: Carcinoma metastatic to the anterior ocular segment: Response to chemotherapy. Cancer 1980;45:2521. 311. Font RL, Kaufer G, Winstanley RA: Metastases of bronchial carCinoid to the eye. AmJ Ophthalmol 1966;62:723. 312. Shields JA, Shields CL, Shakin EP, et al: Metastasis of choroidal melanoma to the contralateral choroid, orbit and eyelid. Br J OphthalmoI1988;72:456. 313. Orcutt JC, Char DH: Melanoma metastatic to the orbit. Ophthalmology 1988;95:1033. 314. Sawyer RA, Selhorst JB, Zimmerman LE, et al: Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Ophthalmol 1976;81:606-613. 315. Kornguth SE, Klein R, Appen R, Choate J: Occurrence of antiretinal ganglion cell antibodies in patients with small cell carcinoma of the lung. Cancer 1982;50;1289-1293. 316. Thirkill CE, Roth AM, Keltner JL: Cancer associated retinopathy. Arch Ophthalmol 1987;105:372-375. 317. Thirkill CE, Tait RC, Tyler NK, et al: The cancer-associated retinopathy antigen is a recoverin-like protein. Invest Ophthalmol Vis Sci 1992;33;2768-2772. 318. Rizzo JF, Volpe.J\U: Cancer associated retinopathy. In: Pepose JS, Holland GN, Wilhelmus KR, eds. Ocular Infection and Immunity. St Louis, Mosby, 1996, pp 585-599. 319. Thirkill CE, Keltner JL, Tyler NK, Roth AM: Antibody reactions with retina and cancer-associated antigens in 10 patients with cancer associated retinopathy. Arch Ophthalmol 1993;111:931937. 320. Gehrs K, TiedmanJ: Hemeralopia in an older adult. Surv Ophthalmol 1992;37:185-189. 321. Jacobson DM, Thirkill CE, Tipping SJ: A clinical triad to diagnose paraneoplastic retinopathy. Ann Neurol 1990;28:162-167. 322. Ohkawa T, Kawashima H, Makino S, et al: Cancer associated retinopathy in a patient with endometrial cancer. Am J Ophthalmol 1996;122:740-742. 323. Klenchin VA, Kalvert PD, Mounds MD: Inhibition of rhodopsin kinase by recoverin. A further evidence for a negative feedback system in phototransduction. J BioI Chem 1995;270:16147-16152. 324. Murphy MA, Thirkill CE, Hart WlVI: Paraneoplastic retinopathy: A novel autoantibody reaction associated with small cell lung carcinoma. J Neuroophthalmol 1996;17:77-83. 325. Thirkill CE, Keltner JL: Commonality and diversity in melanomaassociated retinopathy (MAR). ARVO abstracts. Invest Ophthalmol Vis Sci 1998;39(suppl 4) :S363. 326. KeltnerJL, Thirkill CE: Cancer-associated retinopathy vs recoverinassociated retinopathy. Arch Ophthalmol 1993;111:931-937. 327. Weinstein JM, Kelman SE, Bresnick GH, Kornguth SE: Paraneoplastic retinopathy associated with antiretinal bipolar cell antibodies in cutaneous malignant melanoma. Ophthalmology 1994;101: 1236-1243. 328. Guy J, Aptsiauri N: IVIg protocol: Reversal of carcinoma-associated retinopathy (CAR) induced blindness with IVlg. Neurology 1997;48(suppl) :A329-A330.

c.

Michael Samson and C. Stephen Foster

Intraocular inflammations due to infections are among the most challenging entities capable of masquerading as autoimmune uveitis. Clues implicating infectious microbes can be subtle or absent. And unlike the other masquerade syndromes, initiating treatment with corticosteroids or immunomodulators in this class of disorders can result in devastating consequences. Two forms of endophthalmitis can masquerade as noninfectious inflammation: chronic postoperative endophthalmitis and endogenous endophthalmitis. The other forms, acute postoperative endophthalmitis and traumatic endophthalmitis, are mote easily recognized and rarely pose the diagnostic dilemma often associated with the aforementioned forms. This chapter addresses the characteristics of chronic postoperative and endogenous endophthalmitis, and the approach to their management.

CHRONIC POSTOPERATIVE ENDOPHTHAlMITIS

Definition Chronic postoperative endophthalnntis is a clinical syndrome characterized by recurrent episodes of low-grade inflammation secondary to microbes introduced into the eye during intraocular surgery. Some authors distinguish this syndrome from acute postoperative endophthalmitis by assigning a specific time of onset: inflammation beginning more than 1 month after surgery is defined as the chronic form, whereas inflammation beginning less than 1 month after surgery is considered acute. 1, 2 However, this is a potential source of confusion, since no single cutoff time can reliably differentiate between the two forms, which are strikingly different clinical entities. More potential confusion can result from the term delayed-onset endophthalmitis being used synonymously with chronic postoperative endophthahnitis. I Although it is technically accurate, other authors have used delayed onset to describe cases of postoperative endophthalmitis that occur 8 days to 2 weeks after surgery that clinically resemble the more explosive acute form. 3 To the authors' knowledge, there is no consensus on the appropriate use of these terms. Table 49-1 displays our proposed use of these three terms based more on clinical presentation and less on arbitrarily assigned times of onset. For the purpose of this book, the definition of chronic postoperative endophthalmitis is as displayed in this table.

History The term chronic postoperative endophthalmitis was first used by Roussel and colleagues in a report describing two cases of endophthalmitis due to Propionibacterium acnes. 4 The first report implicating microbes as a cause of chronic postoperative intraocular inflammation was the first case report of chronic P. acnes endophthalmitis, pub-

lished the previous year. 5 Since then, other case reports have identified other organisms capable of producing a clinical picture similar to that caused by P. acnes. These reports allowed clinicians to recognize that postoperative intraocular infection could present very differently from the well-recognized acute form.

Epidemiology The incidence of postoperative endophthalmitis following cataract surgery has been reported as being between 0.07% and 0.33%. There are no clear estimates of the incidence of chronic postoperative endophthalmitis, because cases are rare and others go undiagnosed. No specific risk factors have been found in these patients: Most reports indicate that these subjects do not share those risk factors known to be associated with acute postoperative endophthalmitis (e.g., wound abnormality). P. acnes was the first organism described as a cause of this disorder. It is an anaerobic gram-positive pleomorphic bacillus normally found on the skin, external ear canal, mouth, and upper respiratory tract. It has been known to cause infection of the skin, nasal passages, heart, and eye. It is a normal inhabitant of the lids and conjunctiva, and has been associated with ocular infections such as blepharitis, keratitis, canaliculitis, and orbital cellulitis. Since the first P. acnes case reports, other microbes have been shown to present with a similar clinical picture. Notably, these organisms resemble P. acnes in that they lack the virulence factors commonly found in those Inicrobes associated with acute postoperative endophthalmitis. The organisms associated with the chronic form include coagulase-negative Staphylococcus, Corynebacterium, sp., Actinomyces, Nocardia, and Candida sp.

Chronic postoperative endophthalmitis occurs following cataract extraction with intraocular lens implantation in the vast majority of cases. It may also occur following cataract surgery in which an intraocular lens is not ilnplanted. Inflammatory episodes begin well after the im-

TABLE 49-1. DEfiNiTIONS Of DiffERENT CATEGORiES Of ENDOPHTHALMiTIS Acute postoperative endophthalmitis-intraocular inflammation secondary to an infectious cause characterized by an explosive onset and occurring in the immediate postoperative period following ocular surgery (typically within 7 days of the operation) Delayed-onset endophthalmitis-intraocular inflammation secondary to an infectious cause characterized by an explosive onset, but occurring up to four weeks after an ocular surgery Chronic postoperative endophthalmitis-intraocular inflammation secondary to an infectious cause characterized by indolent inflammation occurring any time following an ocular surgery

s

CHAPTER 49: MASQUERADE SYNDROMES: ... ,"' ............

mediate postoperative recovery period, first occurring from months to years after the operation. 6 It is when the delay is prolonged that clinicians may not immediately link the new-onset uveitis with potential postoperative infection. The episodes tend to run an indolent, seemingly benign course, responding well to topical or periocular steroid therapy, and uniformly recur as steroid therapy is tapered. Subsequent attacks can remain low grade or may increase in severity.7 The first cases of chronic postoperative endophthalmitis were presented by Meisler and colleagues in the American Journal of Ophthal1Jwlogy in 1986, and were found be due to P. acnes. 5 Subsequent reports of P. acnes endophthalmitis shared many clinical characteristics, and it was considered by some to represent its own unique syndrome. Ocular inflammation due to P. acnes is usually noted around 3 to 4 months following an uncomplicated cataract surgery.s, 9 It resembles a granulomatous uveitis. s Initially, inflammation responds well to topical steroids, only to relapse when the steroids are tapered. Recurrences become progressively worse. Cases initially presenting as nongranulomatous inflammation may become granulomatous, considered by some as an ominous sign. 7,10 One of the signs considered to be a hallmark of the syl1.drome is the presence of a white plaque, usually situated between the intraocular lens and the lens capsule. 4,9,11,12 The plaque can also be present on the corneal endothelium. 13 , 14 It shoold be noted that such plaques are not unique to P. acnes, and have been seen in chronic postoperative endophthalmitis due to other organisms, which include Candida, Torulopsis magn 0 liae, Corynebacterium sp., and Mycobacterium chelonae. 15 Other clinical signs seen in P. acnes endophthalmitis include hypopyon/' 9-12 iris nodules,l1 vitritis,4, 9, 10, 16 and vascular occlusion with retinal heluorrhages. 9, 16 Intraocular pressure is often elevated,lO, 13, 16, 17 which is consistent with the known association of uveitic glaucoma and infectious etiologies (e.g., herpes zoster virus [HZV] keratouveitis). P. acnes has been known to masquerade as an intermediate uveitis. 1s It has subsequently become clear that the classic clinical presentation first described due to P. acnes can occur in the setting of other bacterial species. 15 , 19,20 Notably, these organisms tend to be slow-growing gram-positive bacteria. Undoubtedly, there are more yet unidentified common pathogenic factors shared by the organisms that allow them to present in such a similar manner. Postoperative endophthalmitis due to fungal organisms are much rarer than their bacterial counterparts. However, clinical suspicion of fungal infection should be considered in all cases of chronic postoperative inflammation, because delayed diagnosis of intraocular fungal infection is almost always associated with a poor visual outcome and, in many cases, loss of the eye. Chronic postoperative endophthalmitis due to fungal organisms can present similarly to the picture described for P. acnes. Inflammation does not occur episodically but rather is constantly present. A hypopyon usually becomes apparent. Certain other clinical signs suggest a fungal etiology. An iris or ciliary body mass should make one

suspicious of a fungal etiology. Also, intraocular fungal organisms have been known to produce a keratitis from within the eye. So-called fluff balls classically described to be present in the vitreous, can also be seen in the anterior chamber. 21 Fungus can also cause necrotizing scleritis. Finally, aggressive topical, periocular, or intraocular steroid therapy may exacerbate the infection and worsen the course. 21 This is an ominous sign, and would prompt the treating physician to obtain an intraocular specimen in search of fungal organisms.

Pathophysiology and Etiology Postoperative endophthalmitis is a result of the introduction of microbes into the eye at the time of surgery. Studies examining anterior chamber speciluens during cataract surgery have demonstrated a contamination rate of 26%.22 One can show that in the majority of cases, these organisms can be isolated from conjunctival swab cultures of the same eye. 22 Despite this high rate of anterior chamber contamination, postoperative endophthalmitis, acute or chronic, remains relatively rare, and thus other factors must be involved in the development of these clinical entities. . One factor that must contribute to the unique characteristics of this syndrome is the kind of microbes known to cause it. Multiple organisms have been cited, and include P. acnes,coagulase-negative staphylococcus, Corynebacterium sp., Actinomyces, and Nocardia. 1, 9,19,23,24 These organisms are thought to be less virulent than organisms that cause acute postoperative endophthalmitis. However, the seemingly less-virulent coagulase-negative micrococcus is also the most common organism found in acute postoperative endophthalmitis. Other species that are believed to be indolent, like P. acnes, are also capable of producing acute postoperative endophthahuitis. Although low virulence obviously plays an important part in the chronic form, other factors, like the amount of organisms inoculated and patient risk factors, may explain why some cases of endophthalmitis due to these organisms can present in the fulminant form. Another characteristic of these organisms is their ability to cause chronic infection. Histologic studies reveal that P. acnes is able to persist within the capsule. Histology of the plaque demonstrates numerous intracellular and extracellular organisms adjacent to a normal lens capsule. 25 Reaction against organisms harbored in the capsule is unlikely, because no inflammatory cells are seen on microscopic examination of the capsule. s, 25 Recurrent inflammatory episodes are most likely due to the periodic release of sequestered organisms into the anterior chamber. This is further supported by imluunohistochemistry studies of vitreous samples from patients with P. acnes, which reveal a neutrophilic predominance and lack of lymphocytes, characteristic of an acute immune response. Fungal organisms capable of presenting a P. acnes-like syndrome include Candida parapsilosis, Candida fa1Jwta . (Torulopsis candida), and Acennonium kiliense. 21 Although' some fungal sources can be traced to the patient's flora (e.g., Candida), environmental factors in the operating room can contribute to infections due to fungal organisms not normally found as commensals of the skin. One study traced the source of four cases of endophthalmitis

CHAPTER 49:

B·R~'';:»Y'IUJIl:;n.A'-'I''IJe;;;;

SYNDROMES: ENDOPHTHAlMITIS

due to A. kiliense to the ventilation systelu, after noting that all four cases were performed very early on the first operating day of the week. It was believed that the organisms were introduced into the operating room environment when the ventilation system was switched on. Phenotypically identical organisms were cultured from humidifier water in the vent above the operating room. 21 Wound abnormalities, a well-known risk factor for acute postoperative endophthalmitis, can lead to introduction of fungus from the outside environment and the development of the chronic form. One case report describes endophthalmitis due to Histoplasma in a patient living in an area endemic for Histoplasma. The patient had a wound abnormality (vitreous wick), and testing revealed negative serology and absence of systemic infection.

Diagnosis Diagnosis relies on isolation of the causative organisms. This is done by either demonstrating the organisms on Gram's stain or by culture of an aqueous or vitreous sample. Ideally, both procedures are performed. because neither method alone is completely reliable. Many times, the ophthalmologist is unwilling to have the patient undergo a vitreous biopsy owing to good visual acuity and control of the inflammatory episodes by topical steroids. In these cases, an anterior chamber (AC) tap alone may be initiated. Owens and colleagues reported successful culture of P. aGnes when the AC tap I,eedle was directed into the capsular plaque or bag. 26 One must remember that successful yield of a positive Gram's stain or culture from the aqueous is less likely than that of a vitreous specimen. Additionally, with modern instruments and good surgical technique, a vitreous biopsy does not pose an unreasonable risk to the patient in the absence of other existing ocular conditions. Case reports of endophthalmitis by P. aGnes have shown that multiple vitreous biopsies can yield negative results. This can be due to several reasons. First, P. aGnes is a slow-growing organism. Reports indicate that it can take longer than 2 weeks for the specimen to grow in culture 12 ; most institutions do not carry out cultures for more than 5 days. Second, as an anaerobe, it has fastidious physiologic requirements. 27 Experiments show that a delay of more than 8 hours from delivery from the operating room to the appropriate culture environment results in a significant drop in yield of organisms. Last, the bulk of the organisms reside within the confines of the capsule (at the capsular plaque, if present) .25 Many authors recommend that attempts to retrieve capsular specimens for pathologic and microbiologic examination should be made in order to maximize the chance' of isolating the causative organism. 10, 28 On the other hand, false-positive results can also be a problem. P. aGnes is a known contaminant among blood cultures. Chern and colleagues demonstrated that it is possible to obtain false-positive P. aGnes cultures from uninfected eyes. 29 Potential contamination sources are many, because P. aGnes is ubiquitous. Contamination can occur at the level of the patient, the surgeon, operating room nurse and staff, or at the microbiology laboratory. Needless to say, it is important to eluphasize that equal

care must be taken in delivering and processing the speciluen as the care needed to obtain it. When fungal organisms are in the differential, the same techniques and approaches used for bacterial organisnls will aid in finding the causative organisms. Gram's stain is not as sensitive in demonstrating fungal microbes; Giemsa's or Gomori's methenamine staining should be performed if fungal infection is suggested. 21

Differential Diagnosis Although this chapter has dealt primarily with infectious etiologies thus far, there are many noninfectious causes of chronic postoperative inflammation that can masquerade as chronic autoimmune uveitis (Table 49-2). Among these causes is inflammation associated with the intraocular lens implant. Lens malposition causing constant iris trauma (e.g., iris chafing) can result in chronic inflammation. 2 An intraocular lens positioned in the posterior sulcus can also cause iris chafing, either from the contact with the pupillary margin by the optic or trauma to the ciliary body by the haptics. Intraocular lens material has also been implicated as the cause of chronic cells in the anterior chamber after cataract surgery although this is becoming less common with newer and safer lenses. 2 In the past, the uveitis-glaucoma-hyphema (UGH) syndrome was associated with the trauma induced by anterior chamber lenses, although with newer manufacturing techniques and intraocular lens design, this syndrome is seen less often. Retained cortical material associated inflamluation, classically resembling acute postoperative endophthalmitis, can also result in persistent chronic low-grade inflammation. 2 Retained cortex may be present in the capsular bag (e.g., incomplete cleanup), or may be a result of cortical pieces lost into the vitreous after capsular rupture. The amount of inflammation usually parallels the amount of cortical material left in the eye, although individual factors also playa role, because some patients seem to tolerate cortex floating in the vitreous cavity for years without experiencing inflammatory episodes. Retained cataract constituents were thought to account for most chronic postoperative inflammation before the m.ultitude of reports citing microbes as potential etiologies, so one should not become complacent and should avoid the erroneous notion that all postoperative cells are due to retained cortex.

TABLE 49-2. CAUSATIVE ORGANISMS IN ENDOGENOUS ENDOPHTHAlMITIS BACTERIA

FUNGI

Streptococcus sp. Staphylococcus sp. Clostridia septicum Bacillus cereus

Candida albicans Aspergillus sp. Histoplasma Coccidioides Blastomyces Oryptococcus SjJomthrix Pseudallescheria boydii Bipolar hawaiiensis

Coagulase-negative Staphylococcus Escherischia coli Klebsiella pneumoniae Serratia manescens Pseudomonas aeruginosa Neisseria meningitides Listeria monoeytogenes

CHAPTER 49: MASQUERADE SYNDROMES: ENDOPHTHALMITIS

Finally, the new onset of intraocular inflammation following surgery may not be related to the surgery at all. Patients may be experiencing their first episodes of uveitis from other causes. In the elderly, one should be careful to consider central nervous system/intraocular lymphoma as a possibility, because there is at least one case report in the literature of lyrnphomamasquerading as a chronic postoperative endophthalmitis from microbial causes.

Treatment Winward and coauthors reviewed the management and outcomes of 22 cases of P. acnes endophthalmitis. 30 They found treatment with intraocular antibiotics alone resulted in a failure rate of 88 %. Other investigators have shared similar poor outcomes with intravitreal antibiotics alone. 1 Winward also found that patients with P. acnes endophthalmitis who underwent partial removal of the capsule had a better success rate. Success in this subgroup seemed dependent on the "identification and removal of a intracapsular plaque: Those in whom a plaque was not visualized often required additional surgical procedures. Winward and colleagues found that the group of patients who did best were those who underwent total capsulectomy during their initial surgery: Every patient in this group was successfully cured. The authors also found that simultaneous secondary intraocular lens implantation in this group did not seem to affect the outcome adversely. 30 These finding suggest that Ofganisms harbored in the capsule are somewhat protected from treatment with antibiotic injection. Histology confirms that the majority of organisms are sequestered within the capsule. This helps explain both the stuttering course of the disease, as well as the high success rate in patients who underwent total capsulectomy. However, theories and conjecture concerning pathogenic mechanisms must ultimately stand the test of clinical experiences. Despite Winward's findings suggesting that treatment of this disorder is ultimately surgical removal of the capsule, other authors have reported successful treatment of P. acnes with intraocular antibiotic injection alone, intravenous antibiotics,31 and oral antibiotics alone. 17 P. acnes responds best to vancomycin and is also sensitive. to penicillins, cephalosporin, clindamycin, and chloramphenicol. The organism is relatively resistant to aminoglycosides. 32 There is no consensus on the best approach to treat these cases. Some authors advocate treating with topical steroids if visual acuity is better than 20/40 and the inflammatory episodes are nonprogressive. 31 Others advocate that the disease is similar to an abscess, in which microbes are confined in a region with poor access of antibiotics, and hence, surgical treatment is required. Most authors lean toward surgical treatment with supplemental antibiotics. 5,25 We agree with this approach. Treatment of fungal endophthalmitis from all causes is difficult. Patients often require prolonged therapy, and in many cases, fungal organisms cannot be eradicated from the eye despite aggressive therapy. Weissgold and colleagues reported on the onset of fungal infection of the cornea in two patients who previously were thought

to have had successfully treated postoperative fungal endophthalmitis. 21 It is not unusual for fungal endophthalmitis to recur despite repeat vit:rectomies and intraocular amphotericin. At times, adjunctive intravenous therapy is indicated, putting the patient at significant risk of drug toxicity. Because of the difficulty of treating such cases, it is a reminder to all surgeons that although the risk of postoperative endophthalmitis cannot be completely eliminated (at this time), careful attention to sterile technique, good operating room management of surgery supplies and media, meticulous attention to creation of the surgical wound, and education of the patient with regard to good hygiene in the immediate postoperative period, may reduce the chance of introduction of infectious organisms in the first place.

Complications The complications are similar to those seen in other chronic uveitis entities. These complications usually occur because of the failure of diagnosis. Glaucoma, from inflammation and chronic steroid use, can be difficult to control. Severe or prolonged inflammation leads to proliferative vitreoretinopathy, at which point salvage of the eye is unlikely. Although death from subsequent sepsis has not been associated with cases of chronic postoperative endophthalmitis, it has been seen in acute postoperative endophthalmitis; the absence of reports may be due to the fact that presumably if the infectious agent had been discovered, the patient would have been cured.

Prognosis In many cases, chronic postoperative endophthalmitis due to bacterial causes has a good outcome and is thought to have a better outcome than acute endophthalmitis due to the less virulent organisms. It is highly likely that there exist many undiagnosed patients that are being managed with chronic topical steroids who are doing well.

Endogenous endophthalmitis is intraocular infection due to bacterial or fungal microbes seeded to the eye from the vascular circulation. Clinically, it presents as acute uveitis without history or evidence of penetration of the globe, and occurs in patients who have a focus of infection distant from the eye. Occasionally, signs of a systemic infection are subtle or absent, and in these cases, the condition masquerades as an autoimmune uveitis.

Epidemiology Endogenous endophthalmitis is a uncommon entity. Study reports estimate that it accounts for between 2% and 8% of cases of all forms of endophthalmitis. 33 The overall incidence in predisposed patient populations is not known. The incidence of fungal endophthalmitis in patients with candidemia has ranged between 1 % and 40%. This wide range may be due in part to some authors broadening the definition of Candida to include patients with fundus lesions that do not extend into the vitreous;

CHAPTER 49: MASQUERADE SYNDROMES: ENDOPHTHAlMITIS

this does not necessarily meet the more literal terminology of endophthalmitis. 34 Endogenous endophthalmitis often occurs in the setting of an immunocompromised patient. Predisposing medical conditions include diabetes mellitus,33, 35-38 malignancy,33, 38--41 sickle cell anemia,42 systemic lupus erythematosus,42, 43 and human immunodeficiency virus (HIV).44-47 Iatrogenic immunosuppression in the form of chemotherapy for treating malignancy and immunosuppressives and systemic corticosteroids for organ transplant patients 33 , 38, 43, 47-49 also appear to predispose the patient to endogenous bacterial endophthalmitis. Although endophthalmitis luay occur as the only obvious site of infection in the immunocompromised patient, the presence of a focus of infection is the rule. Okada and colleagues found prior medical conditions in 90% of their patients with endogenous bacterial endophthalmitis. 33 Urinary tract infection, liver or gastrointestinal abscess, meningitis, cellulitis, cholecystitis, and pneumonia encompass the most commonly cited sources of infection. 33, 35 Several· other conditions that can lead to hematogenous dissemination of microbes in immunocompetent individuals have been associated with endogenous endophthalmitis. Patients who develop subacute bacterial endocarditis have been shown to be at increased risk for spread to the eye. 33, 49, 50 One series found endocarditis accounted for the source of infection in 46% of cases. 33 Periodontal infection,51 indwelling intravenous catheters 45, 50, 52, 53 contaminated intravenous solutions 54 and , intravenous drug abuse 33,55-58 have also been shown as risk factors in patients with a good immune status. Endogenous Candida endophthalmitis has been reported following induced abortion in healthy women.59 Endogenous endophthalmitis can present in the neonate. 52 ,60-63 The immune system is not fully luatured during the first 6 months after birth and perhaps for up to 1 year. The fact that physicians overlook this fact is apparent in case reports of children undergoing enucleation for retinoblastoma, only to discover that the diagnosis was endophthalmitis. Given that in many of these cases a systemic infection was not apparent, it underscores the importance of remembering that imnlune function cannot be considered completely competent in an otherwise healthy-appearing neonate.

"

Clinical Characteristics The onset of ocular inflammation in a patient with a systemic infection helps greatly in raising the suspicion that the microbe is also responsible for the eye disease. In most cases, patients will already be under the care of a physician for a systemic illness. The risk factors predisposing to infection are readily apparent by the medical history and the current illness. Some patients may have multiple risk factors for infection. For example, certain systemic diseases require prolonged intravenous therapy, which may predispose the patient to intravenous line-related infection. In malignancy· or autoimmune disease, the specific chemotherapeutic treatment may further compromise the patient's imluune status. It is when a systemic infection is not present or obvious that ophthalmologists may overlook the possibility of an infectious etiology. Some infections are either difficult to

diagnose (e.g., osteomyelitis) or are dismissed as a less serious infection (e.g., sinusitis or pneumonia misinterpreted as a common cold). In the latter case, the patient luay present to the ophthalmologist focused only on the ocular symptoms, creating further potential to misdiagnosed intraocular inflammation as an autoimmune process. Unfortunately, even obvious cases can be overlooked by the ophthalmologist who does not keep infection in his differential, as illustrated by the following case:

CASE PRESENTATION A 56-year-old dentist with a history of type II diabetes mellitus was scheduled to go on a trip to China when he began to have fever, chills, and a nonproductive cough. He took over-the-counter medications for symptomatic relief. When he arrived in China, he noted blurring vision of his left eye. Over the next 4 days, his left eye became increasingly red and painful, prompting him to seek medical attention. He was seen at the local eye clinic, where he was diagnosed with acute anterior uveitis and started on topical steroid drops and cycloplegics, and told to follow up at the hospital-based ophthalmology service. He was seen there 2 days later, with worsening of his condition: 3 plus anterior chamber cells, corneal edema, granulomatous keratic precipitates, and a hypopyon. He was also noted to be confused, for which he was transferred to the emergency room. Testing revealed a glucose level of higher than 400, and the patient was admitted for glucose control. Incidental chest radiograph revealed a pulmonary infiltrate; the patient was placed on intravenous antibiotics. During hospitalization, the ophthalmology service started the patient on a daily regimen of periocular steroid injections, supplemented by topical atropine and steroids drops. The hypopyon resolved, but a fibrin membrane developed, covering the pupil. He was discharged on topical prednisolone, tropicamide, and timo101, with vision of light perception. He returned to the United States and was seen at the Massachusetts Eye and Ear Infirmary and was eventually referred to the Ocular Immunology & Uveitis Service. On examination, vision of the left eye was bare light perception, with lid edema, 4 + conjunctival injection, 3 + conjunctival chemosis, corneal edema, hypopyon, and the dense fibrin membrane obscuring the pupil. We recommended urgent anterior chamber tap and vitreous biopsy to rule out infection, which was performed. Gram's stain of the anterior chamber specimen was negative, but the vitreous specimen revealed gram-negative rods. Intraocular antibiotics were injected, and the patient was placed on oral antibiotics. Twenty-four hours later, Klebsiella pneumoniae had grown out of culture from the vitreous specimen. By this time, the vision was no light perception, with early signs of limitation of extraocular movements. Because of the patient's unimproved ocular status and the possibility of early orbital cellulitis, the patient underwent evisceration.

As mentioned several times in this text, a detailed review of systems is an essential step in the evaluation of all patients with uveitis. Because of the previously mentioned circumstances that can lead. to overlooking an

c

CHAPTER

infectious cause, the review of systems may provide the only clue to the ophthalmologist that an infection should be suspected. The possibility of endophthalmitis cannot be excluded even when the review of systems is unrevealing. Use of intravenous drugs is an obvious potential source of microbes for endogenous endophthalmitis, and most patients will not readily volunteer this information during the initial encounter with the physician. Physical examination for tell-tale signs of drug use on the patient's skin may provide the only clue of this etiology.57 This fact underscores that the ophthalmologist keen on saving the vision of a patient with uveitis of unknown etiology cannot limit the physical examination to the globe. Finally, there are cases in which no systemic disease or predisposing risk factors can be found. 63 , 64 Diagnosis in these patients relies heavily on the clinician's level of suspicion. If symptoms progress slowly in these patients, delay in diagnosis is often the rule, with one study revealing a mean duration from symptoms to diagnosis of 61 days in patients eventually found to have Candida endophthalmitis. 65 The presenting symptoms and signs are similar to those of uveitis of autoimmune causes. Classically, endogenous endophthalmitis from bacteria presents more explosively than does fungal infection. Symptoms include blurred vision, pain, and photophobia. Pain l:lOwever is not a constant feature. 66 Floaters are rarely a complaint in rapidly progressive cases but may be noted in cases with a more insidious onset ,(i.e., fungal endogenous endophthalmitis) . Examination reveals severely reduced visual acuity in the affected eye, often in the count-fingers to light perception range. Periorbital edema can vary from severe to absent. If periocular swelling is associated with proptosis, an associated orbital cellulitis may be present. 49 This may be an ominous sign in immunocompromised patients. Usually, both anterior and posterior segments are involved. Anterior signs include cells, flare, and inferior keratic precipitates. A hypopyon is cited in most reported cases,41 but this may be due to a selection bias, because all of these reports are retrospective cohort studies. A so-called dark hypopyon may be suggestive of Listeria. 4o Anterior chamber fibrin or an inflammatory membrane can also be seen. Another noted feature is corneal edema,36, 39, 42, 67 although this feature can also be seen in severe noninfectious uveitis. Intraocular pressures may be extremely elevated,40 which is consistent with what is found clinically in uveitis entities from other infectious organisms not normally associated with concomitant sepsis (e.g., herpesvirus, toxoplasmosis, and syphilis). Iris nodules can be seen in fungal endophthalmitis. 41 ,67 Rubeosis iridis and angle-closure glaucoma can be seen in severe inflammation or in a prolonged course. Some posterior signs can al~o be suggestive of an infectious process. Although vitreal cells are nonspecific, vitreal condensations of inflammatory cells, or so-called fluff balls and pearls on a string are usually associated with fungal infection. 68 This picture is even more suggestive of fungal infection when the fluff balls are localized in the posterior vitreous near the posterior pole 57 (as opposed to the anterior vitreous or inferior vitreous

MASQUERADE SYNDROMES: ENDOPHTHALMITIS

base). White or creamy discrete deep choroidal lesions are also seen in fungal infection, representing separate foci of disseminated organisms. Alternatively, a white chorioretinal infiltrate with indistinct borders can also be seen. 41 ,67 Roth spots can be seen in both bacterial and fungal infections. 69 An inflamlnatory exudate may occur in either the subhyaloid or subretinal space (e.g., subretinal abscess), capable of forming a pseudohypopyon. 58 ,67, 70 Disc edema,46 subretinal abscess,71 vasculitis,69, 72 retinal cyst,37 retinal necrosis,35 and choroidal mass 73 are uncommon signs. It should be noted that although they are suggestive, none of these signs are specific: Fluff balls at the vitreous base are seen in intermediate uveitis, and pseudohypopyon has been described in syphilis and Adamantiades-Behc;et disease.

Pathogenesis The type of microbe that infects the eye is related to the patient's specific risk factors. Streptococcus sp. causes endophthalmitis in endocarditis patients, whereas Klebsiella sp. can be isolated in patients with liver abscesses and Candida endophthalmitis is associated with indwelling intravenous catheters and intravenous drug abuse. Gram-positive bacteria (s. aureus and streptococcal species) account for the majority of bacterial causes,33 whereas Candida species is the most COlnmon cause of fungal endogenous endophthalmitis. A list of reported organisms can be found in Table 49-3. The majority of infections are presumably the result of hematogenous dissemination of the organisms. Rabbit models demonstrate that disseminated microbes initially colonize the choroid, and then spread inward to the retina. Endogenous endophthalmitis has been reported in patients with meningitis, which raises the possibility that spread of organisms from the cerebral spinal fluid may represent an alternative way of infection seeding to the eye.

Diagnosis Diagnosis relies on isolation of the causative microbes. This requires 'obtaining intraocular fluid, usually in the form of a vitreous biopsy. An anterior chamber tap can also isolate causative microbes but is usually performed as a supplemental procedure to the vitreous biopsy. Retinal biopsy may be necessary in selected cases. 70 Identification of organisms from systemic infected sites is potentially usefup3 When a patient develops endophthalmitis in the presence of a systemic infection, one TABLE 49-3. NONINFECTIOUS CAUSES OF CHIRC.NIC POSTOPERATIVE INTRAOCULAR INFLAMMATION Lens-induced uveitis (phacoantigenic uveitis) Retained cortical material Retained intravitreal lens fragments Intraocular lens-related uveitis Iris chafing intraocular lens implant malposition Uveitis-glaucoma-hyphema (UGH) syndrome Intraocular lens implant material related Other causes Masquerade (intraocular lymphoma) Sympathetic ophthalmia Uveitis of other causes unrelated to surgery

CHAPTER 49: MASQUERADE SYNDROMES: ENDOPHTHAlMITIS

often presumes that the causative organism of each infection is the same. However, this is not always the case. Often, the patient population at risk for endogenous endophthalrhitis is predisposed to infection from multiple sources. For example, a cancer patient admitted for bacterial pneumonia may develop fungal endophthalmitis from infection of the line used for his antibiotics and other intravenous medications. Furthermore, certain organisms may be difficult to isolate from systemic sites, because one series of culture-proven endogenous fungal endophthalmitis found positive blood cultures in only two of 16 patients. 65

Treatment The mainstay of treatment consists of intraocular antibiotics. If Gram's and fungal staining is performed at the initial harvesting of undiluted vitreous material, therapy can be targeted against· a narrower spectrum of microbes immediately. This approach, which can categorize the infection into gram-positive bacteria, gram-negative, or fungal infection at the time of biopsy, can potentially save the eye, because delay in the institution of the appropriate antimicrobial therapy of 24 hours can sometimes mean the difference between salvage of the eye and evisceration. Some authors advocate that intraocular antibiotics are not needed in all cases of endogenous endophthalmitis, citing the potential macular toxicity of these medications when given intraocularly, as well as the reports of endogenous fungal endophthalmitis successfully treated with vitrectomy and systemic flu'tonazole. 65 Often, when the clinical picture is suggestive, empiric intraocular antibiotics with or without steroids is given at the time of initial biopsy (see Table 49-4). Intravitreal steroid has not been associated with exacerbation of a fungal endophthalmitis when injected with intravitreal amphotericin B.74,75 The use of systemic antimicrobial therapy in endogenous endophthahnitis is usually not controversial. In many cases, patients are already receiving antibiotics for the source infection. However, when a focus of infection outside the eye is not identified, the usefulness of systemic treatment for localized eye disease is not as clear. Antibiotics against bacteria in general carry little risk, and thus their use in this circumstance is rarely problematic. The benefit of systemic antifungals in isolated fungal endophthalmitis is less certain. Although they demonstrate good vitreous penetration, use of oral antifungal agents should be seriously considered given the high incidence of Candida. 76 ,77 Intravenous amphotericin carries significant risk of renal toxicity. Futhermore, it is known that intravenous amphotericin does not penetrate the eye well. There is evidence in the literature supporting both its usefulness and its uselessness. Case reports describe patients who were successfully treated with vitrectomy and intraocular antifungals without systemic antifungals,34, 78 as well as patients who were successfully treated with systemic antifungals without vitrectomy.47, 48 When employed, the dosage of systemic amphotericin given is commonly around 0.5 to 1.0 mg/kg/ day. Similarly, the role of vitrectomy in the management of endogenous endophthalmitis is not clear. Reports of successful treatment both with and without surgery have

been cited. 58, 66, 78-80 Although one usually assumes that vitrectomy can enhance visual recovery by both "debulking" the amount of intraocular organisms, as well as removing debris that will impair optimum visual recovery, there also exist reports of clearance of the vitreous with excellent visual acuity with systemic treatment alone. 66 Today, most experts lean toward the use of pars plana vitrectomy with intravitreal antibiotics in most cases, whereas systemic treatment alone may be considered in those with mild vitritis. A prospective controlled clinical trial cOlnparing the various combinations of treatment modalities is not feasible, because cases of endogenous endophthalmitis are rare and the patient population in which they occur is extremely heterogeneous. With the current available therapies, success relies heavily on prompt diagnosis, as well as the clinical judgment and experience of the treating ophthalmologist.

Complications The most serious complication among patients with endogenous endophthalmitis is death. 52 This pertains to the subgroup of patients who have either sepsis or a systemic illness rendering them immunocompromised. Often, they are extremely ill, and sometimes terminally so. Under these circumstances, the ocular process is overshadowed by the primary systemic illness. Diagnostic surgical procedures in the operating room need to be deferred if they pose a significant risk to the patient's survival. Sometimes, the ophthalmologist may need to perform a vitreous biopsy and intravitreal injection of antibiotics at the bedside, if salvaging vision has a chance of preserving the patient's quality of life, or if eventual recovery from the systemic illness is likely. Ocular complications from endophthalmitis are as varied as those found in other uveitic entities. Cataract formation represents a relatively mild complication, whereas neovascular glaucoma, optic neuropathy, and retinal detachment65 represent the more severe end of the spectrum. Recurrence of infection can become a frustrating sequela, with fungal infections historically described as being able to persist in the eye even after multiple attempts at cleanup.65 Development of orbital cellulitis by direct spread of intraocular microbes has been cited anecdotally as a reason to pursue evisceration in hopeless cases. This contention is supported by histopathologic identification of fungal organisms present within scleral emissarial canals and reports of spontaneous scleral perforation from Klebsiella endophthalmitis. 35 Last, complications can occur secondary to antibiotic treatlnent. Intravitreal antibiotics, particularly gentamicin and vancomycin, are known to have potential macular toxicity. Systemic antimicrobial therapy may present a risk of specific organ toxicity (e.g., amphotericin and the kidneys) as well as the risk carried by the presence of an intravenous line, a significant danger in this patient population.

Prognosis Successful treatment of endogenous endophthalmitis requires prompt diagnosis and therapy. Like acute postoperative endophthalmitis, the endogenous form can pre-

CHAPTER 49: MASQUERADE SYNDROMES: ENDOPHTHAlMITIS

sent in an explosive manner, with progression to loss of useful vision in a matter of days. Unlike postoperative or post-traumatic infection, a clear history suggesting an infectious etiology is not always present. Assumption that the process is autoimmune and ought to respond to highdose steroids can be disastrous. Even when appropriately diagnosed, virulence of the offending microbe and poor health status of the patient may delay resolution and limit visual recovery. It is one of the masquerade syndromes that absolutely should not be overlooked in any patient presenting with intraocular inflammation of unknown etiology.

References 1. Fox GM, Joondeph BC, Flynn HW, et al: Delayed-onset pseudophakic endophthalmitis. AmJ Ophthalmol 1991;111:163-173. 2. Mandelbaum S, Meislel~ D: Postoperative chronic microbial endophthalmitis. Int Ophthalmol Clin, 1993;3:71-79. 3. Jiraskova N, Rozsival P: Delayed-onset Pseudomonas stutzeri endophthalmitis after uncomplicated cataract surgery. J Cataract Refract Surg 1998;24:866-867. 4. Roussel T, Culbertson W, Jaffe N: Chronic postoperative endophthalmitis associated with Propionibacterium acnes. Arch Ophthalmol 1987;105:1199-1201. 5. Meisler D, Palestine AG, Vastine DW, et al: Chronic Propionibacterium endophthalmitis after extracapsular cataract extraction and intraocular lens implantation. AmJ Opthalmol 1986;102:733-739. 6. Posenauer B, Funk]: Chronic postoperative endophthalmitis caused by Propionibacterium acnes. Eur J Ophthalmol 1992;2:94-97. 7. Jaffe GJ, WhitcherJP, Biswell R, et al: Propionibacterium acnes endophthalmitis seven months after extracapsular cataract, extraction and intraocular lens implantation. Ophthalmic Surg 1986;17:791-793. 8. Meisler D, Mandelbaum S: Propionibacterium-associated endophthalmitis after extracapsular cataract ~xu-action. Review of reported cases. Ophthalmology 1989;96:54-61. 9. Zambrano W, Flynn HW, Pfulgfelder SC, et al: Management options for Propionibacterium acnes endophthalmitis. Ophthalmology 1989; 96: 11 00-11 05. 10. Piest K, Apple DJ, Kincaid MC, et al: Localized endophthalmitis: A newly described cause of the so-called toxic lens syndrome. J Cataract Refract Surg 1987;13:498-510. 11. Stokes D, O'Day D: Iris nodule and intralenticular abscess associated with Propionibacteruim acnes endophthalmitis. Arch Ophthalmol 1992;110:921-922. 12. Omerod D, Edelstein M.A., Schmidt GJ, et al: The intraocular environment and experimental anaerobic bacterial endophthalmitis. Arch Ophthalmol 1987;104:1571-1575. 13. Abrahams IW: Propionibacterium, acnes endophthalmitis: An unusual manner of presentation. J Cataract Refract Surg 1989;15:698-701. 14. Chien AM, Raber 1M, Fischer DH, et al: Propionibacterium acnes endophthalmitis after intracapsular cataract extraction. Ophthalmology 1992;99:487-490. 15. El-Asrar AM, Tabbara K: Chronic endophthalmitis after exu-acapsular cataract extraction caused by Mycobacte1iwn chelonae subspecies abcessus [Letter]. Eye 1995;9:798-801. 16. Keyser B, Maguire J, Halperin L: Propionibacterium acnes endophthalmitis after Staphylococcus epidennidis endophthalmitis. Am J Ophthalmol 1993;116:505-506. 17. Pivetti-Pezzi P, Accorinti M: Propionibacte1iwn endophthalmitis [Letter]. Ophthalmology 1992;99:1753-1754. 18. Omerod D, Puklin J, Giles C: Chronic Propionibacterium acnes endophthalmitis as a cause of intermediate uveitis. Ocul Immunol Inflamm 1997;4:67-68. 19. Zimmerman P, Mamalis N, Alder JB, et al: Chronic Nocardia asteroides endophthalmtiis after extracapsular cataract exu-action. Arch OphthalmoI1993;111:837-840. 20. Von Below H, Wilk CM, Schall KP, et al: Rlwdococcus luteus and Rhodococcus erythropolis chronic endophthalmtiis after lens implantation [Letter]. AmJ OphthalmoI1991;112:596-597. 21. Weissgold DJ, Orlin SE, Sulewski ME: Delayed-onset fungal keratitis after endophthalmitis. Ophthalmology 1998;105:258-262. 22. Egger S, Huber Spitzy V, Scholda C: Bacterial contamination during extracapsular cataract extraction. Ophthalmologica 1994;208:77-81.

23. Manners RM, Canning' CR: Posterior lens capsule abscess due to Propionibacterium acnes and Staphylococcus epidennidis following extracapsular cataract exu-action. Br J Ophthalmol 1991;75:710-712. 24. Roussel T, Olson ER, Rice T: Chronic postoperative endophthalmitis associated with Actinomyces species. Arch Ophthahnol 1991;109:60-62. 25. Meisler DM, Zakov ZN, Bruner WE, et al: Endophthalmitis associated with sequestered inu-aocular Propionibacteriunz acnes. AnIJ Ophthalmol 1987;104:428-429. 26. Owens S, Lam S, Tessler HH, et al: Preliminary study of a new inu-aocular method in the diagnosis and u-eaunent of Propionibactelium acnes endophthalmitis following cataract exu-action. Ophthal Surg 1993;24:268-272. 27. Hall G, Pratt Rippin K, Meisler DM, et al: Growth curve for Propionibacteliwn acnes. Curl' Eye Res 1994;13:465-466. 28. Sawusch MR, Michels RG, Stark V\Q", et al: Endophthalmitis due to Propionibacteritmz acnes sequestered between IOL optic and posterior capsule. Ophthalmic Surg 1989;20:90-92. 29. Chern K, Meisler DM, Hall GS, et al: Bacterial contamination of anaerobic vitreous cultures: Using techniques employed for endophthalmitis. Curt Eye Res 1996;15:697-699. 30. Winward KE, Plugfelder SC, Flynn HW, et al: Postoperative Propionibacte1ium endophthlamitis. Ophthalmology 1993;100:447-451. 31. Brady SE, Cohen EJ, Fischer DH: Diagnosis and treatment of chronic postoperative bacterial endophthalmitis. Ophthalmic Surg 1988;19:580-584. 32. Beatty RF, Robin JB, Trousdale MD, et al: Anaerobic endophthalmitis caused by Propionibacterium acnes. Am J Opthalmol 1986; 101:114-116. 33. Okada A.A, Johnson RP, Liles WC, et al: Endogenous bacterial endophthalmitis. Report of a ten-year retrospective study. Ophthalmology 1994;101:832-838. 34. Donahue SP, Greven CM, Zuravleff jJ, et al: Intraocular candidiasis in patients with candidemia. Clinical implications derived from a prospective multicenter study. Ophthalmology 1994;101:1302-1309. 35. Liao HR, Lee HW, Leu HS, et al: Endogenous Klebsiella pnewnoniae endophthalmitis in diabetic patients. Can J Ophthalmol 1992; 27:143-147. 36. Margo CE, Mames RN, Guy JR: Endogenous Klebsiella endophthalmitis. Ophthalmology 1994;101:1298-1301. 37. Sipperley JO, Shore JW: Septic retinal cyst in endogenous Klebsiella endophthalmitis. AmJ OphthalmoI1992;94:124-125. 38. Ambler JS, Meisler DM, Zakov ZN, et al: Endogenous Mycobactelium chelonae endophthalmitis. AmJ Ophthalmol 1989;108:338-339. 39. Davitt B, Gehrs K, Bowers T: Endogenous Nocardia endophthalmitis. Retina 1998;18:71-73. 40. Eliott D, O'Brien TP, Green WR, et al: Elevated inu-aocular pressure, pigment dispersion and dark hypopyon in endogenous endophthalmitis from Listeria rnonocytogenes. Surv Ophthalmol 1992;37:117-124. 41. Blumenkranz MS, Stevens DA: Therapy of endogenous fungal endophthalmitis. Arch Ophthalmol 1980;98:1216-1220. 42. Werner MS, Feist RM, Green JL: Hemoglobin SC disease with endogenous endophthalmitis. AmJ OphthalmoI1992;113:208-209. 43. Ishibashi Y, Watanabe R, Hommura S, et al: Endogenous Nocardia asteroides endophthalmitis in a patient with systemic lupus erythematosus. Br J Ophthalmol 1990;74:433-436. 44. Scherer V\Q", Lee K: Implications of early systemic therapy on the incidence of endogenous fungal endophthalmitis. Ophthalmology 1997;104:1593-1598. 45. Tufail A, Weisz JM, Holland GN: Endogenous bacterial endophthalmitis as a complication of inu-avenous therapy for cytomegalovirus retinopathy [Letter]. Arch Ophthalmol 1996;114:879-880. 46. Glasgow BJ, Engstrom RE, Holland GN, et al: Bilateral endogenous Fusmium endophthalmitis associated with acquired immunodeficiency syndrome. Arch Ophthalmol 1996;114:873-877. 47. Pavan PR, Margo CE: Endogenous endophthalmitis caused by Bipolans hawaiiensis in a patient with acquired immunodeficiency syndrome. AmJ Ophthalmol 1993;116:644-645. 48. Graham DA, Kinyoun JL, George DP: Endogenous Aspergillus endophthalmitis after lung transplantation. Am J Ophthalmol 1995;119:107-1 09. 49. Patel AS, Hemady RK, Rodrigues M, et al: Endogenous Fusarium endophthalmitis in a patient with acute lymphocytic leukemia. Am J Ophthalmol 1994;117:363-368.

CHAPTER 49:

BYBM'''Y'VIl;;nM~IU'O;;;

SYNDROMES: ENDOPHTHAlMITIS

50. Ishak MA, Zablit KV, Dumas J: Endogenous endophthalmitis caused by Actinobacillus actinomycetemcomitans. Can j Ophthalmol 1986; 21:284-286. 51. Hornblass A, To K, Coden Dj, et al: Endogenous orbital cellulitis and endogenous endophthalmitis in subacute bacterial endocarditis. Amj OphthalmoI1989;108:196-197. 52. Parke DW, jones DB, Gentry LO: Endogenous endophthalmitis among patients with candidemia. Ophthalmology 1982;89:789-796. 53. Wolfensberger Tj, Gonvers M: Bilateral endogenous Candida endophthalmitis. Retina 1998;18:280-281. 54. Daily Mj, Dickey jB, Packo KH: Endogenous Candida endophthalmitis after intravenous anesthesia with propofol. Arch Ophthalmol 1991 ;109:1081-1 084. 55. Lance SE, Friberg TR, Kowalski RP: Aspergillus flavus endophthalmitis and retinitis in an intravenous drug abuser. Ophthalmology 1988;95:947-949. 56. Gabriele P, Hutchins RK: Fusarium endophthalmitis in an intravenous drag abuser. Amj Ophthalmol 1996; 122:119-12l. 57. Doft BH, Clarkson jG, Rebell G, et al: Endogenous Aspergillus endophthalmitis in drug abusers. Arch Ophthalmol 1980;98:859-862. 58. Weishaar PD, Flyn.n HW, Murray TG, et al: Endogenous Aspergillus endophthalmitis. Ophthalmology 1998;105:57-65. 59. Chen Sj, Chung YM, LiujH: Endogenous Candida endophthalmitis after induced abortion. Am j Ophthahnol 1998;125:873-876. 60. Shields jA, Shields CL, Eagle RC, et al: Endogenous endophthalmitis simulating retinoblastoma. Retina 1995;15:213-219. 61. Palmer EA: Endogenous Candida endophthalmitis in infants. Am j Ophthalmol 1980;89:388-395. 62. Clinch TE, DukerjS, Eagle RC, et al: Infantile endogenous Candida endophthalmitis presenting as a cataract. Surv Ophthalmol 1989;34:107-112. 63. Friedlander SM, Raphaelian PV, Granet DB: Bilateral endogenous Escherichia coli endophthalmitis in a neonate with meningitis. Retina 1996;16:341-343. 64. Pfeifer jD, Grand MG, Thomas MA, et al: Endogenous Pseudallescheria boydii endophthalmitis. Arch Ophthalm91 1991;109:1714-1717. 65. Essman TF, Flynn HW, Smiddy WE, et al: T~eatment outcomes in a 10-year study of endogenous fungal endophthalmitis. Opthalmic Surg Lasers 1997;28:185-194.

66. Luttrull jK, Wan WL, Kubak BM, et al: Treatment of ocular fungal infections with oral fluconazole. Am j Ophthalmol 1995;119:477481. 67. Heidemann DG, Murphy SF, Lewis M: Endogenous Listeria monocytogenes endophthalmitis presenting as keratouveitis. Cornea 1990; 9:179-180. 68. Kostick DA, Foster RE, Lowder CY, et al: Endogenous endophthalmitis caused by Candida albicans in a healthy woman. Amj Ophthalmol 1992;113:593-595. 69. Gross jG: Endogenous Aspergillus-induced endophthalmitis. Retina 1992;12:341-345. 70. Sheu Sj, Chen YC, Kuo NW, et al: Endogenous cryptococcal endophthalmitis. Ophthalmology 1998;104:377-381. 71. Yang SS, Hsieh CL, Chen TL: Vitrectomy for endogenous Klebsiella pneumoniae endophthalmitis with massive subretinal abscess. Ophthalmic Surg Lasers 1997;28:147-150. 72. jones DB, Green MT, Osato MS, et al: Endogenous Candida albicans endophthalmitis in the rabbit. Arch Ophthalmol 1981;99:21822187. 73. Berman Aj, Del Priore LV, Fischer CK: Endogenous Ochrobactmm anthropi endophthalmitis. Am j Ophthalmol 1997;123:560-562. 74. Gottlieb jL, McAllister IL, Guttman FA, et al: Choroidal blastomycosis. A report of two cases. Retina 1995;15:248-252. 75. Coats ML, Peyman GA: Intravitreal corticosteroids in the treatment of exogenous fungal endophthalmitis. Retina 1992;12:46-51. 76. O'Day DM: Ocular uptake of fluconazole following oral administration. Arch Ophthalmol 1999;108:1006-1008. 77. Savanyi DV, Perfect jR, Cobo LM, et al: Penetration of new azole compounds into the eye and efficacy in experimental Candida ei1.dophthalmitis. Antimicrob Agents Chemother 1987;31:6-10. 78. Brod RD, Flynn HW, Clarkson jG, et al: Endogenous Candida endophthalmitis: Management without intravenous amphotericin B. Ophthalmology 1990;97:666-674. 79. Laatikainen L, Tuominen M, von DickhoffK: Treatment of endogenous fungal endophthahnitis with systemic fluconazole with or without vitrectomy. Amj OphthalmoI1992;113:205-207. 80. Christmas Nj, Smiddy WE: Vitrectomy and systemic fluconazole for treatment of endogenous fungal endophthalmitis. Ophthalmic Surg Lasers 1996;27:1012-1018.

Lijing Yao and C. Stephen Foster

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Masquerade syndromes are defined as a group of disorders characterized by the presence of intraocular cells secondary to noninflammatory diseases, and are often misdiagnosed as chronic idiopathic uveitis. In 1957, Cooper and Riker 1 reported the first relationship between systemic lymphoma and "uveitis." Although several subsequent reports documented cases of intracraniallYlTIphomas associated with intraocular inflammation 2 and retinal detachments (RDs) associated with scleritis,3 ocular masquerade sYl1drOlTIeS were not yet given a formal ophthalmic definition. Until 1967, the term masquerade sYl1drome was first cited in the ophthalmic literature by Theodore to describe a case of conjunctival carcinoma that manifested as chronic conjunctivitis. 4 Today, the term masquerade syndrome is most widely accepted to describe some disorders that simulate chronic idiopathic uveitis. Reports of masquerade sYl1dromes are rare. Only one case of masquerade syndrome in 426 cases of uveitis was reported in a large prospective study of general uveitis. 5 Review of the literature between 1967 and most current published series discloses that the most COlTIlTIOn conditions that can masquerade as idiopathic uveitis are malignancies and infectious endophthalmitis. Other nonmalignant and noninfectious diseases, including peripheral RD, retinitis pigmentosa, intraocular foreign body, pigmentary dispersion sYl1drome, ocular ischemic sYl1drome, juvenile xanthogranuloma, and others have also been mentioned. Malignancy and endophthalmitis are discussed in the preceding chapters. In this chapter, we discuss only nonmalignant and noninfectious masquerade disorders, which can be misdiagnosed as uveitis. We stress the common and different clinical manifestations of each masquerade disorder, its diagnosis, and its differential diagnosis in more detail.

Definition RD is defined as a separation of the sensory retina from the retinal pigment epithelium (RPE) with an accumulation of fluid in the potential space between them. It is often classified into three distinct types: (1) rhegmatogenous, (2) traction, and (3) exudative. A primary, or spontaneous, RD is a rhegmatogenous detachment that is caused by retinal breaks-tear~, holes, and dialyses in the retina, in which fluid from the vitreous cavity seeps through the retinal breaks, accumulates in the potential subretinal space, and separates the retina from the RPE. Rhegmatogenous RD is the most common form of RD. RDs secondary to other disease processes, not primarily caused by retinal holes, are termed nonrheglTIatogenous detachments, which include traction and exudative RD.

A traction RD is often caused by vitreoretinal fibroproliferative membranes that mechanically pull the retina off from the underlying retinal pigment. An exudative RD results from retinal or choroidal conditions that disturb the RPE or blood-retinal barrier, accumulating fluid in the subretinal space from either the retinal or the choroidal circulation. When a retinal tear forms idiopathically and a detached retina ensues, the fluid accumulated in the subretinal space can stimulate an inflammatory response, leading to increased vascular permeability and leakage of cells and protein into the anterior chamber and vitreous. Therefore, these inflammatory features can mask the primary RD itself.

History The development of RD concepts can be divided into two major periods-early and modern. The early stage (1851-1918) started with the invention of the direct ophthalmoscope by von Helmholtz in 1851. 6 Shortly after that invention, Coccius first observed a retinal break in 1853. 7 Since then, numerous works and debated theories were made in an attempt to find the etiology of RD.8-17 Among those early studies, the theory of vitreous and retinal breaks as the possible etiology of RD suggested by de Wecker and de Jaeger in 1870,12 Leber in 1882,13 and de Wecker in 1888 14 was the representative landmark work. But the theory and its full importance went unrecognized until 1919, when Gonin 18 conclusively confirmed that retinal breaks cause RDs; he demonstrated that sealing retinal tears cures the detachment. Gonin's procedure received widespread acceptance in 1929. Gonin's pioneer work between 1919 and 1935 brings the pathogenesis study and treatment of rhegmatogenous detachment into the modern era. During the lTIodern period (1936-present), major landmark works include the method of intraocular air tamponade to displace the retina toward the eyeball wall and to provide temporary internal tamponade of retinal breaks by Rosengren in 1938 19 ; the development of complete retinal examination through binocular indirect ophthalmoscopy by Schepens in 194720 and 195121; the introduction of scleral indentation ("buckling") by Custodis in 1953 22 ; the method of photocoagulation by Meyer-Schwickerath in 195423 ; the "re-discovery" of modern buckling for treatment of RD by Schepens and colleagues in 195724; the introduction of silicone oils to retinal surgery by Cibis et al in 1962 25 ; the technique of modern vitrectomy by MachelTIer and colleagues in 1971 26 ; athermal buckling by Zauberman and Garcia Rosell in 1975 27 ; the first use of perfluorocarbon liquids in vitreoretinal surgery by Chang in 1987 28 ; and the methods of Nd:YAG laser vitreolysis by Berglin and associates in 1987. 29 In addition to typical features of retinal breaks and

CHAPTER 50: NONMALIGNANT, NONINfECTIOUS

itreous traction, inflammatory response associated with hegmatogenous RD was also mentioned in many of these :arly papers. Usually, the inflammation is mild and does lot affect making the correct diagnosis. Recently, some musual cases of rhegmatogenous RD-associated uveitis vere reported, and the importance of inflammation as m accompanying clinical sign of RD and its possible liagnostic confusion with other clinical entities was gradlally stressed and gained attention. 30-34

:pidemiology [he observed incidence of rhegmatogenous RD varies )ecause of the difference in inclusion criteria and meth)ds of data collection. An annual incidence of 12.4 to l7.9per 100,000 population was reported in the United 'tates. 25-37 In Europe, the earliest report of the incidence vas 3.8 per 100,000. 38 Recent reports, however, suggested hat it is higher, with an annual incidence of 6.9 to 14 Jer 100,000 population. 39-41 The incidence ofRD presents m increasing tendency in the United States and Europe; t has been suggested that increasing cataract surgery night be a significant factor for increasing the long-term :umulative probability of RD.37, 40 An incidence of 8.9 to 10.8 per 100,000 population vas reported in IsraeL 42 Two early reports from Mrica 'evealed a low incidence rate, from 0.5 to 1.0 per 100,000 )opulation. 43 ,44 In Asia, an annual incidence of 10.4 and lO.5 per 100,000 population was reported from Japan 45 m.d Singapore,46 respectively. Although there are no reliable studies o~ racial differ~nces in the incidence of rhegmatogenous RD, it has )een suggested that the incidence is lower in blacks than n whites,43, 44, 47, 48 which may be related to the relative nfrequency of myopia in blacks. In Asia, the incidence Nas the highest in Chinese because of a higher prevalence )f myopia, followed by Malays, and lowest for Indians. 46 \fo apparent gender preference was reported in smne ;tudies,35, 36, 39, 49 although sex predilection at some age sroups was found in others. 37, 40, 41, 45, 46, 50 Men were more ::>rone to retinal detachment than women, which is ex::>lained by the greater liability to trauma in men. 51 - 60 However, a higher risk in women confined to the noncraumatic rhegmatogenous RD group was also reported. 40 The incidence of RD increases after the age of 20 and progresses until its zenith in the 50- to 60-year-old age sroup for both sexes. 35- 37 , 51-55, 61-63 Relatively few cases vvere seen after the age of 70 years. The mean age of the ::>verall rhegmatogenous RD population was reported to be ab9ut 54 to 60 years in the United States35 ,36 and Europe. 39 ,40 In Israel, the average age at detachment was reported to be 48 years. 40 In Asia, the mean age was 70.2 years old for aphakic RD, and the highest risk for nontraumatic phakic RD was in the 60- to 69-year-old age s-roup for both sexes. 45 Chinese showed the highest annual incidence of RD operations in the 40- to 50-year-old category.46

OVU"'lI,';::»'I.J'UlII::In._1UI11::

SYNDROMES

stimulation resulting from vitreoretinal traction or tearing of the retina. 64-68, 70 The floaters often indicate vitreous hemorrhage that occurs when papillary or retinal vessels are torn by vitreous traction or when retinal vessels crossing retinal tears are avulsed. Many individuals with myopia also report vitreous floaters without RD or retinal breaks; those patients, however, note them chronically. Some patients may never experience floaters or flashes, presenting instead with the symptoms of a shadow or curtain with visual field loss or decreased visual acuity.66, 67 Decreasing visual acuity can be secondary either to macular detachment or to ocular media clouding by pigment floaters, vitreous hemorrhage, or inflammatory debris. A peripheral retinal break with a relatively immobile corrugated fold is a· typical and primary sign of rhegmatogenous RD on fundus examination. The retinal break can commonly present as a full-thickness flap tear or a horseshoe tear caused by vitreous traction or by an atrophic round or oval hole. Almost all patients with rhegmatogenous RD have posterior vitreous detachment (PVD) ,66,67 and approximately 15% of all patients with acute PVD may develop a retinal tear. 69- 74 Vitreous hemorrhage can also be seen and is found in 13% to 19% of rhegmatogenous RD patients with acute PVD,69-72 and relative hypotony is common in patients with rhegmatogenous RD.30, 31, 34, 75-79 Other clinical features that may masquerade as uveitis include pigment cells ("tobacco dust") 80, 81 and inflammatory cells in the anterior chamber and vitreous. Some patients with asymptomatic or not recently symptomatic rhegmatogenous RD may show a substantial number of cells in the vitreous. 73 ,82 Some degree of intraocular inflammation is always associated with rhegmatogenous RD, which may present as iridocyclitis or anterior uveitis,6'1, 65, 81 posterior uveitis, and panuveitisY' 80 In severe cases, patients may develop aqueous flare, concentric iris folds, deepened anterior chamber, iridodonesis, posterior synechiae, hazy vitreous or vitreous cells, and detachment of the ciliary body and choroid with hypotony.30, 31, 34 It is not surprising, therefore, that misdiagnoses are often made when dealing with this clinical entity. Pigmented cells in the aqueous humor may lead to improper grading of anterior chamber inflammation. In some cases, the obvious features of inflammation associated with rhegmatogenous RD can lead to misdiagnosis as uveitis, and the detachment may be completely overlooked. It is important to stress here that all cases of persistent ocular inflammation with relative hypotony and a substantial number of vitreous cells should be viewed with a high index of suspicion for a possible underlying rhegmatogenous RD. Longstanding RD with peripheral retinal tears can also present as an anterior cellular reaction with accompanying elevation of ocular pressure (Schwartz' syndrome).77. 83-86 If the detachment is not detected, the patient may also be mistakenly treated for uveitis or glaucoma.

Clinical Features The main symptoms of rhegmatogenous RD include floaters, flashes (photopsia), shadows or blind areas, and clouded vision. Lightning flashes last an instant or a few seconds and probably represent mechanical retinal

Pathogenesis and Etiology The most causative conditions that may increase the risk of retinal breaks and subsequent RDs include PVD, lattice degeneration of the retina, myopia, especially axial myo-

CHAPTER 50:

pia, cystic retinal tufts, degenerative retinoschisis, idiopathic retinal dialyses, a history of previous cataract surgery and trauma to the globe. PVD usually results from age-related vitreous liquefaction (syneresis) .74,87-92 Liquefaction of the posterior part of the vitreous and its detachment from above results in increased mobility of the posterior part of the vitreous and forms the posterior vitreous detachment. When PVD occurs with the traction forces shortly thereafter, the traction forces are transmitted to physiologic and pathologic areas of firm vitreoretinal adhesion. These areas include the vitreous base, margins of lattice retinal degeneration, cystic retinal tufts and retinoschisis, retinal dialyses, and paravascular retina. Retinal tears often occur when the traction forces are exerted on these pathologic areas. Fluid coming from the liquefied vitreous then seeps through the retinal tears and accumulates in the subretinal space and elevates the retina. The incidence of PVD is higher with increasing age 74 and in individuals with myopic eyes,86, 93, 94 cataract surgery, and YAG capsu10tomy.35, 60, 69, 95-106 Intraocular inflammation, diabetes, trauma, and certain hereditary conditions also increase the incidence of PVD. Lattice degeneration typically consists of equatorially oriented patches of crisscrossing white lines. The peripheral degeneration area is thinned and associated with liquefaction of the overlying vitreous gel and strong vitreoretinal adhesions along the margin of the lesions. Atrophic round holes are often present within the areas of lattice degeneration. 107 It is wore common in myopic eyes,108-111 especially in highly myopic eyes with increasing axial length. 69 , 110, 112,-117 Lattice degeneration causes 21 % to 30% of rhegmatogenous RDy8, 119 Myopia increases the incidence of both lattice degeneration 69,113 and PVD,69, 120 and causes 34% to 40%60,94,121 of rhegmatogenous RD. Some asymptomatic retinal breaks that cause clinical RD are mainly seen in young myopic patients,12 older patients,117, 122 and most aphakic eyes. Other factors such as chOl~oidal ischemia,123 thinning of the myopic retina,121 genetic factors, or unknown variables may also be related to development of retinal breaks and detachment in myopic eyes. Cystic retinal tufts are congenital small discrete white lesions. Histologically, they are composed of degenerated retinal cells and some glial proliferation. Cystic retinal tufts are commonly associated with retinal breaks 12 4-127 and may be responsible for approximately 10% of clinical rhegmatogenous detachments. 128 Age-related degenerative retinoschisis occurs when the cysts of peripheral cystoid degeneration coalesce,129-132 with resultant lamellar splitting of the retina, and most frequently precedes hole formation. Degenerative retinoschisis is associated with RD in 2% to 6% of rhegmatogenous RD cases. 133, 134 Aphakic and pseudophakic. eyes increase the risk of RD because of an increased rate of vitreous liquefaction, posterior vitreous detachment, vitreous loss and a destabilization effect on the vitreous. Approximately 23 % to 40% of rhegmatogenous detachments occur after cataract extraction,35, 97-100 and the risk is especially high if the eye is also myopic. Nd:YAG laser capsulotomy after extracapsular cataract extraction also increases the rate of RD,100-105

NONINFECTIOUS MASQUERADE

suggesting a direct destabilization effect on the hyaluronic acid infrastructure of the vitreous gel and the rapid loss of hyaluronic acid content. Blunt trauma often produces a traction force at the vitreous base or other pathologic areas, which predisposes to rhegmatogenous RD in 7% to 16% of cases. 135 The incidence is especially high in an eye with high myopia or lattice degeneration. When a retinal tear forms as a result of the vitreous traction on pathogenic areas of retina, an RD ensues. Retinal pigment granules disperse in the vitreous or anterior chamber from the RPE through the retinal tear and mimic a feature of intraocular inflammation. RD itself in some way also triggers an inflammatory response. It has been suggested that vitreous in contact with the pigment epithelium stimulates an inflammatory reaction in the choroid and subretinal fluid, causing uveitis. 136 Other studies indicate that some histamine or histamine-like substances in the subretinal fluid might be elaborated from the mast cells in the uvea and incite the inflammatory response. 30, 137 Ocular inflammation adversely increases capillary permeability, causing leakage of fluid and protein into the extravascular space, hyperemia of the choroid and ciliary body, eventual ciliary body and choroidal detachment, and subsequent hypotony.138 Therefore, some degree of inflammatory response is always associated with rhegmatogenous RD.

Diagnosis Diagnosis of RD depends on a detailed ophthalmic history and a thorough ophthalmic exalnination. Ophthalmic history should include the following: 1. Present illness-its specific symptom and duration. Light flashes or a sudden onset of floaters, or both, followed by progressive visual field loss of one eye are typical and important symptoms that strongly suggest rhegmatogenous RD. 2. Pre-existent eye diseases. Many pre-existent factors predispose to the development of rhegmatogenous RD; these include PVD, aphakia, high myopia, lattice degeneration and retinoschisis, retinal cystic degeneration, a family history of RD, prior RD in the patient's other eye, and others. 3. Current and past head or eye trauma. History of trauma should be suspected in all cases of unilateral aphakia, particularly when the ~ontralateral eye is completely normal. 4. Family history. There is a significantly increased incidel1Ce of rhegmatogenous RD in some pedigrees with myopia and lattice degeneration. Because cataract surgery, YAG laser capsulotomy, and trauma itself can cause intraocular inflammatory reaction, when taking an ocular history, clinicians must have a clear mind that these features can also mask an underlying ocular disease. A detailed ophthalmic examination should include visual acuity and visual field tests, slit-lamp examination, indirect ophthalmoscopy, and special tests. The visual acuity may decrease if vitreous hemorrhage, iridocyclitis, vitritis, or detachment of the macula occur. The defects in visual field correspond to the area of

CHAPTER 50: NONMAUGNAN"f, NONINfECTIOUS MASQUERADE SYNDROMES

detached retina and may also result from a dense vitreous hemorrhage associated with a retinal tear. Slit-lamp biomicroscopy evaluations will stress anterior segment, anterior and posterior vitreous gel, and measurement of the intraocular pressure (lOP) by applanation tonometry. Pigment debris within the anterior chamber and anterior vitreous is regularly seen in patients with rhegmatogenous detachment. 80 ,82 Other cells in the vitreous are also commonly present. The cells may be red cells from torn retinal blood vessels or inflamluatory cells (white blood cells and macrophages) from coincident iridocyclitis. Liquefaction of the central vitreous gel followed by collapse and forward displacement of the posterior cortical vitreous can be visible with the slit lamp in most cases of rhegmatogenous RD.139,140 The ocular pressure is expected to be somewhat lower in the eye with detachment. 7o ,78, Hl-145 Sometimes the involved eye is hypotonous, in which case choroidal detachment may be present. The lOP may also be ekvated in eyes with RD, and an association between open-angle glaucoma and detachment has been demonstrated. 76 , 146-151 Examination of both eyes with dilated indirect ophthalmoscopy is important in the evaluation of patients with uveitis. The "uveitis" may be secondary to a peripheral retinal break and RD. The presence of a detached retina and a retinal break is the typical sign of a rhegmatogenous RD. However, 5% to 10% of cases of true rhegluatogenous detachments have no definite retinal break discovered on clinically evaluation. The detached retina is slightly opaque and often has a corrllgated appearance. The subretinal fluid is usually clear and nonshifting. In certain cases, it may be difficult to diagnose and localize retinal breaks and detached retina because of opaque media such as vitreous hemorrhage. Ultrasonography and electroretinography are most valuable for these cases. Because some degree of intraocular inflammation 3o ,31, 34,80 is often present in rhegmatogenous RD cases and occasionally may be severe,30, 31, 3'1 the primary disorder can masquerade as uveitis. The diagnosis and subsequent treatment may be missed or delayed because the masquerade features resulted from the RD itself. Today, it is not surprising for us to see that, in many routine eye exams, clinicians so easily and simply classify some intraocular inflammation with no special or obvious finding of systemic disease as idiopathic uveitis, neglecting to look further for other possible underlying ocular diseases. This incorrect diagnosis may then adversely playa misleading role for other ophthalmologists when a patient who has an initial misdiagnosis seeks further consultation from other ocular services. Accurate diagnostic strategies are very important for any disorder that may present some degree of intraocular inflammation and may masquerade as uveitis. The correct diagnostic strategies will stress a detailed ophthalmic history including predisposing conditions and clinical appearance of the disease at presentation, careful ophthalmic examination, and ultrasonography. The original diagnosis should be reviewed and the effects of any treatment must be re-evaluated periodically. If a treatment is ineffective, re-evaluation of the previous diagnosis should be considered immediately.

Dia.gnosis

,

Because of the inflammatory characteristics associated with rhegmatogenous RD, the differential diagnosis should be considered between rhegmatogenous RD and an inflammatory disorder. Findings on the ophthalmic examination, including pigment and inflammatory cells in the anterior chamber and vitreous, are consistent with either a rhegmatogenous RD or an inflammatory disorder. In the absence of previous intraocular surgery or a choroidal malignant melanoma, pigmented cells or "tobacco dust" in the anterior chamber and vitreous and the presence of PVD are almost pathognomonic of RD or retinal tear 77 , 83, 84 In addition, the presence of deepened anterior chamber, PVD, iridodonesis, detachment of the ciliary body and choroid with relative hypotony, and a typical break in the retina (Fig. 50-1) all favor the diagnosis of a rhegmatogenous RD. Other diagnoses, including an inflammatory or exudative RD, traction detachment, and choroidal effusion syndromes, should also be considered. Exudative RD is caused by exudation of fluid from the choroid or retina in the absence of retinal breaks. Neoplasms such as melanoma30 , 152 and metastatic carcinoma, and inflaluluatory diseases such as Harada's disease 153 and scleritis3 are the leading causes of exudative detachluents. The choroidal neoplasm can usually be found by indirect ophthalmoscopy and confirmed by fluorescein angiography and ultrasonography. In addition to the mass, other features common to exudative RD, such as shifting fluid, a biomicroscopically clear vitreous, and the absence of retinal break, are likely to be distinguished from rhegmatogenous RD. Vogt-Koyanagi-Harada syndrome (VKH) is a bilateral uveitis associated with headache, malaise, tinnitus, nausea, and meningeal inflammation. Exudative RD is also an essential feature of VKH. Most cases of VKH respond well to high doses of systemic corticosteroids. Posterior scleral inflammation can cause exudative RD.154,155 It can be differentiated by showing a thickened sclera on ultrasonography,154 with accompanying pain.

FIGURE 50-I. Peripheral retinal detachment. The detachment has progressed to the point at which it is now quite obvious. However, it has existed for approximately 6 weeks and has slowly progressed to this point. Once the detachment was repaired and the peripheral retinal break was successfully closed, the "chronic uveitis" vanished without further (medical) treatment. (See color insert,)

CHAPTER 50:

The inflammation usually responds well to corticosteroids or nonsteroidal anti-inflammatory drugs. 154 The uveal effusion syndrome is an inflammatory condition characterized by peripheral choroidal separation and secondary RD.156-159 The detached retina shows the characteristic smooth contours and shifting fluid. In rhegmatogenous RD, the retina shows a tear and a relatively immobile corrugated surface, and the vitreous usually presents inflammation. Vitreous membranes caused by proliferative retinopathies or penetrating injuries can pull the sensory retina away from the pigment epithelium, causing a traction RD. In most cases, the causative vitreous membrane can be seen ophthalmoscopically or with the three-mirror lens. The detachluent may resolve after the traction ligaments are relieved by vitrectomy.

Treatment The goal of rhegmatogenous retinal reattachment surgery is to bring the retina into contact with the choroid and sclera, to establish a chorioretinal adhesion around all retinal breaks, and to offset all important vitreoretinal traction. Operative procedures include the alteration of scleral contour, the establishment of chorioretinal adhesions, and the drainage of subretinal fluid. The scleral contour may be altered by scleral buckling techniques, and retina can be pushed outward to contact choroid and sclera by the application of a variety of foreign materials such as intravitreal gas, silicone oil, and hyaluronic acid. Cryotherapy, diathermy, and photocoagulation may achieve chorioretin~ adhesion reaction. Subretinal fluid can be drained from one or more sites internally or externally, and vitreous traction can be released by vitrectomy. Intraocular inflammation associated with rhegmatogenous RD often clears postoperatively if the retina is successfully reattached. In eyes with marked inflammation, preoperative steroid treatment is suggested. Surgery must be postponed in some cases with severe inflammation, hypotony, and choroidal detachment until these are reversed with corticosteroid treatment. Suprachoroidal fluid is drained intraoperatively and a balanced salt solution is injected into the vitreous cavity in an eye with sizable choroidal detachments. 16o

NONINFECTIOUS MASQUERADE SYNDROMES

complications. About 37% to 50% 100,163,166-168 of patients with successful reattachment Iiow can achieve final visual acuity of 20/56 or better. The prognosis of surgery and visual improvement is very poor in rhegmatogenous RD complicated by severe ocular inflammation, choroidal detachment, and hypotony.30,34

Conclusions Rhegmatogenous RD is usually caused by retinal breaks, in which fluid from the vitreous cavity seeps through the breaks, accumulates in the potential subretinal space, and separates the retina from the RPE. Peripheral breaks with a relatively immobile corrugated fold in retina are a typical feature of rhegmatogenous RD. Other clinical manifestations include posterior vitreous detachment, vitreous hemorrhage, and mild intraocular inflammation. Intraocular inflammation may be severe in some cases. Slight proteinaceous flare and occasional cells in the anterior chamber and vitreous are common in eyes with rhegmatogenous RD. Eyes with more severe inflammation may show intense flare in the anterior chamber and debris in the vitreous. Therefore, the features of intraocular inflammation with rhegmatogenous RD can masquerade as uveitis. Misdiagnosis can be avoided by a detailed ophthalmic history and thorough ocular examination. Knowledge of the clinical features of each disease, the possible masquerade syndromes, and the diagnosis and differential diagnosis between an ocular inflammatory disorder and other ocular or systemic diseases is important for making a correct diagnosis.

RETINITIS Definition

Prognosis

Retinitis pigmentosa (RP) is a group of hereditary retinal degenerative diseases characterized by progressive degeneration of retinal photoreceptors with associated pigmented epithelial changes, which often manifest as bilateral night blindness, progressive visual field loss, and abnormal or nonrecordable findings on electroretinogram (ERG). Classification of RP is important and complicated. At present, there is no generally agreed-upon classification for RP disorders.169-179 In general, RP can be divided into two large groups: primary and secondary RP.180 Primary RP is a disease confined to the eye with no other systemic manifestation, which can include rod degeneration, cone degeneration, and congenital onset disorders such as Leber's congenital amaurosis. Secondary RP is a pigmented retinal degeneration associated with single or multiple organ system diseases. The most common secondary forms of associated RP include Usher's syndrome, Bardet-Biedl syndrome, Senior-Loken syndrome and abetalipoproteinemia. 180

By arriving at the correct diagnosis and using the appropriate application of surgical methods, retinal reattachment can be achieved in more than 90% of cases of rhegmatogenous RD. 160 , 161 Ten to twenty percent of eyes require more than one operation to reattach the retina.162-165 Visual recovery depends on the extent of macular damage caused by the detachment and any surgical

Either primary or secondary RP can be inherited as an autosomal recessive, autosomal dominant, or X-linked trait, based on the features of genetic inheritance. 18o There is also another group named simplex RP or nonhereditary RP, which presents as an isolated case. Sometimes, the term multiplex is also· used to describe this group of RP when more than one person is affected (e.g.,

Complications Complications usually include intraocular inflammation, glaucoma, hemorrhage, and later development of proliferative vitreoretinopathy. Visual acuity may be damaged if the detachment involves the macula. In some complicated cases, the rhegmatogenous RD may initiate a series of exaggerated pathophysiologic changes in the eye, with the severe inflammation leading to choroidal detachment and hypotony.

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NONINFECTIOUS MASQUERADE SYNDROMES

in a sibling of a family).181 SimplexRP is frequently seen in the diseases of pigmented paravenous retinochoroidopathy, nonspecific RP, unknown RP type, pericentral RP, some rod-cone degeneration, and rod degeneration forms. RP can also be subdivided into two broad categories: typical and atypical,182 based on clinical mode of inheritance, age of onset, rate of progression, severity, and ERG findings. Typical RP refers to those patients with an obvious hereditary . pattern characterized by the onset of night blindness in childhood or young adulthood, progressive contraction of the peripheral visual field, the characteristic pigmented retinopathy, and abnormal or extinguished ERG. Atypical forms of RP often present clinical symptoms and signs that are closely related to typical RP but are often incomplete forms of the disease such as sector RP, retinitis pigmentosa sine pigmenti, and retinitis punctata albescens. 182 The hereditary pattern can be complete or uncertain in atypi~al RP. Not only is the classification of RP complicated but the clinical features of RP are also various. Except for the typical symptoms and pigmentary retinopathy, patients with RP can also frequently exhibit some features consistent with underlying inflalnmatory disease such as pigmented vitreous cells, posterior subcapsular cataract, and cystic macular edema.183-185 Clinically, vitreal cells and macular edema may occur in all age groups and in patients with typical pigmentary changes, but with a higher incidence in younger patients and in the cases with minimal retinopathy.182 These features can'inasquerade as ocular inflammatory disease, especially in some patients with no defined hereditary history. For this reason, today, with the increase of some isolated or atypical cases, RP has been considered as one of the masquerade syndromes of ocular inflammatory disease.

History The development of RP concepts is consistent with a number of clinical observations, fundus examinations, and the hereditary nature of the disease over the years. The early observations of familial complicated night blindness were first made by Ovelgun in 1744. 186 Since then, other clinical features, including poor vision and pigmented lesions in the retina, were also reported. 187, 188 Shortly after the invention of the ophthalmoscope by von Helmholtz in 1851, some cases that most assuredly represented the characteristics of RP were further confirmed. 189 , 190 But no defined term was offered until 1855 and 1857, when Donders first used the term retinitis pigmentosa to describe the disease. 191 , 192 Other terms, such as tapetoretinal degeneration,193 pigmentary retinopathy, primary pigmentary retinal degeneration, and rod-cone dystrophy, have also been used to describe the disorder, but the term retinitis pigmentosa is still widely accepted as describing the entire class of inherited pigmentary degenerations of the retina. The hereditary and consanguineous nature of RP was subsequently noted169 , 194-197 soon after the recognition of the clinical features of RP. Over the years, the clear hereditary pedigree of typical RP, including autosomal recessive, autosomal dominant, and X-linked transmission, has been further reported and confirmed in more

studies of large populations in various parts of the world. 172 , 174, 198-221 Abnormal to extinguished ERG associated with RP was also observed by Karpe in 1945. 221 Since then, numerous ERG documentation studies220-238 and other spectral sensitivity studies, including the early receptor potential of ERG,239 electro-oculogram (EOG) ,240-245 dark adaptation,246-250 perimetry,251-254 psychophysical flicker testing,255,256 and color vision,257-260 have been done, with a peak period for these types of studies from the 1950s to the 1980s. From the early 1970s to the present, ultrastructural and genetic studies of RP explored the pathogenesis of the disease. During this period, one of the most striking concepts for RP pathogenesis was dysfunction of the integration between retinal photoreceptors and pigment epithelia. It has been suggested that micrometabolic disorders of the outer segment portions of the photoreceptors and dysfunction of RPE in the maintenance of photoreceptor cell homeostasis may cause degeneration, either primarily or secondarily, of rods, cones, or a combination of both.261-276 . Gene defects and point mutations in the rhodopsin gene on chromosomes 3, 6, 7 and 8 in patients with autosomal dominant retinitis pigmentosa (ADRP) have been reported in many studies.277-282 At present, at least 80 or more genes causing retinal degenerative diseases have been identified. 271-;-318 In addition, advanced studies in immunology also further improve the recognition of immunologic or autoimmunologic processes associated with RP. Some antiretinal antibodies in RP patients have been reported.319-321 It has been suggested that ocular inflammation associated with RP may be due to a secondary immunologic reaction against retinal antigens released into the vitreous as the retina degenerates; and these antibodies might also be related to cystoid macular edema in RP patients.319-325 For this reason, recently, the possible immune mechanism and associated inflammation with RP, especially seen in atypical cases, has been stressed as a possible uveitis masquerade syndrome.

Epidemiology The incidence of RP is estimated to be as high as 1 in 3500 to 4000 worldwide.326-337 In Switzerland,326 a low prevalence of RP was found (1 in 7000), whereas in American Navajo Indians, 1 in 1878 has the disease. 338 In various surveys of the genetic types of RP, the estimates of percentage of autosomal recessive cases of RP have been reported to be from 13% to 69% (average: 41 % in the United States, 15% in England, and 33% in China) .329-332,336, 337, 339, 340 Autosomal dominant RP is believed to account for 10% to 24% of cases (16% in the United States,24% in England, and 11 % in China) .329-332, 336,337,339,340 X-linked RP represents from 5% to 21 % of cases (9% in the United States, 18% in England, and 8% in China) .179, 329-332, 337, 339, 340 Although most RP cases are believed to be genetic, the frequency of silnplex or multiplex cases with no family history of affected relatives has also been reported to range from 15% to 63% (the average across studies is 35% in the United States, 42% in England, and 48% in China) .179,329-332,337,339,340 Some atypical disorders are also often seen in routine eye clinics. The high rate of simplex

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NONINFECTIOUS MASQUERADE SYNDR.OMES

cases and the rising rate of atypical RP cases has increased the diagnostic challenges for clinicians.

or white, with greater visibility of underlying choroidal vessels.340-344 The anterior segment, vitreous, and macula also frequently show abnormalities in patients with RP. Posterior Clinical Features Night blindness is one of the most common early symp- subcapsular opacity is common in most types of RP. The toms in patients with RP. Usually, patients with typical RP vitreous changes include dustlike reflective particles, have poor vision and constricted visual fields in the dark cells, posterior vitreous separation, cottonball-like opacibeginning in childhood or adolescence (autosomal reces- ties, interwoven filaments in the retrocortical space, and sive and X-linked recessive) or young adulthood (autoso- spindle-shaped vitreous condensations.340-344, 352, 353 Astermal dominant). As the disease progresses, patients gradu- oid hyalosis can also be seen. Macular changes may inally lose their far-peripheral field of vision, typically clude early broadening or loss of foveal reflexes; as the leaving a small central field of vision until eventually even disease progresses, cystoid macular edema,185, 313, 354--362 difcentral vision is affected.340-343 Central visual acuity can be fuse retinal vascular leakage,363 wrinkling of the internal seriously affected early in the course of the disease by limiting membrane,184 and macular preretinal fibrosis can cystoid macular edema, macular atrophy, or the develop- also sequentially occur. 185, 189,362,364,365 ment of a posterior subcapsular cataract. 169, 17'1, 184, 185, 343-349 In some patients with RP, the vitreous changes may be Ten percent to 15% of patients may not be aware of the earliest finding, and bilateral macular edema can also symptoms until central vision is affected. 182, 343 In addition, occur in the early stage of the disease. Most patients with some RP patients may have severe myopia and astigma- macular edema have 1 + or 2 + vitreous cells. 182 Because tism, especially seen in X-linked RP and the congenital of these features of anterior chamber cells and macular form.340-344, 3.50, 351 Other complaints such as headache edema, consistent with ocular inflammatory features, it is (53%) and light flashes (35%) can be associated with RP· not surprising that the inflammation associated with RP in the early course of the disease. 352 can masquerade as idiopathic uveitis. In some conditions, At early stages of RP, fundus examination usually re- especially when RP occurs as an isolated case with a veals granularity or tiny focal depigmented spots in the negative family history or in atypical cases in which the midperiphery and far periphery. Retinal vessels may be symptoms and characteristic retinopathy are minimal in relatively normal or mildly attenuated. As the disease the early course of the disease, patients may initially be progresses, widespread hypopigmentation, peripheral seen with only visual loss secondary to ocular inflammapigment migration and clumping, and the characteristic tion and macular edema; the underlying diagnosis of RP bone-spicule pattern of retinal .pigment are consistently may be missed. Therefore, in routine eye clinic examinafound in a midperipheral annular zone of both eyes tions, correct recognition of the features of the disease is (Fig. 50-2). The retinal vessels, particularly the arteries, very important. Because the classification of RP is complicontinue to become more narrow, and the optic disc cated and the clinical features associated with RP are appears waxy and pale. The entire midperipheral and various at different stages, any inflammation involving far peripheral fundus is replaced by dense bone-spicule both eyes with subtle retinal pigmented changes or macupigmentary formations, which present a reticular or lobu- lar edema should be highly suspect as a masquerade lar structural appearance in advanced RP. The retinal syndrome that may be confounding the diagnosis. vessels become quite constricted and appear threadlike. The optic nerve head becomes pale. In some cases with severe RPE loss, the overall fundus may appear yellow Pathogenesis and Etiology RP may result from a primary defect in the rod and cone photoreceptors and dysfunction of retinal pigmented epithelium cells. 366 Numerous histopathologic studies of patients' eyes with RP have corroborated this idea. 265 , 268, 269, 275, 276, 367 In the degenerative area of RP, there is loss of outer segments and a decrease in photoreceptor numbers. Other histopathologic changes include degeneration of the retinal receptor elements; depigmentation of the RPE; migration of RPE cells into the overlying retina, particularly in the perivascular areas; hyalinization and thickening of the retinal vessel walls; diffuse atrophy of the whole retina; and gliosis. These changes are usually most prominent in the midperipheral fundus.265, 268, 269, 273, 275, 366, 367

FIGURE 50-2. Retinitis pigmentosa. Note in particular the bonespicule, mid and far peripheral retinal pigmentary changes, and retinal arteriolar narrowing. This patient had had chronic vitritis for 2 years before the appearance of the characteristic, diagnostic l'etinal pigmentary changes. (See color insert.)

At present, the concept of the photoreceptors as the primary degeneration site in RP has been further supported by advanced molecular biologic techniques. At least 50 or more different mutations in rhodopsin in families with ADRP have been identified.278-320 It has been suggested that alteration and dysfunction of various genes coding for proteins that are specific for the function or structure of the photoreceptor or pigment epithelium

CHAPTER 50: NONMALIGNANT, NONINfECTIOUS MASQUERADE SYNDROMES

can lead to the degenerative changes of these cells and the final common pathologic picture of RP. Ultrastructural studies of the vitreous of patients with RP show the presence of RPE cells; uveal melanocytes; retinal astrocytes; lynlphocytes, which are mostly T cells; and macrophage-like cells. 266 , 368-~'I70 The presence of these inflammatory cells indicates possible immunologic or autoimmunologic processes involved in the pathogenesis of photoreceptor degeneration in RP. Retinal outer segments and pigment epithelia are known to be antigenic,371-375 and an immune response to these antigens may cause an inflamlnatory reaction and retinal edema in patients with genetically determined retinal degeneration. 323 Antibodies directed against photoreceptors,32o-322 elevation of serum IgM,324, 375 the presence of circulating immune complexes, and reduction in the total number of T cells in RP patients have been reported. 37 6-382 It has been suggested that ocular inflammation associated with RP may be due to the increase of-vascular permeability to immune complexes or to a secondary immune reaction against retinal antigens released into the vitreous as the retina degenerates; and this mechanism has also been considered as a. factor in cystoid macular edema associated with RP. Although the exact role of immune or autoimmune responses in the pathogenesis of RP has not been confirmed,171, 291, 292, 345, 346 the features of a variable amount of cellular infiltration in vitreous and the detectable antiretina antibodies associated with RP reported in recent studies have increased the c9mplexity of the disease concepts, and this clearly needs to be carefully evaluated by clinicians dealing with RP patients, because it can Inimic an ocular inflammatory disease.

Diagnosis The diagnosis of RP is based on a complete ocular, systemic, and family history, a thorough ocular examination, and laboratory evaluation. The detailed history should include information regarding the nature of the symptoms, age of onset, progression, systemic associations, and family pedigree.~>40, 343, 352 Bilateral involvement, night blindness, and progressive loss of peripheral vision starting in childhood or adolescence, with a feature of family and consanguinity occurrence, are the typical symptoms and history for considering the diagnosis. 34~1 When the symptoms of blindness or very low vision with nystagmus, sluggish pupillary reaction, and high hyperopia occur at birth, the diagnosis of a congenital form of RP such as Leber's amaurosis is considered. 182, 228, 343, 352 Systemic symptoms, including sensorineural hearing loss, cerebellar dysfunction, various nutritional deficiencies, valvular heart disease or vascular insufficiency, exposure to drugs or toxins,347 and possible immunologic or autoimmunologic processes are most helpful in diagnosing typical or atypical RP associated with systemic disorders (such as Usher's syndrome) and in excluding other diagnoses (infectious disease such as syphilis -or viral infection). Medical or neurologic examination and consultation are recommended in patients with RP associated with these systemic symptoms, in order to avoid misdiagnosis and delayed therapy.181, 343 Abnormal signs of typical RP. on ocular examination usually include narrowed retinal vessels, depigmentation

of RPE, intraretinal bone spicule pigmentation, waxy pallor of the optic discs, and the presence of posterior subcapsular cataract. Vitreous abnormalities, and cystoid macular edema in some cases, are consistent with the diagnosis of RP.340-344 ERG is invaluable in assessing retinal function and progression, and in providing prognostic information for patients with RP. It is clearly useful for all patients in whom the diagnosis of RP is in question. In patients with typical RP, the ERG shows a dilninished amplitude of the a-wave and b-wave in individuals with early disease, or extinguished a-wave and b-wave responses in patients with advanced RP, particularly in the dark adapted state, with a delay in b-wave implicit time. 175 , 221, 228-230, 239, 383-390 Quantitative diminishment of the ERG over time, with comparison of serial visual field testing, especially provides valuable information regarding the course of progression. 337 Progressive visual field loss is one of the cardinal features of typical RP. In the early stage of RP, visual field loss usually begins as a group of isolated ring scotomas in the midperiphery. As the disease progresses, multiple scotomas gradually coalesce to form partial to full-ring scotomata. In advanced disease, the superior and nasal field can be completely lost, leaving a small oval of intact central island of field. 239 ,384, 391, 392 The periodic evaluation of visual field functiori,in RP is most useful for RP diagnosis and differential diagnosis. Other electrophysiologic methods as aids for diagnosis of RP include the dark-adaptation test, the electro-oculogram (EOG), the visually evoked response (VER) , and contrast sensitivity testing. Th-e observed abnormalities of these tests in patients with RP can include low ratio of light peak to dark in the EOG test,241, 242, 244, 256 prolonged dark adaptation thresholds,246-25o and poor contrast sensitivity.251, 253 These tests are not specific and are not recommended when the diagnosis of RP is otherwise clear. Fluorescein angiography can also be valuable in dOCllmenting early deterioration of the RPE in patients with RP, and especially in female carriers of X-linked RP.337,343 It also has a role in the evaluation of patients with possible cystoid macular edema and some atypical pigmentary patterns. 353 Although complete ocular, systemic, and farnily history and other various laboratory Inethods described earlier help in the diagnosis of RP, the challenge for clinicians to make a correct diagnosis is greatly increased with the increasing clinical reports of atypical and isolated RP cases. Many cases present as an atypical form or show nonhereditary family history. These atypical symptoms and signs and negative family history can manifest or mimic the features of other diseases. In general, the possible masquerade features of RP include simplex case presence with a poor hereditary family history, the absence of pigment migration in an initial stage of the disease, shorter duration of symptoms, less severe night blindness, and less impairment of the ERG. Other features include the presence of vitreous cells, posterior subcapsular cataract (PSC) , and cystoid macular edema. Because the visual decrease or loss secondary to vitreous opacity, PSC, or cystoid macular edema may be an initial reason for RP patients to have a routine eye examination,

s

CHAPTER SO: NONMALIGNANT, NONINFECTIOUS MASQUERADE SYNDROMES

when the pigment migration is minimal, these RP patients may be misdiagnosed as having uveitis. Therefore, in routine eye examinations, clinicians must have a high index of suspicion for the possible underlying RP in any patient with persistent visual loss with bilateral ocular inflammation.

Differential Diagnosis There are a number of disorders that may produce a pigmentary retinopathy and mimic RP. Clinically, these disorders are called pseudoretinitis pigmentosa. The main pseudoretinitis pigmentosa cases include retinal infectious or inflammatory diseases; drug toxicities such as chloroquine, thioridazine, and chlorpromazine 393-406; some hereditary vitreoretinopathy diseases such as pigmented paravenous retinochoroidal atrophy; and uniocular retinitis pigmentosa. ISI , 342 Rubella retinopathy, the most common ocular manifestation of congenital rubella, can be mistaken for a panretinal degeneration such as RP. 340 ,407 Rubella retinopathy commonly produces scattered pigmentary deposits, or on occasion, the pigmentation may be bone spicule-like; more often one sees subretinal clumps or salt-and-pepper pigmentation, and the retinal vessel caliber tends to be normal. lSI, 340, 40S The correct diagnosis can usually be established by a combination of clinical features and the ERG, which is either normal or only mildly depressed in rubella retinopathy, but which is almost invariably severely to profoundly abnormal in RP. Some rubella patients can also present with full ~r partial deafness, which can masquerade as Usher's syndrome, but the lack of progression of the visual field does not favor this diagnoSIS. Both congenital syphilis with pigmentary retinopathy and attenuated visual field and acquired syphilisassociated chorioretinitis can mimic the features of RP.IS1, 340,409 However, congenital syphilis usually also includes interstitial keratitis, and pigmentary changes in the fundus appear more patchy and postinflammatory in nature. 340 Most patients with luetic retinopathy have no relevant family history, and the change of visual field is often asymmetric. Moreover, symptoms and signs of underlying systemic disease are usually present. These features, together with positive serology for syphilis, serve to distinguish the disease from RP. Other infectious or inflammatory entities that occasionally result in pigmentary retinopathy are also considered in the differential diagnosis, including measles retinopathy, cytomegalovirus infection, toxoplasmosis, herpes infection, birdshot retinochoroidopathy, advanced cases of Harada's disease, disseminated choroiditis, chorioretinitis, and serpiginous or geographic atrophy. lSI, 340 However, most of these conditions present with asymmetric ocular involvement, and the absence of a genetic component in the nature of the diseases also distinguishes these disorders from RP. lSI Ocular abnormalities resulting from drug toxicities may present with blurring of central vision, poor night vision, a brownish discoloration to the vision, and retinopathy,40~3-406 which can mimic RP. However, nlost patients with drug toxicity retinopathy have a long history of therapy for underlying chronic diseases such as collagen

vascular disorders and arthritis. Most drug toxicity retinopathy appears to regress when the drug is stopped, although continuous progressive cases such as thioridazine and chloroquine toxicity have also been reported. lSI, 404 Pigmented paravenous· retinochoroidal atrophy is a pigmentary retinopathy without a definite inheritance pattern. lSI, 410-415 The cause and pathophysiologic mechanisms of this condition are presently poorly understood, but may represent an acquired response pattern to an infectious or inflammatory disease.412-419 Almost all of the cases are sporadic.341 The characteristic fundus appearance is that of pigmentary changes closely associated with retinal veins. 341 The ERG in this disease is usually only mildly to moderately abnormal, if at all,340, 414, 415, 419-421 but the EOG is usually abnorma1 420 and can be severely SO.421 The features of isolated presence and paravenous retinopathy are the criteria for correct diagnosis. Unilateral pigmentary retinopathy exhibits regional or generalized loss of the RPE with migration into the retinallayers. The most common cause of unilateral pigmentary retinopathy is traumatic injury. lSI, 340, 422 The positive traumatic history and uniocular involvement can differentiate this condition from RP.

Treatment Because a definitive or effective therapeutic strategy has not been established for RP, the main efforts in management of RP include improvement of visual function, periodic routine ocular examination and evaluation, and psychological and genetic consultation. 32s ,340, 342,343,423 Most patients can benefit from the treatment of complications such as refractive errors and cataracts and from use of a variety of optical aids for peripheral visual loss and preserved central vision. 32s, 342, 3'13, 414 In RP patients with cystoid macular edema (CME) , peribulbar or oral steroids and carbonic anhydrase inhibitors (acetazolaInide and methazolamide) can be considered to reduce the edema and improve visual acuity. 340, 42'1-426 Periodic visual field and ERG evaluation with conlpassionate explanation of visual field defects can help patients appreciate the rate of progression and hence plan for future disability.340 Psychological consultation, genetic counseling, and support groups are often of great benefit for patients to gain more knowledge about the disorder and learn various skills for handling low vision. lSI, 340 Combined deficiency of vitamins A and E may cause nyctalopic and progressive retinal degeneration in humans. 427 ,42S Vitamin A administered orally or by injection has been used for many years as therapy for RP.429 However, the effect of vitamin A treatment for RP is still controversial,32S, 430-431 and at present, there is no proven effective treatment to slow the loss of visual function in patients with retinitis pigmentosa. 432-434 It is conceivable that vitamin A therapy is helpful in retinal degeneration from abetalipoproteinemia.435-437 Large doses of vitamin A have been reported to return dark-adaptation thresholds and ERG responses to normal in the early stages of this disorder. 43s Vitamin E has also been advocated to prevent the progression of this retinal degeneration. 439

50: NONMALIGNANT, NONINfECTIOUS MASQUERADE SYNDROMES

Complications/Prognosis Cataract and CME can occur with RP. Recurrent serous detachment of the pigment epithelium and retina can also occur as a complication in patients with RP.18l, 3'10 RP's chronic course extends over many years. 18l , 340 Eventually, patients with RP may experience profound visual loss and blindness in middle or later life.

Conclusions Retinitis pigmentosa is a group of hereditary retinal degenerative diseases characterized by progressive degeneration of retinal photoreceptors with associated piglnented epithelial changes, which often first manifest as bilateral night blindness, progressive visual field loss, and an abnormal or nonrecordable ERG. RP can occur as a primary disorder inherited in an autosomal dominant, autosomal recessive, or X-linked recessive manner, or it may occur in systemic diseases that usually present as an autosoma~ recessive pattern. However, clinical observation has revealed that more than 50% of cases of RP occur as simplex cases with no family history of the disorder. In addition to the characteristic fundus changes (narrowed retinal vessels, depigmentation of RPE, intraretinal bone spicule pigmentation, waxy pallor of the optic discs), patients with RP also have other signs, including posterior subcapsular cataract, vitreous cells, and cystoid macular edema. The vitreous changes and macular edema can occur in the early stage of RP, and patients with RP may initially be seen with only vis-cial loss secondary to the media opacity and edema. Clinically, because these initial symptoms and signs associated with RP are consistent with features of uveitis, the disease can be misdiagnosed as uveitis. Especially with the increase in the number of nonhereditary cases and atypical cases that· have less severe symptoms of night blindness and minimal retinopathy, the masquerade features of these atypical presentations have greatly challenged the ability of clinicians to establish a correct diagnosis. It is important to stress here that clinicians must be suspicious that any persistent visual loss with bilateral ocular inflammation and minimal pigment changes might represent RP. Further evaluation and examination, as well as retinal· function evaluation, are crucial in clarifying the suspicious initial diagnosis and in excluding other entities.

INTRAOCULAR

BODY

Definition A foreign body within the eye after a penetrating ocular injury is called intraocular foreign body (IOFB). The site of an IOFB varies with its point of entry and velocity. IOFBs may lodge in both the anterior segment (cornea, anterior or posterior chamber, anterior 'chamber angle, iris and ciliary body, lens, and anterior vitreous) and the posterior segment (choroid, vitreous, retina, and optic nerve). Most IOFBs are magnetic (iron, steel, nickel)440 or nonmagnetic (aluminum, copper, magnesium, lead, silicon and zinc, gold, and silver) metals and are associated with activities involving striking metal against metal 44l -443 or the use of motorized machines. 444 Other

materials, such as vegetable material (thorn, wood, soil) and non-magnetic substances (glass, plastic, stone, coal, sand) may also be found. 44l , 443, 445-449 The size of retained IOFBs varies, but as a general rule, they are usually small and sharp, thereby leaving a relatively small entry site that may be self-sealing. 442 ,448 Retained IOFBs can cause various degrees of inflammation. Persistent anterior or posterior uveitis is one of the most common complications associated with IOFBs. It has been reported tllat the inflalnmatory feature secondary to an IOFB may masquerade as uveitis. 450 , 451 Therefore, intraocular foreign bodies should always be considered in the differential diagnosis of uveitis.

History and Epidemiology Retained intraocular foreign bodies have been reported since the early 1800s. 448 As social and industrial economies developed, ocular injuries have become so common that their social and economic burdens involving a huge cost in human unhappiness, economic inefficiency, and monetary loss have received a great deal of attention by ophthalmologists over the past 3 decades. 44 1, 448, 452 Epidemiologic data concerning intraocular foreign bodies are incomplete and not well organized in the ophthalmic literature, but studies of general injuries have been investigated. It has been reported that in the United States, approximately 2.4 million general ocular injuries occur each year. 453 ,454 The annual incidence of general ocular injuries was estimated to be 7.7 to 13.2 per 100,000 population. 455-459 A report from other countries indicated an annual incidence of 8.1 per 100,000 individuals in Scotland,460 6.1 per 100,000 in Sweden,46l and 15.2 per 100,000 in Australia. 462 In Singapore, an annual incidence rate of open globe injury was 3.7 per 100,000 population, and nearly 15% of open globe injuries were associated with an IOFB.463 A study on IOFB has shown that 15% of IOFBs after a penetrating injury may lodge in the anterior chamber, 8% in the lens, and 70% in the posterior segment. 448 There are high rates of ocular injury in young adults,464-467 with a peak age-incidence from about 18 to 25 years of age and an additional peak rate after age 70. 456 ,458 Males have a higher incidence than females. 455-459,468-470

Clinical Features The clinical features following the entrance of a foreign body into the eye vary with the size, composition, and location of the particle concerned. Most foreign bodies are relatively small and sharp, and the globe is not disorganized. Patients can have a transient stinging sensation with a history of a high-risk activity such as hammering metal on metal. Little pain may be experienced at the time of impact. 448 If a particle is large, vision may be immediately blurred owing to the collapse of the anterior chamber, or lost owing to an intraocular hemorrhage either into the anterior chamber or the vitreous. If the particle is small, no further symptoms may arise, and the patient's vision may remain normal for weeks or years. Unless the entry wound is extensive, it usually heals rapidly. Patients with an IOFB mayor may not have a clinically detectable corneal or scleral perforation site or a readily detectable intraocular foreign body. A corneal

CHAPTER 50:

wound, however, always leaves a permanent track, and although it may eventually become inconspicuous, it can be seen by slit-lamp biomicroscopy. Seidel's test can be used to evaluate a corneal wound. 443 A conjunctiva-scleral wound tends to become invisible unless it has been of considerable size, when its presence may be betrayed by the migration of uveal pigment to the surface. 448 Other possible associated signs of IOFBs, including iris hole, localized iris hemorrhage, iris distortion or transillumination defect, an irregular pupil, rupture in the lens capsule, cataract, vitreous hemorrhage, and decreased lOP, may also be detected by slit-lamp biomicroscopy. When a foreign body in the anterior or the posterior segment is irritative, an anterior or posterior uveitis can be excited. A particle in the vitreous may cause the gel to degenerate and become turbid. Small vitreous hemorrhages can eventually become organized into a fibrous band. The contraction of the balid may eventually lead to a detachment of the retina, which ultimately causes general distortion, disorganization, and atrophy of the globe. When a foreign body strikes the retina and the choroid, a retinal tear can occur; the vitreous usually becomes adherent to the wound and fills the gap by a plug of newly formed fibrous tissue. The foreign body becomes partially or completely encapsulated. Occasionally, the foreign body may lodge in the optic disc and cause an inflammatory reaction involving the optic nerve. The inflammatory reaction can also produce an exudative proliferation of fibrous tissue around the optic disc and cause further damage to the opti't: nerve. Metallic foreign bodies such as iron and copper are electrolytically dissociated or react with the tissue-fluids to form decomposition products, usually by oxidation, and tend to cause specific toxic reactions such as siderosis and chalcosis. Siderosis affects virtually all ocular _structures, but the most characteristic changes involve the iris, lens, and retina, causing rusty brown deposits and discoloration in corneal stroma, iris, and lens, and degenerative pigmentary changes of the retina. 442 , 448, 471 Other signs include mydriasis, uveitis, optic disk hyperemia, and pallor,443 and narrowed arterioles can also occur. Chronic open-angle glaucoma can be a complication of siderosis due to iron-containing phagocytes and cell debris blocking the trabecular meshwork. The clinical feature of chalcosis includes a greenish blue ring in the peripheral cornea (Kayser-Fleisher ring), a sunflower anterior subcapsular cataract, metallic refractile particles in the aqueous humor, a greenish coloration of the iris and sometimes the vitreous, and a brilliant and highly refractile deposit on the surface of the retina, usually in the macula.442, 448, 472 Most foreign bodies, especially nonorganized particles, can be chemically inert for an indefinite time,441, 462, 464-475 sometimes becoming encapsulated in the eye, with tolerance of eye tissues toward the 'presence of the foreign body. The tolerance of the separate tissues of eyes varies considerably. The uveal tissues, especially the ciliary body, usually show the greatest reaction to injury of any kind, even though the foreign body is inert. This reaction may slowly and cumulatively develop into a chronic and persistent uveitis, which can eventually lead to atrophy and shrinkage of the globe with complete loss of func-

NONINFECTIOUS MASQUERADE SYNDROMES

tion. 448 The clinical picture of uveitis secondary to an, IOFB can present with ocular pain, redness, photophobia, fine keratic precipitates, fibrin dusting of the endothelium, anterior chamber, cells and flare, 450 and localized imprints with pigmentary degeneration associated with vitreous opacities,447 as well as local inflammatory reactions mimicking granulomatous uveitis. 476 In many situations, the insidious and recalcitrant uveitis may be the only major complaint. Significant other clinical signs in patients with an IOFB,- especially when the foreign particle is inert and tolerated, may be minimal, and an ophthalmologist may make a misdiagnosis of idiopathic uveitis, particularly when patients have no recall of recent ocular trauma.450, 451 It is particularly important to stress here that any unexplained and persistent uveitis, especially when the uveitis is refractory, should raise suspicion for the possibility of an IOFB.

Pathogenesis and Pathophysiology Mechanical and chemical or toxic, as well as inflammatory, injuries are the major pathophysiologic mechanisms of the eye to IOFBs. This pathophysiologic reaction of eye tissues varies within wide limits with the composition of the particles. 448 Most nonorganic and nonmagnetic substances (e.g., stone, rock, sand, coal, glass, plaster, rubber, porcelain, carbon, clay, gold, silver, lead, platinum, and tantalum) cause nonspecific inflammation by mechanical irritation to the involved tissues. The mechanical effect is essentially exudative and fibroblastic in type, in order to isolate and encapsulate the foreign body. 448 Usually, these mechanical effects on the involved eye tissues are chronic and primarily depend on the locations of particles. The exudative reaction in the ocular anterior segment often causes a chronic and persistent iridocyclitis. The mechanical effect on the posterior segment may produce persistent posterior uveitis, opacification, liquefaction and shrinkage of the vitreous gel, and exudative and proliferative changes in the retina and optic nerve, which eventually may cause RD. Chemical injuries to eye tissues resulting from an IOFB primarily come from various irritative metal materials such as iron, copper, lead, and zinc. The mechanism of chemical damage is thought to be electrolytic dissociation of the metal or reaction with tissue fluids, usually by oxidation, causing diffusion and spread of the toxic products to various ocular structures. 442 , 446, 448 Toxic metal ions can deposit on the cornea, iris and lens epithelia, and retina, and cause degeneration of those tissues and damage retinal photoreceptors and pigment epithelium, which finally leads to siderosis (iron) and chalcosis (copper). Most organic materials such as vegetable particles can produce a considerable tissue-reaction of the foreign body granulomatous type. The pathologic reaction of ocular tissues to vegetable substances often presents with a low-grade chronic inflammatory response of afibroblastic and proliferative nature, characterized by the presence of giant cells, which tend to wall off the foreign material and attempt to phagocytize it. 448 , 477, 478 In general, the pathophysiologic reactions of eyes to an IOFB primarily produce chronic inflammatory responses. The more vascular the tissue and the higher its metabolic

CHAPTER 50:

NONINfECTIOUS MASQUERADE SYNDROMES

activity, the lower the tolerance. 448 The uveal tissues, especially the ciliary body, usually show the greatest reaction to injury of any kind and the lowest tolerance even though the foreign body is inert.

Diagnosis An accurate and detailed history is vital for making the correct diagnosis and providing effective management for IOFBs. Current and past ocular history regarding the exact activities and the amount of time of the patient involvement in high-risk work such as hammering metal on metal should be carefully recorded. Complete ocular examinations, including the visual-acuity assessment and careful evaluation for a possible wound of entry, are always required. Slit-lamp biomicroscopy is an especially important examination step for IOFBs, including che.cking the lens for disruption, cataract, or embedded foreIgn body (Fig. 50-3). Most anterior segment IOFBs can be seen directly with a slit lamp.442 If an IOFB is suspected to be lodged in the anterior chamber angle, gonioscopy should be performed (Fig. 50-4). Dilated retinal examInation using indirect ophthalmoscopy is essential for evaluating an IOFB in the retina and optic disc. Careful biomicroscopic evaluation of the nonpenetrated eye should also be part of the ocular examination. Special tests, including plain film radiography, computed tomography (CT) scanning, ultrasonography, ERG, and EOG testing, can all be useful for identification and localization of suspected IOFBs.452,479-485 Plain radiography is particularly helpful in the dete(~hon of intraocular metallic materials. It has been reported that the rate of detection of metallic IOFB by plain radiography ranges between 40% and 90% .486,487 Because CT scanning can enhance resolution, it has been suggested that it has largely supplanted plain radiography.488 Thin-section CT scanning can provide precise localization of metallic IOFBs as small as 0.7 mm in diameter.489-496 Nonmetallic IOFBs such as plastic materials, glass, wood, insect fragments, and objects located adjacent to the scleral wall may be visualized with less reliability by CT. 491, 497-499 Magnetic resonance imaging (MRI), however, with the

FIGURE 50-3. Foreign body. imbedded in the crystalline lens. Note also the small tear of the iris sphincter. This intraocular foreign body had caused chronic intraocular inflammation. (See color insert.)

FIGURE 50-4. A tiny pebble of sand resting in the inferior angle. Its presence was not inert but rather created continuing iris trauma with stimulation of chronic anterior chamber cells. (See color insert.)

feature of offering superb soft tissue definition, can be ITIOre useful for detection of vegetable, glass, or plastic IOFBs, especially when .CT scanning fails to reveal a suspected IOFB.50o, ~Ol But MRI is generally contraindicated for metallic IOFBs because of the risk of intraocular movement of metallic materia1s.502-505 Modern A-scan and B-scan ultrasonography can give a general idea of the presence and relative position of an IOFB and will be especially useful in eyes with small particles, opaque media, poor patient cooperation, or hidden location (Fig. 50-5).442, 506, 507 ERG and EOG testing have been used to study the degree of ocular injury from metallosis, especially for

FIGURE 50-5. B-scan ultrasonogram showing the presence of an intraocular foreign body in the vitreous cavity in this patient who had not been adequately examined with a depressed, dilated fur1clusco1PlC examination, and therefore the presence of the body had been missed. HH.LaVLLua,

CHAPTER 50: NONMALIGNAN"f, NONINFECTIOUS MASQUERADE SYNDROMES

evaluating retinal function and for monitoring ocular recovery after metallic foreign body removaP08-514 The ERG abnormalities in siderosis are characterized by a decrease in b-wave amplitude or complete flattening of the ERG curves in untreated eyes. Up to 50% b-wave reduction appears to be reversible. 508

Differential Diagnosis Some patients with IOFB may present without any history of trauma. Therefore, IOFB should always be considered in the differential diagnosis of chronic uveitis. Usually, chronic inflammation associated with IOFBs does not respond to standard medical treatment. A detailed history and thorough ocular examination, with some additional tests including ultrasound, radiography, and CT can distinguish this entity from uveitis.

or whenever IOFBs cannot be removed by a magnet. 442 Vitrectomyoffers the advantage of clearing the media and operating under the microscope with good visualization and full control over the extraction process.4'12 IOFBs are usually removed through the limbus, pars plana, or posterior sclera.520, 521, 549-555 The proper surgical procedure of extraction mainly depends on the location, composition, and associated ocular injuries of the IOFBs. When an IOFB is lodged in the anterior challlber, limbal extraction is generally used. Pars plana extraction is mostly used for IOFBs suspended in the vitreous, or lying on the pars plana, ciliary body, retina, and optic nerve. When a magnetic IOFB is lodged in the retina, choroid, or sclera, extraction through the sclera posterior to the pars plana has been suggested. 521 ,530

Complications Treatment Management of IOFBs depends on several factors, including the type and location of the IOFB. In general, most metallic and magnetic IOFBs are considered toxic (such as copper) and relatively toxic (such as iron, steel, lead, zinc, nickel, and aluminum), and should be removed promptly.444,515-528 Vegetable matter such as wood has a high risk of microbial endophthalmitis (bacterial and fungal)442, 449, 528, 529 and should also be removed without delay. Bacterial contamination by metallic intraocular foreign bodies has been reported,530-532 and surgical removal is always considered for these contaminated materials. Most nonorganic and nonmelnllic IOFBs such as glass and plastic materials are usually inert and well tolerated in the eye 445 and need a less emergent approach. However, a large foreign body in the visual axis, even if inert, should be removed promptly.533 Well-encapsulated IOFBs, including most nonmetallic matter (glass, stone, and plastic) and even metallic particles (copper, iron, aluminum), can often be inert or protected against metal dissociation and toxicity and retained within the eyes for months to years without any signs and symptoms of toxicity (metallosis bulbi) or other problem. 445 , 534, 535 A conservative approach has been suggested for those inert and chronic IOFBs,449 but any foreign body associated with severe recurrent inflammation should be surgically removed. 533 Periodic follow-up for many years is required for the inert and encapsulated IOFBs, and special attention needs to be directed toward a possible delayed inflammatory reaction. 533 Because modern microsurgical techniques and instrumentation have lessened the operative risks and increased the efficacy of IOFB removal, it has been recommended in recent years that most IOFBs undergo surgical removal. 442 Current surgical methods for removing IOFBs include external magnets and vitrectomy. Electromagnets have been used to remove magnetic IOFBs for more than 100 years. 535 The magnet techniques, including small, handheld, practical electromagnets, magnetic forceps, and tips with more or less magnetic force, have been improved over the years. 443 , 536-5'18 Magnetic extraction can also be used with iron-containing foreign bodies, especially with magnetic forceps and tips that can grasp the foreign body. Vitrectomy is used to deal with most cases of nonmagnetic, large, or subretinal IOFBs, eyes with opaque media,

An intraocular hemorrhage can occur associated with an immediate mechanical effect by a foreign body on the injured eye. Sometimes, the helllOlThage is so small as to escape clinical notice. If the hemorrhage has been profuse, local or massive bands of fibrous tissue may be formed. Vitreous organization, fibrous proliferation, subretinal neovascularization, and epimacular fibrosis 445 may lead to RD or eventually to gross 'cicatricial distortion of the globe. Most vegetable IOFBs are contaminated and can carry pathogens such as Bacillus cereus and fungi. 445 , 556, 557 Bacillus or fungus endophthalmitis is commonly associated with vegetable or soil intraocular foreign bodies, and has a rapid onset and poor visual prognosis. Endophthalmitis caused by Staphylococcus epidermidis and mixed species (S. aureus and S. epidennidis) has also been reported. 557 An IOFB of pure copper can induce an acutely destructive, violent inflammation.4'15, 558 Endophthalmitis caused by graphite pencil lead has also been reported in a recent article. 559 Although the incidence of sympathetic ophthalmia following the retention of an IOFB is exceedingly low,477 it still may occur following the retention of every type of foreign body.'148 Sympathetic uveitis can develop many years after an IOFB has been retained.

Prognosis Penetrating eye injuries with retained intraocular foreign bodies result in better final visual acuity in general than occurs with other injuries with ocular perforation. 451 Many factors, including the size, the material, and the location of IOFBs, influence the final visual recovery after removal of IOFBs. Small IOFBs with clear media and an IOFB location in the vitreous or overlying the retina or pars plana usually indicate favorable outcome.. 442 , 560 Sixty percent of eyes with an IOFB have been reported to have final visual acuity greater than or equal to 24/40 after magnetic extraction of the IOFB, and three fourths have a final acuity of 20/200 or better.'141, 444, 448, 516, 523, 561-564 With modern vitteous surgery, approximately one third of injured eyes with IOFBs can have recovery of visual acuity of 20/40 or better. Two thirds recover to 20/200 or better, and three fourths have ambulatory vision (5/200 or better) .549,563-566 The advent of vitreous surgery with computed tomography and the use of the intraocular

CHAPTER 50:

NONINfECTIOUS

magnet have decreased the postoperative complication rate and provided a more favorable prognosis. 442 , 557, 567 A favorable prognosis of lOFBs also depends on the correct diagnosis and early surgical intervention. 567 Any delay or misdiagnosis increases the risk of ocular complications such as infectious endophthalmitis and proliferative vitreoretinopathy and brings a less favorable prognosis. Persistent and chronic uveitis is a particular masquerade syndrome associated with lOFBs, and misdiagnosis may occur.

Conclusion Retained lOFBs can cause various degrees of inflammation. Persistent anterior or posterior uveitis is the lllOSt common complication associated with lOFBs. The uveal tissues, especially the ciliary body, show the greatest reaction to injury of any kind, even though the foreign body is inert. This reaction may slowly and cumulatively develop into a chronic and persisteIlt uveitis, which can be misdiagnosed as idiopathic uveitis. Ophthalmologists must remember that any unexplained and persistent uveitis, especially when the uveitis is refractory to treatment, raises a high level of suspicion for the possibility of an lOFB masquerading as idiopathic uveitis. A favorable prognosis of lOFBs depends on the correct diagnosis and early surgical intervention.

PIGMENT DISPERSION

Definition Pigment dispersion syndrome (PDS) is characterized by release of pigment from the pigmented epithelium of the iris or ciliary body, or both, particularly in the midperipheral region in both eyes, with an attendant deposition of pigment on intraocular structures such as the back of the cornea, the trabecular meshwork, the iris, and the lens. 568 PDS can occur with or without elevation of lOP. The dispersion of particles into the anterior chamber can mimic the presence of cells, and some cases of PDS have been mistaken for uveitis. 569 Therefore, in recent years, the disease has been considered as one of the uveitis masquerade syndromes.

.·.M'.;;lI....'um;;;n.A"'~IlJm;;;

SYNDROMES

ment surfaces without associated glaucoma are observed, the term PDS has been advocated. 579

Epidemiology and Risk Factors The true prevalence of PDS is not known. Most cases of mild PDS probably are never detected. 580 The important risk factors for the development and progression of PDS include young age, male gender (male-to-female ratio of approximately 2:1), myopia (62% to 78%), and white race.578, 579, 581-585 The spectrum of pigmentary disorders generally affects young adults, ages 20 to 45 years. 578, 579, 582 The mean age at the time of diagnosis of patients with pigmentary dispersion syndrome for men is about 35 to 45 years and for women is 40 to 50 years 0Id. 583 , 586 Although it has been suggested that PDS also may be seen in older individuals,582 there is a tendency for it to decrease in severity or disappear laterin life. 582 , 587 The ratio of males to females with PDS with normal lOP may be equal or may show a greater proportion of women..583 But PDS with glaucoma tends to be more common in men than in women. 583, 584 Most PDS patients have deep anterior chambers,586,587 and usually, but not always, are myopic and white. 578,579, 581, 586, 588-591 The disease is rare in blacks and Asians. A hereditary basis of this disease,579, 581, 586, 588-591 with probable autosomal dominant inheritance 592 ,593 and autosomal recessive inheritance,594 has been suggested, but this factor has not been clearly established. Accumulation of pigment may result in transient elevation of lOP or irreparable damage to the meshwork accompanied by uncontrolled glaucoma. Patients with PDS may go for years (12 to 20 years) before developing PG,568, 579, 595, 596 or may never have a rise in lOP. The majority of patients with PDS do not develop glaucoma. 568, 579, 595, 596 It has been reported that the transition from PDS to PGwas found in 20% to 35% ofPDS patients. 595 ,597 When glaucoma does occur, it tends to develop bilaterally, more often in men (2.4:1) and at a younger age than in women (average 37 years versus 51 years).598 The main risk factors for the transition from PDS to PG were ocular hypertension and myopia. PG is thought to constitute 1 % to 1.5% of the glaucoma cases in the Western world. 583 ,599

History

Clinical Features

The presence of pigment in the aqueous outflow system was first observed by von Hippel in early 1901. 570 The possible mechanism that suggested pigment release to different parts of the eye from the pigmented epithelium of the iris was then suggested by Levinsohn in 1909. 571 Although some studies supported and debated the concept,572-576 the defined concept and its clinical significance for this entity were not established until 1940, when Sugar described one patient with glaucoma who had degeneration of the pigment epithelium' of the iris and ciliary body and marked deposition of pigment on the anterior segment surfaces. Based on the observation of the case, Sugar first hypothesized the possible relationship between the accumulation of the pigment and glaucoma. 577 Subsequently, in 1949, Sugar and Barbour further reported the details of this entity and applied the term pigmentary glaucoma (PG) to this clinical condition. 578 When the typical findings of pigment depositions on anterior seg-

The most important clinical feature of PDS is the deposition of pigment throughout the ocular anterior segment, including on the lens, zonules, iris surface (Fig. 50-6), corneal endothelium, and trabecular meshwork. The deposition of pigment on the corneal endothelium is generally accumulated in a central, vertical spindle-shaped pattern due to aqueous convection currents,579 producing the Krukenberg spindle. 60o , 601 The spindle can vary from 1 to 6 mm in length and can be approximately 3 mm in width. Pigment deposition on the cornea occasionally occurs as more diffusely distributed punctate deposits,601 but there is no significant difference in central endothelial cell density and corneal thickness in patients with PDS.602, 603 Pigment dispersion is produced by a loss' of pigment from the pigmented epithelium of the iris, particularly in the midperipheral region, which results in radial transillumination defects in the iris and dispersion of melanin

a

CHAPTER 50: NONMALIGNANT, NONINFECTIOUS .'.""'''''''LO''--'

FIGURE 50-6. A patient with pigmentary dispersion syndrome. Note the pigmentary granules deposited on the iris surface. This patient had been treated for multiple episodes of recurrent uveitis. In fact, the cells in the anterior chamber were pig:rr:ent granules. (See color insert.)

pigment into the aqueous humor. G04, G05 The defect can be dotlike or splinter-like, and occasionally two adjacent defects can form a V, with its apex oriented either centrally or peripherally.GOG As the disease progresses, the number of defects can increase, sometimes to the point where there is a full ring of discrete defects of iris.GOG Some patients with PDS or PG may not present with transillumination defects because of having especially dark and thick iris stroma. The anterior chamber in patients with PDS is characteristically deep, and the peripheral iris is slightly concave. Gonioscopic examination usually shows an open angle. The most striking gonioscopic finding is a heavy, dark brown to almost black band of hyperpigmentation in the full circumference of the trabecular meshwork (Fig. 50-7). The dispersed pigment may also accumulate along Schwalbe's line, especially inferiorly, creating a thin dark band (Sampaolesi line) .GOO lOP can be entirely normal or elevated. Another constant characteristic in PDS is the deposi-

FIGURE 50-7. Another patient with pigmentary dispersion syndrome. Note the diagnostic presence of extreme amounts of pigment deposited in the angle. (See color insert.)

SYNDROMES

tion of a ring of pigmentation (complete or incomplete) on the posterior peripheral surface of the lens. G05 , G07 The pigment line on the lens is usually located at the insertion of the zonular fibers on the posterior capsule, which usually is not seen on routine slit-lamp examination even if the pupil is dilated but is easily seen gonioscopically, especially with pupillary dilation. Iris heterochromia and anisocoria can also be seen in eyes with PDS. The iris heterochromia results from pigment granules on the stroma of the iris, which may give the iris a progressively darker appearance and create heterochromia in asymmetric cases. 582 In addition, other findings, including RD (6.4% in one study) ,583 lattice degeneration (20%) ,G08 and full-thickness retinal breaks (11.7%),G09 have also been reported in patients with PDS. Pigment granules can mimic the appearance of inflammatory cells in the anterior chamber, that is, uveitis. Pigment particles in patients with PDS are often seen floating in the anterior chamber, especially following pupillary dilation, and they may be mistaken for inflammatory cells. In some cases, a rapid rise in lOP associated with PDS as a result of exercise 598 can cause corneal edema and halo vision. This feature may further confuse the unsuspecting ophthalmologist who is evaluating the PDS patient with this problem. In addition, iris atrophy can also be seen with herpes zoster and with herpes simplex uveitis, giving additional potential for a misdiagnosis. GOG PDS should always be suspected when the pigment deposition is in multiple locations in both eyes, with iris atrophy and heterochromia, normal or elevated lOP, keratic precipitates in a central, vertical, spindleshaped pattern, and a heavily pigmented trabecular meshwork.

Pathogenesis and Pathophysiology Change and loss of pigment epithelium, including focal atrophy, degeneration of the iris neuroepithelium, and hyperplasia of the dilator muscles, have been suggested as the mechanism of pigment dispersion.GI0-G13 Pigment granules may be dislodged mechanically from the· pigmented epithelium of the iris by a back-and-forth rubbing due to a backward bowing of the posterior peripheral iris surface against zonules that insert anteriorly on the lens surface.GOO, G14 The radial folds of iris pigment epithelimll rubbing against the lens capsule itself may also be an additional mechanism of pigment release. 581 , Gal Electron microscopy studies have confirmed that the iris defects in PDS consistently coincide with the location of the zonular fibers. Gl5 Biometric and ultrasound biolllicroscopic studies of the anterior segment587, GI6-G22 have revealed a deeper anterior chamber with corresponding concavity of the iris posteriorly and flatter lenses in eyes with PDS, further supporting the mechanical theory of the iris rubbing. Released pigment is usually carried to the trabecular meshwork, where a small amount of pigment can quickly be phagocytized by the. endothelial cells .that line the trabecular beams,GI3, G14, G23-G27 and it may not obstruct outflow sufficiently to elevate the lOP. However, if the particulate load is heavy, pigment cells migrate further along the outflow pathway and downstream into the juxtacanalicular region, either obstructing the intertrabecular

CHAPTER 50:

NONINFECTIOUS MASQUERADE SYNDROMES

spaces or luigrating into Schlemm's canaL606,623 Trapped pigment in the meshwork can cause enough obstruction of the outflow facility to elevate the lOP, resulting in PG. The release of pigment from the posterior surface of the iris causes the pigment particles floating in the anterior chamber, which can mimic the cells seen in uveitis. However, although macrophages may be called forth into the stroma of the iris, the floating of pigment in the aqueous lumen does not invoke an inflammatory response in eyes with PDS.606 The inflammatory signs such as ciliary injection or synechias are always absent in the eye with PDS. This noninflammatory pathologic feature in eyes with PDS can be important in distinguishing PDS from an inflammation event.

Diagnosis

.

The diagnosis of PDS is essentially a clinical one, based on a thorough ophthalmic history al~d ocular examination. Affected patients tend to be young white men with myopia. Ocular characteristics associated with PDS usually include peripheral slitlike iris transillumination defects, increased trabecular meshwork pigmentation, Krukenberg's spindle on the posterior surface of the cornea, a posterior concave iris, and normal or elevated lOP. The presence of pigment particles in the anterior chamber with increased pigmentation of both eyes, and the absence of synechiae and ciliary injection serve to solidify the diagnosis. One should also be able to discriminate between inflammatory cells and pigm~ent cells and granules. A typical transillumination defect presenting as a radial and slitlike or wedgelike pattern in the midperipheral iris has been suggested to be an essential feature in the diagnosis of PDS.606 Examination for transillumination defects should be considered as a routine part of the ophthalmic examination in patients with uveitis. The defects are best seen with low magnification and narrow slit-lamp beam, which is positioned coaxial to the observer in the patient's pupiL A shielded fiberoptic transilluminator and Koeppe gonioscope lens are also good for testing the loss of pigment from the posterior layer of the iris. 606 In some patients, however, with a dark and thick iris stroma that may prevent transillumination of the defects, the absence of this finding does not rule out the diagnosis of PDS. A digitizing infrared videographic technique usually allows visualization of discrete iris transillumination defects that were not visible by slit-lamp examination.628 Gonioscopy is an important and essential step in making a diagnosis of PDS and grading the extent of pigment dispersion. The most essential gonioscopic finding is a dense, dark or almost black pigment band, which covers at least the posterior three fifths of the trabecular meshwork in the full circumference. 606 The dispersed pigment may also accumulate along Schwalbe's line, especially inferiorly, creating a thin, dark band. Other findings in gonioscopy include a deep anterior chamber with a concave posterior iris. The angle of the anterior chamber in the eye with PDS or PG is wide and open all around. A detailed examination of an increase or decrease in the degree of pigmentation within the trabecular meshwork

can be observed consistently by a pigment scale gonioscopy lens. 606, 629 High-frequency, high-resolution anterior segment ultrasound biomicroscopy can also provide a cross-sectional view of the peripheral iris configuration and define the relationships of the iris to the anterior chamber and lens surface in patients with PDS or PG.621, 622, 630-635 The examination by ultrasound biomicroscopy in the living eye has confirmed the original postmortem histologic studies that showed iridozonular contact,621 which will be helpful· in making a diagnosis and considering further treatment for PDS or PG.606 Tomography for facility of outflow determination can document the facility at the time of presentation; decreased facility correlates with disease progression, and this worsens with episodes of active dispersion of pigment. This method has been suggested as an additional test for longitudinal monitoring. 606 , 636 Fundus examination is most helpful in evaluating optic nerve damage in PDS patients with elevation of lOP and in excluding other conditions associated with increased anterior segment pigmentation, including SOlue forms of uveitis, trauma, ocular melanosis, and melanoma. The optic nerve is usually normal in most patients with PDS but can be daluaged if elevation of lOP occurs. The peripheral retina can be normal or abnormal in patients with PDS. RDs, lattice· degeneration, and full-thickness retinal breaks are common abnormal findings on fundus examination in eyes with PDS.583, 608, 609 The increase of pigmentation in multiple parts of the anterior segment of both eyes, with no inflammatory features throughout the ophthalmic examination, is particularly helpful in considering a correct diagnosis of PDS and differentiating this disease from uveitis.

Differential Diagnosis In addition to PDS, other abnormal conditions in which pigluent is disseminated into the anterior chamber include some forms of uveitis, cysts of the iris and ciliary body, dispersion of melanoma cells:' postoperative conditions, trauma, and aging changes. 6oo These conditions constitute the differential diagnosis for PDS. Pigment granules associated with PDS are often seen floating in the anterior chamber and depositing on the surface of the lens and cornea; this may mimic uveitis. Inflammatory diseases involving the posterior surface of the iris occasionally can disperse a moderate amount of pigment, often settling into the inferior angles; and local patches of pigment loss can also be seen in patients with severe uveitis. The inflammatory signs and symptoms, such as pain, photophobia, ciliary injection, or synechiae, are typically absent in eyes with PDS. Patients with peripheral iris or ciliary body cysts occasionally may produce a moderate amount of pigment in the anterior chamber and trabecular meshwork,637,638 similar to the feature of PDS. However, the presence of the characteristic peripheral iris irregularities, the absence of typical Krukenberg's spindle, and the feature of less dense pigment in the trabecular meshwork can distinguish this entity from PDS. Iris, ciliary body, or even posterior segluent luelanoma (if the anterior hyaloid face is disrupted) can be associ-

CHAPTER 50: NONMAUGNAN"f,.NONINfECTIOUS MASQUERADE SYNDROMES

ated with dispersed pigment. The pigmented tumor cells, or pigment-laden macrophages, may cause considerable darkening of the anterior and posterior segments. 606 ,639 Melanoma usually has an apparent intraocular mass with only monocular involvement, and the typical signs of PDS, such as Krukenberg's spindle and transillumination defects, are absent. Pigment dispersion associated with postoperative conditions or trauma usually presents irregular patches of iris loss. In addition, most cases occur unilaterally and have characteristic features of surgical or traumatic history, which can be easily distinguished from PDS. With the increase of age, cells on the posterior surface of the iris oC,casionally release small amounts of pigment, which can deposit in the trabecular meshwork and gradually darken the structure. However, the degree of piglnentation within the trabecular meshwork generally is less dense than that seen in PDS, with' an uneven distribution throughout the circumference of the trabecular meshwork. 6oo ' PDS with elevation of lOP (PC) must be distinguished from the pseudoexfoliation syndrome, the glaucoma disorder most similar to PC. Like PC, exfoliation syndrome with glaucoma is characterized by a loss of pigment from the iris neuroepithelium and has the same clinical symptoms, including iris transillumination defects, Krukenberg's spindle, clumping of pigment in the angles, and elevation of lOP. However, pseudoexfoliation syndrome is usually seen in the older patient, without preference to sex, race, and refractive err{!)r. Pigmentation of the trabecular meshwork in exfoliation is less intense than in PC, and the iris transillumination defects are located more at the pupillary border rather than in the midperiphery of the iris. Most patients (50%) with exfoliation syndrome have only one eye involved, compared with patients with pigmentary dispersion, which is usually bilatera1,6°o In addition, pseudoexfoliation syndrome, as its name implies, is characterized by the presence of white flakes of exfoliation material at the pupillary border and on the anterior lens surface, the hallmark of the exfoliation in the pseudoexfoliation syndrome.

Regular examination and follow-up are the most il11.portant management strategies for patients with PDS. Patients with early pigment dispersion should be followed with a careful evaluation of the number of iris transillulnination defects, the configuration .of the iris, and the degree of pigmentation in the various areas of the eye, especially in the trabecular meshwork by gonioscopy. lOP, facility of outflow changes, optic nerve, and visual fields should be measured regularly. Therapeutic interventions should be considered and performed appropriately if PC develops. A general treatment approach to PC has been suggested: medical treatment first, laser therapy second, and incisional surgical intervention third. Medical therapy for PD includes adrenergic antagonists and agonists, and mitotic agents, which typically suffice for mild cases. Laser surgery, including laser trabeculoplasty583, 640 and peripheral iridotomy,598, 641 has proved to be effective in eyes with PD or PC. If adequate control cannot be ob-

tained by medication or laser surgery, then filtration surgery should be undertaken. 606

Complications/Prognosis The transition from PDS to PC has been found to be 20% to 35%.595,597 Patients with PDS may go for years (12 to 20 years) before developing PC,568, 579, 595, 596 or may never have a rise in lOP. A majority of patients with PDS may not develop glaucoma. 568 ,579, 595, 596 Slow regression over the years, as the amount of pigment released from the posterior surface of the iris decreases, has been reported in PDS and PC.606 In some patients, it has been reported that pigmentation and damage to the trabecular meshwork may be partially or almost totally reversible. 584, 618 Remission of PC has also been reported after glaucoma surgery583 and lens subluxation. 642 PDS patients who have a normal tonographic facility of outflow on initial presentation have a good prognosis. 568 If intraocular pressure cannot be controlled and the trabecular function does not improve, irreversible damage to the optic nerve and visual field loss eventually develop. It has been reported that visual field loss in pigment dispersion with glaucoma is high. 642

Conclusions PDS is characterized by release of pigment from the pigmented epithelium of the iris or ciliary body, or both, particularly in the midperipheral region in both eyes, with an attendant deposition of pigment on intraocular structures such as the back of the cornea, the trabecular meshwork, the iris, and the lens. Affected patients tend to be young white men with myopia. Ocular characteristics associated with PDS usually include peripheral slit-like iris transillumination defect~, increased trabecular meshwork pigmentation, Krukenberg's spindle, a posterior concave iris, and normal or elevated lOP. Pigment granules associated with PDS are often seen floating in the anterior chamber, and these granules may mimic the features of inflammatory diseases and masquerade as uveitis.

OCULAR

Definition Ocular ischemic syndrome. (OIS) is a rare condition of chronic vascular insufficiency in which abnonnalities may occur in both the anterior and posterior segments of eyes as a result of reduced orbital blood flow secondar'y to severe carotid artery occlusive disease. 643 ,64'1 Usually, the gradual diminution in the blood supply to eyes secondary to severe carotid artery obstruction predominantly affects the posterior segment, causing peripheral retinal hemorrhages, peripheral microaneurysms, narrowed retinal arteries, and dilated retinal vessels. However, this disorder may progress to cause anterior segment ischemia. 644-647 Red eye, pain, anterior chamber cells, and flare are the common manifestations of the advanced form of this disorder. These features may mimic anterior uveitis. Hence, OIS should be considered as one of the masquerade syndromes in dealing with any ocular inflammatory disorder. 644 , 648, 649

History and Epidemiology OIS secondary to severe carotid artery obstruction was first reported by Kearns and Hollenhorst in 1963. 643 , 650

CHAPTER 50:

NONINfECTIOUS MASQUERADE SYINDROIME:S

The disorder was initially described as venous stasis retinopathy by an observation of hemorrhage retiIiopathy from retinal hypoperfusion at an abnormally low arterial pressure in approximately 5% of patients with severe carotid artery insufficiency or thrombosis. 643 , 650 Since then, a number of additional alternative terms have been proposed, including ischemic ocular inflammation,644 ischemic oculopathy,651 and ocular ischemic syndrome. 652 ,653 Because histopathologic examination of eyes with the entity generally does not reveal inflammation,654,656 currently, the term ocular ischemic syndrome has been documented to appropriately describe the features of ocular ischemic disorders secondary to carotid artery occlusive diseases. 655 OIS is a rare disorder. The. prevalence of this disease has not been extensively studied, but an annual incidence of 7.5 OIS cases per million population has been reported. 645 It has been estimated that a number of misdiagnosed cases in clinics may exist that probably contribute to the low estimated incidence. 65o The mean age of patients with OIS is about 65 years old, with a range generally from age 50 to 80 years 01d. 645 , 646,650-653,656 No racial predilection has been identified, and men are affected more than women by a ratio of about 2: 1.650, 653, 656 Either unilateral (80%) or bilateral disease can occur, and approximately 20% of patients have bilateral ocular involvement. 650

Clinical Characteristics Visual loss and ocular pain are the mo'~t frequent presenting ocular complaints. More than 90% of patients with OIS have a history of visual loss in the affected eye or eyes. 653 The episodes of visual loss may be fleeting, including amaurosis fugax (15%), gradual (28%), or sudden (41 %),657 but generally occur over weeks to months. 653 The degree of visual loss is variable, with visual acuity ranging from 20/20 to 20/50 or 20/200, or from counting fingers to no light perception in the later stage of the disease secondary to neovascular glaucoma. 658, 659 Ocular pain is characteristically described as a dull ache in the periocular or orbital region in about 40% of cases,653 which is thought to be due either to the ischemia itself or to the secondary neovascular glaucoma. 653 , 659 Anterior segment signs with OIS by slit-lamp biomicroscopy examination usually show episcleral vascular congestion; corneal edema and striae; keratic precipitate; mid-dilated, sluggish, or unreactive pupil; anterior chamber cells and flare (18% of eyes); and rubeosis iridis (67% of eyes) with secondary neovascular glaucoma (35%).647,651,653,657,659 About two thirds of eyes with OIS have rubeosis iridis at the time of initial examination.651, 653, 657 Posterior segment changes with OIS, characterized by hypoperfusion retinopathy and choroidal perfusion defects, primarily result in narrowed retinal arteries, dilated but nontortuous retinal veins, dot and blot retinal hemorrhages and microaneurysms, and optic disc and retinal neovascularization (35% and 8% of eyes, respectively) .651 Retinal hemorrhages are seen in about 80% of affected eyes with OIS, and are most commonly present in the midperiphery, but can also extend into the posterior pole.651, 653 Other signs, including cherry-red spot (12%

of eyes), cotton-wool spots (6% of eyes), spontaneous pulsation of the central retinal artery in 4%, a change in the ophthalmic-artery pressure in 4%, vitreous hemorrhage in 4%, cholesterol emboli within the retinal arteries in 2%, and anterior ischemic optic neuropathy in 2%, can also be seen by fundus examination. 644, 647, 651, 653, 657-660 Usually, most ocular ischemic syndrome manifestations begin in the posterior segment. 643,661 If it is left unchecked, this clinical entity may progress to the anterior segment and cause panocular ischemia, which can eventually cause iris neovascularization, neovascular glaucoma, and ultilnately blindness. 644, 647, 662 In addition to ocular abnormalities, systemic diseases, primarily including atherosclerosis and systemic arterial hypertension as well as diabetes mellitus, can be seen in patients who have OIS.651, 657 Nearly 38% to 50% of patients may also have evidence of ischemic heart disease, whereas about 25% to 31 % of patients have been reported to have a history of a previous stroke or transient ischemic attack. 651 , 657, 663 The inflammatory features with which OIS patients prilnarily present are those of anterior uveitis. Iritis has been reported in approximately 20% of eyes with OIS, although it is usually fairly mild. 651 , 653 Iritis is characterized by the presence of anterior chamber cells and flare, and rubeosis iridis is routinely associated with flare in the anterior chamber. The cellular response is typically mild, never exceeding grade 2 as per the Schlaegel classification.653, 664 Iritis, with other clinical symptoms of OIS, such as red eye and pain, iris atrophy with an irregularly dilated and poorly responsive pupil, hypotony, rapidly progressive cataracts, corneal edema, keratic precipitates, and Descemet's folds, may mimic a primary ocular inflammatory disease. 476 , 644, 649, 665 In addition, clinically, the syn.drome of ocular inflammation secondary to chronic ischemia is uncommon, and neither ophthalmologists nor other specialists dealing with patients with carotid artery disease have much experience of this disorder, which further increases the difficulty of diagnosis.646 Without a correct cognition of this disorder, the clinical features, especially the inflammation, result in OIS masquerading as uveitis. Ophthalmologists must pay particular attention to any patient over the age of 50 years with a new-onset iritis, especially with the observation of rubeosis iridis in an individual without diabetic history and without any evidence of venous obstructive disease or other obvious predisposing cause, with a high index of suspicion of OIS.

Pathogenesis and Etiology Carotid artery stenosis or obstruction is one of the major causes of OIS. In general, a 90% or greater stenosis of the ipsilateral carotid arterial system is present in patients with OIS.651, 653 The obstruction can occur within the common carotid or internal carotid artery. It has been shown that 90% carotid stenosis will slowly reduce the ipsilateral central retinal artery perfusion pressure by about 50%.651,666-668 The subsequent chronic reduction in blood flow in the ophthalmic artery leads to increasing ocular ischemia, tissue hypoxia and varying degrees of focal ischemic necrosis, and neovascularization. 647 , 652, 667 Moreover, the decreased flow in the ophthalmic artery

CHAPTER 50: NONMAUGNAN"f, NONINfECTIOUS MASQUERADE SYNDROMES

can increase blood viscosity and red blood cell aggrega- been reported. 679 It has been suggested that the abnortion and decrease red blood cell deformation. 669 The mality of recovery time of the b wave in the ERG may be subsequent tissue hypoxia may further damage the endo- a valuable test for the detection of minor degrees of thelial cells of vessels and cause loss of endothelial cells ischemic damage to retina caused by insufficiency of the and pericytes that may lead to the increased permeabil- . retinal and choroidal circulation. 68o Visual evoked potenity.654,655 All of these factors could cause chronic intermit- tials have also been used to study eyes with severe carotid tent ischemic symptoms and ocular inflammatory reac- artery stenosis. 653 The recovery time of the amplitude of tions, eventually leading to rubeosis iridis and subsequent the major positive peak after photostress has been shown neovascular glaucoma. 647 , 652 to improve in patients with severe stenosis after endarterPartial or complete thrombosis of the internal carotid ectomy.68] artery secondary to atherosclerosis is one of the major Noninvasive assessment of carotid artery circulation, causes for most OIS cases. 670 Atheromatous plaques of such as by duplex ultrasonography, should be obtained to the aorta and carotid arteries are the most common verify the clinical suspicion. 649 Continuous-wave Doppler sources of emboli to the internal carotid. Other systemic sonography is helpful in establishing whether or not disorders, such as dissecting aneurysm of the carotid a significant stenosis is present at the carotid bifurcaartery,671 giant cell arteritis,672, 673 fibromuscular dyspla- tion. 646 , 682 Real-time ultrasound can reveal the presence sia,674 Adamantiades-Beh<;:et's disease,675 trauma,676 and in- of atheromatous plaques even if they do not have a flammatory entities that cause carotid artery obstruc- significant hemodyn.amic effect. 646 ,683 Oculoplethysmogration,651 also have been reported as causes of carotid artery phy and ophthalmodynamometry assess carotid artery stenosis. Diabetes mellitus and systemic arterial hyperten- patency by detection of the ophthalmic artery pulse pression, as well as the manifestations of cardiac ischemia sur~. The test usually reveals a decreased ocular perfusion such as myocardial infarction, angina, heart failure, pe- pressure in the eye with OIS.646, 683, 684 Noninvasive tests ripheral vascular disease requiring bypass surgery, and have been reported to have an accuracy of approximately cerebrovascular accident, have been proposed as possible 95% to 97% in detecting carotid stenosis of 75% or risk factors for the development of atherosclerotic vascu- greater.685-689 lar disease. 656 If clinical symptoms and signs strongly suggest OIS, or the suspicion of significant stenotic carotid vascular disDiagnosis ease has been detected by noninvasive carotid studies, Diagnosis of chronic ocular ischemia can usually be made the possibility of chronic ophthalmic artery obstruction clinically, based on a detailed m~dical and ocular history, should be confirmed by conventional carotid arteriogracomplete ophthalmic examination, and carotid artery phy or intravenous digital subtraction angiography.665,690 evaluation. New-onset unilateral visual loss and the pres- Arteriography is the most reliable method of revealing ence of the characteristic ischemic symptoms in the eye carotid artery lesions. It has been reported that carotid of an elderly person are all important clues to suggest angiography typically discloses a 90% or greater obstructhe diagnosis. The past medical history of atherosclerotic tion of the ipsilateral internal or common carotid artery vascular disease and other risk factors for the develop- in patients with OIS,691 but this test has a complication ment of atherosclerotic vascular disorders such as diabe- rate of approximately 3.7%.692 Intravenous digital subtractes mellitus and systemic arterial hypertension are highly tion angiography is safer and has been reported in as suggestive for considering a possible diagnosis of OIS. many as 96% of selected cases to show a lesion at the Laboratory and ancillary testing, including fluorescein carotid bifurcation.692 angiography, electroretinography, ultrasonography, carotid Doppler, and angiography studies (arteriography or Differential Diagnosis intravenous digital subtraction angiography), are usually OIS may be confused with diabetic retinopathy and cennecessary to establish the diagnosis of OIS. tral retinal vein obstruction. Differentiation from diabetic Fluorescein angiography is most helpful in visualizing retinopathy can' be difficult in some instances, because a number of signs that are highly suggestive of ocular many patients with OIS may also have diabetes mellitus, ischemic syndrome. The most prominent findings on and the retinal manifestations of both disorders may be fluorescein angiography in patients with OIS include pro- superimposed. 69 ], 693 However, the retinopathy in OIS is longed arm-to-choroid time and delayed or patchy cho- usually unilateral (80% unilateral eye) in the older age roidal filling in 60% of patients,651, 653, 677 increased retinal group from 50 to 80 years old, whereas diabetic retinopaarteriovenous transit time (in 95% of patients) ,651,653 late thy is usually bilateral with a population of variable ages. staining of the retinal vessels, particularly the arteries (in The midperipheral location of retinopathy is the typical 85% ofpatients),653 macular edema,678,679 microaneu- feature with OIS, whereas diabetic retinopathy is more rysms, and retinal capillary nonperfusion. 654, 655 Insuffi- often seen first in the posterior pole and macular area. In ciency of ocular blood flow and tissue hypoxia and endo- addition, delayed fluorescein choroidal filling and retinal thelial damage within small retinal and choroidal vessels arterial fluorescein staining, as well as decreased ophthalmay account for the abnormalities presented on fluores- modynamometry reading, are generally absent in eyes cein angiography. with diabetic retinopathy, whereas they are the characterERG usually, but not always, reveals a diminution or istic manifestations in OIS. absence of the amplitude of both a- and b-waves in the Both OIS and central retinal vein obstruction can be eyes with OIS.652,653 A delayed recovery time of b wave in unilateral and occur in the older age population. Howthe affected eye after exposure to bright light has also ever, in OIS, the retinal veins are typically dilated but not

CHAPTER 50:

NONINFECTIOUS •. ,_,.:».............. 11-.""..........

tortuous, whereas venous tortuosity is commonly seen in central retinal vein occlusion. 65 Furthermore, in contrast to OIS, the retinal arterial perfusion pressure is normal in eyes with central retinal vein obstruction. In addition, both entities usually have a prolonged retinal arteriovenous transit time; however, choroidal filling defects and prominent retinal arterial staining are usually absent on fluorescein angiography in eyes with central retinal vein obstruction. 666 The obstruction caused by an embolus within the central retinal artery can also present the same fundus appearance as OIS. However, in contrast to OIS, fluorescein angiography of eyes with central retinal artery obstruction rarely shows late vascular staining. In addition, the ERG usually reveals that the. b wave is diminished and the a wave is unaffected in the eye with central artery obstruction. However, in the eye with OIS, choroidal compromise and outer retinal ischemIa are also presented, and both a and b wave can be affected. 666

Treatment The major therapeutic goal for patients with OIS i's to preserve visual function and reduce carotid artery stenosis. Full-scatter panretinal laser photocoagulation has been advocated to decrease the ocular oxygen requirements and reduce the ischemic drive for neovascularization. 650 , 694-697 This approach does not improve circulation to the needy eye, but it does reduce the metabolic deffiqnd. 649 Approximately 36% of eyes with 01S have been reported to demonstrate regression of ipls neovascularization after full-scatter treatment. 694 However, this method is not indicated if the anterior chamber angle is completely dosed by fibrovascular tisstle. Cyclocryotherapy, cyclodiathermy, or filtering procedures can be considered as further therapy for the elevation of lOP with a closed angle. 650 Carotid endarterectomy is generally used to reverse the carotid stenosis in order to maintain or improve the vision in eyes with OIS.657, 698, 699 'The treatment is recommended only if there is partial occlusion of the internal carotid artery, and it would not be useful for a patient who has 100% carotid artery obstruction, because in this situation? a thrombus usually propagates distally, thus generally precluding a, successful endarterectomy.650, 651, 691 A paradoxical worsening may occur after carotid endarterectomy. The increased perfusion of the carotid obstruction may 'improve ciliaiy body perfusion and increase aqueous formation,. causing a marked elevation in lOP and an incr~ase in '. the size and the number of retinal hemorrhages. Although it has been reported that stabilization or amelioration of vision occurs in about 25% of eyes following endarterectomy,658 clinical data and their value concerning the benefit of this treatlnent for this entity are still controversial and varied. 647, 700-702

0=

SYNDROMES

two thirds of patients with OIS., Of those patients with rubeosis, approximately one half will develop neovascular glaucoma. 659 The visual prognosis in ocular ischemic syndrome is generally poor, particularly in the presence of rubeosis.656, 658 OIS-associated cardiovascular disease (63%) is the major cause of mortality or significant morbidity in these patients, whereas stroke is second. Other associated diseases include systemic arterial hypertension, diabetes mellitus, and peripheral vascular diseases. 658 The 5-year mortality rate secondary to associated systemic disease has been reported to be approximately 40% in OIS patients. 656

Conclusion OIS is a rare condition of chronic vascular insufficiency in which abnormalities may occur in both the anterior and posterior segments of the eyes as a result of reduced blood flow secondary to severe carotid artery occlusive disease.643, 644 Iritis with red eye and pain is one of the clinical symptoms associated with OIS, and this may mimic uveitis. Because OIS is an uncommon disorder, diagnosis may be delayed or missed. A detailed systemic and ophthalmic history, as well as ancillary tests, with the discovery of extensive peripheral anterior synechiae associated with rubeosis in one eye of a',patient older than 50 years of age with a new-onset iritis should make one suspicious. Although the prognosis for the eyes, affected by chronic ischemia is generally poor, early and correct diagnosis with treatment has been reported to improve the prognosis. Furthermore, discovery of the underlying carotid pathology provides an opportunity for therapy that may improve the outlook for the patient's overall well-being and longevity.

Definition Juvenile xanthogranuloma (JXG) is a benign inflammatory disorder occurring in infants and young children, mainly affecting skin, characterized by multiple cutaneous papules. It occasionally involves the eye. Although ocular involvement in this disorder is not frequent, JXG has been reported to affect the iris and ciliary body,671, 704-706 eyelid,707 epibulbar area,708 cornea, conjunctiva, sclera/09 optic nerve, disc, retina, and choroid/ 10 as well as the orbit. 704,707-712 The iris is the structure most commonly involved clinically in JXG, characterized by the presence of an asymptomatic fleshy iris nodule, spontaneous hyphema, unilateral glaucoma, heterochromia iridis, and red eye with signs of uveitis. 705 Without a complete recognition of this disorder, the clinical features involving the iris in JXG may produce confusion with anterior uveitis in childhood, and misdiagnosis may consequently occur.

Complications and Prognosis The progression of OIS varies considerably by individual. The early retinopathy may resolve spontaneously or a stable course may persist for years, with the development of collateral circulation despite hypoperfusion. 649 , 661 Significant loss of vision due to OIS is irreversible when tissue infarction occurs.645, 703 Rubeosis may be present in

History and Epidemiology Juvenile xanthogranuloma was first reported as causing cutaneous lesions in infants and young children by Adamson in 1905,713 who called the condition congenital multiplex xanthoma. The disorder was further described as a separate clinical entity under the name of nevoxantho-

systemic neously and very rarely are <.l_,~.~V·~~~· involVement. JXG can also present with a red eye, anterior flare and cells, as well as local inflammatory 705 X'Qimicking iridocyclitis. With~ut a correct Of. this disorder, the feature ·of m.flalumation, ClInic:alxnanifestations associated with JXG such as heterochromia iridis, hyphema, and secondary. glaucoma, masquerade as uveitis in childhood. 741 It IS of paramount importance to suspect in any infant or very young child with unilateral spontaneous hyphema and glauC?ma, heterochromia iridis and an inflamed eye with SIgns of uveitis. '

H.istopa~hology

~IcrOSC~PIC examination reveals that the ocular lesion In JXG. IS c~a~'acterized by iris infiltration with normalappe~nng h~stlOcytes, along with occasional inflammatory cells, I~lcludIng lym~hocytes, eosinophils, and multinuclea~ed gI~n~ cells, typlCally of the Touton type (giant cells

Clinical Features The clinical features of intraocular involvement with JXG vary with the tissue affected. 740 Iris infiltration, which represents the most frequent ophthalmic manifestation, ~s characterized by either an a~ymptomatic localIzed tumorous nodule or a diffuse thickening of iris 7 5TIle Ins .. IeSlOns . ' stroma. 705 ,_. may b e hIghly vascular, which can cause spontaneous hemorrhage into the anterior chamber (hyphema) and secondary glaucoma due to either tumor infiltration in the anterior chamber angle or to obstruction of aqueous outflow by blood in the anterior chamber. 705 , 740 Hyphema is the initial clinical sign ~f JXG in many cases. Diffuse iris infiltration by the dIsease process or blood can' cause heterochromia iridis.705, 740 Other ocular manifestations of JXG may include a salmon pink or yellow lymphomatous infiltration in conjunctiva, sclera, and cornea; nodules in the lids; and proptosis due to orbital granuloma. 705 Massive infiltration of the optic nerve can lead to obliteration of the central retinal vein and artery with hemorrhagic necrosis of the retina and serosanguineous detachment of retina. 709 Chorioretinal infiltration in JXG may present as multiple subretinal lesions in the posterior pole with associated exudative detachment. 741 However, involvement of those sites, especially the optic disc, choroid, retina, and orbit, is exceedingly rare. Ocular manifestations may occur concomitantly with, or more rarely without, the skin lesions. 705 ,721 Skin lesions mayor may not be associated with the ocular manifestatio~s at first presentation, and sometimes do not appear untll weeks to months and sometimes years after ocular involvement. The skin lesions usually consist of single or multiple, discrete, yellowish or pink nodules up to 1 em in diameter, most conlmonly located on the scalp, head, and neck. 705 , 735 Cutaneous lesions usually regress sponta9

WIth a lIpId cytoplasm ringed by nuclei) .671,705,740 Nuclear m?rphology sh?ws. no abnormal mitoses. 742 Many large, thIn-walled capIllanes throughout the lesion can also be seen, and spontaneous hemorrhages are caused by rupture of these thin-walled vessels. 743 Skin lesions have the same histopathologic features as those in the but Touton giant cells are often greater in number skin than in typical iris lesions. 705 , 740

Diagnosis Diagnosis of ocular involvement with JXG should be considered in any child who has the typical skin lesions and a diffuse or nodular iri~ or ciliary lesion with hyphema or secondary glaucoma. Clinical diagnosis can often be confirmed by skin biopsy. However, in some cases, the ocular involvement may occur without the presence of cutaneous lesions. 705 , 740 Also, the diagnosis may be more difficult, and detailed ophthalmic examination and histopathologic examinations are required for establishing the diagnosis in this situation. Aqueous paracentesis with or without iris biopsy, with careful histopathologic examination, reveals foamy histiocytes and Touton giant cells, confirming the diagnosis of ocular involvement with ]XG. 73 5, 740, 744, 745 In some cases with advanced buphthalmos, diagnosis has been established following enucleation of the blind eye. 705 ,740 Because JXG is a rare disorder, and many ophthalnlologists may be insufficiently familiar with the clinical features, misdiagnosis or delay in providing optimal therapy can occur. Red eye with inflammatory reaction in the anterior chamber and recurrent hyphema and unilateral ~econdary glaucoma ~re the common symptoms and signs 111. JXG masquerade. 7-1, 741 Complete ophthalmic and systemic examination, as well as correct recognition of the clinical features, will always be helpful in making a correct diagnosis.

Differential Diagnosis An asymptomatic iris mass in JXG should be differentiated from an amelanotic melanoma, iris leiomyoma, hemangioma, or lymphangioma. 742 The orbital involvement

CHAPTER SO: NONMALIGNANT, NONINfECTIOUS

in JXG should also be differentiated from rhabdomyosarcoma,· fibrosarcoma, idiopathic orbital inflammation, teratoma, or other rare congenital orbital tumors. 704 The diagnosis for these disorders is generally based on histopathologic features of a biopsy.

Treatment If patients with JXG present only skin lesions, no active intervention is indicated, but careful ophthalmologic follow-up is strongly recommended. 746 The management of patients with ocular involvement with JXG depends on the condition of the involved eye. Ocular involvement limited to the eyelid or the epibulbar tissue also does not require specific treatment. But when there is uveal infiltration, prompt treatment is necessary.747 Early treatment of iris involvement is important because without it, uncontrolled glaucoma, corneal blood staining, or amblyopia may occur. 742 The major principles of treatment are to limit or stop the inflammatory reaction in the anterior chamber and to reduce elevated lOP. Several methods of therapy, including steroids, local excision, irradiation, and combined irradiation and corticosteroids, have been advocated in ocular involvement with JXG. Topical or subconjunctival steroids are generally recommended as the initial treatment for a JXG uveal lesion without glaucoma. 74o , 742, 747, 748 Antiglaucoma therapy with acetazolamide can be added, if necessary. 749, 750 In some cases with mild ocular involvement, spontaneous regression might occur with simple observation or a short course of steroids. Systemic steroids,724, ,¥5 low dose irradiation (300 to 400 cGy) ,750-753 or a combination of irradiation and steroids 739 should be considered further if the initial treatment cannot prevent recurrent hyphema and secondary glaucoma. An excisional biopsy of the lesion, if it is smaller than one quadrant in size, has also been advocated. 724 , 754, 755 Surgical excision of the lesion can provide a pathologic specimen when diagnosis is in doubt, but surgery may increase the risk of hyphema and lens trauma, especially if lOP is significantly elevated with ocular inflammation. 705 , 720, 725, 746 It has been suggested by Cadera that in most instances, the risks of surgery outweigh any advantage, especially because the lesions are extremely sensitive to both steroids and radiation. 746 We agree that it is probably unwise to operate on an eye for recurrent spontaneous hyphema unless all other treatments have failed. 748

Complications and Prognosis The prognosis for life in patients with JXG is excellent. JXG is a benign inflammatory process that is generally self-limited. 740 However, the visual prognosis is variable and depends on the condition of ocular involvement. In cases with mild ocular involvement, the condition might completely resolve with simple observation or with a short course of steroids. The visual outcome can be very poor in severe cases with iris and ciliary body involvement and complicated secondary glaucoma, corneal blood staining, and amblyopia. 740

Conclusion Juvenile xanthogranuloma is a rare disorder of unknown etiology in infants and very young children. The lesions

IVIM,;;»y'uu;;;nAWUJU;;;

SYNDROMES

primarily involve the skin and, occasionally, the eye, especially the iris and ciliary body. The clinical manifestations of ocular involvement in JXG mainly include an asymptomatic iris mass with unilateral spontaneous hyphema or secondary glaucoma, heterochromia iridis, and signs of uveitis. The diagnosis of JXG is challenging for ophthalmologists, especially when a skin lesion is absent, because the clinical features ofJXG can mimic those of a primary uveitis. The correct diagnosis can be established from a correct recognition of this disorder and inclusion of it in the differential diagnosis of uveitis in infants and very young children, and from the histologic appearance by skin or iris biopsy.

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CHAPTER 50:

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CHAPTER 50:

NONMAUGNAN~ NC)NINF:ECTiC::J1

614. Campbell DG: Pigmentary dispersion and glaucoma: A new theory. Arch Ophthalmol 1979;97:1667. 615. Kampik A, Green WR, Quigley HA, et al: Scanning and transmission electron microscopic studies of two cases of pigment dispersion syndrome. AmJ OphthalmoI1981;91:573. 616. Strasser G, HauffW: Pigmentary dispersion syndrome: A biometric study. Acta Ophthalmol 1985;63:721. 617. Richardson TM: Pigmentary glaucoma. In: Rich R, Shields MB, eds: The Secondary Glaucoma. St. Louis, CV Mosby, 1982, P 84. 618. Ritch R, Manusow D, Podos SM: Remission of pigmentary glaucoma in a patient with subluxed lenses. Am J Ophthalmol 1982;94:812. 619. Karickhoff, JR: Pigmentary dispersion syndrome and pigmentary glaucoma: A new mechanism concept, a new treatment, and a new technique. Ophthalmic Surg 1992;23:269. 620. Pavlin q, Macken P, Trope G, et al: Ultrasound biomicroscopic features of pigmentary glaucoma. Can J Ophthalmol 1994;29:187. 621. Potash SD, Tello C, Liebmann J, et al: Ultrasound biomicroscopy in pigment dispersion syndrome. Ophthalmology 1994;101:332. 622. Pavlin q, Harasiewicz K, Foster FS: Posterior iris bowing in pigmentary dispersion syndrome caused by accommodation. Am J Ophthalmol 1994;118:114-16. 623. Rohen ]W, Van del' Zypen EP: The phagocytic activity of the trabecular meshwork endothelium: An electron microscopic study of the vervet (Cercopithecus aethiops). Graefes Arch Clin Exp Ophthalmol 1968;175:143. 624. Bill A: Blood circulation and fluid dynamics in the eye. Pharmacol Physiol Rev 1975;55:383. 625. Richardson TM, Hutchinson BT, Grant WM: The outflow tract in pigmentary glaucoma: A light and electron microscopic study. Arch Ophthalmol 1977;95:1015. 626. Sherwood M, Richardson TM: Evidence for in vivo phagocytosis by trabecular endothelial cells. Invest Ophthalmol Vis Sci 1980;21 (Suppl) :66. 627. Campbell DG: Iridotomy and pigmentary glaucoma. Humphrey Lecture. Richmond, University of Virginia Press, 1991. 628. Alward WLM, Munden PM, Vertlick RE, et al: Use of infrared videography to detect and record iris transillumination defects. Arch Ophthalmol 1990;108:748. 629. Boys-Smith J, Woods WD, Alken DG, et al: A new gonioscopy lens for the gradation of trabecular meshwork pigmentation. Invest Ophthalmol Vis Sci 1984;25 (Suppl): 173. 630. Pavlin CJ, Sherar MD, Foster FS: Subsurface ultrasound microscopic imaging of the intact eye. Ophthalmology 1990;97:244. 631. Pavlin q, Harasiewicz K, Sherar MD, et al: Clinical use of ultrasound biomicroscopy. Ophthalmology 1991;98:287-295. 632. Pavlin q, Ritch R, Foster FS: Ultrasound biomicroscopy in plateau iris syndrome. AmJ Ophthalmol 113:390, 1992. 633. Pavlin q, Harasiewicz K, Foster FS: Ultrasound biomicroscopy of anterior segment structures in normal and glaucomatous eyes. Am J Ophthalmol 1992;113:381. 634. Tello C, Chi T, Shepps G, et al: Ultrasound biomicroscopy in pseudophakic malignant glaucoma. Ophthalmology 1993; 100:1330-1334. 635. Tello C, LiebmannJ, Potash SD, et al: Measurement of ultrasound biomicroscopy images: Intraobserver and interobserver reliability. Invest Ophthalmol Vis Sci 1994;35:3549-3552. 636. Epstein DL, Boger WP II, Grant WM: Phenylephrine provocative testing in the pigmentary dispersion syndrome. Am J Ophthalmol 1978;85:43. 637. Chandler PA, Braconier HE: Spontaneous intra-epithelial cysts of iris and ciliary body with glaucoma. AmJ Ophthalmol 1958;45:64. 638. Chandler PA, Grant WM: Lectures on Glaucoma. Philadelphia, Lea and Febiger, 1965. 639. Van Buskirk EM, Leure-duPree AE: Pathophysiology and electron microscopy of melanomalytic glaucoma. Am J Ophthalmol 1978;85:160. 640. Lichter PR, Shaffer RN: Iris processes and glaucoma. Am J Ophthalmol 1970;70:905. 641. Breingan PJ, Esaki K, Ishikawa H, et al: Iridolenticular contact decreases following laser iridotomy for pigment dispersion syndrome. Arch Ophthalmol 1999;65:249. 642. Spaeth GL: Early primary open-angle glaucoma: Diagnosis and treatment. Int Ophthalmol Clin 1979;19:168. 643. Kearns TP, Hollenhorst RW: Venous-stasis retinopathy of occlusive disease ofthe carotid artery. Mayo Clin Proc 1963;38:304-312.

H'HM'"",,,",''lJIb;n.e-U''p!b;

SYNDROMES

644. Knox DL: Ischemic ocular inflammation. Am J Ophthalmol 1965;60:995-1002. 645. Sturrock GD, Mueller HR: Chronic ocular ischemia. Brj Ophthalmol 1984;68:716-723. 646. Jacobs NA, Ridgway AE: Syndrome of ischemic ocular inflammation: Six cases and a review. Br J Ophthalmol 1985;69:681-687. 647. Ros MA, Magargal LE, Hedges TR, et al: Ocular ischemic syndrome: Long-term ocular complications. Ann Ophthalmol 1987;19:270. 648. Nicholas PJ: Al1.terior uveitis syndromes. In: Nicholas Pj, ed: Uveitis. Boston, Butterworth-Heinemann, 1998. 649. Rizzo JF III: Neuroophthalmologic disease of the retina. In: Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology. Philadelphia, WB Saunders, 2000, p 4083. 650. Brown GC: Ocular ischemic syndrome. In: Guyer DR, Yannuzzi LA, Chang S, et aI, eds: Retina-Vitreous-Macula. Philadelphia, WB Saunders, 1999, p 372. 651. Young LHY, Appen RE: Ischemic oculopathy, a manifestation of carotid artery disease. Arch Neurol 1981;38:358-361. 652. Brown GC, Magargal LE, Simeone FA, et al: Arterial obstruction and ocular neovascularization. Ophthalmology 1982;89:139-146. 653. Brown GC, Magargal LE: The ocular ischemic syndrome. Clinical fluorescein angiographic and carotid angiographic features. Int Ophthalmol Clin 1988;11 :239-251. 654. Michelson PE, Knox DL, Green WR: Ischemic ocular inflammation: A clinicopathologic case report. Arch Ophthalmol 1971; 86:274-280. 655. Kahn M, Green WR, Knox DL, et al: Ocular features of carotid occlusive disease. Retina 1986;6:239-252. 656. Sivalingam A, Brown GC, Magargal LE, et al: The ocular ischemic syndrome. II. Mortality and systemic morbidity. Int Ophthalmol Clin 1989;13:187-191. 657. Mizener JB, Podhajsky P, Hayreh SS: Ocular ischemic syndrome. Ophthalmology 1997;104:859-864. 658. Sivalingam A, Brown GC, Magargal LE: The ocular ischemic syndrome. III. Visual prognosis and the effect of treatment. Int Ophthalmol Clin 1991;15:15-20. 659. DestTo M, Gragoudas ES: Arterial occlusions. In: Albert DM, Jakobiec FA, eds: Principle and Practice of Ophthalmology. Philadelphia, WB Saunders, 1994. 660. Waybright EA, Selhorts JB, Combs J: Al1.terior ischemic optic neuropathy with internal carotid artery occlusion. Am J Ophthalmol 1982;93:42-47. 661. Hedges TRJr: Ophthalmolscopic findings in internal carotid artery occlusion. AmJ Ophthalmol 1963;55:1007-1012. 662. Hoefnagels KLJ: Rubeosis of the iris associated with occlusion of the carotid artery. Ophthalmologica 1964;148:196-200. 663. Brown GC: Anterior ischemic optic neuropathy occurring in association with carotid artery obstruction. j Clin Neuroophthalmol 1986;6:39-42. 664. Schlaegel T: Symptoms and signs of uveitis. In: Duane TD, eds: Clinical Ophthalmology, Vol 4. Hagerstown, MD, Harper & Row, 1983, pp 1-7. 665. Bullock JD, Falter RT, Downing JE, et al: Ischemic ophthalmia secondary to an ophthalmic artery occlusion. Am J Ophthalmol 1972;74:486-493. 666. Kearns TP: Ophthalmology and the carotid artery. Am j Ophthalmol 1979;88:714-722. 667. Kobayashi S, Hollenhorst RW, Sundt TM Jr: Retinal arterial pressure before and after surgery for carotid artery stenosis. Stroke 1971 ;2:569-575. 668. Smith VH: Pressure changes in the ophthalmic artery after carotid occlusion (an experimental study in the rabbit). Br J Ophthalmol 1961;45:1-26. 669. Ross RT, Morrow 1M: Ocular and cerebral mechanisms in disease of the internal carotid artery. Can J Neurol Sci 1984;11:262-268. 670. Green WR: The uveal tract. In: Spencer WH, ed: Ophthalmic Pathology. Philadelphia, WB Saunders, 1985, p 1352. 671. Duker JS, Belmont JB: Ocular ischemic syndrome secondary to carotid artery dissection. AmJ Ophthalmol 1988;106:750'-752. 672. Hamed LM, Guy JR, Moster ML, et al: Giant cell arteritis in the ocular ischemic syndrome. AmJ Ophthalmol 1992;113:702-705, 673. Hwang JM, Girkin CA, Perry JD, et al: Bilateral ocular ischemic syndrome secondary to giant cell arteritis progressing despite corticosteroid treatment. AmJ Ophthalmol 1999;127:102-104.

CHAPTER 50: NONMALIGNANT, NONINFECTIOUS MASQUERADE SYNDROMES 674. Effeney DJ, Krupski WC, Stoney RJ, et al: Fibromuscular dysplasia of the carotid artery. Aust N Z J Surg 1983;53:527-531. 675. Dhobb M, Ammar F, Bensaid Y, et al: Arterial manifestations in Beh<;:et's disease: Four new cases. Ann Vase Surg 1986;1:249-252. 676. Sadun AA, Sebag J, Bienfang DC: Complete bilateral internal carotid artery occlusion in a young man. J Clin Neuroophthalmol 1983;3:63-66. 677. Ridley M, Walker P, Keller A, et al: Ocular perfusion in carotid artery disease. Poster presentation. New Orleans, American Academy of Ophthalmology, 1986. 678. Brown GC: Macular edema in association with severe carotid artery obstruction. Am J Ophthalmol 1986;102:442-448. 679. Campo RV, Reeser FH: Retinal telangiectasia secondary to bilateral carotid artery occlusion. Arch Ophthalmol 1983;101:1211-1213. 680. Russell RW, Ikeda H: Clinical and electrophysiological observations in patients with low pressure retinopathy. Br J Ophthalmol 1986;70:651-656. 681. Banchini E, Franchi A, Magni R, et al: Carotid occlusive disease. An electrophysiological investigation. J Cardiovasc Surg 1987; 28:524-527. 682. Jones AM, Biller J, Cowley AR, et al: Extracranial carotid artery arteriosclerosis. Diagnosis with continuous wave doppler and real time ultrasound studies. Arch Neurol 1982;39:393-394. 683. Weibel'S DO, Folger GS, Younge BR, et al: Ophthalmodynamonetry and ocular pneumoplethysmography for detection of carotid occlusive disease. Arch Neurol 1982;39:690-691. 684. Kearns TP: Differential diagnosis of central retinal vein obstruction. Ophthalmology 1983;90:475-480. 685. Bosley TM: The role of carotid noninvasive test in stroke prevention. Semin Neurol 1986;6:194-203. 686. Castaldo JE, Nicholas GG, Gee W, et al: Duplex ultrasound and ocular pneumoplethysmography concordance in detecting severe cartoid stenosis. Arch Neurol 1989;46:518-522. 687. Miiller HR: Doppler sonography of the carotid vascular system. Internist (Berl) 1976;17:570-579. 688. Reutern GM, Biidingen HJ, Hennerici M",et al: The diagnosis of stenoses and occlusions of the carotid art~ries by means of directional Dopplersonography. Arch Psychiatr N ervenkr 1976; 222:2-3, 191-207. 689. Diener HC, Dichgans J: Atraumatic diagnosis of extracranial vaSCLllar stenoses and occlusions. Internist 1979;20:531-538. 690. Madsen PH: Venous-stasis retinopathy insufficiency of the ophthalmic artery. Acta Ophthalmol 1966;44:940-947. 691. Brown GC: Ocular ischemic syndrome. In: Ryan SJ, eds: Retina. St. Louis, CV Mosby, 1994, P 1515. 692. Campo RV, Aaberg TM: Digital subtraction angiography in the diagnosis of retinal vascular disease. Am J Ophthalmol 1983;96:632-640. 693. Ino-ue M, Azumi A, I\";~iura-Tsukahara T, et al: Ocular ischemic syndrome in diabetic patients. Jpn J Ophthalmol 1999;43:31-35. 694. Johnston ME, Gonder JR, Canny CL: Successful treatment of the ocular ischemic syndrome with panretinal photocoagulation and cerebrovascular surgery. CanJ OphthalmoI1988;23:114-119. 695. Eggleston TF, Bohling CA, Eggleston HC, et al: Photocoagulation for ocular ischemia associated with carotid artery occlusion. AIm Ophthalmol 1980;12:84-87. 696. Carter JE: Pam'etinal photocoagulation for progressive ocular neovascularization secondary to occlusion of the common carotid artery. AIm Ophthalmol 1984;16:572-576. 697. Duker J, Brown GC, Bosley TM, et al: Asymmetric proliferative diabetic retinopathy and carotid artery disease. Ophthalmology 1990;97:869-874. 698. Kearns TP, Sicken RG, Sundt TM Jr: The ocular aspects of bypass surgery of the carotid artery. Mayo Clin Proc 1979;54:3-11. 699. Kearns TP, Younge BR, Peipgras DG: Resolution of venous stasis retinopathy after carotid artery bypass surgery. Mayo Clin Proc 1980;55:342-346. . 700. European Carotid Surgery Tlialists' Collaborative Group: MRC European carotid surgery trial: interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet 1991;337:1235-1243. 701. Mayberg MR, Wilson SE, Yatsu F, et al: Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. JAMA 1991;266:3289-3294. 702. North American Symptomatic Carotid Endarterectomy Trial Col-

703. 704. 705.

706.

707.

708.

709.

710.

711. 712. 713. 714. 715. 716. 717. 718. 719. 720.

721.

722. 723.

724. 725. 726. 727. 728. 729. 730. 731. 732.

733.

laborators: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445-453. Brown GC, Magargal LE, Shields JA, et al: Retinal arterial obstruction in children and young adults. Ophthalmology 1981;88:18-25. Shields CL, Shields JA, Buchanon H: Solitary orbital juvenile xanthogranuloma. Ophthalmology 1990;108:1587-1589. Zimmerman LE: Ocular lesions of juvenile xanthogranuloma. Nevoxanthoendothelioma. Trans Am Acad Ophthalmol OtolaryngolI965;69:412-439. Cleasby GW: Nevoxanthoendothelioma Uuvenile xanthogranloma) of the iris: Diagnosis by biopsy and treatment with x-ray. Arch Ophthalmol 1961;66:26-28. Fleischmajer R, Hyman AB: Juvenile giant cell granuloma (Nevoxanthoendothelioma). In: Fleischmajer R, ed: The Dyslipidoses. Springfield IL, Thomas, 1960, pp 329-372. Lewis JR, Drummond GT, Mielke BW, et al: Juvenile xanthogranuloma of the corneosclerallimbus. Can J Ophthalmol 1990;25:351354. Wertz FD, Zimmerman LE, McKeown CA, et al: Juvenile xanthogranuloma of the optic nerve, disc, retina, and choroid. Ophthalmology 1982;89:1331-1335. Staple TW, McAlister WH, Sanders TE, et al:Juvenile xanthogranuloma of the orbit: report of a case with bone destruction. AJR Am J Roentgen 1964;91:629-632. Gaynes PM, Cohen GS: Juvenile xanthogranuloma of the orbit. AmJ Ophthalmol 1967;63:755-757. Sanders TE, Miller JE: Infantile xanthogranuloma of the orbit. Trans Am Acad Ophthalmol Otolaryngol 1965;69:458-464. Adamson HG: Society intelligence: the Dermatologic Society of London. Br J Dermatol 1905;17:222. McDonaugh JER: Spontaneous disappearance of endotheliomata (nevo-xanthoma). Br J J:')erm 1909;21:254. Adamson HG: A note on multiple eruptive xanthoma in infants: naevo-xanthoendothelioma (McDonagh). Br J Derm 1936;48:366. Senear FE, Caro MR: Nevoxantho-endothelioma or juvenile xanthoma. Arch Dermatol 1936;34:195. Nomland R: Nevoxantho-endothelioma of benign xanthomatous disease of infants and children. J Invest Dermatol 1954;22:207. Blank H, Eglick PG, Beerman H: Nevoxanthoendothelioma with ocular involvement. Pediatrics 1949;4:349-54. Helwig EB, Hackney VC: Juvenile xanthogranuloma (nevoxanthoendothelioma) Am J Ophthalmol J Path 1954;30:625. Maumenee AE: Ocular lesions of nevoxanthoendothelioma (infantile xanthoma disseminatum). Trans Am Acad Ophthalmol Otolaryngol 1956;60:401-405. Sanders TE: Intraocular juvenile xantho-granuloma (nevoxanthoendothelioma): A survey of 20 cases. Am J Ophthalmol 1962; 53:455-462. Sanders TE: Infantile xanthogranuloma of the orbit: A report of three cases. AmJ Ophthalmol 1966;61:1299-1306. Maumenee AE, Longfellow DW: Treatment of intraocular nevoxanthoendothelioma (juvenile xanthogranuloma). Am J Ophthalmol 1960;49:1-7. Gass JDM: Management of juvenile xanthogranuloma of the iris. Arch Ophthalmol 1964;71:344-347. Moore JG, Harry J: Juvenile xanthogranuloma. Report of a case. Br J Ophthalmol 1965;49:71-75. Smith ME, Sanders TE, Bresnick GH: Juvenile xanthogranuloma of the ciliary body in an adult. Arch OphthalmolI969;81:812-814. Hedges CC: Nevoxanthoendothelioma of eye treated with superficial x-ray therapy. AmJ Ophthalmol 1959;47:683-684. Howard GM: Spontaneous hyphema in infancy and childhood. Arch Ophthalmol 1962;68:615-620. De Villez RL, Limmer BL: Juvenile xanthogranuloma and urticaria pigmentosa. Arch Dermatol 1975;111:365-366. Grice K: Juvenile xanthogranuloma (nevoxanthoendothelioma). Clin Exp Dermatol 1978;3:327-329. Lamb JH, Lain ES: Nevo-xanthogranuloma-endothelioma: Its relationship to juvenile xanthoma. South Med J 193;30:585~594. Webster SB, Reister HC, Harman LEJr:Juvenile xanthogranuloma with extracutaneous lesions: a case report and review of the literature. Arch Dermatol 1966;93:71-76. Tahan SR, C, Bhan AK, et al: Juvenile Xantl10!;;T21l111loma: Clinical and characterization. Arch Lab Med

CHAPTER 50:

NONMAUGNAN~

734. Fishman SJ, Brodie S, Popkin G: Juvenile xanthogranuloma. Gate 1973;11:499-501. 735. Harley RD, Romayananda N, Chan GH: Juvenile xanthogranuloma. J Pediatr Ophthalmol Strabismus 1982;19:33-39. 736. Bruner WE, Stark VB, Green WR: Presumed juvenile xanthogranuloma of the iris and ciliary body in an adult. Arch Ophthalmol 1982;100:457-456. 737. Brenkman RF, Oosterhuis JA, Manschot WAL: Recurrent hemorrhage in the anterior chamber caused by a (juvenile) santhogranuloma of the iris in an adult. Doc Ophthalmol 1977;42:329-333. 738. Hamburg A: Juveniles xanthogranuloma uveae beieinem erwachsenen. Ophthalmologica 1976;72:273-281. 739. Hadden OB: Bilateral juvenile xanthogranuloma of the iris. Br J Ophthalmol 1975;59:699-702. 740. Shields JA, Shields CL: Fibrous and histiocytic tumors. In: Shields JA, Shields CL, eds: Intraocular Tumors. Philadelphia, WB Saunders, 1992, p 295. 741. DeBarge LR, Chan CC, Greenberg SC, et al: Chorioretinal, iris, and ciliary body infiltration by juvenile xanthogranuloma masquerading as uveitis. Survey of Ophthalmology 1994;39:65-71. 742. Cassteels I, Olver J, Malone M, et al: Early treatment of juvenile xanthogranuloma of the iris with sllbconjunctival steroids. Br J Ophthalmol 1993;77:57-60. 743. Duke-Elder S: Disease of the uyea: Juvenile xanthogranuloma. In: Duke-Elder S, ed: System of Ophthalmology. St. Louis, CV Mosby, 1966, pp 656-662. 744. Shields MB: Glaucomas associated with elevated episcleral venous pressure. In: Shields MB, ed: Textbook of Glaucoma. Baltimore, Williams & Wilkins, 1987, p 278.

NONINFECTIOUS MASQUERADE SYNDROMES

745. Schwartz LW, Rodrigues MM, Hallett JW: Juvenile xanthogranuloma diagnosed by paracentesis. Am J Ophthalmol 1974;77:243246. 746. Cadera W, Silver MM, Burt L: Juvenile xanthogranuloma. Can J Ophthalmol 1983;18:169-174. 747. Clements DB: Juvenile xanthogranuloma treated with local steroids. Br J Ophthalmol 1966;50:663-665. 748. Smith JLS, Ingram RM: Juvenile oculodermal xanthogranuloma. Br J Ophthalmol 1968;52:696-703. 749. Stern SD, Arenberg IK: Infantile nevoxanthoendothelioma of the iris treated with topical steroids and antiglaucoma therapy. J Pediatr Ophthalmol Strabismus 1970;7:100-102. 750. Thieme R, Lukassek B, Keinert K: Problems injuvenile xanthogranuloma of the anterior uvea. Klin Monatsbl Augenheilkd 1980;176:893-898. 751. Hertzberg R: Nevoxantho-endothelioma (juvenile xanthogranuloma) of the eye cured with x-ray therapy. Med J Aust 1964;2:2428. 752. MacLeod PM: Case report: Juvenile xanthogranuloma of the iris managed with superficial radiotherapy. Clin Radiol 1986;37:295296. 753. MiUler RP, Busse H: Radiotherapy in juvenile xanthogranuloma of the iris. Klin Monatsbl Augenheilkd 1986;189:15-18. 754. Newell FW: Nevoxanthoendothelioma with ocular involvement. Arch Ophthalmol 1957;58:321-327. 755. Shusterman M: Nevoxanthoendothelioma with ocular involvement: Report of a case. Trans Canad Ophthalmol Soc 1959;22: 206-215.

I I QJtan Dong Nguyen

Intraocular inflammation can occur after any ocular trauma, directly or indirectly. The common causes of traumatic uveitis include sports injuries,I-3 combat injuries,4 household accidents, and various recreational activity il~uries, including those from water balloon slingshots. 5 In a study of 125 patients with ocular injuries secondary to engaging in sports, 48 suffered traumatic uveitis. 3 The great majority of patients were injured while participating in unsupervised sporting activities without wearing protective eyewear. 3 A 2-year study from New Zealand disclosed that about 30% of all sports injuries to the eye evaluated at a major hospital were caused by indoor cricket; traumatic iridocyclitis was one of the most common presentations. 1 During Operations Desert Shield and Desert Storm led by the United States in 1991, ocular injury and disease accounted fpr 14% (108/767) of the visits by the soldiers to the emergency department at a combat support hospital, Fitzsimmons Army Medical Center in Aurora, Colorado. Eight of the 108 patients incurred traumatic uveitis. 4 In some cases, the evaluation and management of the traumatic uveitis may unmask occult uveitic conditions or the presence of underlying diseases, infections, malignancy (melanoma),6 or intraocular foreign bodi' 8 which may be associated with the uveitis. Ocular inflammation also can occur after any ocular surgical procedure. During the postoperative period, it is important to differentiate infectious causes of uveitis from other causes of intraocular inflammation, as infectious etiologies such as bacterial and fungal endophthalmitis require prompt treatment with antimicrobial therapy. Patients with preexisting uveitis typically have exacerbation of their intraocular inflammation after ocular trauma or surgery, even though the uveitis has been brought to remission prior to the event.

POSTSURGICAL A surgical procedure can markedly exacerbate intraocular inflammation in an eye that previously had uveitis. 9 The flare-up of the uveitis usually occurs 3 to 7 days after the surgery, and it may occur· earlier in patients who do not receive proper perioperative immunosuppressants. The uveitis can be substantial, with severe pain and hypopyon, and it can be misdiagnosed as infectious endophthalmitis. Noninfectious uveitis associated with intraocular surgery is often low grade and self-limited. lO The uveitis may be of three different forms: the acute and early uveitis that resolves quickly, the late-occurring uve-

itis, and the chronic, recurring uveitis. l l Prolonged mild traumatic iritis, secondary to surgery, has been shown to cause abnormal corneal endothelial configuration. 12 The possible etiologies of postsurgical uveitis are listed in Table 51-1.

Cystoid Macular Edema The cystoid macular edema that occurs after ocular surgery such as cataract extraction has a higher incidence in more severely traumatized eyes. 13 It is characterized by increased perifoveal capillary permeability that may be related either to prior vasoconstriction or to vasodilation, and it may be accompanied by a cellular inflalnmatory response either in the ciliary body, the vitreous, or the retina, or in combination. 13 Most of the physiologic, metabolic, and morphologic responses to trauma may be secondary to the liberation of endogenous mediators such as prostaglandins. Adequate prophylaxis may be provided by cyclo-oxygenase inhibitors or corticosteroids. However, "atraumatic" surgery with minimal disruption of the blood-ocular barrier is probably the best prophylaxis for this mostly iatrogenic disease.

Infectious Endophthalmitis Infectious endophthalmitis may occur following any type of intraocular surgery; it is one of the true ophthalmic TABLE 51-I. ETIOLOGIES OF POSTSURGICAL INTRAOCULAR INFLAMMATION Postoperative day 1 to day 30 Bacterial endophthalmitis Sterile endophthalmitis Recurrence or increased activity of previous uveitis Phacogenic (lens-related) uveitis Reaction to intraocular lens Responses to laser procedure New onset of idiopathic or previously unrecognized uveitis Postoperative day 15 to years Fungal endophthalmitis Propionibacterium acnes or other anaerobic endophthalmitis Low virulence aerobic bacterial endophthalmitis Phacogenic (lens-related) uveitis Sympathetic ophthalmia Reaction to intraocular lens Iris-ciliary body irritation related to physical contact with intraocular lens New onset of idiopathic or previously unrecognized uveitis Modified from Nussenblatt RE, vVhitcup SM, Palestine AG: Postsurgical uveitis. In: Nussenblatt RE, Whitcup SM, Palestine AG, eds: Uveitis: Fundamentals and Clinical Practice, 2nd ed. S1. Louis, Mosby-Yearbook, 1996, pp 256-261.

CHAPTER 51:

UVEITIS

emergencies. The three common types of postsurgical endophthalmitis include acute bacterial endophthalmitis, chronic bacterial endophthalmitis, and fungal endophthalmitis. Infectious endophthalmitis is described in detail in Chapter 49.

Penetrating Ocular Trauma Trauma to the eye can lead to numerous ocular complications. When the injury is penetrating, the consequences are often more severe. Early complications include hyphema, ocular hypertension, iridocyclitis, lens dislocation or rupture, corneal and scleral lacerations, endophthalmitis, choroidal rupture, retinal detachments-every ocular damage is possible, depending on the nature of injury. Late sequelae may include narrow-angle glaucoma, sympathetic ophthalmia, and retinal and choroidal neovascularization. Traumatic uveitis can coexist with any of these conditions. When ocular trauma has occurred, the patient will need annual ophthalmologic follow-up throughout life even if there are no complications, and more frequent visits if there are complications, as the number of potential future ocular problems is high. Choroidal neovascularization is a potentially sightthreatening complication of penetrating ocular trauma. 14 The growth of new choroidal vessels beneath the retinal pigment epithelium may be stimulated, in part, by inflammatory mediators and the loss o£vintegrity of the Bruch's membrane-retinal pigment epithelium (RPE) photoreceptor complex arising in the context of trauma. Wilson and colleagues described histopathologically the focal choroidal granulomatous inflammation as a result of penetrating ocular trauma;15 this finding is thought to represent a reaction to a foreign body. Another devastating complication after trauma in the human eye is the development of proliferative vitreoretinopathy (PVR). In a study of 1654 injured eyes, 71 (4%) developed PVR, which is often the primary cause of retinal detachment and visual 10ss.16 Severe traumatic uveitis with persistent intraocular inflammation, long and posteriorly located wounds, and vitreous hemorrhage were the strongest independent predictive factors for the development of PVR. When there is traumatic angle recession or traulnatic uveitis, fluorescein gonioangiography may be helpful in detecting newly formed vessels in the anterior chamber angle;17 these vessels often originate from the ciliary body, and they extend predominantly onto the surface of the angle wall via the ciliary body band. Occasionally, funduscopic fluorescein angiography may be helpful to examine changes in the retina and vascular coating in traumatic and post-traumatic conditions. IS In some cases, the penetrating ocular injury is so small that the entrance and presence of a foreign body may be missed; an occult intraocular foreign body is an important and frequently overlooked differential diagnostic consideration in the work-up of unilateral uveitis. Meyer and Ritchey reported a case of persistent post-traumatic inflammation with the development of a vitreous mass. 19 Histologic examination of the enucleated eye showed that the lens had been replaced by a wooden foreign body

that filled the pupillary space and was surrounded by lens capsule. Cases of penetrating ocular trauma that lead to persistent, chronic, occasionally fulminant, intraocular inflammation require additional investigations (e.g., anterior chamber paracentesis, scleral biopsy, and diagnostic vitrectomy) to find the cause of the traumatic uveitis. Cases of post-traumatic iridocyclitis secondary to Mycobacterium lepra,20 Enterobacter agglomerans, 21 Exophiala jeanselmei,22 Sporothrix schenckii,23 Pseudomonas aeruginosa,24 Klebsiella oxytoca,24 Aeromonas caviae,24 and Flavobacterium odoratum,24 among others, have been reported. The com-

mon organisms that cause traumatic endophthalmitis are Bacillus species (post-traumatic) 25,26 and Staphylococcus epidermidis (postoperative) .27 A1nong children with posttraumatic endophthalmitis, the most common isolates are streptococcal and staphylococcal species. 2s In addition, ocular trauma is known to cause reactivation of herpes (simplex or zoster) keratitis and keratouveitis. Endophthalmitis associated with penetrating injury often represents a distinct kind of intraocular infection. The preceding trauma, infective agents, and inflammatory changes determine the functional outcome. In a recent retrospective study,29 the risk factors for penetrating traumatic endophthalmitis that were found to be significant were a purely corneal wound, surgical primary repair more than 24 hours after injury, and initiation of intravenous antibiotic therapy later than 24 hours after trauma. A twofold increase in relative risk was related to the presence of an intraocular foreign body, lens injury, or a wound length less than 5 mm. Punnonen examined 48 eyes enucleated after a perforating eye injury.30 The time between injury and enucleation varied from 0 to 1145 days. The inflammatory signs were most marked in eyes with a corneoscleral or double perforation. Proliferation of the RPE cells or fibrous proliferation from the wound or ciliary body was found 9 to 10 days after trauma, and epiretinal membranes from the optic nerve head or from the surface of the retina were found after J month. Massive fibrous proliferation was seen in 94% of eyes enucleated 1 month or later after injury.

Sympathetic Ophthalmia Sympathetic ophthalmia is an uncommon but well-known complication of ocular trauma. It is probably the intraocular inflammatory condition best known to practitioners outside ophthalmology. Although the number of patients afflicted with this condition per year is small, the concern of losing not only the involved eye but the contralateral, untouched eye as well, in a potentially sightthreatening process, is understandably great. The bilateral granulomatous uveitis in sympathetic ophthalmia can begin as early as several days after the penetrating insult and up to decades later, with the clinical diagnosis becoming apparent in 80% of cases approximately 3 months after injury to the exciting eye. 31 SYlnpathetic ophthalmia seems to occur more often after nonsurgical trauma. Liddy and Stuart reported that the disorder occurred in 0.2% of nonsurgical wounds,32 whereas Holland found the condition in 0.5% of eyes with trauma. 33 In one study, the incidence of this disease

CHAPTER 51: TRAUMATIC UVEITIS

is estimated to be less than 10 cases per 100,000 surgical penetrating wounds. 31 Gass gathered data frOlU a survey of 26 eye pathology laboratories during a 5-year period from 1975 to 1980; sympathetic ophthalmia was diagnosed in 53 eyes (2 of every 1000 eyes examined); 29 eyes (55 %) were post-traumatic. 34 Recent studies have shown that serum beta-2-microglobulin 35 and sialic acid 36 may parallel the disease severity of sympathetic ophthalmia. Interestingly, there was no significant elevation of either marker in patients with traumatic uveitis. However, the levels were increased significantly in patients with sympathetic ophthalmia and decreased during the remission stage. When the sympathetic ophthalmia relapsed, the serum beta-2-microglobulin and sialic acid levels again were elevated. The authors suggested that beta-2-microglobulin and sialic acid levels may be used as a diagnostic aid when the diagnosis of sympathetic ophthalmia remains equivocal on clinical grounds. In addition, they also suggested that a rise in serum levels of beta-2-micro'globulin and sialic acid in patients with traumatic uveitis may point to the onset of sympathetic ophthalmia. 35 ,36 Indocyanine green angiography (ICGA) has been used to follow patients with posterior uveitis, including sympathetic ophthalmia. Bernasconi and colleagues reported various patterns of ICGA in patients with sylupathetic ophthalmia, which were confirmed by histopathologic examination of the eyes that were eventually enucleated. 37 The ICGA showed numerous hypofluorescent dark dots visible at the intermediate phase; some became isofluorescent during the late phase and resolved after long-term corticosteroid therapy, and others remained hypofluorescent until the late phase. The pattern of hypofluorescence that persisted throughout the angiography was interpreted as resulting from cicatricial, inactive lesions, whereas the hypofluorescence that faded in the late phase was thought to represent active lesions. 37 The characteristics, diagnosis, and management of sympathetic ophthalmia are discussed in Chapter 66.

Nonpenetrating Ocular Trauma Penetrating ocular trauma is a well-recognized cause of uveitis. 38 In some cases, severe uveitis can develop even after minor, nonpenetrating ocular trauma. The nonpenetrating traumatic iridocyclitis may present in association with hyphema, miosis, ocular hypotony, ciliary flush, or hemorrhage with excessive fibrin in the anterior chamber. 39 In such cases, evaluation for underlying causes of the uveitis should be initiated. Cases of significant anterior uveitis following minor corneal trauma have been described. 40 Investigation revealed ankylosing spondylitis in the patients who previously had not experienced any uveitis. Thus, the possibility of occult disease should be considered in cases of a disproportionately large amount of intraocular inflammation following minor ocular trauma. Sorr and Goldberg reported a case of traumatic iritis in an 8-year-old black boy who suffered blunt, nonpenetrating trauma to his brow and globeY Secondary glaucoma and perimacular edema as well as central retinal artery occlusion also were present. Evaluation revealed that the child had sickle cell trait. Rosenbaum and colleagues reported that nearly 5% of

patients attending a uveitis referral clinic attributed their inflammation to nonpenetrating traluua. 42 Patients with nonpenetrating trauma were more often male, were more likely to have unilateral disease, and were younger than the majority of patients in the uveitis clinic. Many of the patients had an identifiable cause of uveitis, such as ankylosing spondylitis, Reiter's syndrome, sarcoidosis, or acute retinal necrosis, but most patients had no known predisposition. The authors suggested that nonpenetrating trauma may precipitate intraocular inflammation. In some cases, the inflammation may have preceded the trauma and the trauma merely brought to attention a disease process that had begun insidiously and therefore had been undetected. In other cases, the trauma may have had a more causal role. In the same study, there were cases of bilateral inflammation after unilateral nonpenetrating trauma. These cases suggest coincidence rather than causality. The early onset and brief duration of the inflammation make sympathetic ophthalmia seem unlikely. Other benign nonpenetrating eye trauma such as eye rubbing also exerts an inflammatory effect. Greiner and associates reported their studies on ratsY Immediately after eye rubbing, the conjunctival epithelium was histologically disrupted and 50% of the mast cells showed evidence of degranulation. At 4 hours after trauma, the increase in the number of neutrophils was luore than 2300%. Neutrophils were in the margins in the conjunctival vessels, had migrated into the substantia propria, and were aligned subjacent to the epithelial basement membrane.

Lenticular trauma, especially when the lens is luxated posteriorly and severely traumatized, can lead to lensinduced uveitis with granulomatous inflammatory reaction. Such reaction has been observed in humans 44 as well as animals (e.g., owl) .45, '16 In a mouse model of lens-induced uveitis, intraperitoneal injection of dimethyl sulfoxide resulted in a reduction of retinal vasculitis, hemorrhage, and necrosis. 47 Morphometric analysis of choroidal inflammation also revealed significant reduction of choroidal thickness in the treated animals. These findings suggest that hydroxyl radicals may playa role in producing ocular tissue damage in the acute Arthus-type of ocular inflammation. In some cases, the inflammation from the phacoanaphylaxis is so severe that it can lead to phthisis and enucleation. 48 Histopathology revealed lymphogranulomatous inflammation with epithelioid cells and polynuclear giant cells near the lens capsule, confirming the clinical diagnosis of a lens-induced endophthalmitis. 48 Lens-induced uveitis is a potentially curable ocular inflammation. Early lens removal in cases of tramuatic cataract with lenticular capsular rupture would lead to resolution of inflammation and better visual results. 44 Readers are encouraged to review Chapter 76 for more information.

Yttrium-aluminum-garnet (YAG) laser capsulotomy, a common procedure in patients who have had cataract

CHAPTER 51: TRAUMATIC UVEITIS

extraction and intraocular lens implantation, has been associated with initiating low-grade inflammation or worsening of pre-existent uveitis. 49 The shock wave created by the laser is capable of causing a physical alteration in the blood-ocular barrier. There have been several cases of patients with a history of ongoing intraocular inflammation in which the YAG laser capsulotomy caused a significant increase in inflammation. 10 Therefore, increased topical, periocular, or even systemic corticosteroids may be required at the time of the laser procedures in some patients. In addition, YAG laser iridectomy has been reported to induce endophthalmitis. lO

PATHOGENESIS AND PATHOLOGY Ocular tissues, like those of other organs, exhibit limited morphologic reactions to trauma (e.g., hyperemia, abrupt vasodilation, increased blood flow, increased permeability of blood vessels, edema, increased tissue pressure [disrupted blood-ocular barrier], and, later, a cellular inflammatory response) .13 Serum fibrin degradation products are elevated in patients with acute idiopathic anterior uveitis but not in those with traumatic anterior uveitis. 50 Intraocular inflammation after ocular surgeries and trauma are mediated by leukotrienes, prostaglandins, cytokines, and growth factors, and it can be inhibited by prostaglandin inhibitors. 51 Using radioimmunoassay technique, Latanza and colleagues showed elevations in leukotrienes B4 and C4 in the aqueous humor of eyes of rabbits subjected to blunt ocular traum~.52 Such increases in leukotriene levels preceded the infilhation of neutrophils into the aqueous humor. Miyano and Chiou induced ocular inflammation using lens protein to mimic the traumatic injury of the eyes.53 They noted that pretreatment of the eyes with indomethacin resulted in marked reduction of the ocular inflammation in the early phase. Pretreatment of the eyes with phenidone and nordihydroguaiaretic acid, on the other hand, reduced ocular inflammation during both early and late phases. These results indicate that prostaglandins are involved in the early phase of the inflammation, and that this can be reduced with cyclo-oxygenase inhibitors such as indomethacin. Further, leukotrienes are responsible primarily in the 'later phase; they are suppressed by lipo-oxygenase inhibitors such as phenidone and nordihydroguaiaretic acid.53 Other serologic markers that have been found to be elevated in post-traumatic uveitis include circulating immune complexes formed by the retinal S antigen and S antibodies,54 and red blood cell surface immune complex rosette. 55 There is a higher CD4+ /CDS+ cell ratio in the aqueous and blood samples of patients who suffered from traumatic iridocyclitis than in the samples of patients with cataract. 56 Interestingly, there is no difference in ratio between the aqueous and blood samples of the traumatized patients. It is possible that one of the most important factors in maintaining a lower CD4 + /CDS + cell ratio in normal aqueous compared to peripheral blood is an intact blood-aqueous barrier. Prostaglandins E 2 (PGE 2) and PGF2a are released from iris and other tissues. 57 These prostaglandins are leukotactic and induce vasodilation, increased capillary permeability, and an increase in protein content of the aqueous.

The influx of leukocytes also leads to increased concentration of PGE 1. Thus, the cascade of molecular and cellular events seen in ocular inflammation of various origins seem to result in a reaction largely mediated by prostaglandins. 57 Prostaglandins in small doses administered topically or intraocularly produce some of the responses of injury and inflammation, such as hyperemia, miosis, breakdown of the blood-aqueous barrier, and rise in intraocular pressure. 58 E-type prostaglandins administered topically with histamine (but not the individual components) cause cellular infiltration and produce edema in conjunctival tissues. Nonsteroidal aspirin-like drugs at concentrations that inhibit prostaglandin biosynthesis markedly block injury responses but have only a moderate inhibitory effect on acute inflammatory reactions of the eye. Studies have suggested that prostaglandins as well as the intermediates of arachidonic acid metabolism, especially hydroxy fatty acids, may playa role in inflammatory responses. 58 Prostaglandins also have been shown to mediate, at least in part, x-ray-induced inflammation. 59 Interestingly, topical administration of PGE I and PGF2a prior to ocular trauma has been shown to reduce the ocular inflammatory response in rabbits. 60 The model of ocular trauma consisted of puncture of the cornea without aspiration of aqueous. Pretreatment with PGE1 and PGF2a led to a lower rise·in the aqueous PGE 2 concentration and a reduced inflammatory response after corneal puncture; the increase in the aqueous protein concentration was smaller and the aqueous ascorbate level was higher. The smaller increase in the aqueous PGE 2 concentration after pretreatment with prostaglandins correlated with reduced changes in intraocular pressure. The authors suggested that PGE I and PGF2a reduced the traumainduced inflammatory response by decreasing the formation of endogenous prostaglandins, as reflected by their concentration in aqueous. 60 Inflammation may involve a feedback loop that ordinarily does not terminate without treatment intervention. In a predisposed eye, trauma may initiate this positive feedback loop. Several conditions-the HLA-B27 spectrum of disease, sarcoidosis, and acute retinal necrosisseem particularly predisposed to being triggered by trauma. Trauma has been observed to initiate iritis associated with HLA-B27 and ankylosing spondylitis40 as well as HLA-B27-associated joint disease. 61 The relative contribution of trauma in initiating inflammation outside the eye is also difficult to ascertain. For example, in rheumatoid arthritis, the role of trauma is not well determined. 62 In one study, about 5% of the patients with rheumatoid arthritis had previous trauma. 63 Rahi and colleagues reported the histopathologic and immunologic findings in 10 cases of post-traumatic granulomatous and six cases of nongranulomatous uveitis. 64 Most cases of granulomatous uveitis showed evidence of cell-mediated immunity to uveoretinal antigens. Three patients with post-traumatic nongranulOlnatous uveitis showed a positive immunologic response to ocular antigens, and two of these later developed clinical evidence of sYlnpathetic (granulomatous) ophthalmitis, which suggests that post-traumatic nongranulomatous uveitis in such cases may represent a presympathetic

CHAPTER 51: TRAUMATIC UVEITIS

stage of the disease. Grishina and colleagues also showed the presence of cellular reaction in eyes with traumatic uveitis, indicating that there is an autoilnmune process developed in response to release of the antigenic tissue substances of the eye into the blood flow, and reactive flow of immunocompetent cells toward ocular tissues because of injury to the blood-eye barrier. 65

TREATMENT Treatment of traumatic uveitis follows the guidelines and principles used for treating other types of uveitis. A stepladder algorithm of different intensities of therapy is applied. In general, traumatic uveitis responds well to corticosteroids. In many cases, topical prednisolone may be sufficient to suppress the inflammation. In others, periocular steroid injection or oral prednisone may be required. A topical cycloplegic agent such as atropine sulfate 1% or scopolamine hydrobromide 0.25% is often used in conjunction with corticosteroids; cycloplegia helps to relieve ocular discomfort secondary to the inflammation and to prevent the formation of pupillary synechiae. Evaluation for herpes virus reactivation caused by the ocular trauma should be performed if the patient is treated with steroids. If there is reactivation of dendritic keratitis or keratouveitis, antherpetic therapy, topically and/or systemically, is indicated. In some cases, antiglaucoma medications may be employed to control ocular hypertension, which is secondary to the uveitis, the structural changes of the angle and/or trabecular meshwork caused by the trauma, or the use '~f steroids. It is rare that a steroid-sparing agent is required in managing traumatic uveitis. If the traumatic uveitis persists despite steroid therapy, evaluations for possible underlying diseases should be performed thoroughly. If such is found, control of the primary condition is required to suppress the secondary uveitis. Any patient with a history of uveitis requires close observation and immunosuppressive therapy in the perioperative period. Depending on the status of the uveitis and the duration between the most recent flare-up of the uveitis and the surgery, the patients may require intensive topical or oral corticosteroids prior to surgery. Prednisolone acetate (1 % solution) may be initiated hourly 3 days prior to surgery. Prednisone (1 mg/kg) can be instituted 2 days prior to surgery. Intraoperatively, patients with uveitis often receive intravenous steroids, typically 60 mg to 80 mg of solumedrol, and subconjunctival injection of dexamethasone at the end of the procedure. The steroid therapy is tapered in the postoperative period; the tapering rate is based on the degree of inflammation. Incases of persistent posterior post-traumatic uveitis, vitrectomy may be indicated in an effort to elucidate the possible underlying etiology or to achieve regression of the uveitis. 66 If vitrectomy is performed, proper evaluations of the vitreous, including -microbiologic, serologic, immunologic, and cytologic studies, should be performed. In one review study of diagnostic pars plana vitrectomies,67 bacteria were identified from the vitreous in six (18%) of 34 cases of post~traumatic ocular inflammation. Whenever there is a strong suspicion that the uveitis may be secondary to an infection or that infectious etiol-

ogy also contributes to the ocular inflammation, aggressive therapy with antimicrobial therapy is indicated to prevent the development of infectious, often bacterial, endophthalmitis. In recent studies, the combination of intraocular vancomycin and amikacin, and systemic ciprofloxacin appears to be an adequate regilnen for the treatment of suspected bacterial endophthalmitis resulting from ocular trauma. 68, 69 With respect to the use of intraocular steroids in a setting of ocular trauma, no categorical recommendation can be made, as it depends on the clinical context. For example, it is often difficult to exclude the possibility that a traumatic wound might be contaminated by fungus, particularly if the injury was caused by an organic substance. In such settings, the use of corticosteroids clearly should be avoided. In other settings, when the history is reliable and the presence of organic intraocular material can be excluded, the use of intraocular steroids may be quite beneficial. Traumatic endophthalmitis in association with retinal breaks or detachments is known to have uniformly poor visual and anatomic outcomes. However, attention to the possibility of infection, selective use of broad-spectrum antibiotics, and prompt surgical intervention may help to improve the visual outcome. 70 In cases of severe traumatic uveitis, enucleation is often debated as a potential approach to prevent the development of sympathetic ophthalmia. In a study from Russia, Valeeva and colleagues analyzed 37 cases with significant traumatic uveitis with poor prognosis. 71 In 10 patients, signs of sensitization to ocular tissues were detected at various times after the injury, using the leukocyte migration inhibition test. The authors regarded the results as indicating a response to release of tissue antigens in the blood because of impairment of the blood-eye barrier caused by the trauma. Thus, they suggested that the results of the leukocyte migration inhibition test in traumatic uveitis may be regarded, together with the clinical symptoms, as an additional indication for enucleation.

Traumatic uveItIs categorizes any ocular inflammation resulting from direct or indirect penetrating or nonpenetrating trauma to the eye. Ocular trauma encompasses ocular surgical procedures, laser applications, and vio- lence _to the eyes. Primary traumatic uveitis is ocular inflammation directly secondary to the trauma; there is no associated underlying disease. Secondary traumatic uveitis refers to ocular inflammation that is associated with or secondary to a systemic disease or an infection, which is unmasked or worsened by the trauma. Often, trauma to the eye, especially if there is penetration, can lead to bacterial or fungal endophthalmitis, which may present initially with marked ocular inflammation. Sympathetic ophthalmia is a rare but devastating complication of ocular trauma. Prostaglandins and leukotrienes are among the important factors that playa role in mediating the inflammation in traumatic uveitis. Inhibitors of cyclo-oxygenases and lipo-oxygenases seem to be able to halt or iInprove the ocular inflammation. It is important to identify any actual etiology of the traumatic uveitis, as such knowledge will dictate proper

CHAPTER 5 i: TRAUMATIC UVEITiS

therapy. Primary traumatic uveitis often responds well to steroid therapy-topical, oral, or by perioculai- injection. On the other hand, secondary traumatic uveitis necessitates therapy for the underlying diseases. Infectious endophthalmitis requires prompt and aggressive antimicrobial treatment. Any patient with a history of uveitis needs to be evaluated carefully for immunosuppressive therapy in the perioperative period, as the uveitis often worsens or reactivates after surgery.

25. 26. 27.

28. 29.

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with multiple water pathogens. KEn Monatsbl Augenheilkd 1997;210:388-391. Mfeldt]C, Flynn HW, Forster RK, et al: Microbial endophthalmitis resulting from ocular trauma. Ophthalmology 1987;94:407-413. Verbraeken H, Rysselaere M: Post-traumatic endophthalmitis. Eur] Ophthalmol 1994;4:1-5. Nobe jR, Gomez DS, Liggett P, et al: Post-traumatic and postoperative endophthalmitis: A comparison of visual outcomes. Br] Ophthalmol 1987;71: 614-617. Alfaro DV, Roth DB, Laughlin RM, et al: Paediatric post-traumatic endophthalmitis. Br] Ophthalmol 1995;79:888-891. Schmidseder E, Mino de Kaspar H, Klauss V, Kampik A: Posttraumatic endophthalmitis after penetrating eye injuries. Risk factors, microbiological diagnosis and functional outcome. Ophtha1mologe 1998;95:153-157. Punnonen E: Pathological findings in eyes enucleated because of perforating ir~jury. Acta Ophthalmol (Copenh). 1990;68:265-269. lVlarak GE: Recent advances in sympathetic ophthalmia. Surv Ophthalmol 1979;24:141-156. Liddy N, Stuart]: Sympathetic ophthalmia in Canada. Can] Ophthalmol 1972;7:157-159. Holland G: About the indication and time for surgical removal of an injured eye. Klin Monatsbl Augenheilkd 1964;145:732-740. Gass]DM: Sympathetic ophthalmia following vitrectomy. Am] Ophthalmol 1982;93:552-558. Sen DK, Sarin GS, Mathur MD: Serum beta-2 microglobulin level in sympathetic ophthalmitis. Acta Ophthalmol (Copenh) 1990;68:200-204. Lamba PA, Pandey PK, Sarin GS, Mathur MD: Serum sialic acid levels in patients with sympathetic ophthalmitis. Acta Ophthalmol (Copenh) 1993;71:833-835. Bernasconi 0, Auer C, Zografos L, He"bort CP: Indocyanine green angiographic findings in sympathetic ophthalmia. Graefes Arch.Clin Exp Ophthalmol 1998;236:635-638. Lubin jR, Albert DM, Weinstein M: Sixty-five years of sympathetic ophthalmia. Ophthalmology 1980;87:109. Gelatt KN: Traumatic hyphema and iridocyclitis in the horse. Mod Vet Pract 1975;56:475-479. Seymour R, Ramsey MS: Unusually severe traumatic uveitis associated with occult ankylosing spondylitis. Can] Ophthalmol 1991;26:156-158. Sorr EM, Goldberg RE: Traumatic central retinal artery occlusion with sickle cell trait. Am j Ophthalmol 1975;80:648-652. Rosenbaum ]T, Tammaro j, Robertson ]E: Uveitis precipitated by nonpenetrating ocular trauma. Am] Ophthalmol 1991;112:392395. Greiner ]V, Peace DG, Baird RS, Allansmith MR: Effects of eye rubbing on the conjunctiva as a model of ocular inflammation. Am ] Ophthalmol 1985;100:45-50. Perlman EM, Albert DM: Clinically unsuspected phacoanaphylaxis after ocular trauma. Arch Ophthalmol 1977;95:244-246. Miller WW, Boosinger TR, Maslin WR: Granulomatous uveitis in an owl.] Am Vet Med Assoc 1988;193:365-366. Pfleghaar S, Schaffer EH: Lens-induced uveitis (endophthalmitis phakoanaphylactica) in domestic animals. Tierarztl Prax 1992;20:718. Rao NA, Bowe Be, Sevanian A, et al: Modulation of lens-induced uveitis by dimethyl sulfoxide. Ophthalmic Res. 1986;18:193-198. Necker HP, Weidle EG, Steuhl KP: Endophthalmitis phakoanaphylactica witl1 anterior uveitis of the partner eye. Klin Monatsbl Augenheilkd 1989;195:248-253. Flohr Mj, Robin AL, Kelley]S: Early complications following' Qswitched neodymium YAG laser posterior capsulotomy. Ophthalmology 1985;92:360-363. Sen DK, Sarin GS, Mathur MD: Serum fibrin degradation products in acute idiopathic anterior uveitis. Acta Ophthalmol (Copenh) 1986;64:632-636. Huang K, Paeyman GA, McGetrickj, et al: Indomethacin inhibition of prostaglandin mediated inflammation following intraocular surgery. Invest Ophthalmol Vis Sci 1977;16:1760-1762. Latanza L, Alfaro DV, Bockman R, et al: Leukotriene levels in the aqueous humor following experimental ocular trauma. Retina 1988;8:199-204. Miyano K, Chiou GC: Pharmacological prevention of ocular inflammation induced by lens proteins. Ophthalmic Res 1984;16:256263.

CHAPTER 51: TRAUMATIC UVEITIS 54. Slepova OS, Kodzov MB, Bykovskaia GN: Specific immune complexes formed by retinal S antigen and S antibodies in infectiousallergic and post-traumatic uveitis. Vestn Oftalmol 1991;107:28-31. 55. Hou M: A study on RBC immunofunction in experimental trauri1atic uveitis. Chung Hua Yen Ko Tsa Chih 1993;29:233-235. 56. Avunduk MI, Avunduk MC, Tekelioglu Y, Kapicioglu Z: CD4 + T cell/CD8 + T cell ratio in the anterior chamber of the eye after penetrating injury and its comparison with normal aqueous samples. ]pn] Ophthalmol 1998;42:204-207. 57. Nelson EL: Prostaglandins and inflammation in the eye. Mod Probl Ophthalmol 1976;16:125-130. 58. Bhattacherjee P: Prostaglandins and inflammatory reactions in the eye. Methods Find Exp Clin Pharmacol 1980;2:17-31. 59. Bito LZ, Klein EM: The role of the arachidonic acid cascade in the species-specific x-ray-induced inflammation of the rabbit eye. Invest Ophthalmol Vis Sci 1982;22:579-587. 60. Hoyng PF, Verbey N, Thorig L, van Haeringen NJ: Topical prostaglandins inhibit trauma-induced inflammation in the rabbit eye. Invest Ophthalmol Vis Sci 1986;27:1217-1225. 61. Olivieri I, Gemignani G, Christou C, Giampiero P: Trauma and seronegative spondyloarthropathy. Report of two more cases of peripheral arthritis precipitated by physical injury. Ann Rheum Dis 1989;48:520. 62. Wallace DJ: The role of stress and trauma in rheumatoid arthritis and systemic lupus erythematosus. Semin Arthritis Rheum 1987;16:153.

63. Short CL, Bauer W, Reynolds WE: Rheumatoid Arthritis. Cambridge, MA, Harvard University Press, 1957. 64. Rahi A, Morgan G, Levy I, Dinning W: Immunological investigations in post-traumatic granulomatous and non-granulomatous uveitis. Br ] Ophthalmol 1978;62:722-728. 65. Grishina VS, Valeeva T, Iluridze SL, Isaeva RT: Immunological reactions in pathogenesis of posttraumatic uveitis and eyeball subatrophy. Vestn Oftalmol 1997;113:30-34. 66. Freyler H, Velikay M: Vitrectomy in uveitis. Klin Monatsbl Augenheilkd 1984;185:263-267. 67. Palexas GN, Green WR, Goldberg MF, Ding Y: Diagnostic pars plana vitrectomy report of a 21-year retrospective study. Trans Am Ophthalmol Soc 1995;93:308-314. 68. Alfaro DV, Davis], Kim S, et al: Experimental Bacillus cereus posttraumatic endophthalmitis and treatment with ciprofloxacin. Br ] Ophthalmol 1996;80:755-758. 69. Okhravi N, Towler HM, Hykin P, et al: Assessment of a standard treatment protocol on visual outcome following presumed bacterial endophthalmitis. Br] Ophthalmol 1997;81:719-725. 70. MieleI' WF, Glazer LC, Bennett SR, Han DP: Favourable outcome of traumatic endophthalmitis with associated retinal breaks or detachment. Can J Ophthalmol 1992;27:348-352. 71. Valeeva RG, Grishina VS, Iluridze SL: Clinical aspects of traumatic uveitis and causes of enucleation. Vestn Oftalmol 1997; 113:38-41.

s

I

Maite Sainz de la Maza

Anterior uveitis is the most prevalent form of intraocular inflammatory disease. It accounts for approximately three fourths of cases, with an annual incidence rate of 8.1 new cases per population of 100,000. The differential diagnosis of anterior uveitis includes many disorders (Table 52-1). Some conditions that can cause panuveitis, such as sarcoidosis, Beh~et's disease, toxoplasmosis, and bacterial endophthalmitis, may begin as anterior uveitis. The challenge to the ophthalmologist caring for a patient with anterior uveitis is to elucidate treatable causes so as to limit long-term sequelae of intraocular inflammation. In cases that are associated with systemic disease, the physician must arrange appropriate management with other specialists to minimize pen;panent disability or lifethreatening sequelae. A careful history, complete review of systems, ophthalmologic and general medical examination, and ancillary laboratory testing are clearly all important steps in the management of patients with anterior uveitis. There is a definitive correlation between the prevalence of certain systemic diseases (seronegative spondyloarthropathies) associated with anterior uveitis and the

TABLE 52-I. DIFFERENTIAL DIAGNOSIS IN ANTERIOR UVEITIS Seronegative spondyloarthropathies Ankylosing spondylitis Reiter's syndrome Psoriatic arthritis Enteropathic arthritis Idiopathic inflammatory bowel disease Whipple's disease Juvenile rheumatoid arthritis HLA-B27-associated anterior uveitis (ocular only) Fuchs' heterochromic iridocyclitis Herpetic uvetis Glaucomatocyclitic crisis Lens-related iridocyclitis Intraocular lens-related iridocyclitis Traumatic iridocyclitis Syphilis Tuberculosis Renal disease-associated anterior uveitis Kawasaki disease Schwartz' disease Anterior segment ischemia Malignancy Idiopathic

HLA-B27 haplotype. However, there is also a correlation between the prevalence of anterior uveitis and HLA-B27 even without an associated systemic condition. In one study, 47% of anterior uveitis patients had HLA-B27associated anterior uveitis; only a quarter of these had an associated systemic condition such as one of the seronegative spondyloarthropathies. HLA-B27-associated anterior uveitis (ocular involvement only) appears to be a distinct clinical disorder that differs from idiopathic anterior uveitis. Patients with HLA-B27-associated uveitis are more often male and they tend to develop uveitis at a younger age than do patients who are HLA-B27 negative. However, some studies indicate that the long-term visual prognosis is similar for both groups. The spondyloarthropathies are a group of disorders that share many clinical, pathologic, and immunogenetic features. l These features include (1) radiographic sacroiliitis with or without accompanying spondylitis, (2) inflammatory asymmetric peripheral arthritis with lack of rheumatoid nodules, (3) absence of rheumatoid factor or antinuclear antibodies, (4) strong association with HLAB27, (5) tendency for ocular inflammation (mainlyanterior uveitis), (6) variable mucocutaneous lesions, and (7) occasional cardiac abnormalities. These disorders include ankylosing spondylitis, Reiter's syndrome (RS), psoriatic arthritis (PA) , enteropathic arthritis (idiopathic inflammatory bowel disease [IBD] and Whipple's disease), and a form of juvenile chronic arthritis (juvenile-onset spondyloarthropathy). The term seronegative contrasts these diseases from rheumatoid arthritis, as most patients with rheumatoid arthritis have a positive serum test for rheumatoid factor.

ANKYLOSING SPONDYLITIS Ankylosing spondylitis (AS) (Bechterew's disease, MarieStnlmpell disease, rheumatoid spondylitis) is a chronic systemic disease of unknown cause, characterized primarily by inflammation of both sacroiliac joints and the spine, and also by a variety of extra-articular manifestations. Anterior uveitis, the most common extra-articular manifestation of AS, occurs in approximately 25% of patients either before the onset of the AS or at smne point thereafter. 2,3 Conversely, AS is the most common systemic condition known to be associated with anterior uveitis in men: 17% to 31 % of men with anterior uveitis have AS.4 Once considered a rare disease, affecting primarily men and

CHAPTER 52: SERONEGATIVE SPONDYlOARTHROPATHIES

progressing to total spinal fusion, AS is now recognized as relatively common, affecting about 1% of the general population; it has a more equal sex distribution, although it is frequently more severe in males.

History AS has been described in Egyptian mummies and even Inore ancient skeletons,5-s although many of those may in fact have been cases of diffuse idiopathic skeletal hyperostosis or other spondyloarthropathies such as psoriatic spondylitis or RD. 9 The first documented case was the classic skeleton unearthed by the Irish Inedical student Bernard Connor in Paris in 1691. 10 Detailed case reports were described separately by Bechterew, Stn1mpell, and Marie in the second half of the 19th century.l1

Epidemiology AS has a prevalence of about 1% in the general population. It is seen mainly in whites and is exceptionally rare in Japanese and black MricansY On'set is more frequent in the second or third decade of life. Clinical evidence of AS is three to four times more frequent in men than in women. However, the prevalence of AS in women may approach that of men. The fact that AS is diagnosed less frequently in women is partly explained by the fact that the disease is less severe and progressive in women, presenting vvith more peripheral joint involvement and less dramatic spinal changes. 13 There isa definitive correlation between the prevalence of the disease and the presence of HLA-B27. 14 Approximately 96% (!)f white patients with AS and 52% of their first-degree relatives have the HLA-B27 haplotype, compared with 6% of a control population. 14 , 15 Nevertheless, only 1.3% of all HLA-B27positive individuals and 20% to 30% of the HLA-B27positive first-degree relatives of AS patients will have the disease. 16

Clinical Features

Systemic Manifestations AS begins with an insidious onset of low back pain and stiffness. About half of the patients are initially relatively asymptomatic and often deny or minimize the nature and extent of their complaints. The pain is dull in character, felt deep in the gluteal region or the lumbosacral area, and it is unilateral or intermittent at first, although persistent and bilateral within a few months. Low back pain duration is usually greater than 3 months before medical attention is sought. Both the pain and the stiffness, usually worse in the morning after resting, improve with a hot shower, mild activity, or exercise. Direct pressure over the sacroiliac joints frequently, but not always, elicits pain. Findings in advanced disease include ankylosing of the sacroiliac joints and spine (Fig, 52-1), with loss oflmnbar lordosis, marked dorsocervical kyphosis, and decreased chest expansion; however, few patients progress to the end stage of "bamboo spine" now, because of the earlier recognition and better treatment of AS today compared with 30 years ago. Peripheral arthritis may be the initial manifestation of AS in 20% of patients. Although any joint may be involved, the hips, shoulders, and knees are most frequently

FIGURE 52-I. Pelvic x-ray studies showing the closure sacroiliac joints in a patient with ankylosing spondylitis.

01'

sclerosis of

affected. In one study, 10% of patients had temporomandibular involvementP Peripheral arthritis occurs in 35% of AS patients at some point of the disease and may start many years after spinal inflammation. IS Enthesopathy, such as Achilles tendonitis, plantar fasciitis, intercostal muscle tendonitis, and dactylitis, is common and may be painful and recurrent. 19 Although extra-articular systemic manifestations are uncommon in AS patients, aortic regurgitation,20 upper lobe pulmonary fibrosis,21 chronic prostatitis,22 cauda equina syndrome,23-26 and amyloid deposition 27 , 2S may appear, especially after years of active disease. A few patients may have constitutional symptoms such as lowgrade fever, anorexia, fatigue, and weight 10ss.29

Ocular Manifestations Anterior uveitis, the most common ocular manifestation in AS, is typically unilateral but is recurrent and can be bilateral or alternating. The main symptoms are sudden onset of ocular pain, photophobia, and blurred vision, although it may be mild or even asymptomatic. The main signs are limbal hyperemia, fine whitish gray keratic precipitates, and prominent cellular reaction with fibrinous exudation in the anterior chamber that contributes to the formation of posterior synechiae. 30 The cellular response can be severe enough to cause hypopyon (Fig. 52-2). In fact, AS and other HLA-B27-associated arthropathy disorders are much more commonly associated with hypopyon uveitis than is Adamantiades-Beh<;;et's disease, at least in western Europe and America. Secondary glaucoma and cataract may appear. The posterior segment is usually spared, but severe vitreous inflammation, papillitis, and retinal vasculopathy may occasionally occur. 31 ,32 Cystoid macular edema may be associated with prolonged or severe cases of anterior uveitis. The presence of anterior uveitis does not correlate with the severity of the spondylitis. AS is frequently undiagnosed before the onset of the ocular disease, especially in women, who appear to have more atypical spondy10arthropathies. 33 Although anterior uveitis is the most common manifestation in AS, conjunctivitis and scleritis may occasionally

CHAPTER 52: SERONEGATIVE SPONDYLOARTHROPATHIES

FIGURE 52-2. Hypopyon, in a patient with HLA-B27-associated uveitis in the context of ankylosing spondylitis. (See color insert.)

occur. The reported incidel~ce of AS in patients with scleritis ranges from 0.34% to 0.93%.34-36 Scleritis in AS generally takes the form of mild to moderate diffuse anterior scleritis without corneal lesions or decrease in visual acuity.34, 37, 38 Although scleritis may be the initial manifestation of AS, it usually occurs after years of active AS disease, especially in patients with marked articular and extra-articular manifestations. Anterior uveitis may appear following the onset of scleritis, in which case it is impossible to know whether the uveitis is a consequence of the associated scleritis or it represents an independent effect of the disease, or both.

Pathology and Pathogenesis The primary pathologic site for AS is at the insertion of ligaments and capsules into bone (enthesopathy). Those lesions lead to a process of ossification in the apophyseal and sacroiliac joints as well as in the intervertebral discs. 39 The reason for the association between HLA-B27 and AS remains unknown. The fact that infections with gramnegative bacteria such as Klebsiella pneumoniae or Shigella flexneri are associated with the development of the arthritis in AS has led to several hypotheses. The cross-tolerance or molecular mimicry hypothesis suggests that an antigenic similarity exists between bacterial and HLA-B27 structures, and an immune response to Klebsiella therefore could cause autoimmune disease. 4o The receptor hypothesis suggests that HLA-B27 is a receptor for the infectious agent or for factors released by bacteriaY The chemotaxis hypothesis suggests that enhanced neutrophil chemotaxis found in HLA-B27 individuals with and without AS and reactive arthritis may contribute to susceptibility to spondyloarthropathy.42-44 Another hypothesis suggests that proteoglycans could act as autoantigens. 45 , 46 These ideas help one to think about the pathogenesis of the arthritis in AS, but the reasons for the associated anterior uveitis remain obscure.

Diagnosis The presence of a recurrent, alternating, nongranulomatous, acute anterior uveitis in a 30- to 40-year-old man with lower back pain is suggestive of anterior uveitis associated with AS.

Although the diagnosis of longstanding AS with typical articular deformities is straightforward, early disease may be overlooked. Currently, the widely used criteria (modified New York criteria, 1984)47 for diagnosis include the following: (1) a history of inflammatory back pain of at least 3 months' duration, improved by exercise and not relieved by rest, (2) limitation of motion of the lumbar spine in both the sagittal and frontal planes, (3) limited chest expansion, and (4) definite radiologic evidence of sacroiliitis. Definite diagnosis of AS is established by the presence of definite radiographic sacroiliitis and anyone of the other three clinical criteria (Table 52-2). The diagnosis of AS depends, therefore, on history, clinical evaluation, and radiologic confirmation. Bone scanning or magnetic resonance imaging (MRI) may be helpful if plain films are normal. HLA-B27 typing in AS with or without anterior uveitis is useful only as an adjunct to diagnosis, as the majority of HLA-B27 individuals in the general population remain unaffected, and AS may occasionally occur in HLA-B27-negative individuals. Furthermore, no significant differences in ocular complications and visual outcomes are found between HLA-B27positive and HLA-B27-negative acute anterior uveitis patients. 48 HLA-B27 documentation is most helpful in patients with clinical criteria of AS who have not yet developed radiologic sacroiliitis.

Differential Diagnosis The anterior uveitis associated with AS usually has a presentation similar to the anterior uveitis associated with other systemic diseases that are also characterized by sacroiliitis and spondylitis, such as RS or PA: It occurs as a unilateral, alternating, recurrent, acute iritis with symptoms such as pain, photophobia, and blurred vision, and signs such as redness, intense anterior chamber reaction, and frequent posterior synechiae. Differentiation between those systemic diseases depends on the presence or absence of the clinical and radiologic characteristics.

Treatment Acute episodes of anterior uveitis associated with AS usually respond to short courses of frequent topical corticoTABLE 52-2. MODIFIED NEW YORK CRITERIA, 1984 FOR ANKYLOSING SPONDYLITIS 1. Clinical criteria 1.1. Low back pain and stiffness for more than 3 months improved by exercise and not relieved by rest 1.2. Limitation of motion of the lumbar spine in sagittal and frontal planes 1.3. Chest expansion decreased relative to normal values for age and sex 2. Radiologic criteria* 2.1. Sacroiliitis grade 2 to 4 bilaterally or grade 3 to 4 unilaterally Definitive Diagnosis: Radiologic criteria associated with anyone of the three clinical criteria. Probable Diagnosis: Three clinical criteria without the radiologic sacroiliitis or radiologic sacroiliitis without any of the clinical criteria. *Radiologic grading of sacroiliitis: 0, normal; 1, suspicious; 2, minimal abnormality-small localized areas or erosion or sclerosis without alteration in the joint width; 3, unequivocal abnormality-erosions, sclerosis, change in joint width or partial ankylosis; and 4, severe abnormality-total ankylosis.

CHAPTER 52: SERONEGATIVE SPONDYlOARTHROPATHIES

steroids (one drop every hour) and cycloplegic/mydriatic agents started at the onset. If treatment is delayed or insufficient, it can become difficult to achieve control with topical treatment only. Particularly in severe cases, or in those that have associated cystoid macular edema, periocular injections of triamcinolone (40 mg/l ml) or short-term systemic corticosteroid therapy may be required. Although data from large controlled trials are lacking, frequent recurrent disease may be treated with a maintenancetourse of oral nonsteroidal anti-inflammatory drugs (NSAIDs) to slow the frequency of the attacks. 49 Refractory cases may be controlled with weekly, low-dose methotrexate (e.g., 7.5-15 mg/week) or daily azathioprine (1-2 mg/kg/day); careful monitoring for side effects and complications of immunosuppressive therapy is required. It is very important to detect the AS in patients with anterior uveitis, because if the disease is treated early, spinal deformity can be prevented. Patient education should start with the diagnosis. PhysiCal therapy, including posturing exercises, local heat, and job modification, is designed to maintain muscle strength and flexibility even if ossification and ankylosing progress. Oral NSAIDs are helpful in decreasing acute inflammation and relieving pain. 5o

Natural Histot"'y, Prognosis, and Complications The typical course of anterior uveitis associated with AS is characterized by recurrent bouts of acuteV inflammation, usually affecting only one eye at a time, with a diseasefree interval ranging from weeks to years. The prognosis is generally good if the episodes are treated with early and aggressive therapy. Severe or refractory cases may have associated cataract, glaucoma, or cystoid macular edema. Although progressive impairment of spinal mobility occurs in at least half the cases of AS, functional outcome with physical and anti-inflammatory therapies is often satisfactory.51 The disease-related mortality is related to the presence of cervical spinal subluxation, aortic regurgitation, respiratory failure, and amyloidosis. RS is classically defined as a clinical triad conSIStlng of arthritis, urethritis, and conjunctivitis (in 98%, 74%, and 58% of patients, respectively, in one large study) .52 However, the arthritis is frequently accompanied by only one of the other characteristic manifestations. Other common findings include mucocutaneous lesions such as keratoderma blennorrhagica, balanitis circinata, and other genital or oral mucosal lesions. Although ocular involvement most commonly consists of conjunctivitis, anterior uveitis may occur in 3% to 12% of the patients.

History Hans Reiter, in 1916, described the classic triad of arthritis, nongonococcal urethritis, and conjunctivitis following a dysenteric episode (in a lieutenant in the Prussian army who developed first urethritis and conjunctivitis, and later arthritis, after abdominal pain and diarrhea) .53 However, a search of the literature discloses that even before, in

1776, Stoll demonstrated· that those three characteristics may follow dysentery,54 and in 1818 Sir Benjamin Brodie found the same to be true following a venereal infection. 55 In 1947, Harkness reaffirmed that RS may follow both dysenteric and venereal infections. 56 Two major epidemics of RS, one described by Paronen 57 in 1948 and tlle other by Noer58 in 1966, have conclusively linked epidemic dysentery with the onset of the disease.

Epidemiology Accurate epidemiologic studies in RS are difficult to perform because there are no definitive diagnostic tests, it frequently occurs in young patients who tend to be mobile and difficult to follow, venereal or dysenteric episodes may be mild or silent or may have been forgotten, cervicitis in women may be asymptomatic, or ocular or mucocutaneous lesions may be clinically inapparent or silent. Furthermore, some cases have been misdiagnosed as seronegative rheumatoid arthritis, whereas others were diagnosed as AS because of overlapping features. Finally, as RS is a multisystem disorder, care is often fragmented and the patient may be followed independently by an ophthalmologist, rheumatologist, urologist, or other subspecialty physician. Nevertheless, a few studies have shown that RS is a relatively common rheumatic disease: RS develops in 1% to 3% of men following anonspecific urethritis caused by Chlamydia trachomatis,59 in 1% to 4% of individuals following enteric infections caused by Shigella, Salmonella, and Campylobacter,6o and in a higher proportion of patients following enteric infection caused by Yersinia. 61 -65 The onset of symptoms is most frequently between the ages of 18 and 40 years. It has been reported, however, in children and in octogenarians. 66 ,67 The sex distribution shows a definitive male predilection, but the extent of this is unclear because the diagnosis in females is more difficult to establish. 66 Postvenereal RS is more common in men, whereas postdysenteric RS affects men and women equally.6o, 66, 68 The histocompatibility antigen HLA-B27 is present in about 75% to 90% of patients with RS and in only 6% of normal control western white populations. 66 RS is rarely reported in black populations, probably reflecting the lower incidence of HLA-B27; in fact, when RS occurs in black patients, they usually are HLA-B27 negative. 69

Clinical Features Systemic Manifestations ARTICULAR INVOLVEMENT

The symptoms of reactive arthritis typically develop within a month of the inciting episode of urethritis or diarrhea. However, despite careful questioning, many patients fail to recall prodromal urethral or enteric symptomatology. Arthritis is usually of acute onset, chronic or recurrent, migratory, asymmetric, and 0ligoarticular. 66 Lower extremity joints (i.e., knees, ankles, and toes) are the joints most commonly affected.. Articular involvement may ·later progress in an additive fashion to affect the joints of the upper extremities, particularly the fingers or wrists, and the sacroiliac and spine joints leading to sacroiliitis or

CHAPTER 52:

FIGURE 52-3. Dactylitis, with so-called sausage digit formation in a patients with Reiter's syndrome. (See color insert.)

spondylitis. Sacroiliitis and spondylitis are most common in the most severely affected individuals with chronic disease; sacroiliitis develops in 20% to 30% of patients overall and is related to the presence of HLA-B27. 1 RS should always be suspected in a young man who presents with subacute arthritis of the knees, chronic hindfoot pain, metatarsalgia, and tenderness in the low back over the sacroiliac joints. Other rheumatologic manifestations involve ligaments, tendons, and fascias (enthesopathy); they include dactylitis ("sausage" digits) (Fig. 52-3), Achilles tendonitis, plantar fasciitis or calcaneal perio~titis (painful heel syndrome) (Fig. 52-4), and chest wall pain. EXTRA-ARTICULAR INVOLVEMENT

Constitutional symptoms include malaise, fatigue, and weight loss; fever, if present, is low grade and without accompanying chills. Genitourinary involvement occurs in RS regardless of whether the disease follows a venereal or enteric infection. The most common problem, occurring in 90% of patients, is urethritis; prostatitis, seminal vesiculitis, epididymitis, cystitis, orchitis, and urethral strictures may also occur. Women • may have cervicitis, vaginitis, or urethritis, all of which are usually asymptomatic. 66

FIGURE 52-4. Periostitis of the calcaneus, with spur formation in a patient with Reiter's syndrome.

FIGURE 52-5. Circinate balanitis in three patients with Reiter's syndrome. (See color insert.)

Mucocutaneous lesions occur in over 50% of RS patients. The most frequent skin lesion, described in 23% of patients, is circinate balanitis, which presents as vesicles that rupture to form large, shallow ulcerations or plaques on the glans or shaft of the penis with a serpiginous border (circinate) (Fig. 52-5). Keratoderma blennorrhagicum, while less frequent (12% to 14% of patients), is a characteristic hyperkeratotic skin lesion that affects primarily soles (Fig;" 52-6), palms, and glans penis, and less often limbs, trunk, scrotum, and scalp. It begins as small mantles that evolve into papules, vesicles, or pustules that coalesce to form hyperkeratotic scaly nodules, which usually heal without scarring after days, weeks, or months but can recur. Oral mucosal lesions are seen in about 10% of the patients; they begin as vesicles and progress to painless, small, shallow, sometimes confluent ulcers that heal within a few days or weeks. Nail changes are common and often appear as onycholysis (Fig. 52-7), yellowish discoloration, or subungual hyperkeratosis. 66

FIGURE 52-6. Keratoderma blennorrhagica in a patient with Reiter's syndrome. (See color insert.)

52:

SPONDYLOARTHROPATHIES

consists of punctate epithelial lesions that may coalesce to form an ulcer. Occasionally, subjacent anterior stroma infiltrates and disciform keratitis occur. 73 , 74 Disc edema, recurrent retinal edelna, and retinal vasculitis have been reported rarely in RS.75, 76

Pathology and Pathogenesis

FIGURE 52-7. Onycholysis in a patient with Reiter's syndrome. (See color insert.)

Other, less common extra-articular systemic manifestations include cardiac involvement (cardiac conduction abnormalities, pericarditis, aortitis), amyloidosis, thrombophlebitis, pleuritis, nonspecific diarrhea, neuropathy, and meningoencephalitis. As in AS, vasculitis in RS is predominantly a large-vessel arteritis.

Ocular Manifestations Anterior uveitis occurs in 3% to 12?p of patients with RS. 52 The initial attack is always acute ~nd unilateral, but recurrent episodes often affect the other eye. It is usually nongranulomatous, with fine to medium-size white keratic precipitates, a mild cellular reaction, and flare. Posterior synechiae and some cells in the vitreous are occasionally seen. Hypopyon may occur in severe cases. Secondary glaucoma can develop from posterior synechiae (pupillary block), peripheral anterior synechiae, or trabeculitis. 52 ,53 Anterior uveitis is more frequent in patients who are HLA-B27 positive and/or who have sacroiliitis. 70 Conjunctivitis is the most common ocular problem in RS, occurring in 58% of patients. 52 It usually appears within a few weeks of the onset of arthritis or urethritis but occasionally may be the first manifestation of the disease. 70 The conjunctivitis is mild and bilateral, and it occurs with a mucopurulent discharge and a papillary or follicular reaction. It lasts 7 to 10 days without treatment, and cultures are negative. Rarely, a small, nontender, enlarged preauricular lymph node and mild syInblepharon formation may occur. Although conjunctivitis and anterior uveitis are the most common ocular manifestations in RS, scleritis and episc1eritis may occasionally occur. 36 Diffuse anterior scleritis, although rare, is the most frequent type of scleritis in patients with RS.71 It usually occurs in the later stages of the disease, and after conjunctivitis and/or anterior uveitis have developed. Diffuse anterior scleritis may be recurrent but it never progresses to necrotizing scleritis. Episcleritis is also rare in RS.36, 52, 70, 72 It may take the form of simple or nodular episcleritis and, like scleritis, it usually appears after years of active RS. Keratitis in RS may be isolated but more frequently occurs associated with conjunctivitis and, less often, with anterior uveitis. It

As in AS, the primary site of articular inflammation in RS is at the insertion of ligaments and capsules into bone (enthesopathy). This explains the frequently found Achilles tendonitis, plantar fasciitis, and arthralgias. 66 Although the disease mechanism remains unknown, a specific genetic background and several different infective agents are now recognized. The reason for the association between HLA-B27 and RS remains unknown. The fact that enteric (caused by Shigella, Sabnonella, Yersinia, and Campylobacter species) and urogenital infections (caused by Chlamydia or Ureaplasma species) are associated with the development of the arthritis in RS has led to several hypotheses. The cross tolerance or molecular mimicry hypothesis,77-79 the receptor hypothesis,80 the peptide-presenting hypothesis (HLA-B27, as a class I major histocompatibility antigen, could present antigenic peptides to cytotoxic T lymphocytes and induce arthritis) ,81 and the chemotaxis hypothesis82 are some of them. These data help to understand the pathogenesis of the arthritis in RS, but the reasons for the associated anterior uveitis remain obscure.

Diagnosis The diagnosis of RS is essentially clinical. One classification system includes as major manifestations arthritis, conjunctivitis or anterior uveitis, urethritis or cervicitis, and mucocutaneous lesions (Table 52-3). The presence of arthritis and at least two of the other manifestations establishes the definite diagnosis of RS. The diagnosis of RS depends, therefore, on history, clinical evaluation, and radiologic confinnation. Bone scanning OT MRI may be helpful if plain films are normal. As in AS, the finding of HLA-B27 positivity increases the probability that the presumptive diagnosis is correct but does not establish the diagnosis.

TABLE 52-3. DIAGNOSTIC CRITERIA FOR REITER'S SYNDROME* MAJOR CRITERIA

MINOR CRITERIA

Polyarthritis Conjunctivitis or anterior uveitis Urethritis/ cervicitis Balanitis circinata or keratoderma blennorrhagicum

Plantar fasciitis, Achilles tendonitis, lower back pain, sacroiliitis, spondylitis Keratitis Cystitis, prostatitis Psoriasiform eruptions, oral ulcers, nail changes Diarrhea, leukocytosis, increased serum globulins, inflammation in the synovial fluid

*Reiter's syndrome (RS) diagnosis (modified from Ref. 52): definite RS: arthritis (seronegative asymmetric) and two or more other criteria; probable RS: two major and two minor (found in different systems) criteria; possible RS: two major and one minor criteria.

CHAPTER 52: SERONEGATIVE SP(:lNIDYI

Differential The anterior uveitis associated with RS usually has a presentation similar to anterior uveitis associated with AS or PA. It occurs as a unilateral, alternating, recurrent, acute iritis characterized by pain, photophobia, blurred vision, redness, intense anterior chamber reaction sometimes leading to hypopyon, and frequent posterior synechiae. Differentiation between those diseases depends on the specific clinical and radiologic characteristics. Hypopyon, anterior uveitis, arthritis, and oral ulcers can occur in Beh.;;:et's disease; however, in Beh.;;:et's disease the retina and choroid are frequently involved, oral ulcers are painful, and genital lesions are ulcerative.

Treatment Anterior uveitis can be treated with short courses of frequent topical corticosteroids and cycloplegic/mydriatic agents. Hypopyon, cystoid macular edema, or the rare instances of disc or retinal involvement may also be treated with periocular injections of triamcinolone (40 mg/l ml) and/or short-term systemic corticosteroid therapy. Although data from large controlled trials are lacking, frequent recurrent disease may be treated with a maintenance course of oral NSAIDs to slow the frequency of the attacks. 49 Corticosteroid-refractory and -intolerant patients and those with severe chronic disease may benefit from weekly, low-dose methotrexate (a total of 7.5 to 15 mg/week) or daily azathioprine (l to 2 mg/kg/day); careful monitoring for side effects and complications is required. Oral NSAIDs are helpful in suppressing the systelnic signs and symptoms; indomethacin, sulindac, naproxen, diclofenac, phenylbutazone, and enteric-coated salicylates may be beneficial. Control of "triggering" infections may be necessary for those patients with sexually acquired reactive arthritis. A large percentage of these patients have Chlamydia-induced arthritis that responds to doxycycline, tetracycline, or lymecycline therapy.83-85 Whether there are benefits of antibiotic therapy in patients with postdysenteric or idiopathic RS is unknown, but it is unlikely.

Natural History, Prognosis, and Complications Anterior uveitis associated with RS is characterized by recurrent episodes of unilateral, often alternating, acute inflammation with intervals between exacerbations ranging from weeks to years. Prognosis is generally good if the episodes are treated with early and aggressive therapy. Severe or refractory cases may have associated cataract, glaucoma, or cystoid macular edema. The natural history of the systemic disease is highly variable and related to the particular infective organism. l,66 Most patients have an initial episode of arthritis with or without extra-articular disease of 2 to 3 months' duration; whereas some patients experience recurrent attacks with prolonged disease-free intervals, 20% to 50% have a chronic course of peripheral arthritis with the potential for· progressive spondylitic changes resembling those seen in AS.l Severe disability occurs in less than 15% of patients and is frequently secondary to unrelenting lower extremity disease, aggressive axial involvement,

or progressive visual impairment. 86 The disease-related mortality is related to the presence of cardiac complications or amyloidosis. 1, 66

Psoriatic arthritis is defined as the triad of psoriasis (skin and/or nail); a chronic, recurrent, erosive polyarthritis (peripheral and/or spinal); and a negative test for rheumatoid factor. 87

History The French must be credited with initiating the concept ofPA. While Alibert in 1818 was the first to draw attention to the association between psoriasis and arthritis,88 Pierre Bazin in 1860 was the first to use the term psoriatic arthritis ("psoriasis arthritique") .89 Charles Bourdillon in 1888 provided a detailed description of psoriasis-associated arthritis. 90 It was not until the association of rheumatoid factor and rheumatoid arthritis was described in 1948 that the seronegative PA was accepted as a true, independent entity.91 Large, well-conducted surveys performed by Wright92 and by Baker and colleagues93 helped to establish the definite characteristics of PA.

Epidemiology Psoriasis occurs in 1% to 2% of the white population and affects individuals in the second or third decade of life. PA occurring in about 5% to 7% of patients with psoriasis94 has an estimated prevalence in the population of 0.1 %.95 The onset is most frequent between 30 and 40 years of age, and women are slightly more frequently represented (1. 04: 1). Psoriasis also may occur in children between 9 and 12 years of age, more commonly in girls. 96 A positive family history may be obtained in one third of patients, implying a role for genetic and/or environmental factors. Psoriasis and PA are reportedly associated with HLA-A2, B17,97 B38, B39,98,99 CW6,100 and DR7alOl genes. The association of HLA-B27 is with psoriatic sacroiliitis and spondylitis (50%) but not with psoriatic peripheral arthri~is or psoriasis. l02 There is a well-recognized association between trauma to a joint and a flare of PA in that same joint103 ; the frequent involvement of the distal interphalangeal joints suggests that excessive microtrauma may predispose to the development of PA.

Clinical Features

Systemic Manifestations PA is characterized by skin and articular involvement. Other systemic findings such as amyloidosis, apical pulmonary fibrosis, and aortic insufficiency are seen only rarely.l Constitutional signs and symptoms, such as fever and fatigue, may occur. Pustular skin lesions, caused by small vessel vasculitis, may occasionally appear. In most cases, the skin disease precedes the articular involvement by many years, but in about 15% to 20% of patients the psoriasis develops after the arthritis. 104, 105 Skin lesions in patients with PA do not follow a particular pattern. They may vary from small hidden patches in the axilla, under the breast, umbilicus, or genitalia to a generalized exfoliation involving elbows, legs, scalp,

CHAPTER 52: SERONEGATIVE SPONDYLOARTHROPATHIES

scleritis is often seen,113 it may take almost any form of scleritis, including the anterior necrotizing and the posterior types. 7l Mild retinal vasculitis has been reported rarely in PA.

Pathology and Pathogenesis

FIGURE 52-8. Psoriatic arthlitic nail changes with so-called sausage digits and onycholysis. (See color insert.)

abdomen, and back.l()6, 107 Nail changes are ITIOre frequent in patients with PA (80%) than in patients with psoriasis without arthritis (15% to 30%) .107 They are characterized by onycholysis, pitting, ridging, and nail discoloration or fragmentation. A synchronous flare of the joints and nails occurs more commonly than a: flare of the joints and skin. Patients with more severe arthritis tend to have greater nail involvement. los There are at least five patterns of joint involvement in PA: (1) Asymmetric monoarticular art~-itis (5% to 10%) involves the distal interphalangeal joints of the fingers ;:l.l1d toes and is often associated with diffuse swelling of the digits (sausage digits) and with nail lesions (Fig. 52-8); (2) chronic asymmetric oligoarticular arthritis (50% to 70%) affects two or three joints at a time; (3) chronic symmetric polyarthritis (15% to 25%) resembles rheumatoid arthritis but the test for rheumatoid factor is negative; (4) spondyloarthritis (20% to 30%) is characterized by sacroiliitis with or without spondylitis, is more common in men than in women, and has a strong association with HLA-B27; (5) arthritis mutilans (5%) shows a progression to osteolysis with resulting severe deformities and ankylosing of joints. Apart from this deforming group, the arthritis of PA is not severe; the pain and disability are much less than those produced by rheumatoid arthritis. l09

Ocular Manifestations Anterior uveitis occurs in 7% to 20% of patients with PA,u°, 111 It is usually acute and nongranulomatous, occurring with fine endothelial keratic precipitates and a mild cellular reaction, similar to the anterior uveitis associated with AS or RS. Hypopyon,112 posterior synechiae, mild vitritis, and secondary cystoid macular edema are occasionally seen. Anterior uveitis is more frequent in patients who are HLA-B27 positive or who have sacroiliitis or spondylitis, mainly in the male subset of patients with deforming arthritis. Other eye lesions in PA may occur, including conjunctivitis in 20%, episcleritis in 2%, and scleritis in 1% to 2%.71, 73, 110 Episcleritis and scleritis usually appeat after many years of active disease. Although diffuse anterior

The primary pathologic lesion in the arthritis of PA is a synovitis that is generally indistinguishable from that of rheumatoid arthritis. 114 There are also microvascular abnormalities in both normal and involved skin, including excessive capillary tortuosity and coiling.115 Nail-fold capillary microscopy shows a decrease in the number of vessels with engorged capillary tufts,u6 Although the disease mechanism remains unknown, a specific genetic background (50% of patients with psoriatic spondylitis have HLA-B27) and some infective agents (Streptococcus and Staphylococcus species in psoriatic plaques and nails) 117-119 appear to playa role. The finding of increased HLA-DR expression on keratinocytes frOITI psoriatic plaques has led to. the hypothesis that keratinocytes might process bacterial antigens and activate T cells directly. 120 These data help to understand the pathogenesis of the arthritis in PA but the reasons for the associated anterior uveitis remain obscure.

Diagnosis The diagnosis of PA is essentially clinical. It is characterized by the presence of psoriasis or psoriatic nail disease and a seronegative inflammatory peripheral arthritis, with or without sacroiliitis or spondylitis. Radiologic changes compatible with PA are (1) erosions, with widening of the joint space and expansion of the base of the terminal phalanx in distal interphalangeal joints; (2) terminal phalangeal osteolysis; (3) dissolution of bones, especially the metatarsal (arthritis mutilans) resulting in a "pencil-incup" appearance or "fish tail" deformity; and (4) sacroiliitis and spondylitis. Elevated circulating immune complexes have been found in 50% of patients with PA.12l As in AS or Reiter's disease, the finding of HLA-B27 positivity increases the probability that the presumptive diagnosis is correct but does not establish the diagnosis.

Differential Diagnosis The anterior uveitis associated with PA usually has a presentation similar to the anterior uveitis associated with AS or RS. Diffel~entiation between those diseases depends on the specific clinical and radiologic characteristics. The differentiation of PA from RS is particularly difficult, because both diseases are associated with HLA-B27 and involve the sacroiliac joint and the spine, and because keratoderma blennorrhagicmTI is indistinguishable both clinically and histologically from pustular psoriasis. A helpful clinical distinction is the greater likelihood of upper extremity involvement in PA.

Treatment Anterior uveitis can be treated with topical corticosteroids and cycloplegic/mydriatic agents. Cystoid macular edema may be also treated with periocular il~ections of triamcinolone (40 mg/1 ml) and/or short-term systemic corticosteroid therapy.111 Although data from large controlled trials are lacking, frequent recurrent .disease may be

CHAPTER 52: SERONEGATIVE SPONDYlOARTHROPATHIES

treated with a maintenance course of oral NSAIDs to slow the frequency of the attacks. Corticosteroid-refractory and -intolerant patients and those with chronic or recurrent disease may benefit from weekly, low-dose Inethotrexate (a total of 7.5 to 15 mg/week) 122 or daily cyclosporin (2.5-5 mg/kg/day) 123,124; careful monitoring for side effects and complications is required. Oral NSAIDs are helpful in suppressing the systemic signs and symptoms. When NSAID-resistant or progressive erosive deforming peripheral arthritis develops, methotrexate, cyclosporine, leflunomide, etanercept, and photochemotherapy (methoxypsoralen and long-wave ultraviolet-A light [PUVA]) may assist in managing both the joint and the skin disease.

Natural History, Prognosis, and Complications The ocular prognosis is generally good. Severe or refractory cases may have associ?-ted cataract, glaucoma, or cystoid macular edema. The systemic prognosis is generally benign. Apart from the deforming group of arthritis mutilans (5% of patients), the arthritis of PA is not severe; most patients have relatively asymptomatic periods with episodic flares of synovitis. The mortality in PA is usually caused by unrelated disease, but fatal complications from treatment with cytotoxic drugs may occur. 125

ENTEROPATHIC ARTHRITIS Enteropathic arthritis can be deffned as arthritis induced by or occurring with intestinal disease. Some forms, mainly the idiopathic IBDs and Whipple's disease, are included in the concept of spondyloarthropathies because they are characterized by the absence of rheumatoid factor, by both sacroiliitis (with or without spondylitis) and inflammatory peripheral arthritis (usually pauciarticular and asymmetric), by ligament and tendon involvement (enthesopathy), by strong association with HLA-B27, by mucocutaneous lesions, and by tendency for ocular manifestations, including anterior uveitis.

Idiopathic Inflammatory Bowel Disease-Associated Arthritis Crohn's disease (CD) and ulcerative colitis (DC) are IBDs that may have articular manifestations such as peripheral arthritis or spondyloarthropathy.126 Both diseases may have ocular manifestations, including anterior uveitis.

History and E.pidemiology Although described in 1895,127 joint manifestations in DC were not appreciated until much later. 128 , 129 Similar observations were made in CD. 130-132 Peripheral arthritis appears in 20% of patients with CD132, 133 and in 10% of patients with DC,134 usually those with other extraintestinal manifestations. It most commonly begins between the ages of 25 and 45 years, and women and men are equally involved. 135 Sacroiliitis with or without spondylitis appears in 10% of patients with CD or DC and affects men more commonly than women. This form of arthritis is strongly associated with HLA-B27, which is present in 50% to 70% of patients. 136, 137

SYSTEMIC MANIFESTATIONS

Gastrointestinal and articular manifestations are the hallmarks of IBD-associated arthritis. Other systemic manifestations include skin lesions (erythema nodosum or pyoderma gangrenosum), oral ulcerations, hepatobiliary disorders, urogenital involvement (ureteral obstruction, nephrolithiasis, or prostatitis), and thrombophlebitis. Some of these manifestations, particularly the skin lesions, are caused by small-size-vessel vasculitis. Gastrointestinal symptoms in CD include relapsing right-lower-quadrant colicky pain associated with diarrhea, constipation, nausea, vomiting, fever, anorexia, and weight loss. Patients with DC present with left-lower-quadrant cramping pain, relapsing bloody mucoid diarrhea leading to dehydration and electrolyte imbalance, fever, anorexia, and weight loss. Peripheral arthritis usually occurs 6 months to several years after the onset of intestinal manifestations, although occasionally it may appear at the same time as, or preceding, the colitis. 138 Clinically, the arthritis is usually of acute onset, mono- or pauciarticular, and primarily affecting the knees and the ankles, and it resolves within a few weeks without residual joint damage. Other joints that may be involved are the metacarpophalangeal and metatarsophalangeal joints, hips, shoulders, elbows, and wrists. The arthritis waxes and wanes with the intestinal activity and is more common in patients with severe bowel disease or when associated systemic complications are present, such as skin lesions, mouth ulcerations, anduveitis. 135 Joint involvement in DC is more frequent in patients with colon disease than in patients with isolated rectal involvement. In CD, arthritis is Inore common in patients with colon disease than in patients with small bowel involvement. 139 Surgical removal of an inflamed colon has a therapeutic effect in many patients with DC but in only a small number of patients with CD.126, 137 Enthesopathy (Achilles tendinitis or plantar fasciitis), clubbing of finger~ (up to 30%), and periostitis may appear. 140, 141 Sacroiliitis with or without spondylitis, indistinguishable from AS, frequently precedes overt evidence of bowel involvement and progresses independently of the intestinal disease or proctocolectomy.126 OCULAR MANIFESTATIONS

Ocular manifestations, occurring in 1.9% to 11.8% of the patients with IBD, include most commonly anterior uveitis, episcleritis, scleritis, and keratitis.142-145 Eye lesions are more frequent in IBD patients with colitis or ileocolitis than in those with isolated small bowel or rectal involvement. They are also more common in IBD patients with arthritis or other extraintestinal manifestations such as anemia, skin lesions, oral ulcerations, and hepatobiliary disease. 142 , 143,146 The degree of ocular inflamlnation tends to parallel the activity of the intestinal or articular disease.1'12-147 In some patients with DC, proctocolectomy has resulted in resolution of the ocular disease; however, removal of the diseased bowel does not necessarily prevent recurrences of the ocular inflamlnation. 142 Anterior uveitis, occurring in about 2% to 11 % of IBD patients, is usually insidious in onset, bilateral, recurrent

CHAPTER 52:

or chronic, nongranulomatous, with fine white keratic precipitates, moderate cells, and flare. 142 ,143 Cystoid macular edema may be associated in severe cases. Episcleritis, scleritis, and glaucoma may accompany the uveitis. Anterior uveitis may occur before, during, or after the initial bowel attack, and it is associated with the presence of arthlitis, particularly spondylitis. Posterior uveitis, luuch less frequent, may also occur, and it is characterized by granulomatous panuveitis with choroidal infiltrates. 148 Retinal vasculitis can develop and may be secondary to immune complex vasculitis or thromboembolic disease.149, 150 Other posterior segment manifestations include serous retinal detachment, retrobulbar neuritis, and papillitis.146 Episcleritis is common inpatients with IBD, particularly in those with CD.144, 146, 151, 152 Knox and coworkers 144 reported that the presence of episcleritis in DC is a good indicator to consider changing the diagnosis to CD, because, in their experience, episcleritis is associated only with CD. The reported incidence of IBD in patients with episcleritis (all of them with CD) is 3.19%.36 Although episcleritis may precede bowel disease,151 it usually occurs some years after the onset of gut symptoms, particularly during active episodes. 146 Episcleritis is more commonly associated with the presence of arthritis and other extraintestinal manifestations (anemia, skin lesions, oral ulcerations, or hepatobiliary disease) .142, 144, 146 The reported incidence of IBD in patients with scleritis ranges from 2.06% to 9.67%.35,36, 71, 15~,(Although scleritis may appear prior to the onset of the intestinal involvement, it usually occurs after some years of bowel disease, especially during periods of disease exacerbation. 145 , 146, 151 Scleritis is more commonly associated with the presence of arthritis and other extraintestinal manifestations. 144, 146 It may be diffuse anterior, nodular anterior, necrotizing anterior, scleromalacia perforans anterior, or posterior, and it is usually recurrent. 38,113, 146, 154, 155 Systemic or surgical treatment of the bowel manifestations mayor may not control the scleritis. Keratitis in IBD may take the form of peripheral, small, round, subepithelial, white-to-gray infiltrates, probably the result of acute inflamluation,156 which may lead to limbal thinning. 157 It also may take the form of peripheral nebulous subepithelial infiltrates, probably the result of scarring.156 Other, less common ocular manifestations are conjunctivitis, orbital pseudotumor, extraocular muscle paresis, orbital cellulitis, and orbital myositis. 146, 151, 158

Pathology and Pathogenesis

increased gut permeability permitting exogenous factors to enter the body, and to a defective local immunoregulatory mechanism; the latter could act by inducing a switch of the protective local IgA response to a more systemic IgG and IgE response, and by enhancing T-celldependent immune reactions. 159 Peptides shared by colon, joint, and eye may provide further understanding of the association of anterior uveitis and IBD-associated arthritis. 160

Diagnosis The diagnosis of IBD is made on the basis of tissue biopsy from colonoscopy. Clinical signs and symptoms combined with radiologic studies including barium enema and upper gastrointestinal series support the diagnosis. l6l In CD, radiologic studies show deep ulcerations (collar button), long strictured segments (string sign) and skip areas, and biopsy shows granuloma formation with transmural inflammation. In DC, radiologic studies show lack of haustral markings, fine serrations, large ulcerations, and pseudopolyps, and biopsy shows microabscesses of the crypts of Lieberki..'thn and macroscopic ulcerations with inflammation limited to the mucosa. Radiographs of involved joints in IBD-associated arthritis show minimal destructive signs such as cystic changes, narrowing of the joint space, and erosions. As in AS, RS, and PA, HLA-B27 positivity increases the probability that the presumptive diagnosis is correct but does not establish the diagnosis.

Differential Diagnosis Anterior uveitis in IBD-associated arthritis patients is usually nongranulomatous, with fine white keratic precipitates, moderate cells, and flare; these characteristics may be similar to the ones of anterior uveitis associated with other spondyloarthropathies including AS, RS, or PA. Anterior uveitis in IBD-associated arthritis patients may also be insidious in onset, bilateral, and chronic in duration; these characteristics are in contrast to the ones of anterior uveitis associated with the other spondyloarthropathies, which is usually acute in onset, unilateral, and limited in duration. Differential diagnosis of posterior involvement in IBD includes various causes of intermediate uveitis, pars planitis, idiopathic retinal vasculitis, Beh~et's disease, and sarcoidosis. Episcleritis, scleritis, and glaucoma more commonly accompany the anterior uveitis in IBD-associated arthritis than the anterior uveitis in the other spondyloarthropathies. 162 Differentiation between those systemic diseases depends on the presence or absence of the clinical and radiologic charactelistics. Anterior uveitis and bowel manifestations can also be noted in Whipple's disease, giardiasis, and amebiasis. Whipple's disease is associated with more constitutional symptoms, normal radiologic studies, and a characteristic small intestine biopsy. Stools for ova and parasite can help differentiate parasitic diseases.

CD is a chronic focal granulomatous disease characterized by transmural inflammation of the gastrointestinal tract, predominantly the ileum and cecum. DC is a chronic inflammatory disease that ;iffects the colonic mucosa and submucosa, predominantly the rectosigmoid area. 126 The etiology of IBD is unknown and the relationship Treatment between gut and joint inflammation is not fully under- Antelior uveitis can be treated with topical corticosteroids stood. There is evidence of genetic predisposition in IBD- and cycloplegic/mydriatic agents. Cystoid macular edema associated sacroiliitis and spondylitis, because 50% to and posterior segment involvement may also be treated 70% of those patients possess HLA-B27. The pathogenesis with periocular injections of triamcinolone (40 mg/l ml) of IBD-associated peripheral arthritis could be related to . and/ or short-term systemic corticosteroid therapy.163 Fre-

CHAPTER 52:

quent recurrent disease may be treated with a maintenance course of oral NSAlDs to slow the frequency of the attacks. Corticosteroid-refractory and -intolerant cases and those with severe chronic disease may benefit from weekly, low-dose methotrexate (a total of 7.5 to 15 mg/ week); careful monitoring for side effects and cOlnplications is required. Oral NSAlDs are helpful in suppressing the systemic signs and symptoms, although they may occasionally cause exacerbation of diarrhea and colitis. Sulfasalazine may assist in controlling bowel inflammation and SOlnetimes also benefits the arthritis,164 but it has no effect on the uveitis. Corticosteroids can be successfully used intraarticularly or orally; they might have an effect on the peripheral arthritis but not on the axial joint involvement. They should be used only as necessary to control the bowel disease. Surgical excision of the inflamed bowel might assist in managing the extraintestinal symptoms, including peripheral arthritis and ocular manifestations. 142 When resistant cas'es develop, methotrexate, azathioprine, and/or anti-TNF-a agents may assist in managing both the bowel and the joint disease. 165 As in AS, physiotherapy is mandatory to prevent deforming ankylosing in patients with spinal disease and in some patients with peripheral joint disease.

Natural History, Prognosis, and Complications The ocular prognosis is generally good. Severe or refractory cases may have associatetl cataract, glaucoma, or cystoid macular edema.

Whipple's Disease Whipple's disease is a rare systemic infectious disorder characterized by malabsorption causing chronic diarrhea. Identification of the organism, Tropheryma whippelii, has led to earlier diagnosis and a better understanding of the pathogenesis of the disease. Seronegative sacroiliitis and spondylitis may be present. Based on this and the increased prevalence of HLA-B27, Whipple's disease is classified as a spondyloarthropathy.

History In 1907, Whipple described a case of a 36-year-old male physician with diarrhea and malabsorption, wasting, joint inflammation, mesenteric lymphadenopathy, and widespread intestinal fat infiltration as "intestinal lipodystrophy."166 Whipple hypothesized the cause was infectious, as rod-shaped organisms were detected in silver-stained sections. In 1948, Black-Schaffer first reported the histologic criteria for diagnosing Whipple's disease and described positive periodic acid-Schiff (PAS) staining of macrophages throughout the lamina propria of the intestines. 167 He proposed changing the name suggested by Whipple (intestinal lipodystrophy) to Whipple's disease. In 1960, the organism was visualized under electron Inicroscopy as bacillary, gram-positive bacteria, located intracellularly and extracellularly.168 The mechanism responsible for malabsorption was bacterial invasion of the intestinal epithelium. Molecular biology techniques have allowed identification and classification of the gram-positive actinomycete Tropheryma whifJpelii. 169

SPONDYLOARTHROPATHIES

E.pidemio/ogy Whipple's disease is a rare disorder occurring mainly in middle-aged (average age, 49 years) white (99%) men (9: 1 male-to-female ratio). Familial cases have been observed and the incidence of HLA-B27 is 30%.170 Many of the patients (66%) have an occupation with soil or animal COlitact.

Clinical Features Gastrointestinal manifestations, mainly diarrhea with malabsorption (steatorrhea) and ill-defined abdominal pain, are the most prominent symptoms. Other common systemic findings include weight loss, hypotension, lymphadenopathy (including mesenteric and retroperitoneal), fever, peripheral edema, endocarditis, pneumonia, pleurisy, hyperpiginentation of the skin, and migratory polyarthritis. l71 Central nervous system manifestations including dementia, ophthalmoplegia, and myoclonus have also been reported. 172 Seronegative peripheral oligoarthritis or polyarthritis is present in 90% of the patients. It may precede other disease manifestations by decades, is often migratory, and involves large joints. Arthritis activity fluctuates independently of intestinal symptoms. Sacroiliitis is present in 7% and spondylitis in 4% of the cases. 173 Ocular manifestations were first reported in 1949. 174 They are usually,neuro-ophthalmic findings such as ophthalmoplegia (external, internal, supranuclear), gaze palsies, pupillary abnormalities, nystagmus, and papilledema. 175 Other eye findings are anterior uveitis, choroiditis, retinitis, vitritis, retinal vasculitis, conjunctivitis, and keratitisp6--179

Pathology and Pathogenesis Granules of PAS-positive material and rod-shaped bacteria can be seen within macrophages of the intestinal villi on jejunal biopsy and in other involved tissues. 168 Opacities in the vitreous consist of macrophages that have migrated from the inner layers of the retina into the vitreous body. Whipple's disease is caused by an unculturable microbe, a gram-positive actinomycete that is not closely related to any other microbe. The mechanism responsible for malabsorption seems to be bacterial invasion of the intestinal epithelium and not blockage of the lymphatics.

Diagnosis Patients with anterior and/or posterior uveitis or retinal vasculitis associated with abdominal pain, diarrhea, weight loss, and migratory arthralgias should be suspected of having Whipple's disease. Jejunal biopsy demonstrates an abundance of macrophages filled with PASpositive granules and bacilliform gram-positive microorganisms in the lamina propria of the small intestine. 171 Vitrectomy may be diagnostic. 179 Polymerase chain reaction (PCR) has been used to identify Tropheryma whippelii from intestinal tissue 168 as well as from vitreous fluid. 180 PCR is available to investigators, but it is not routinely performed in commercial laboratories to diagnose Whipple's disease.

Differential Diagnosis The differential diagnosis must include idiopathic IBD, because both disorders may have gastrointestinal manifes-

CHAPTER 52: SERONEGATIVE SPONDYLOARTHROPATHIES

tations, and uveitis. Systemic lupus erythematosus, polyarteritis nodosa, Beh<;et's disease, and sarcoidosis can have multisystemic involvement, retinal vasculitis, and uveitis. Jejunal biopsy may be crucial to the differentiation.

Treatment Ten to 14 days of intravenous penicillin and streptomycin followed by a year of trimethoprim/sulfamethoxazole is the treatment of choice. 170 , 171 Clinical experience with ceftriaxone is limited although promising. Other alternative agents are tetracycline or doxycycline. Intraocular inflammation can be controlled with topical, regional, or oral corticosteroids.

Natural History, Prognosis, and Complications A correct diagnosis is essential, because the condition responds well to appropriate antibiotic therapy, and, untreated, Whipple's disease can be f<;tta1. 17l Relapse after short courses of antibiotics (less than 1 year) are frequent. Death occurs in about 26% of cases, either because of lack of treatment, relapse, or predisposing factor for other illness.

JUVENilE ARTHRITIS Uveitis may occur in association with juvenile arthritis. Chronic inflammatory arthritis in childhood is a heterogeneous group of disorders for which there is 110 universally agreed upon classification. The American College of Rheumatology (ACR) differentiates j"Lfvenile spondyloarthropathies, juvenile rheumatoid arthritis ORA), and other arthritides in childhood (sarcoidosis and neonatal onset multisystem inflammatory disease). lSI In practice, however, early recognition· and differentiation of juvenile spondyloarthropathies from JRA is difficult. Sacroiliac inflammation and spondylitis are late manifestations of these diseases. 1s2 Initial presentation with inflamlnation in a lower limb peripheral joint may be consistent with subsequent development of juvenile spondyloarthropathy.1s2, 1S3 Because of that, I will focus not only on juvenile spondyloarthropathies, which are the subject of this chapter, but also on JRA. The ACR classification will be used.

Juvenile-Onset Spondyloarthropathies Juvenile-onset spondyloarthropathy, occurring in children under the age of 16 years, includes juvenile AS, cervical spondylitis in girls, RS, PA, and IBD-associated arthritis. As for the adult spondyloarthropathies, the characteristics of these diseases include (1) radiographic sacroiliitis with or without accompanying spondylitis, (2) inflammatory asymmetric peripheral arthritis with lack of rheumatoid nodules, (3) absence of rheumatoid factor or antinuclear antibodies, (4) strong association with HLAB27, (5) a tendency for ocular inflammation (mainly anterior uveitis), and (6) variable mucocutaneous lesions. 1s3

Epidemiology Spondylitis is uncommon in children. Difficulties in diagnosis make the actual incidence of juvenile spondyloarthropathies hard to determine. Children with inflammation of the lumbosacral spine and sacroiliac joints

have a high frequency of the histocompatibility antigen HLA-B27. American surveys show that about 20% of both boys and girls who are HLA-B27 positive will develop AS. 1s4, 1S5 These rates are higher than for European populations. Is3 In children with AS, HLA-B27 is associated with unilateral anterior uveitis of sudden onset.

Clinical Features JUVENILE ANKYLOSING SPONDYLITIS

Juvenile AS is a chronic arthropathy that most frequently affects boys (2: 1 male-to-female ratio) after the age of 10 years. All patients ultimately develop back pain with radiographic involvement of the lumbosacral spine and sacroiliac joints; however, peripheral arthritis, which usually affects hips, knees, ankles, or heels, together with enthesitis (especially around the knees and feet) may precede spondyloarthropathy by years. IS3 Because HLAB27 is positive in about 91 % of these patients, the presence of peripheral arthritis in an HLA-B27-positive boy without radiographic evidence of sacroiliac involvement could be compatible with a future development of AS. By the definition of spondyloarthropathy, tests for rheumatoid factor and antinuclear antibodies are negative. Recurrent attacks of acute anterior uveitis, in contrast to the chronic progressive iri~ocyclitis of JRA, occur in 5% to 15% of these children. 1s6,Is7 The attacks are usually unilateral, although either eye may be involved at different times. Topical corticosteroids and, if necessary transeptal injections of corticosteroids are effective. The longterm visual prognosis is good. CERVICAL SPONDYLITIS IN GIRLS

Cervical apophyseal joint fusion and symmetric destructive polyarthritis involving small joints of the hands and wrists with deformities of the fingers and fusion of the wrists are seen in HLA-B27-positive girls. ISS Cervical apophyseal joint fusion is clinically indistinguishable from cervical joint disease in JRA. Most of the patients (65%) are seronegative for rheumatoid factor and for antinuclear antibodies. HLA-B27-positive and antinuclear antibody-negative patients are more likely to develop recurrent attacks of acute anterior uveitis, in contrast to the chronic progressive iridocyclitis of JRA. On the other hand, HLA-B27-positive and antinuclear antibodypositive patients are more likely to develop chronic progressive iridocyclitis similar to the one seen in JRA. JUVENILE REITER'S SYNDROME

RS is extremely infrequent in children. 1s9 However, when present, it exhibits the same pathogenetic and clinical characteristics seen in RS in· adults. By the definition of spondyloarthropathy, tests for rheumatoid factor and antinuclear antibodies are negative, and HLA-B27 is positive for close to 90% of children. About 2% of patients develop acute anterior uveitis. I90 The attacks are usually unilateral, although either eye may be involved at different times. Topical corticosteroids and, if necessary, transeptal injections of corticosteroids are effective. The longterm visual prognosis is good.

CHAPTER 52:

SPONDYlOARTHROPATHIES

berger in 1890,197 it was not until 1897, that George PSORIATIC ARTHRITIS Juvenile PA can be defined as arthritis occurring with Frederick Still provided the basis to establish the disease psoriasis or with three of the following criteria: dactylitis, as JRA.198 Ocular inflammation in JRA has been recognail pitting, family history of psoriasis, or a rash that is nized since Ohm's first description in 1910. 199 not entirely typical of psoriasis. It is more frequent in girls (3:2 female-to-male ratio), with a mean age of onset E.pidemiology of psoriasis of about 9 years and a mean age of onset of JRA has an estimated prevalence of about 113.4 per arthritis of about 11 years. Arthritis is typically mono- 100,000 children in the United States. 200 No race or cliarticular at presentation, most frequently involving the mate is excluded from its attack. It is much more comknees, although over time, asymmetric polyarthritis may mon in girls (70% to 75%) than in boys. The oligoarticudevelop. Rheumatoid factor is negative. Antinuclear anti- lar (pauciarticular) onset type is the lllOSt common bodies may be positive. There is no particular HLA associ- (about 50%), followed by the polyarticular (40%), and ation, except in those children with sacroiliitis who are the systemic (l 0%) onset; each of those categories has its likely to be HLA-B27 positive. Between 8% and 15% of own clinical characteristics (Table 52-4) .194 Genetic facchildren with PA develop a chronic iridocyclitis similar to tors play a role in the association between arthritis and the one seen in JRA. These patients are usually antinu- uveitis. HLA-DR5 is associated with uveitis in children clear antibody positive (80%), with oligoarticular disease with oligoarticular JRA.201 Conversely, HLA-DRI and presenting at earlier age (about 3 years) and dermato- HLA;..DR4 are negatively associated with uveitis. logic disease presenting at older age (about 13 years). In these cases, an initial diagnosis of oligoarticular JRA is Clinical Features usual before dermatologic disease appears. ARTICULAR MANIFESTATIONS JUVENILE lBO-AsSOCIATED ARTHRITIS

IBD-associated arthritis is uncommon in children. 193 It is usually mild and pauciarticular and affects primarily large joints. A less frequent articular manifestation is spondylitis and sacroiliitis, which is chronic and associated with HLA-B27. Anterior uveitis may be acute or chronic; while acute anterior uveitis is more common in HLA-B27positive children, chronic anferior uveitis is more frequent in children with peripheral joint disease. In children with CD, anterior uveitis is more common in those with arthritis and in those with colon disease (rather than small bowel involvement).

Juvenile Rheumatoid Arthritis JRA is defined as a chronic seronegative peripheral arthritis in a child under the age of 16, and it can be classified by type of onset into oligoarticular, polyarticular, and systemic JRA.194

History An. early adolescent skeleton with changes compatible with JRA was entombed in the Andes of Peru between AD 900 and 1050. 195 Although children with polyarthritis were first described by Cornil in 1864196 and by Diament-

Oligoarticular (Pauciarticular) Onset JRA. Oligoarticular (pauciarticular) onset JRA accounts for at least 50% of children withJRA. It is common in girls (5:1) with a peak age of onset at 2 years. Oligoarticular onset JRA involves four or fewer joints during the first 6 months of the disease; the knees and, less frequently, the ankles and wrists may exhibit painless swelling. The arthritis may be evanescent, rarely destructive, and radiologically insignificant. About 75% of these patients test positive for antinuclear antibody. This mode of onset is rarely associated with systemic signs. Polyarticular Onset JRA. Polyarticular onset JRA accounts for at least 40% of children withJRA. It is common in girls (3:1) with a peak age of onset at 3 years. Polyarticular onset JRA involves five or more joints during the first 6 months of the disease; small joints of the hand are characteristically inflamed but larger joints of the knee, ankle, or wrist may also become involved. The aSYlllmetric polyarthritis may be acute or chronic and may be destructive in 15% of the patients. IgM rheumatoid factor is present in 10% of children with this subgroup ofJRA and is associated with the presence of subcutaneous nodules, erosions, and a poor prognosis. About 40% of these patients test positive for antinuclear antibody. Systemic

TABLE 52-4. CHARACTERISTICS OF JUVENilE RHEUMATOID ARTHRITIS BY TYPE OF ONSET

Frequency of cases Number of joints involved Age at onset Sex ratio (F:M) Systemic involvement Chronic anterior uveitis Rheumatoid factor present Antinuclear antibody present Prognosis

OliGOARTICULAR

POLYARTICULAR

SYSTEMIC

50% Less than five Early childhood Peak: 2 yr 5:1 None 20% Rare 75% to 85% Good to excellent*

40% More than four Throughout childhood Peale 3 yr 3:1 Moderate 5% 10% 40% to 50% Fair to good

10% Variable Throughout childhood No peak 1:1 Prominent Rare Rare 10% Poor to good

*Visual prognosis may be guarded Modified from Cassidy JT, Petty RE: Textbook of Pediatric Rheumatology, 3rd eel. Philadelphia, W.B. Saunders, 1994.

CHAPTER 52:

SPONDYlOARTHROPATHIES

symptoms, including anorexia, anemia, and growth retardation, are moderate. Systemic Onset JRA. Systemic onset JRA accounts for at least 10% of children with JRA. It occurs with equal frequency in boys and girls and can appear at any age. In addition to symmetric polyarthritis, children have fever (39°C or 40°C during the evening and normal during the morning), macular rash, leukocytosis, lymphadenopathy, and hepatomegaly; pericarditis, pleuritis, splenomegaly, and abdominal pain are less frequently observed. 202 Articular disease is symmetric and may be destructive in 25% of patients; hands, wrists, feet, ankles, elbows, knees, hips, shoulders, cervical spine, and jaw may be involved. Antinuclear antibody is positive in only 10% of the patients. OCULAR MANIFESTATIONS

About 20% of children with the oligoarticular JRA and 5% of children with the polyarticular JRA develop anterior uveitis. 182 Because oligoarticular JRA is more commonly associated with anterior uveitis, known risk factors for the presence of anterior uveitis are young age, female sex, antinuclear antibody positivity, rheumatoid factor seronegativity, and oligoarticular onset. 203 Joint inflammation usually precedes anterior uveitis by several years, but occasionally eye inflammation may precede the development of arthritis by montl1s to years. JRA-associated uveitis is usually a chronic, nongranulomatous, bilateral (75%) iridocyclitis, and it is often asymptomatic until damage to intraocular S!ructures becomes substantiap04 The keratic precipitates'" are usually nongranulomatous, small to medium in size, and localized in the inferior half of the corneal endothelium. Many hundreds of minute keratic precipitates (endothelial dusting) may appear during exacerbations of ocular inflammation. Mutton fat and Koeppe nodules may (rarely) be present. Anterior chamber reaction, usually graded from 1 to 2 + cells, and associated chronic flare are characteristic. Anterior chamber cells and not flare should be used as an indicator of inflammatory activity or need for treatment. Because the severity of uveitis is unrelated to the exacerbation of joint inflammation, articular disease should not be used as a proxy indicator of ocular inflammation. Both eyes are usually involved either. simultaneously or within a few months of each other. 182 The onset of uveitis is usually asymptOluatic (over 50%) and its presence is often initially detected by routine slit-lamp biomicroscopic examination or school vision screening detection of impaired vision. Frequently, the first sign of uveitis is an irregular pupil as a result of posterior synechiae. Although the eye is usually noninjected, even during exacerbations (Fig. 52-9), it is important to emphasize to parents that a red eye should not be dismissed as conjunctivitis. Sometimes, the initial presentation of uveitis includes visual loss, cataract, band keratopathy, and glaucoma. Therefore, girls with oligoarticular arthritis, who are antinuclear antibody positive and rheumatoid factor negative, should be screened every 3 to 4 months for the development of chronic iridocyclitis. 205 Ocular complications may be sight threatening and include glaucoma, cataract, cyclitic membrane and hypotony, and band keratopathy.206--210 Glaucoma may be

fiGURE 52-9. The typical quiet eye of a patient with active juvenile rheumatoid arthritis-associated iridocyclitis with an undilatable pupil secondary to dense posterior synechial formation. (See color insert.)

present in up to 20% of patients and may be caused by pupillary block or from chronic inflammation with presumed damage to the trabecular meshwork. Cataract formation may occur in 42% to 92% of patients and in children may lead to amblyopia. Cyclitic melubrane formation and ocular hypotony can develop in longstanding inflammation in the.presence of posterior synechiae and a small pupil (Fig. 52-10), or after eye surgery. Band keratopathy is present in about 41 % of these children and can cause significant visual loss (Fig. 52-11). Although uveitis in JRA is usually anterior, vitritis, cystoid macular edema, and optic nerve edema may be seen.

Pathology and Pathogenesis Pathologic findings show that the synovium becomes hyperplastic, with subsynovial lymphocytic infiltration, vascular endothelial hyperplasia, and edema. 211 Similar histologic pictures are seen in the eyes of these patients. Lymphocytes, plasma cells, and scattered giant cells infiltrate the iris and ciliary body.212, 213

fiGURE 52-10. Ultrasound biomicroscopy of a patient with juvenile rheumatoid arthritis-associated iridocyclitis. Note the membrane on the ciliary body.

CHAPTER 52: SERONEGATIVE SPONDYlOARTHROPATHIES

FIGURE 52-II. Band keratopathy in a patient with juvenile rheumatoid arthritis-associated iridocyclitis.

The cause of uveitis and arthritis in JRA is unknown. Immunity to ocular antigens (S antigen or iris antigen)214-216 has been studied, but whether the immune reactions play a role in the pathogenesis or whether they are simply responses to damage by other mechanisms is unknown.

Diagnosis Oligoarticular, polyarticular, and systemic onset JRA have their own clinical and serologic characteristics (see Table 52-4). Routine ocular examin<:1tions by an ophthalmologist are mandatory every 3 or 4 months to early detect and treat chronic iridocyclitis. Antinuclear antibody positivity is present in almost all children with oligoarticular onset JRA and uveitis, but is present in up to 80% of those without uveitis. Therefore, the antinuclear antibody negativity may be of some help in predicting that a child will not develop uveitis, but its positivity does not assist in the prediction of the development of uveitis.

Differential Diagnosis Ocular sarcoidosis in children is the disease that most closely mimics uveitis in JRA, because both entities may develop skin, joint, and eye manifestations without radiographic evidence of pulmonary disease. 217 Antinuclear antibody positivity, characteristic distribution of involved joints, and chronic nongranulomatous iridocyclitis and band keratopathy can help diagnose JRA. Skin biopsy showing noncaseating granulomas may prove sarcoidosis. Anterior uveitis associated with the spondyloarthropathies is characterized, unlike the chronic iridocyclitis, by acute, symptomatic onset of anterior uveitis, limited course, unilateral involvement, and good visual prognosis without vision-threatening complications. Other diseases to consider in the differential diagnosis of juvenile arthritis and uveitis are LYlue disease, trauma, keratouveitis caused by herpes simplex or herpes zoster, and Kawasaki disease.

Treatment Patients with uveitis associated with JRA need to be seen by an ophthalmologist regularly, every 3 or 4 months. The mainstay of therapy for the ocular inflammation

in these patients consists of. topical corticosteroids and mydriatics. Topical corticosteroids should be used fre" quently (up every to 1 to 2 hours) during exacerbations, and tapered as the inflammation resolves. It is important to find the lowest dose required to keep the iridocyclitis under control and minimize complications such as cataract formation or glaucoma. Eyes that have flare but no cells in the anterior chamber do not require corticosteroids, because these agents would increase the chances of secondary cataract or glaucoma. A short-acting mydriatic such as tropicamide is preferred to the longer-acting agents, to keep the pupil mobile and help prevent the formation of posterior synechiae. In patients who cannot be controlled with topical therapy alone, regional corticosteroids (triamcinolone 40 mg/1 ml) can be useful; however, this may be difficult to deliver in this age group and frequently requires general anesthesia. Oral NSAIDs have been shown to help control both articular and ocular inflammation and can help decrease the aluount of topical corticosteroid needed to control the uveitis. 218 , 219 Tolmetin or naproxen are the NSAIDs more commonly used in children. Short courses of oral corticosteroids (1 mg/ kg/ day) can be used in severe cases and tapered according to the clinical response. However, they should not be used chronically because of their multiple and severe side effects in children. Refractory cases may be controlled with weekly, low-dose methotrexate; careful monitoring for side effects and complications of immunosuppressive therapy is required. Since 1950, the prevalence of blindness in children with JRA-associated uveitis has dropped from approximately 50% to its current 12% level as a result of two important sea-changes in medicine and ophthalmology: the advent of corticosteroid therapy and the widening recognition of the importance of regular slit-lamp examinations of children with JRA. It is my impression that the next revolutionary change in this matter is already underway. Increasing numbers of ophthalmologists and pediatric rheumatologists are recognizing the long-term ben~fits of early intervention with low-dose, once weekly methotrexate therapy, and the extraordinary safety record of this treatment approach, compared with chronic steroid or NSAID therapy. 220, 221 I have the very distinct impression, as I travel to diverse regions to lecture and to see patients, that in those areas that are well served with modern-trained pediatric rheumatologists there are many fewer children with JRA-associated uveitis that has produced or is producing ocular damage, compared with the numbers of such children seen in areas devoid of such specialists. I attribute this to the more proactive therapeutic intervention, especially with low-dose systemic methotrexate, by the collaborative liaisons between ophthalmologists and pediatric rheumatologists in some communities. This is incredibly gratifying, given the extraordinarily cruel toll JRA-associated uveitis has "silently" extracted from its victims over the past half century: "silently" because of its nearly imperceptibly slow vision-robbing damage. Indeed, far too few ophthalmologists seem to be aware of eloquent documentation of researchers frOlu many different countries on this silent epidemic. Medical management of glaucoma is difficult. Topical

CHAPTER 52: SERONEGATIVE SPONDYlOARTHROPATHIES

A team approach including pediatricians, rheumatologists, orthopedists, and ophthalmologists offers the greatest potential for limitation of both ocular and articular complications in JRA.

References

fiGURE 52-12. Left eye of a young woman with juvenile rheumatoid arthritis-associated iridocyclitis, status post cataract extraction with implantation of a posterior chamber lens implant. Note not only the pupillary seclusion but also the obvious in~ammatory membrane cocoon around the lens implant. Contraction of this membrane is displacing the lens implant anteriorly and is detaching the ciliary body, producing progressive hypotony. (See color insert.)

l3-blockers and sYInpathomimetic agents may be sufficient, but many patients require carbonic anhydrase inhibitors. Laser iridotomy is indicated in glaucoma caused by pupillary block with iris bombe. Surgery is often needed in uveitis associated with JRA. Cataract removal should be perfonned only in eyes that have been without inflammation for ai~least 3 months. Phacoemulsification combined with pars plana vitrectomy or pars plana lensectomy/vitrectomy can be used. 209 ,222 Intraocular lenses are contraindicated in these patients (Fig. 52-12). Aggressive anti-inflammatory therapy before and after surgery is recommended. 209 Traditional glaucoma surgery with trabeculectomy has shown poor results because of both the low scleral rigidity and the fibrous proliferation seen at the filtration site in young patients. 202 The use of aqueous drainage devices such as Molteno implants may improve success rates. 223 Chemical chelation with topical application of ethylenediaminetetraacetic acid (EDTA) solution after debridement of the epithelium with 70% alcohol and scraping is helpful in removing band keratopathy. The excimer laser may have some role.

Prognosis The severity of intraocular inflammation that is observed on the initial examination correlates with the degree of final vision loss and with the extent of ocular complications. However, earlier detection and earlier and aggressive treatment improve visual outcome and decrease ocular complications. Factors that correlate with poor visual prognosis are onset of uveitis before onset of arthritis, oligoarticular arthritis, young age at onset, female sex, antinuclear antibody positivity, and rheumatoid factor negativity. In children with uveitis associated with JRA, 10% develop mild uveitis, 15% moderate uveitis, 50% moderate to severe uveitis, and 25% are unresponsive to therapy. Overall, 75% of children with moderate to severe uveitis experience visual loss resulting from ocular complications. 222

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120. Gottlieb AB, Fu SM, Carter DM, et al: Marked increase in tlle frequency of psoriatic arthritis in psoriasis patients witll HLA-DR + keratinocytes. fu-thritis Rheum 1987;30:901. 121. Hall RP, Gerber LH, Lawley TJ: IgA-containing immune complexes in patients with psoriatic arthritis. Clin Exp RheumatoI1984;2:221. 122. Black RL, O'Brien WM, Van Scott EJ, et al: Methotrexate therapy in psoriatic arthritis. JAMA 1964;189:743. 123. Ellis CH, Gorsulowsky DC, Hamilton TA, et al: Cyclosporine improves psoriasis in a double-blind study. JAMA 1986;256:3110. 124. Faulds D, Goa KL, Benfield P: Cyclosporin. A review of its phannacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 1993;45:953. 125. Roberts MET, Wright V, Hill AGS, et al: Psoriatic arthritis: Followup study. Ann Rheum Dis 1976;35:206. 126. Palumbo PJ, Ward LE, Sauer WG: Musculoskeletal manifestations of IBD: Ulcerative and granulomatous colitis and ulcerative proctitis. Mayo Clin Proc 1973;48:411. 127. White MH: Colitis. Lancet 1895;1:583. 128. Bywaters EGL, fulsell BM: fu-thritis associated with ulcerative colitis. Ann Rheum Dis 1958;17:169. 129. Wright V, Watkinson G: Articular complication of ulcerative colitis. AmJ ProctoI1966;17:107. 130. Van Patter WN, Barger JA, Dockerty MB, et al: Regional enteritis. Gastroenterology 1954;26:347. 131. Acheson ED: ful association between ulcerative colitis, regional enteritis, and ankylosing spondylitis. QJ Med 1960;29:489. 132. Ansell BM, Wigley RAD: fu-thritis manifestations in regional enteritis. fum Rheum Dis 1964;23:64. 133. Mi.inch H, PurmanJ, Reis HE, et al: Clinical features of inflammatory joint and spine manifestations in Crohn's disease. Hepatogastroenterology 1986;33: 123. 134. Greenstein AJ, Janowitz HD, Sachar DB: The extraintestinal complications of Crohn's disease and ulcerative colitis: A study of 700 patients. Medicine 1976;55:401. 135. Gravallese EM, Kantrowitz FG: fu-tllritic manifestations of inflammatory bowel disease. fun J Gastroenterol 1988;83:703. 136. Mallas EC, McIntosh P, Asquith P, et al: Histocompatibility antigens in inflammatory bowel disease: ,Their clinical significance and their association witll arthropathy with special reference to HLAB27. Gut 1976;17:906. 137. Van Den Berg-Loonen, Dekker-Saeys BJ, Meuwissen SGD, et al: Histocompatibility antigens and other genetic markers in ankylosing spondylitis and inflammatory bowel disease. J Immunogenet 1977;4:167. 138. Haslock I, Wright V: The musculoskeletal complications of Crohn's disease. Medicine 1973;52:217. 139. Isdale A, Wright V: Seronegative arthritis and the bowel. Baillieres Clin Rheumatol 1989;3:285. 140. fulders0l1 DO, Mullinger MA, Bagoch A: Regional enteritis involving tlle duodenum with clubbing of the fingers and steatorrhea. Gastroenterology 1957;32:917. 141. Kitis G, Thompson H, Allan RN: Finger clubbing in inflammatory bowel disease: Its prevalence and pathogenesis. Br Med J 1979;2:825. 142. Hopkins DJ, Horan E, Burton IL, et al: Ocular disorders in a series of 332 patients with Crohn's disease. BrJ Ophtllalmol 1974;58:732. 143. Wright R, Lumsden K, Luntz MH, et al: Abnormalities of tlle sacroiliac joints and uveitis in ulcerative colitis. Q J Med 1965;34:229. 144. Knox DL, Schachat AP, Mustonen E: Primary, secondary, and coincidental ocular complications of Crohn's disease. Ophthalmology 1984;91:163. 145. Billson FA, de Dombal FT, Watkinson G, et al: Ocular complications of ulcerative colitis. Gut 1967;8:102. 146. Salmon JF, Wright JP, Murray ADN: Ocular inflammation in Crohn's disease. Ophtllalmology 1991;98:480. 147. Ellis PO, Gentry JH: Ocular complications of ulcerative colitis. Am J Ophthalmol 1964;58:779. 148. Salmon JF, Wright JP, Bowen RM, et al: Granulomatous uveitis in Crohn's disease. fu-ch Ophthalmol 1989;107:718. 149. Ruby AJ, Jampol LM: Crohn's disease and retinal vascular disease. AmJ Ophthalmol 1990;110:349. 150. Duker JS, Brown GC, Brooks L: Retinal vasculitis in Crohri's disease. funJ Ophthalmol 1987;103:664. 151. Petrelli EA, McKinley M, Troncale FJ: Ocular manifestations of inflammatory bowel disease. fum Ophthalmol 1982;14:356.

CHAPTER 52: SERONEGATIVE SPONDYlOARTHROPATHIES 152. Macoul KL: Ocular changes in granulomatous ileocolitis. Arch Ophthalmol1970;84;95. 153. Lyne AJ, Pitkeatheley DA: Episcleritis and scleritis. Arch Ophthalmol 1968;80: 171. 154. Jameson Evans P, Eustace P: Scleromalacia perforans associated with Crohn's disease. Br J Ophthalmol 1973;57:330. 155. Sainz de la Maza M, Foster CS: Necrotizing scleritis after ocular surgery. A clinicopathologic study. Ophthalmology 1991;98:1720. 156. Knox DL, Snip RC, Stark ~: The keratopathy of Crohn's disease. AmJ Ophthalmol 1980;90:862. 157. Geerards AJ, Beekhuis WH, Remeyer L, et al: Crohn's colitis and the cornea. Cornea 1997;16:227. 158. Durno GA, Ehrlich R, Taylor R: Keeping an eye on Crohn's disease: Orbital myositis as the presenting symptom. Can J Gastroenterol 1997;11:497. 159. Kirsner JB, Shorter RG: Shorter developments in "nonspecific" inflammatory bowel disease. N Engl J Med 1982;306:775. 160. Bhagat S, Das KM: A shared and unique peptide in the human colon, eye, and joint detected by a monoclonal antibody. Gastroenterology 1994;107:103. 161. Clark RL, Muhletaler GA, Margulies SI: Colitic arthritis: Clinical and radiographic manifestations. Radiology 1971;101:585. 162. Lyons JL, Rosenbaum JT: Uveitis associated with inflammatory bowel disease compared with uveitis associated with spondyloarthropathy. Arch Ophthalmol 1997;115:61. 163. Soukiasian SH, Foster CS, Raizman MB: Treatment strategies for scleritis and uveitis associated with inflammatory bowel disease. AmJ Ophthalmol 1994;118:601. 164. Mielants H, Vel's EM: HLA-B27 related arthritis and bowel inflammation. Part: I: Sulphasalazine (Salazopyrin) in HLA-B27 related reactive arthritis. J Rheumatol 1985;12:287. 165. Wilke WS: Methotrexate use in miscellaneous inflammatory diseases. Rheum Dis Clin North Am 1997;23:855. 166. Whipple GH: A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesen teric lymphatic tissues. ;~J ohns Hopkins Hosp Bull 1907;18:382. 167. Black-Schaffer B: Tinctoral demonstration of glycoprotein in Whipple's disease. Proc Soc Exp BioI Med 1949;72:225. 168. Cohen AS, Schimmel EM, Holt PR, et al: Ultrastructural abnormalities in Whipple's disease. Proc Soc Exp BioI Med 1960;105:411. 169. ReIman DA, Schmidt TM, MacDermott: RP, et al: Identification of the uncultured bacillus of Whipple's disease. N Engl J Med 1992;327:293. 170. McKinley R, Grace CS: Whipple's disease in an HLA-B27 positive female. Aust N Z J Med 1985;15:758. 171. Maizel H, Ruffin JM, Dobbins WO III: Whipple's disease: A review of 19 patients from one hospital and a review of the literature since 1950. Medicine 1970;49:175. 172. Dobbins WO III: Whipple's disease. In: Mandell GL, Douglas RG Jr, Bennett JE, eds: Principles and Practice of Infectious Diseases, 3rd ed. New York, Churchill Livingstone, 1990. 173. Canoso lJ, Saini M, Hennos JA: Whipple's disease and ankylosing spondylitis. Simultaneous occurrence in HLA-B27 male. J Rheumatol 1978;5:79. 174. Jones FA, Paulley JW: Intestinal lipodystrophy (Whipple's disease). Lancet 1949;1:214. 175. Badenoch J, Richards WCD, Oppenheimer DR: Encephalopathy in a case of Whipple's disease. J Neurol Neurosurg Psychiatry 1963;26:203. 176. Leland TM, Chambers JR: Ocular findings in Whipple's disease. South Med 1978;71:335. 177. Disdier P, Harle JR, Vidal-Morris D, et al: Chemosis associated with Whipple's disease. N EnglJ Med 1991;112:217. 178. Avila MP, Jalkh AE, Feldman E, et al: Manifestations of Whipple's disease in the posterior segment of the eye. Arch Ophthalmol 1984;102:384. . 179. Durant~, Flood T, Goldberg MF, et al: Vitrectomy and Whipple's disease. Arch Ophthalmol 1984;102:848. 180. Rickman L, Freeman WR, Green WR, et al: Brief report: Uveitis caused by Tropherym.a whippelii (Whipple's bacillus). N Engl J Med 1995;332:363. 181. Kanski lJ, Petty RE: Chronic childhood arthritis and uveitis. In: Pepose JS, Holland GN, Wilhelmus KR, eds: Ocular Infection and Immunity. St. Louis, Mosby, 1996, P 485.

182. Kanski JJ: Juvenile arthritis and uveitis. Surv Ophthahnol 1990;31:253. 183. Calabro lJ: Clinical aspects of juvenile and' adult ankylosing spondylitis. Br J Rheum 1983;22:104. 184. Calin A, FriesJF, Schurman D, et al: The close correlation between symptoms and disease expression in HLA-B27 positive individuals. J Rheumatol 1977;4:277. 185. Cohen LM, Mital KK, Schmid FR, et al: Increased risk for spondylitis stigmata in apparently healthy HLA-W27 men. An.n Intern Med 1976;84:1. 186. Hafner R: Die juvenile Spondarthritis. retrospektive Untersuchung an 71 patients. Manatsschr Kinderheilkd 1987;135:41. 187. Schaller J: Ankylosing spondylitis of childhood onset. Arthritis Rheum 1977;20:398. 188. Arnett FC, Bias WE, Stevens MB: Juvenile onset chronic arthritis: Clinical and roentgenographic features of a unique HLA-B27 subset:. AmJ Med 1980;69:369. 189. Rosenberg AM, Petty RE: Reiter's disease in children. Am J Dis Child 1979;133:394. 190. Iveson JMI, Nanda BS, Hancock JAH, et al: Reiter's disease in three boys. Ann Rheum Dis 1975;34:364. 191. Shore A, Ansell BM: Juvenile psoriatic arthritis: An analysis of 60 cases. J Pediatr 1982;100:529. 192. Southwood TR, Petty RE, Malleson PN: Juvenile psoriatic arthritis-An analysis of 60 cases. Arthritis Rheum 1989;32:1007. 193. Lindsley CB, Schaller JG: Arthritis associated with inflammatory bowel disease in children. J Pediatr 1974;84:16. 194. Cassidy JT, Petty RE: Textbook of Pediatric Rheumatology, 3rd ed. Philadelphia, W.B. Saunders, 1994. 195. Buikstra JE, Poznanski A, Cerna ML, et al: A case of juvenile rheumatoid arthritis from pre-Columbian Peru. In: Buikstra JE, ed: A Life in Science: Papers in Honor of J Lawrence Angel. Kampsville IL, Center for Anlerican Archeology, 1990, p 99. 196. Cornil MV: Memoire sur des coincidences pathologiques du rhumatisme articulaire chronique. C R Mem Soc BioI (Paris) 1864;4:3. 197. Diamantberger S: Du rhumatisme noueux (polyarthrite defonnante) chez les infants. Paris, Lecrosnier et Babe, 1890. 198. Still GF: On a form of chronic joint disease in children. Med ChiI' Trans 1897;80:47. (Reprinted in Arch Dis Child 1941;16:156.) 199. Ohm J: Bandformiae Hornhauttrubung bei einem nai~ahrigen madchen und ihre Behandlung mit subkonjunktivalen jodkaliumeinsptritzungen. Klin Monatsbl Augenheilkd 1910;48:243. 200. Towner SR, Michet CJ Jr, O'Fallon WM, et al: The epidemiology of juvenile rheumatoid arthritis in Rochester, Minnesota. Arthritis Rheum 1983;26:1208. 201. Malagon C, Van Kerckhove C, Giannini EH, et al: The iridocyclitis of early onset pauciarticular juvenile rheumatoid arthritis: Outcome in immunogenetically characterised patients. J Rheumatol 1992;19:160. 202. O'Brien JM, Albert DM: Therapeutic approaches for ophthalmic problems in juvenile rheumatoid arthritis. Rheum Dis Clin North Am 1989;15:413. 203. Dana MR, Merayo LlovesJ, Schaumberg DA, et al: Visual outcomes prognosticators in juvenile rheumatoid arthritis associated uveitis. Ophthalmology 1997;104:236. 204. Petty RE: Current knowledge of the etiology and pathogenesis of chronic uveitis accompanying juvenile rheumatoid arthritis. Rheum Dis Clin North Am 1987;13:19. 205. Boone MI, Moore TL, Cruz OA: Screening for uveitis in juvenile rheumatoid arthritis. J Pediatr Ophthalmol Strabismus 1998;35:41. 206. Key SW III, Kimura SJ: Iridocyclitis associated with juvenile rheumatoid arthritis. Am J Ophthalmol 1975;80:425. 207. Wolf MD, Lichter PR, Ragsdale CG: Prognostic factors in the uveitis of juvenile rheumatoid arthritis. Ophthalmology 1987;94:1242. 208. Rosenberg AM: Uveitis associated with juvenile rheumatoid arthritis. Semin Arthritis Rheum 1987;16:158. 209. Tugal Tutkun I, Havrlikova K, Power~, et al: Changing patterns in uveitis of childhood. Ophthalmology 1996;103:375. 210. Foster CS, Barrett F: Cataract development and cataract surgery in patients with juvenile rheumatoid arthritis associated iridocyclitis. Ophthalmology 1993;100:809. 211. Bywaters EGL: Pathologic aspects of juvenile chronic polyarthritis. Arthritis Rheum 1977;20:271. 212. Merrian JC, Chylack LT, Albert DM: Early onset pauciarticular

\RTHROPATHIES 88. Alibert JL: Precis Theorique et Pratique sur Ip' 218. Olson NY, Lindsley CB, Godfrey WA: Nonsteroidal anti-inflammaPeau. Paris, Caille et Ravier, 1818. ~~ tory drug therapy in chronic childhood iridocyclitis. Anl J Dis 89. Bazin P: Leyons Them"iques et Cliniques suy' ~;. Child 1988;142:1289. nees de Nature Arthritique et Arthreux..~ c;;;.", 0 219. Lovell DJ, Giannini EW, Brewer EJ Jr: Time course of response to nonsteroidal antiinflammatory drugs in juvenile rheumatoid P 154. -? ~*' ~ 90. Bourdillon C: These de Paris. No 298. If ~ Cfp 00 arthlitis. Arthritis Rheum 1984;27:1433. 91. Baker H: Epidemiologic aspects of P&(lV: 4~ <;1.0 1,; I. Foster CS: Ocular manifestatim~s of childhood arthritis. Womens Dermatol1966;78:249. ..;;S' ~ '?o'''d::::::? 7,? Health Primary Care 1998;1:823-833. 92. Wright V: Psor~asis and arthritis. Anlt. ~. \'Ib/ 0,... ~ ~ Q' '\lguyen QD, Foster CS: Saving the vision of children with juvenile 93. Baker H, Goldmg DN, Thompson ~ ~ ~ ~ ~,.2 ~L eumatoid arthritis-associated uveitis.JAMA 1998;280:1133-1134. Intern Med 1963;58:909. <% ~? ~ '.A 0 7 ~. 'llond JG, Kaplan HG: Lensectomy and vitrectomy for compli94. Leczinsky CG: The incidence ot; ~ ~ 0,... ~ ~ '?v ~ 1 cataract secondary to uveitis. Arch Ophthalmol 1978; psoriasis cases. Acta Derm Ve1t. ~ '%:.. ~ ~ ~ % 7% 8. 95. Wright V: Psoriatic arthritis ~ '?c;.~ ~ '0<) ~~(' ~7 "'L i J, Airaksinen PJ, Tuulonen A: Molteno implantation for S, Sledge CB, eds: Textb~ ~ ~ ~("; ~ ~ ,.0 ~ '?'1S 0 T glaucoma in juvenile rheumatoid arthritis. Arch OphPhiladelphia, W.B. Saund; ~~ 0...,. Q'".: ~ ~ 'f, 9c,. "'~ ~ ~ \ Q7;115:1253. ;A '? .~. c9 ,::0 Q' 0i. 7 9P ~ 9 6. Southwood TR, Petty RY iJ, <2 ~ C& % ~? 0 0 ~ ~ 0 children. Arthritis Rh~~ ~ 00 %0 4~ 0i. ~ ~~ ~Qt~6 iJO.U' ~o 97. Hamilton ML, Gladr 'f, 7~ ~ Q' tt,? 0 C. 7.: ~ 1-. 0~,::oO ;:.-" arthritis and HLA ~ ~ ~. ~0 ~ Y:' '?~ '?'? ~ ~ 00 ~ 98. Beauleiu AD, Ro' ~ C<'. 9
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(Table 53-1). These criteria are widely accepted and curSystemic lupus erythematosus (SLE) is an autoimmune rently provide the basis for standardized diagnosis of SLE disease characterized by the production of numerous au- in clinical and research work. 7 toantibodies. Many of the clinical manifestations of SLE, such as lupus nephritis and arthritis, result from tissue damage attributed, at least in part, to the deposition The prevalence of SLE varies worldwide. The prevalence of pathogenic immune complexes. Other manifestations, in North America and Northern Europe is 40 per 100,000 such as hemolytic anemia, thrombocytopenia, and the population. The female-to-male ratio is about 9: 1. Black antiphospholipid syndrome, arise from the direct effects Americans and Hispanics appear to have higher inciof autoantibodies on cell surface molecules or serum dence rates. Over 80% of cases involve women in their components. SLE is not organ specific and can affect childbearing years. SLE may affect up to 1 in 1000 young multiple (if not all) organ systems. The wide distribution women (l in 250 black women). The prevalence in chilof systemic involvement is a result of the fact that the dren and older adults is approxilnately 1 per 100,000.8 majority of the autoantibodie's are targeted against components of the cell nuclei. Arthritis, glomerulonephritis, CLINICAL CHARACTERISTICS and dermatitis are the primary clinical manifestations; however, hematologic and neurologic disturbances are Systemic Manifestations The systemic manifestations of SLE are diverse. 8 ,9 To aid also common. The ocular manifestations of SLE include lid derma- in establishing a diagnosis, the American Rheumatism titis, keratitis, scleritis, secondary Sjogren's syndrome, ret- Association has established 11 diagnostic criteria for SLE inal and choroidal vascular lesions, and neuro-ophthal- (see Table 53-1). A,diagnosis of SLE can be Inade when mic lesions. Eye involvement may precede systemic four of these criteria are met. It should be emphasized symptoms. Early recognition of ocular lupus erythemato- that these criteria were primarily intended for the use of sus by the ophthalmologist may,prevent not only the clinical investigators. For patient management, a clinical blinding complications of SLE but also can lead to timely 'diagnosis may be made even when less than four criteria institution of systemic therapy that may prolong the pa- are met. Cutaneous disease affects approximately 85% of patient's life and improve its quality. tients. The characteristic butterfly rash across the nose and cheeks, known as the malar flush, is the most comHISTORY mon finding, appearing as flat or slightly raised, fixed Lupus dermatitis was first described in 1845 by a dermaerythema over the malar eminences, usually sparing the tologist, Hebra, who regarded it as a benign, local skin nasolabial folds (Fig. 53-1). Discoid lupus erythematosus 1 condition. Kaposi, in 1872, conducted the first autopsy consists of erythematous raised areas with adherent keraon a patient with SLE, and he reported that this conditotic scaling and follicular plugging (Fig. 53-2). Cutanetion was in fact a systemic illness with potentially lifeous ulCers, splinter hemorrhages, purpuric skin lesions, threatening consequences. 1 The first report of ocular leand alopecia are other dermatologic manifestations that sions in a patient with SLE was in 1929, with Bergmeister's occur frequently as well. Less common skin lesions indescription of the classic retinal findings of cotton-wool clude maculopapular eruptions, lupus profundus, hyperexudates, irregular white patches along the retinal veins, trophic discoid lesions (Fig. 53-3), bullae, and urticarial and disc hyperemia. 2 Semon and Wolff conducted histologic examinations of the eyes of patients with SLE in 1933 and found mild choroiditis and subretinal exuda- TABLE 53-I. THE 1982 REVISED CRITERIA FOR tion. 3 Baehr and colleagues reported, in 1935, that 50% THE CLASSIFICATION OF SYSTEMIC LUPUS of patients with SLE developed retinal lesions.'" 5 Mau- ERYTHEMATOSUS menee also conducted histologic studies, which revealed 1. Malar rash retinal cytoid bodies, superficial retinal hemorrhages, and 2. Discoid rash mild choroiditis in the eyes of patients with SLE retinopa3. Photosensitivity 6 thy. 4. Oral ulcers In 1971, the American Rheumatic Association pub5. Arthritis (nonerosive, two or more peripheral joints) 6. Serositis (pleuritis, pericarditis) lished a report, "The Preliminary Criteria for the Classi7. Renal disorder (proteinuria, nephritis) fication of Systemic Lupus Erythematosus," which pro8. Neurologic disorder (seizures, psychosis) vided the first published criteria for the diagnosis of SLE. 9. Hematologic disorder (hemolytic anemia, leukopenia, This was followed in 1982 by "The 1982 Revised Criteria lymphopenia, thrombocytopenia) for the Classification of Systemic Lupus Erythematosus," 10. Immunologic disorder (positive LE cell prep, anti-native DNA, anti-Sm, false-positive test for syphilis) which incorporated serologic abnormalities, such as anti11. Antinuclear antibody (in the absence of drugs associated with bodies to DNA, antinuclear antibodies, serum comple"drug-induced" lupus) ment, and other serologic and imInunopathologic assays

CHAPTER 53: SYSTEMIC lUPUS ERYTHEMATOSUS

FIGURE 53-3. Hypertrophic discoid lupus. Note tl1e hypertrophic lesion under tl1e patient's left ear, with silvery keratinization on tl1e surface. (See color insert.)

FIGURE 53-I. Lupus mask or butterfly rash. Note the erythematous dermatitis over the malar eminences of the cheeks and the bridge of the nose. (See color insert.)

skin lesions. Painless oral u1cersmay be found in 30% to 40% of patients. Initiation or exacerbation with sun exposure is characteristic of lupus erythematosus skin lesions. RaY11.aud's phenomenon occurs in about 20% of patients. Arthritis is a very common initial symptom; it may afflict up to 85% of SLE patients. Lupus arthritis presents as painful or tender peripheral joint involvement or nondeforming, migratory polyarthritis. Other, less frequent musculoskeletal manifestations include cutaneous nodules, myalgias, and myositis.

Nonspecific systemic symptoms such as fatigue, fever, and weight loss affect most patients with SLE. Renal involvement occurs in approximately half of the patients and may take the form of either nephrotic syndrome with proteinuria or glomerulonephritis producing "active" urinary sediment. Mesangial disease, focal proliferative nephritis, diffuse pJ;"oliferative nephritis, and membranous glomerulonephritis may manifest in lupus patients. Lupus nephritis is the major cause of morbidity and mortality in patients with SLE. Cardiac involvement may occur, with pericarditis (seen in approximately 20% of lupus patients), myocarditis, and Libman-Sacks endocarditis. Libman-Sacks endocarditis is associated with the presence of phospholipid antibody. Potential pulmonary lesions include pleuritis and pneumonitis. Hepatosplenomegaly and adenopathy, while not part of the diagnostic criteria, can be seen in many patients with SLE. Neuropsychiatric manifestations occur in about a third of patients with SLE. Seizures, organic brain syndrome, and psychosis may occur. Transverse myelitis is a rare manifestation, occurring in only 4% of patients with SLE, but it is often seen in association with optic neuritis. Peripheral neuropathy and cranial nerve palsies are less commonly seen. Hematologic abnormalities are frequently detected in patients with SLE. Chronic anemia or autoimmune hemolytic anemia, leukopenia, lymphopenia, and thrombocytopenia are commonly observed. In addition, lupus patients are prone to thrombotic episodes.

Ocular Manifestations

FIGURE 53-2. Discoid lupus in a patient with chronic blepharitis. Note the subtle erytl1ematous lesions of tl1e skin of the lower eyelid. (See color insert.)

SLE can involve the eye and adnexae. SLE should be considered in the differential diagnosis of mucocutaneous disease, episcleritis, scleritis, keratoconjunctivitis sicca, keratopathy, uveitis, retinal and choroidal microangiopathy, papillitis, and neuro-ophthalmic disease. Io The eyelids may manifest the inflammatory and scaly lesions of discoid lupus erythematosus. The patients complain of recurrent eyelid irritation and redness, more prominent over the lateral third of the lower eyelids. Discoid lupus erythematosus of the eyelids may be pres-

CHAPTER 53: SYSTEMIC LUPUS ERYTHEMATOSUS

FIGURE 53-4. Peripheral keratitis in a patient with systemic lupus erythematosus. Note the perilimbal, circumferential mid to deep stromal infiltrate in the corneal stroma. (See color insert.)

ent for years, until a skin biopsy is performed. Histopathologic features include hyperkeratosis, basal cell vacuolation, perivasculitis, and dermal inflammation. ll We have described a distinct hypertrophic variant of discoid lupus erythematosus involving the conjunctiva. 12 Secondary Sjogren's syndrome, or keratoconjunctivitis sicca, occurs in approximately 20% of patients with SLE and is indistinguishable from the sicca complex seen in other connective tissue disease~13-15 Abnormal Schirmer and rose bengal staining tests may show reduced tear flow and staining of the corneal and conjunctival epithelia. Filamentary conjunctivitis may also develop as part of the sicca syndrome. 10, 16 In addition to keratoconjunctivitis sicca, Halmay and Ludwig in 1965 described a grayish white, band-shaped infiltration in the central corneal stroma (Fig. 53-4) .17 Reeves described a similar diffuse white haze, which progressed to a granular lesion despite topical steroid treatment. lS Scleritis is frequently associated with systemic vascular diseases such as SLE. In a review of 172 patients with scleritis, Sainz de la Maza and coauthors found systemic vasculitic disease present in 82 patients (48%) including seven with systemic lupus erythematosus (4%) .19 Of these seven patients, four manifested with diffuse anterior, two with nodular, and one with posterior scleritis. Scleritis in a patient with systemic lupus generally has a good ocular prognosis, because necrotizing scleritis rarely develops in patients with SLE. Episcleritis may also be associated with SLE. In a review of 100 patients with episcleritis, Akpek and coauthors noted SLE as an underlying disease in 4 of 36 (11 %) patients~ with an identifiable systemic illness. Although episcleritis is generally considered a benign, self-limited disease, a 'careful review of systems and an ocular examination should still be conducted in patients with episcleritis, so as not to miss an associated ocular or underlying systemic condition. 20 Angle-closure glaucoma secondary to uveal effusion may be an initial manifestation of SLE. Recently, Wisotsky and colleagues reported a case of bilateral pleural and uveal effusions with secondary angle-closure and elevated

intraocular pressures. Intraocular pressures were refractory to antiglaucoma medications and laser therapy. Drainage of the choroidal effusion via sclerotomies resulted in resolution of the angle-closure glaucoma. 21 Perhaps the most well recognized ocular manifestation of SLE is lupus retinopathy.22-27 This potentially blinding condition is considered an important marker of disease activity by rheumatologists. Visual loss from lupus retinopathy is viewed as an important index of disease severity.2s Since the initial report by Bergmeister in 1929, numerous authors have described lupus retinopathy.2, 3, 6, 10, 29 In the presteroid era, retinopathy was present in up to half of SLE patients. 4 However, with the advent of steroid and immunosuppressive tl1erapy, the incidence of retinopathy has declined considerably. The prevalence of lupus retinopathy ranges from 3% in an outpatient population with mild to absent disease,ll to 29% among patients with active disease. 3o However, in patients on maintenance therapy with chloroquine, Klinkhoff and associates detected retinopathy in 7 of 43 (16%) patients. Systemic lupus activity was present in five of these seven patients (71 %). The onset of retinopathy may be associated with exacerbation of systemic SLE.29 The lesions of lupus retinopathy are varied in appearance but most are believed to arise from retinal vasculitis. The different manifestations of lupus retinopathy and their complications are listed in Table 53-2. These funduscopic findings may be classified into the five following, ~ closely related categories. lo , 22-25, 31-33

Vasculitis Inflammation of the retinal vasculature may lead to focal leakage from the retinal capillaries and arterioles. Funduscopic signs of vasculitis include retinal arterial sheathing (Fig. 53-5). Fluorescein angiography reveals dye leakage from the retinal blood vessels (Fig. 53-6). Vasculitis of the optic nerve vessels may lead to optic nerve head swelling and subsequent ischemic optic neuropathy.

Vasa-occlusion MICROVASCULAR OCCLUSION

Cotton-wool spots are the classic lesions of lupus retinopathy (Fig. 53-7, and Tables 53-2 and 53-3). These represent focal areas of ischemia where there is interruption TABLE 53-2. SIGNS OF LUPUS RETINOPATHY Cotton~wool spots Retinal hemorrhage: dot, blot, flame-shaped Preretinal hemorrhage Microaneurysms Focal narrowing of retinal vasculature Arterial occlusion with focal deposits Central/branch retinal arterial occlusion with cherry red spot Central/branch venous occlusion Retinal neovascularization Anterior segment ischemia Vitreous hemorrhage Traction retinal detachment Neovascular or hemorrhagic glaucoma Hypertensive changes (arteriolar narrowing, hard exudates, flame hemorrhages, papilledema) 15. Optic disc vasculitis

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

CHAPTER 53: SYSTEMIC LUPUS ERYTHEMATOSUS TABLE 53-3. INTRAOCULAR FINDINGS IN WITH SYSTEMIC LUPUS Cotton-wool spots Retinal hemorrhages Arterial narrowing Papilledema Retinal edema Uveitis

168/1473 111/1473 86/1473 13/1473 9/1473 6/1473

(11.4) (7.5) (5.8) (0.9) (0.6) (0.4)

From Gold DH, Morris DA, Henkind P: Ocular findings in systemic lupus erythematosus. Br] Ophthalmol1972; 56:800.

FIGURE 53-5. Retinal arteritis in a patient with systemic lupus erythematosus. Note the periarteriolar inflammatory cell infiltrate. (See color insert.)

ofaxoplasmic flow within the nerve fibers of the retina, resulting in accumulation ofaxoplasmic material and swelling of the nerve fiber. Cotton-wool spots in SLE are believed to result from occlusion of the small retinal arterioles, or endarterioles, by infiltrating inflammatory cells. They may occur singly and be asymptomatic or they may be extensive in number and cause visual loss when the macula is involved. On fluorescein angiography, cotton-wool spots correspond to areas of focal nonperfusion (Fig. 53-8). In contrast to retinal nonperfusion from hypertension and diabetes, the ischemia produced in lupus retinopathy is often not as extensive and is not associated with widespread arterial narrowing. 26 , 31 ARTERIAL OCCLUSION

FIGURE 53-6. Fluorescein angiogram, late phase, in a patient with arteriolitis secondary to systemic lupus erythematosus. In addition to late vascular staining, note also the fluorescein dye leakage into the macula (cystoid macular edema).

FIGURE 53-7. Extensive lupus retinopathy, with arteriolitis, arteriolar occlusion, and retinal infarcts, with extensive cotton-wool lesions in the nerve fiber layer of the retina. (See color insert.)

Arterial occlusion is a rare form of lupus retinopathy characterized by occlusion of the central retinal artery causing widespread retinal ischemia and severe, permanent visual 10ss.3o The clinical characteristics of central retinal artery occlusion include rapid-onset, painless blurring of vision, a Marcus-Gunn afferent pupil defect, retinal arterial attenuation, and macular edema and whitening that result in a cherry-red spot appearance of the fovea. The prognosis for this type of lesion is as poor as it is for central retinal artery occlusionY' 31 Sudden visual loss with central retinal artery occlusion in a young patient should prompt the clinician to include SLE and other collagen diseases in the list of differential diagnosis. Multifocal branch arterial occlusion or the larger retinal

FIGURE 53-8. Fluorescein angiogram, arterial phase,in a patient with systemic lupus erythematosus. Note the patchy pattern of choroidal filling, indicative of choroidal involvement in the vasculitis process.

CHAPTER 53: SYSTEMIC LUPUS ERYTHEMATOSUS

arteries may also occur, leading to larger areas of retinal ischemia and edema. 24 ,34 VENOUS OCCLUSION

Although lupus retinopathy is not principally a venous disease, central retinal vein occlusion has been reported to occur in association withSLE. It may be that an initial arterial occlusion causes secondary venous stasis and engorgement leading to central or branch vein occlusion. Subsequent reperfusion of the arteries, coupled with inflammatory damage to the venous endothelium, may lead to retinal and papillary hemorrhage. Venous occlusion is a rare manifestation of lupus retinopathy but can be a cause of permanent visualloss. 26 , 35, 36

Vasodisruption Intraretinal hemorrhages are frequent findings in lupus retinopathy. Other vascular abnormalities that develop uncommonly in lupus retinopathy include microaneurysm formation, vascular leakage with retinal edema, and preretinal hemorrhages. 23 , 25 The pathogenesis of these changes is unknown. Stafford-Brady and coauthors believe that the presence of retinal hemorrhages is a significant finding because it is associated with a greater risk of mortality. 33 ISCHEMIC SEQUELAE

Severe retinal ischemia from either arterial or venous occlusive disease may result in retinal neovascularization. 25 ,32 The complications of ~vere ischemia, such as vitreous hemorrhage, traction retinal detachment, and secondary neovascular or hemorrhagic glaucoma, are sight threatening. HYPERTENSIVE SEQUELAE

Renal involvement by SLE will generally lead to secondary hypertension. When prolonged, the retina may develop hypertensive retinopathy characterized by bilateral retinal arterial narrowing, arteriovenous crossing changes, intraretinal hemorrhages, hard exudate formation, and hypertensive papilledema. Rarely, multiple areas of choroidal infarction (Elschnig's spots) may appear as localized brown-red areas ophthalmoscopically. These foci show underlying choriocapillaris nonperfusion on fluorescein angiography and may be associated with transudation of subretinal fluid and neurosensory retinal detachmen t. 14, 34, 37 A review of 1473 SLE patients from several published series 10 revealed the frequencies of ocular findings shown in Table 53-3. In a large prospective study of 550 patients designed to examine the relationship of lupus retinopathy to systemic disease, Stafford-Brady and coworkers found that 41 patients (7.5%) exhibited lupus retinopathy. Of these patients, 34 had microangiopathy (cotton-wool spots in 20 patients; hemorrhages in 7; both cotton-wool spots and hemorrhages in 7), and 3 exhibited transient papilledema. 33 Fluorescein angiography is useful for visualizing the retinal vasculature and often demonstrates abrupt termination of retinal arteries and arterioles, producing areas of poor capillary-bed perfusion. The areas of retinal nonperfusion are often located around the disc or within the

macula, suggesting precapillary arteriole occlusion. Other findings include focal areas of capillary dropout corresponding to cotton-wool spots, irregular retinal artery caliber, and arterial and venous dye leakage (Fig. 53-9). The veins may exhibit marked stasis with segmentation of the blood column and sometimes late dye extravasation. Neovascular tufts may also be seen as points of early dye leakage on fluorescein angiography. 22, 24, 38 As seen in diabetic retinopathy, an early lesion in lupus retinopathy may be retinal capillary lllicroaneurysms. A fluorescein angiographic study of ambulatory, moderately active and inactive SLE patients revealed microaneurysms and/or retinal capillary dilation that leaked fluorescein in 13 of 50 consecutive patients (24%). Only drusen were seen ophthalmoscopically in three of these patients. It is unclear whether these microaneurysms represent the earliest lesions or residual lesions frOlll previous inflalllmatory episodes. 24 , 39 Another large series of fluorescein angiograllls performed on 50, mostly in-patients at the Hammersmith HospitaPO compared angiographic findings of asymptomatic patients, patients with intermediately active disease (arthralgias, mild skin rash, pleuritis, alopecia, and malaise), and patients with severely active disease (arthritis, nephritis, cerebral disease, extensive cutaneous vasculitis). Ten of the 26 patients (38%) with highly active disease had cotton~wool spots, papillitis, or vascular leakage. In the intermediate group, 2 of 13 patients (15%) had angiographic changes (vascular leakage). Only 1 of 11 asymptomatic patients (9% ) manifested angiographic changes (discvasculitis). One of the 50 patients exhibited severe arterial occlusive disease with retinal neovascularization, and another had extensive venous disease. This study concluded that angiographic changes in SLE are more frequently found in patients with active disease. However, the authors were careful to point out previous reports that emphasized that severe retinal vasculitis may occur without systemic illness. 4o This study failed to find an association between retinopathy and cerebral disease. 3o Chproidopathy is an even more rare manifestation of SLE, with only about a dozen cases reported in the English literature. Lupus choroidopathy presents as single or

FIGURE 53-9. Fluorescein angiogram in a patient with systemic lupus erythematosus demonstrating arteriolitis and irregular arteriolar and venular caliber with capillary dropout around areas of retinal infarction.

CHAPTER 53: SYSTEMIC LUPUS ERYTHEMATOSUS TABLE 53-4. SYMPTOMS AND SITES OF NEURO· OPHTHALMIC INVOLVEMENT IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS Neuro-ophthalmic symptoms Transient amaurosis Cortical blindness Visual field defects Papilledema Optic atrophy Strabismus Pseudotumor cerebri Visual hallucinations Sites of neuro-ophthalmic involvement in SLE Extraocular muscle involvement Optic neuritis Retrobulbar neuritis Ischemic optic neuropathy Retrochiasmal tract involvement Occipital lobe infarct Cerebrum

multiple areas of serous elevation of the retinal pigment epithelium and sensory retina with associated retinal pigment epithelial mottling. 41 Fluorescein angiography reveals focal areas of fluorescein leakage through the retinal pigment epithelium, with dye pooling under the sensory retina. Lupus choroidopathy is highly associated with systemic involvement. In the 12 patients reported, six manifested with hypertension and nephritis, three with systemic vasculitis, one with CNS lupus, and one with disseminated intravascular coagulopathy and thrombotic thrombocytopenic purpura. The ocula1 prognosis for lupus choroidopathy is relatively good when systemic immunosuppressive treatment is given. Eleven of the 12 described patients subsequently experienced resolution or improvement of the choroidopathy.24, 29, 41-44 Whereas central nervous system (CNS) disease in SLE is well known, neuro-ophthalmic involvement is probably underrecognized (Table 53-4). Extraocular muscle problems may result from either cranial nerve or muscle involvement. Optic nerve involvement may take several forms. Papilledema is observed frequently but is rarely associated with visual 10ss.45,46 Optic neuritis,47 ischemic optic neuropathy,48 and inflammation of the optic chiasm, retrochiasmal tracts, and occipital lobes may cause visual disturbances and blindness. 49 In optic disc vasculitis, the visual field loss is either complete or an altitudinal hemianopia, and the visual prognosis is poor, whereas in optic neuritis, visual field defects are either central or patchy, and visual recovery is generally considerable. 3o Cerebral involvement may take the form of visual hallucinations and field 10ss.49 Histopathologic studies reveal at least two types of nervous tissue involvement: The first type consists of microangiopathy resulting in focal demyelination, axonal damage, and optic nerve infarcts. 45 , 50-52 The second type is inflammation of the nervous tissues. Transverse myelitis is pr:esent in more than half of patients with lupus optic neuropathy.47 Other rare manifestations include pseudotumor cerebri53 and neuromyelitis optica, a form of multiple sclerosis characterized by spinal cord demyelination and optic atrophy. 50

PATHOPHYSIOLOGY SLE is· generally believed to result from a complex interplay of genetic, infectious, and immunologic factors. Fa-

milial aggregation of autoimmune diseases and the association with the HLA types HLA-DR2 and HLA-DR3 suggest a genetic predisposition. A greater concordance rate of 30% to 50% in monozygotic twins has been reported. Histocompatibility antigens may playa role in the pathogenesis of SLE and discoid lupus erythematosus. HLA-B8 is associated with SLE in females, whereas HLA-B 7 and HLA-B8.42 are associated with discoid lupus erythelnatoSUS. 8,54 An animal model of lupus exists in the MRL-lprmouse, in which a gene for lymphoproliferation has been bred. In this model, accumulation of CD3 + CD4-CD8- T lymphocytes and autoreactive CD4 + T cells leads to massive lymphadenopathy and development of autoimmunity. It is believed that these autoreactive T cells stimulate the growth and differentiation of autoreactive B cells, which in turn produce autoantibodies that cause arthritis and nephritis in these mice. When neonatal MRL-lpr mice are thymectomized, autoimmunity does not develop, further strengthening the theory that T cells are important in the development of autoimmunity. The lpr gene, also identified as the fas gene, is involved in the process of apoptosis (cell death), which has been implicated in the clonal deletion of self-reactive lymphocytes.54, 55 Inheritance of a defective second component of complement (C2) can also produce a lupus-like syndrome. 56 A viral etiology is suspected in the development of human and experimental SLE. Type C virus expression has been identified in NZB mice as well as in the lymphocytes and kidneys of some SLE patients. 46 NZB mice are deficient in CD8 cytotoxic/suppressor T cells. This defect may lead to decreased immune surveillance and allow infection by oncogenic viruses. These viruses may then incorporate their genomes into the host cell genome. These genetic changes may then incite development of antibodies against the now altered host DNA. Viral antigens on infected cell surfaces may provoke development of autoantibodies in an exaggerated humoral response against these infected cells, which are now considered by the immun<: system as nonself. 5L1 Aside from an infectious agent, drugs and environmental triggers such as radiation may damage normal body constituents, resulting in the formation of immunogens. Because these immunogens resemble normal human constituents, an immunologic response may be induced against these normal structures in a process called molecular mimicry.8 SLE is characterized by suppressor T-cell dysfunction, B-cell hyperreactivity, polyclonal B-cell activation, hypergammaglobulinemia, loss of immune tolerance, and autoantibody production. These autoantibodies include antinuclear antibodies, antibodies to DNA, both singlestranded DNA (anti-ssDNA) and double-stranded or native DNA (anti-dsDNA or anti-nDNA), and antibodies to cytoplasmic components. These autoantibodies enter the circulation and are deposited in various target organs throughout the body, where they form pathogenic immune complexes that incite inflammatory responses and activate the complement system. The resulting inflammation then causes organ damage and clinical disease such as vasculitis, nephritis, and arthritis. A variety of autoantibodies are produced by patients with SLE, and different autoantibody "profiles" (antinuclear antibodies, anti-

CHAPTER 53: SYSTEMiC lUPUS ERYTHEMATOSUS

Smith, anti-ribonucleoprotein, anti-histone) appear to be somewhat predictive of the clinical pattern of the patient's disease. 55 Recent studies suggest that a wider than previously appreciated array of autoantibodies are produced in patients with SLE,57 including autoantibodies against annexias,5s the CD45 cell surface glycoprotein,59 calreticulin,50 and nucleosomes. 51 Indeed, it may be that the loss of tolerance for nucleosomes is a primary event, with aberrant apoptosis resulting in their systemic release, and nucleosomes then driving the autoilnmune response, with nucleosome-specific CD4 T cells inducing antidsDNA and anti-histone antibody production. It appears that nucleosomal antigens (histone and DNA) complexed to anti-dsDNA are very efficient at binding to renal glomerular basement membrane and inducing nephritis. Monocyte-macrophage function is depressed in early SLE, and because these cells participate in the processing of antigen and in lymphokine activity, this defect could result in depressed cellular immunity.52 Vasculitis is believed to be the starting point in the pathogenesis of tissue and organ damage in SLE. As early as 1932, Goldstein and Wexler demonstrated extensive fibrinoid necrosis of the vessel walls. 40 Perivascular inflammatory infiltrates have been demonstrated in eyes with SLE vasculitis. Immunoglobulin and complement deposits have been demonstrated in the retinal and cerebral blood vessel walls,53 ciliary body, choroid, and conjunctival basement membrane of SLE patients. 54 An animal model of uveal and retinal vasculitis exists. When antigen is injected into ,the vitreous of hyperimmune rabbits, intense vasculitis develops. Immunohistochemical studies reveal immune complex deposition within the vessel walls. These immune complexes can activate the complement system and trigger rapid neutrophilic infiltration, which in turn causes vascular occlusion and ischemia. This mechanism may occur in lupus retinopathy, leading to vaso-occlusion. 55 Vascular lesions in the eye may mirror vascular alterations in other parts of the body. Intimal and medial thickening of the retinal vessel walls, as well as deposition of fibrinoid material causing vaso-occlusion in the superficial and deep nerve fiber layers, has been observed by Maumenee 7 and by Clifton and Greer. 39 In severe vascular involvement, widespread necrosis of the retina with lymphocytic and plasma cell infiltration may be observed. The similarities between pathologic lesions of the retinal and CNS vasculature are well described and may account for the association between retinal and CNS involvement.5, 40, 55

of any young patient with cotton-wool spots or hemorrhages. An .appropriate referral to a rheumatologist or internist should then be made. Funduscopy and indirect ophthalmoscopy are the most important Ineans of detecting lupus retinopathy. Fluorescein angiography is of limited value in the initial definitive diagnosis of SLE. Angiographic findings in lupus retinopathy are nonspecific and may be mirrored by other retinal vasculitides or vaso-occlusive diseases such as Adamantiades-Beh~et's disease, diabetic and hypertensive retinopathy, and other collagen vascular diseases. Angiographic findings are not predictive of cerebral disease but may indicate systemic activity. No relationship has been found between retinal and cutaneous vasculitisY There has been no prospective study that has investigated the prognostic value of fluorescein angiography. Angiography, however, may be used to evaluate retinal perfusion and detect retinal neovascularization or edema that may be amenable to laser treatment or cryotherapy. Angiography is also useful in confirming the diagnosis of lupus choroidopathy. The Farnsworth 100 hue test may detect abnonnalities in hue discrimination among patients with SLE retinopathy and should be performed in cases of suspected lupus retinopathy. This test, however, is nonspecific and its interpretation should be made cautiously, especially when antimalarial treatment is being given, as these medicines may also affect hue discrimination. 29 The differential diagnosis for multifocal retinal vascular occlusive disease includes Adamantiades-Beh~et'sdisease, polyarteritis nodosa, Takayasu's disease, Wegener's granulomatosis, and syphilis. Cotton-wool spots may. be seen in diabetes, hypertension, and radiation retinopathy. Antiphospholipid antibodies are present in approximately 17% of SLE patients, and these are associated with thrombotic disorders, such as deep vein thrombophlebitis and strokes. Lupus anticoagulant is related to other antiphospholipid antibodies, including the anticardiolipin antibody and the biologic false-positive test for syphilis. Lupus anticoagulant is an immunoglobulin that reacts in vitro ;with negatively charged phospholipids (platelet factor 3), thereby inhibiting the generation of prothrombin activator complex. Lupus anticoagulant together with other related antiphospholipid antibodies, such as the anticardiolipin antibodies, are associated with thrombotic events. Circulating lupus anticoagulant may be found in some patients with SLE. While the role of antiphospholipid antibodies is unclear, it is hypothesized that they may cause thrombotic phenomena by means of induction of platelet aggregation or by inhibition of prostacyclin production by the vascular endothelium. 57-59

DIAGNOSIS The diagnosis of SLE is based on a combination of clinical and laboratory findings (see Table 53-1). The detection of antinuclear antibodies is a good screening test for SLE, as it occurs in 95% of patients. However, antinuclear antibodies are present in most other rhel11natic diseases, as well as in autoimmune liver and thyroid disease, and thus should be considered a nonspecific test. More specific antibodies for the diagnosis of SLE include antibodies to dsDNA and to Slnith antigen. s Occasionally, ocular manifestations may precede systemic findings. The ophthalmologist should be suspicious

Immunosuppressive therapy is the mainstay of treatment for both systemic and ocular lupus. The choice of treatment is dependent on the organ involved and on the severity of the lesions. When only arthritis or serositis is present, nonsteroidal anti-inflammatory agents may be sufficient to control the disease. Antimalarials are primarily used in the treatment of skin disease. Chloroquine retinopathy may result from chloroquine treatment. This may take the form of macular pigmentary changes, blurred vision, and paracentral visual field depression.

CHAPTER 53: SYSTEMIC lUPUS ERYTHEMATOSUS

Steroids are usually reserved for hem.atologic, renal, and CNS involvement. Long-term steroid-sparing m.aintenance therapy may necessitate the use of systemic imlUUnosuppressive agents such as cyclophosphamide or azathioprine. 8, 9,70 It should be noted that ocular relapse or activity may occur independently of systemic signs,26,28 and that the onset of scleritis or retinal vasculitis in a patient with otherwise apparently well controlled SLE is a very ominous sign, portending a lupus flare unless the vigor of therapy is increased considerably. Laser photocoagulation in cases of severe vaso-occlusive disease may be successful in ameliorating the ischemic complications of lupus retinopathy. Care should be taken during panretinal photocoagulation, as anterior segment ischemia can develop after laser treatment. Full control systemically of the SLE may be advisable prior to laser treatment. Vitreoretinal surgery luay be indicated for patients with vitreous hemorrhage or traction retinal detachment. 26

PROGNOSIS With current methods of treatment, the 10-year survival rate of SLE patients approaches 90%. The risk factors for poorer prognosis include nephritis, hypertension, onset at younger age, male sex, and the presence of antibodies to native DNA.9 While retinal lesions may occur frequently in SLE, they are rare causes of visual impairment. Poor visual outcome is associated with severe vaso-occlusive disease, retinal vasculitis, central retinal artery occlusidn, central retinal venous occlusion, and traction retinal detachment. Jabs and colleagues26 and Gold and coworkers25 have demonstrated that severe retinal vascular disease correlated with CNS disease and not with hematologic and renal involvement. Both groups believe that severe retinal involvement should be considered a marker for CNS disease. In contrast, Klinkoff and colleagues 30 and Lanham and coworkers 31 could not find an association between less severe lupus retinopathy and CNS disease in their series. In a large prospective series of 550 patients conducted by Stafford-Brady and coworkers, 88% of patients with lupus retinopathy had active lupus at the time retinopathy was diagnosed. Active CNS lupus was present in 73% of patients with retinopathy. The CNS manifestations included organic brain syndrome, focal neurologic deficit, psychoneurosis, intractable headaches, psychosis, and seizures. Renal disease was present in 63.5% of patients. The study also found that 34% of patients who developed lupus retinopathy died, whereas only 10.8% of patients without retinopathy expired. Patients who developed retinal hemorrhages had the highest risk for mortality (50%). The visual prognosis among these SLE patients was excellent-only 5 of 550 (0.9%) developed blindness. Microangiopathy or transient papilledema was not associated with permanent visual loss. Loss of vision resulted frOlu ischemic optic neuropathy, central retinal vein occlusion, central retinal artery occlusion, or serous retinal detachment. The frequency of lupus anticoagulant among all SLE patients was found to be 17%. An increased frequency of lupus anticoagulant (38%) was detected among patients with lupus retinopathy.34 The study concluded that lupus retinopathy carries a good progno-

sis for vision but a poor prognosis for surviva1. 27 Other authors have suggested that the incidence of retinal thrombosis may occur independently of systemic disease activity.34, 68, 70

SLE is an autoimmune, multisystem disorder with a propensity for involving ocular tissues. Although ocular involvement is generally benign, potentially blinding complications may occur. When lupus retinopathy or neuro-ophthalmic involvement is detected in a patient, the prudent ophthalmologist should also conduct a thorough search for systemic involvement and refer the patient to the appropriate clinical services. Early recognition of SLE and timely institution of systemic therapy may minimize morbidity and mortality from this disease.

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48. Hayreh SS: Posterior ischemic optic neuropathy. Ophthalmologica 1981;182:29. 49. Lessell S: The neuro-ophthalmology of systemic lupus erythematosus. Doc Ophthalmol 1979;47:13. 50. April RS, Vansonnenberg E: A case of neuromyelitis optica (Devic's syndrome) in systemic lupus erythematosus. Neurology 1976;26;1066. 51. Kinney EL, Berdoff RL, Rao NS, Fox LM: Devic's syndrome and systemic lupus erythematosus: A case report with necropsy. Arch Neurol 1979;36:643. 52. Shepherd DI, Downie AW, Best PV: Systemic lupus erythematosus and multiple sclerosis. Arch Neurol 1074;30:423. 53. Carlow T], Glaser ]S: Pseudo tumor cerebri syndrome in systemic lupus erythematosus. ]ANIA 1974;228:197. 54. Abbas AK, Lichtman AH, Pober ]S: Self tolerance and autoimmunity. In: Abbas AK, Lichtman AH, Pober ]S, eds: Cellular and Molecular Immunology, 2nd ed. Philadelphia, W.B. Saunders, 1994, p 384. 55. Theofilopoulous AN, Kofler R, Singer PA, Dixon FJ: Molecular genetics of murine lupus models. Adv Immunol 1989;46:61. 56. Douglass MC, Lamberg SI, Lorincz AI, et al: Lupus erythematosuslike syndrome with a familial deficiency of C2. Arch Dermatol 1976;112:671. 57. ]ayaram N, Sharma BK, Sehgal S: Autoantibody profile in systemic lupus erythematosus. Indian] Pathol Microbiol 1990;33:57-63. 58. Bastian BC: Annexias in cancer and autoimmune diseases. Cell Mol Life Sci 1997;53:554--556. 59. Mamoune A, Saroux A, Delaunoy]L, et al: Autoantibodies to CD45 in systemic lupus erythematosus.] Autoimmune 1998;11:485-488. 60. Boehm], Orth T, Van Nguyen P, Solig HD: Systemic lupuserythematosus is associated with increased autoantibody titers against calreticulin and grp94, but calreticulin is not the RolSS-A antigen. Eur] Clin Invest 1994;24:248-257. 61. van Bruggen MC, Kramers C, Berden ]H: Autoimmunity against nucleosomes and lupus nephritis. Ann Meel Interne (Paris) 1996;147:485-489. 62. Landry M: Phagocyte function and cell-mediated immunity in systemic lupus erythematosus. Arch Derl11atol 1977;113:147. 63. Karpik AG, Schwartz MM, Dickey LE, et al: Ocular immune reactants in patients dying with systemic lupus erythematosus. Clin Iml11unol Immunopathol 1985;35:295. 64. Aronson A], Ordonez NG, Diddie KR, Ernest]T: Immune complex deposition in the eye in systemic lupus erythematosus. Arch Intern Med 1979;139:1312. 65. Levine RA, Ward PA: Experimental acute immunologic ocular vascu~ litis. Am] Ophthalmol 1972;69: 1023. 66. Graham EM, Spalton D], Barnard RO, et al: Cerebral and retinal vascular changes in systemic lupus erythematosus. Ophthalmology 1985;92:444--448. 67. Boey MI, Colaco CB, Gharavi AE, et al: Thrombosis in systemic lupus erythematosus: Striking association with the presence of circulating lupus anticoagulant. Br Med] 1983;287:1021. 68. Harris EN, Gharavi AE, Boey ML, et al: Anticardiolipin antibodies: Detection by radioimmunoassay and association with thrombosis in syst~mic lupus erythematosus. Lancet 1983;2:1211. 69. Petri M, Rheinshl11idt M, Whiting-O'Keefe Q, et al: The frequency of lupus anticoagulant in systemic lupus erythematosus. Ann Intern Med 1987;106:524. 70. Felson DT, Anderson J: Evidence for the superiority of immunosuppressive drugs and prednisone over prednisone alone in lupus nephritis. N Engl] Med 1984;311:1528.

Anthony S. Ekong, Stefanos Baltatzis, and C. Stephen Foster

Scleroderma is a multisystem connective tissue disease characterized by severe alterations in the microvasculature, 1 prominent inflammatory and immunologic alterations, and excessive deposition of collagen and other intracellular matrices in the skin and internal organs, including the lungs, kidneys, and gastrointestinal tract. 2 Scleroderma exists in two forms: a benign form localized to the skin, characterized clinically by thickening and fibrosis (scleroderma), and a systemic form (systemic sclerosis [SSc]) when there is visceral involvement. Localized scleroderma (morphea and linear scleroderma) primarily affects children and young adults, mostly females. 2 Morphea is charactedzed by one or more isolated areas of sclerotic plaques that, after several months to years, spontaneously soften with a residual area of hyperpigmentation or hypopigmentation. 3 The lesions may become multiple or confluent, with a benign clinical course, in which case the term generalized morphea is used. In linear scleroderma, the sclerotic lesions appear as linear streaks or bands, primarily on the extreluities. When the face or scalp is involved, usVally unilaterally, the term en coup de sabre is used. The term evolved because the lesion may resemble a scar from a wound caused by a sabre. This can cause facial asymmetry, with hemifacial atrophy that is indistinguishable from ParryRomberg syndrome. The relationship between progressive hemifacial atrophy (Parry-Romberg syndrome) and en coup de sabre is unclear. There is considerable overlap between morphea and linear scleroderma; both types coexist in many patients. Progression of localized scleroderma to the systemic form of the disease is rare but has been reported.4-6 SSc has been divided into two subgroups of limited or diffuse disease. This division is based solely on the degree and extent of skin thickening. The subgroup characterized by diffuse cutaneous involvement usually presents with rapid widespread thickening of the skin affecting the distal and proximal extremities, and patients with the diffuse involvement are at increased risk of early development of visceral involvement. In contrast, patients with limited cutaneous involvement have skin thickening limited to the distal extremities, with an interval of one or more decades before visceral involvement. 2 Facial skin thickening occurs in both systemic forms and is not a distinguishing feature. There is clinical relevance in classifying patients into the limited or diffuse forms of the disease. Patients with the limited form tend to have a better prognosis, although severe pulmonary hypertension is more common in the late stage. 7 Pulmonary fibrosis may occur in both limited and diffuse disease but is more common in the late diffuse type. The risk of developing severe end organ complications, especially retinal involvement end death, is higher in patients with the diffuse disease. s

The initial description of scleroderma is found in a monograph written by Carlo Curzio and published in Naples in 1753. 9 , .10 Rodnan ll described Curzio's account of a young woman who presented with complaint of excessive tension and hardness of the skin. In 1847, Gintrac,12 after a review of the earlier cases, introduced the term scleroderma (skleros-hard, derma-skin), emphasizing that the skin was the most obvious organ involved. Raynaud documented the association of abnormal vasoconstriction with scleroderma in 1862,13 and Weber first recorded the coexistence of cutaneous calcinosis and scleroderma in 1878. 14 Subsequently, other associations were observed, such as esophageal dysmotility, sclerodactyly, and telangiectasia. Despite the fact that many patients with scleroderma were known to die from systemic complications after the development of cutaneous complaints, the visceral involvement was generally believed to be unrelated to the hardening of the skin. The existence of visceral involvement was first clearly documented in 1924 by Matsui,15 who described sclerosis of the lungs, gastrointestinal tract, and kidney of five patients. Goetz presented a detailed review of the systemic manifestations in 1945 and proposed that the term scleroderma be replaced by progressive SSc (generalized scleroderma).16 Subsequently, SSc was classified into progressive systemic sclerosis (PSS) and the CREST syndrome, the latter consisting of sclerosis, Raynaud's phenomenon, esophageal dysluotility, sclerodactyly, and telangiectasia. The current classification of SSc into diffuse and limited diseases was introduced to replace the above-mentioned classification, which was found unsatisfactory for many reasons. 17 First, skin involveluent in the diffuse variant (the PSS form) is not progressive; rather, it tends to worsen over a 3- to 5-year period, then frequently stabilizes and may even regress. Also the internal organ manifestation is progressive only in a small portion of diffuse disease patients. Second, although the stigmata of the acronym CREST do develop in patients with the limited disease irrespective of the duration, they can also occur in patients with the late stage of diffuse disease. Disregarding the association of renal disease with diffuse scleroderma and pulmonary hypertension with limited scleroderma, there is little difference between these subgroups in very late disease. Scleroderma is a rare disease. Criteria for the classification and diagnosis of the disease were not formulated until 1980 by the American Rheumatism Association, now the American College of Rheumatology, and therefore, available epidemiologic data using current criteda are sparse (Table 54-1). Data based on the two largest studies reported after the publication of these criteria and cov-

CHAPTER 54: SCLERODERMA TABLE 54-I. PRELIMINARY SCLERODERMA'"

FOR

MAJOR CRITERION Sclel;odermatous skin changes (tightness, thickening, and nonpitting induration, excluding localized forms of scleroderma) proximal to the metacarpophalangeal or metatarsophalangeal joints MINOR CRITERIA (In the absence of proximal scleroderma) Sclerodactyly; sclerodermatous skin changes of fingers or toes Digital pitting scars of fingertips or loss of substance of the distal finger pad Bibasilar pulmonary fibrosis not attributable to primary lung disease *One major or two minor criteria have a sensitivity of 97% and a specificity of98% when compared with patients with systemic lupus erythematosus, polymyositis/dermatomyositis, or Raynaud's phenomenon. From the Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581.

ering only a period of two decades place the incidence at approximately 19 cases per million,18, 19 with a prevalence of 240 cases per million. 19 SSc affects more women than men, with a ratio ranging between 3:1 and 8:1, depending on the age of the patient; the ratio is higher during the childbearing years and considerably lower in later adult life. 20 Disease onset is highest between ages 30 and 50 years, with a peak onset at about 50 years. 21 A higher proportion of black patients may have the diffuse rather than the limited Form of the disease, and it may occur at an earlier age than in whites.21' 22 Most cases occur sporadically irrespective of season, occupation, or socioeconomic status. There is an association of scleroderma with exposure to environmental toxins. The disease has a worldwide distribution although it is less frequent in Asia. 23 Familial cases have rarely been reported, and a weak correlation with the human leukocyte antigens HLA-DQl, HLA-DRBl, and HLA-DPBl exists.

CLINICAL

Systemic The initial symptom in most patients with scleroderma is Raynaud's phenomenon, occurring in 90% of cases. Raynaud's phenomenon is characterized by the sequential development of pallor, cyanosis, and rubor of the digits on cold exposure or emotional stress, or both (Fig. 54-1). These symptoms may be present for years before the occurrence of other systemic manifestations, in patients with limited SSe. Both vasospasm and structural abnormalities of the arteriolar and arterial tree have been implicated. 24 An early manifestation of SSc, especially in individuals with the diffuse disease, is bilateral symmetric painless swelling or thickening of the fingers and hands and sometimes the ankle and the feet. 2 This edematous phase, which may result from multiple factors including microvascular disruption, local inflammatory reactions, and deposition of hydrophilic glycosaminoglycan in the dermis, may last for a few weeks to several months. The longer the duration of the edematous changes, the more favorable the long-term prognosis. Subsequently, as the induration phase develops, sclerodactyly (Fig. 54-2), and

FIGURE 54-I. Raynaud's phenomenon in a patient with progressive systemic sclerosis. Note the "cyanotic" appearance of all of the digits on the right hand, and the distal portions of the digits on the left hand.

the classic pursed-mouth, pinched nose, tight face appearance of patients with SSc (Fig. 54-3) are produced. This is followed by the atrophic phase in which the skin may actually soften. With prolonged disease duration, telangiectasias and subcutaneous calcinosis Inay develop; this occurs more frequently in patients with limited cutaneous scleroderma. Polyarthralgias of small and large joints and occasional polyarthritis are commonly present early in diffuse scleroderma, often leading to the erroneous diagnosis of rheumatoid arthritis. Involvement of the gastrointestinal tract ranks only behind Raynaud's phenomenon and scleroderma skin changes as common manifestations of SSe. Esophageal dysfunction is extremely common, occurring in approximately 50% of patients. 25 , 26 Heartburn, dysphagia with solid food, and reflux that can lead to peptic esophagitis, Barrett's metaphasia, and esophageal strictures may occur (Fig. 54-4). Both the diffuse and limited disease subtypes are similarly affected. Histopathologically, there is fibrosis and smooth muscle atrophy of both the lower two .thirds of the esophagus and the lower esophageal sphincter.

FIGURE 54-2. Sclerodactyly in a patient with progressive systemic sclerosis. Note not only the contractures and deformity of the digits but also the dermatologic abnormalities and the shiny character to some of the areas of the skin.

CHAPTER5~SClERODERMA

FIGURE 54-3. Full-face photograph of a patient with progressive systemic sclerosis who has blepharophimosis and, most obvious, the pursed-lip features of a patient with scleroderma; the patient is unable to open her mouth to any appreciable degree. FIGURE 54-4. Esophageal strict(lre in the distal portion of the esophagus, as demonstrated by barium swallow radiography, in a patient with progressive systemic sclerosis. The area of stricture is quite apparent.

Delayed gastric emptying is often associated with esophageal dysfunction. In addition, the patient may complain of nausea, vomiting, or diffuse epigastric discomfort. Small bowel hypomotility can complicate long-standing limited SSc, leading to fecal stagnation with bacterial overgrowth and secondary malabsorption. 25 , 26 Symptoms include intermittent abdominal bloating, distention, pain, diarrhea, and weight loss. The colon may also undergo fibrotic changes, with constipation being the leading symptom. Rectal prolapse and fecal incontinence reflect SSc involvement of the anal sphincter. The two major pulmonary manifestations of SSc are pulmonary hypertension (PHTN) and interstitial fibrosis (Fig. 54-5).27 Isolated pulmonary hypertension is more common in patients with limited cutaneous sclerosis. 7 These patients may present with rapidly progressive dyspnea, although approximately one third may be asymptomatic. 28 Some patients with PHTN may present with symptoms of right-sided heart failure, including pedal edema and congestive hepatomegaly with abdominal discomfort. The most common abnormality on pulmonary function testing is reduced diffusing capacity for carbon monoxide. 29 PHTN may occur in patients with diffuse disease, usually in association with advanced interstitial fibrosis. Interstitial fibrosis is responsible for significant rates of morbidity and mortality among scleroderma patients. Exertional dyspnea and nonproductive cough are the usual complaints, with bibasilar crackles on auscultation. Pulmonary function tests reveal a restrictive pattern, with a decreased forced vital capacity (FVC). Patients with either limited or diffuse disease can be affected, although the disease tends to be more severe in the diffuse subset. Bronchoalveolar lavage reveals increased proportions of

neutrophils, lymphocytes, and occasionally, eosinophils in most patients. 3D Cardiac involvement in SSc is common but rarely clinically signficant. 31 It can be manifested as pericarditis, conduction problems, arrhythmias, myocardial disease, and congestive heart failure 32 (from renal and pulmonary involvement) . Scleroderma renal crisis (SRC) was the leading cause of death among patients with diffuse disease before the introduction of angiotensin-converting enzyme (ACE) inhibitors. 33 Patients in SRC, without warning, develop a renin-mediated malignant arterial hypertension and oli-

FIGURE 54-5. Pulmonary interstitial fibrosis, with the increased interstitial markings on plain chest x-ray study in a patient with scleroderma.

54: SCLERODERMA

guric acute renal failure. 34 SRC is a medical emergency. Azotemia, proteinuria, and hypertension independent of renal crisis are seen in many patients with scleroderma. 35 The nervous system can be (uncommonly) involved in patients with scleroderma. Carpal tunnel syndrome, peripheral neuropathy, autonomic dysfunction and trigeminal neuralgia have been described. 36 Thyroid gland fibrosis with hypothyroidism has also been reported. 37 Impotence occurs in a high proportion of men with scleroderma and may represent penile vascular ischemia. 38

Ocular Scleroderma frequently affects the eyelids and the periorbital tissue. The most commonly reported lid findings relate to fibrotic changes, with stiffness or tightness, resulting in an indurated quality of the lids, sometimes leading to difficulty with lid eversion and blepharophimosis. 39-41 Lid telangiectasia and madarosis can also occur. 39, 41 Morphea of the eyelids has been described. 42 Periorbital edema in association with PSS, as well as linear scleroderma and localized disease, may be early clinical signs. As with the extremities, this edema, which may persist for months, is followed by an atrophic phase. 43- 45 Reduced tear secretion, measured by Schirmer test and rose bengal staining, with associated keratoconjunctivitis sicca (KCS) is common in patients with SSe. 40 In one series, clinical signs of dry eye were found in 75% of patients with scleroderma. 46 The majority of corneal chang'~s result from KCS. Corneal opacification has been induced by cold in patients with Raynaud's disease associated with SScY Conjunctival fornix foreshortening in the absence of clinically evident conjunctival inflammation has been reported (Fig. 546) .39 This is not surprising, given the fact that SSc is characterized by generalized dermal and subepithelial fibrosis. Telangiectasia and sludging of the conjunctival vessels have been observed4 1; this, too, is not surprising given the underlying vascular abnormalities observed in arteries, arterioles, and capillaries. 1 Orbital involvement is limited to the extraocular muscles in both PSS and localized scleroderma, and it has been associated with ocular myopathy, most notably in-

fiGURE 54-6. Foreshortening of the inferior fornix, with obvious subepithelial fibrosis, in a patient with scleroderma.

fiGURE 54-7. An area of scleral loss in a patient with en coup de sabre or linear scleroderma involving the face, including eyelids. The area of scleral involvement is in a direct line with the dermatome involved.

volving the superior rectus muscle. 48 Ocular involvement may also occur along the meridian of an en coup de sabre, involving deep and superficial structures, implicating abnormal embryonal neural crest migration and proliferation in lesion development. 49 We reported the unusual case of a 43-year-old woman with progressive facial hemiatrophy associated with a linear en coup de sabre who presented with spontaneous sclera perforation in the ipsilateral eye (Fig. 54-7). The location of the scleral loss was exactly on the line of the en coup de sabre atrophy. She did not have detectable antinuclear antibody titers, and histopathologic examination of the affected sclera revealed no inflammatory cells. 50 Systemic microvascular abnormalities are the hallmark of SSc, and so it is not surprising that the choroidal vasculature is affected in a large proportion of patients. Greenan and Forster51 found that 5 of 10 patients with scleroderma had patchy areas of nonperfusion of the choroidal vasculature on fluorescein angiography; one patient showed abnormalities of the retina vasculature with microaneurysmal dilatation of the terminal venules in one quadrant. Serup and colleagues 52 performed ophthalmoscopy and fluorescein angiography on 21 patients with generalized (limited) scleroderma. None of these patients had any history of concomitant vascular diseases, including hypertension, diabetes or renal disease, and ophthalmoscopy revealed no abnormalities. However, seven (33 %) of the 21 angiograms were assessed as definitely abnormal. The abnormalities consisted of variable hyperfluorescence of the pigment epithelium layer in the late phase, which may represent damage to the choriocapillaris with atrophy of the overlying retinal pigment epithelium (Fig. 54-8) .52-54 Interestingly, the retina vasculature was not affected. The authors speculated that the absence of neural supply and internal elastic membrane in the retinal arterioles might render them less sensitive to damage. Farkas and associates55 performed a postmortelll ocular study of one patient with SSe. They showed by electronmicroscopy and histochemistry that the choroidal

CHAPTER 54: SCLERODERMA

fiGURE 54-8. Late phase of a fluorescein angiogram performed on a patient with choroidal involvement in scleroderma. Note the choroidopathy, as evidenced by late staining in a patchy pattern of the areas of choroidal inflammation.

vasculature was grossly affected, with diffuse endothelial cell swelling and necrosis obstructing the lumen of capil~ laries. Also, basement membrane thickening and deposition of mucopolysaccharide material in and around the endothelium were found. In contrast, only minor abnormalities of retinal arterioles were noted. These changes are typical of the vascular endothelial abnormalities found elsewhere in patients with SSe. Retinopathy, including cotton wool spots, intraretinal edem~ venous thrombosis, hemorrhage, exudate and parafoveal telangiectasia in association with CREST syndrome has been described. 55-58 These findings appear in advanced disease and may not be primarily due to SSc itself but rather may be secondary consequences of systemic hypertension frequently found in these patients. In general most patients with SSc have minimal funduscopic findings.

IMMUNOLOGY, PATHOGENESIS The susceptible host-external agent-immune response model has been suggested for SSe.59 In this model, a genetically susceptible individual is exposed to some environmental stimulus, which serves as a trigger to incite the immune system to produce vascular injury by a heretofore unclear mechanism. Cytokines are released that may cause further endothelial activation or injury and stimulate fibroblast proliferation and production of collagen. The evidence for genetic influence in SSc is not very strong. Certain class II HLA genes are overrepresented in the patient population with SSc, with HLA-DRl, (DRBl*1302) DR3, and DR5 (HLA-DQBl*0501) being the most commonly reported haplotypes. 6o HLA-DQw7, (HLA-DQBl*0301) and DQW5 genes' may also be important in predisposing an individual to the development of SSc, especially with anticentromere autoantibody production. 61 Clinical variants of SSc have been described in patients after exposure to certain environmental stimuli. Silica dust, polyvinyl chloride, silicone breast ilnplant, ingestion of toxic rapeseed oil, various drugs such as bleomycin,

carbidopa, L-tryptophan, cocaine, and appetite suppressants have been implicated. 31 ,62 Both humoral and cellular immune dysfunction with increased production of certain cytokines and autoantibodies have been found in patients with scleroderma. As in most other connective tissue diseases, antinuclear antibodies (ANAs) are present in sera of most patients with SSe. 63 The antibody titers can be very high but do not correlate with disease activity. Unlike the other connective tissue diseases, the intracellular antigen targets of the ANAs in SSc are different. These SSc-specific ANAs are directed against DNA topoisomerase 1 (topo1); chromosomal centromere; RNA polJInerase (RNAP) I, II, and III; and some nucleolar components. Anticentromere antibodies (specific for limited scleroderma and found in 57% of patients with CREST syndrome), and Scl-70 or antitopoisomerase-l (specific for diffuse scleroderma and present in 40%) are the two most common SSc marker antibodies. Approximately 40% of SSc patients are likely to have neither antibody present. 64 The presence of a dense mononuclear cell infiltrate in the dermis and along blood vessels in the early stage of SSC 65 implicates lJ1TIphocytes and monocytes as major Inediators in the evolution of this disease. Activation of the lymphocytes is evidenced by increased serum levels of factors and receptors associated with T cells. Increased serum levels of interleukins (IL) 2, 4, 6, and 8 and transforming growth factor beta (TGF-[3) 66-69 have been reported, and these appear to play an important role in fibroblast proliferation as well as collagen sJI1.thesis. In addition, elevated levels of IL-2 and soluble IL-2 receptor (CD25 molecule) in the serum of patients with SSc correlate with disease activity and extent of internal organ involvement. 70 Blood vessel abnormalities are central to the pathema seen in SSc patients. In every affected organ, there is remarkable thickening of the intima of arterioles and smaller arteries, with narrowing of the vascular lumen and, in many instances, obliteration of the small arterioles. Endothelial cell injury with reduplication of basement membrane material is routinely observed on histopathologic and ultrastructural studies. Endothelin, the most potent vasoconstrictor yet identified, is present in higher than normal amounts in the blood of patients with SSc,71 and implicates endothelial cell injury. This cytokine is sJI1.thesized by vascular endothelial cells; however, the primary signals responsible for inducing upregulation and perpetuation of endothelin sJI1.thesis are not well understood. The ability of lJ1TIphocytes to adhere to endothelial cells is strongly mediated by cellular adhesion molecules (CAMs).72 In SSc, elevated levels of different CAMs such as intracellular adhesion molecule 1 (ICAM1),73 endothelial leukocyte adhesion molecule 1 (ECAM1) ,74 and vascular cell adhesion molecule 1 (VCAM-l), P-selectin, and E-selectin, have been detected and correlated with both their in situ expression and clinical disease activity in patients with SSe. 75 Mast cells have been considered as potential pathogenic participants in scleroderma, too. Increased numbers of mast cells are found in a variety of fibrotic conditions, including graft-versus-host disease (characterized by collagen proliferation and fibrosis), interstitial fibrosis,

CHAPTER 54: SCLERODERMA

and also in the conjunctiva of patients with scleroderma. 46 Increased eosinophil granule proteins are present in the skin of some patients with SSe. 76 A reasonable working hypothesis for the pathogenesis of SSc probably should also involve abnormalities of the vascular endothelium, and of both the immune and connective tissue systems. 77 Perhaps there is lymphocyte sensitization to antigens, such as type IV collagen or skin along with subsequent proliferation of dermal fibroblasts, an overproduction of immature collagen, and vascular overgrowth. Many factors are implicated in the pathogenesis of SSc; their relative roles or contributions are speculative, making targeted, specific therapy difficult. Histopathologic features of SSc are influenced by the stage of the disease. In the early phase, there is mild lymphocytic and monocytic cell infiltrate, mainly around small blood vessels and in the dermis. Subsequently, a marked increase in collagen and other extracellular matrix components, such as fibronectin and glycosaminoglycans, are observed in the dermis and extend into the subcutaneous fat. In the atrophic phase of the disease, there is a paucity of cellular infiltrate, thinning of the epidermis with loss of rete pegs, and increased collagen contraction corresponding to the clinically observed fibrosis.

DIAGNOSIS There is no single diagnostic test for SSe. Diagnosis is made on clinical grounds, based on criteria established by the American Rheumatism .Association (Table 54-1) that are about 97% sensitive and 98% specific. 78 The major criterion is sclerodermatous skin changes in any location proximal to the metacarpophalangeal joints. Minor criteria include sclerodactyly (sclerosis affecting only the fingers or toes), digital pitting scars of fingertips or loss of substance of the distal pad, and bibasilar pulmonary fibrosis not attributable to primary lung disease. A disease can be classified as scleroderma if the major criterion or if two of the three minor criteria are present.

Organ-specific therapy and disease-modifYing agents are the main modalities in use at present. Raynaud's phenomenon (RP) has been treated with both nonpharmacologic and pharmacologic methods. Avoiding cold exposure, keeping the entire body warm, and total abstinence from smoking are usually effective in mild to moderate cases. Calcium channel blockers are the first-line drug therapy in complicated cases. Short-acting nifedipine has been shown to be highly effective in improving digital blood flow and inducing healing of digital ulcers. 79 Other vasodilating agents, including nitrates and sympatholytics, have been employed in patients with SSc and RP. ACE inhibitors have been used with· increased success in improving survival and reversing renin-mediated SRC.33 Borderline or frank hypertension has also been successfully treated with ACE inhibitors. The use of proton pump inhibitors (e.g., omeprazole) and prokinetic agents (e.g., cisapride) has ameliorated many esophageal dysmotility and delayed gastric emptying sYlnptoms in cases not amenable to life style modifi-

cations. 8°Antacids are useful in relieving sYlnptoms associated with the esophageal reflux. Patients with esophageal strictures benefit from periodic dilatation. No therapy has proved effective in decreasing the mortality or progression of pulmonary hypertension in patients with SSe. Vasodilators, specifically calcium channel blockers, have been used with varying success. 81 Similarly, interstitial lung disease (ILD) has been difficult to treat except in those cases in which bronchoalveolar lavage shows inflammatory alveolitis. Silver and colleagues82 reported improved FVC in patients with moderately severe ILD with active alveolitis who were treated with oral daily cyclophosphamide (approximately 100 mg per day) and low-dose prednisone. Ocular involvement, especially dry eyes, can be treated with artificial tears, lubricating ointments, punctal occlusion, and topical cyclosporin A. Topical corticosteroid cream may provide some relief to skin involvement around the eye. Systemic steroids can be used to treat inflammatory ocular myopathy. In general, the retinal pigment epithelium (RPE) epitheliopathy resulting from choroidal vasculature abnormalities does not affect visual function in the cases reported so far. However, because loss of visual function can result when there is extensive RPE atrophy with degeneration of the retinal layers, we believe periodic fluorescein angiography should be obtained in patients with SSe. Disease-modifYing agents have focused on halting the fibrotic and inflammatory responses characteristic of SSc with limited success. Relatively minimal effort has been directed at the mediators of vascular dysfunction in SSc. D-penicillamine (DPA) , has been used since the 1960s for the treatment of diffuse SSc based on anecdotal reports of effectiveness and on its interference with cross-linking of collagen. In a double-masked, randomized controlled clinical trial involving 134 patients, all of whom had diffuse disease of less than 18 months, high-dose DPA (750 to 1000 mg per day) was compared with low-dose DPA (125 mg every other day) .83 During a mean follow-up of 4 years, skin thickness score, incidence of scleroderma renal disease, and mortality were not different between the two groups. There was a greater improvement in skin scores in the low-dose group than in the high-dose group (not statistically significant). Furthermore, of the 20 adverse events necessitating drug withdrawal, 80% occurred in the high-dose group. It appears from this study that there might not be much advantage in using this therapy. Interferon alfa (IFN-a) and interferon gamma (IFN"I) both have antifibrotic potential and have been evaluated in patients with SSe. So far, only IFN-a has been subjected to a randomized double-masked study comparing its efficacy versus placebo in patients with early diffuse SSe. 84 There were more treatment withdrawals because of drug toxicity, and a greater deterioration was noted· in the treatment group in skin score, FVC, diffusing capacity for carbon monoxide (DLCO) and renal function, raising concerns about the benefit of this drug in the treatment of SSe. Another antifibrotic agent under study is recombinant human relaxin, given its ability to inhibit collagen production through increased collagenase activity.85 The real promise for major advance in the care of patients with SSc may lie in the areas of immunomodula-

CHAPTER 54:

tory therapy. This is not surprising, given the prominent abnormalities of cellular and humoral immune function present at early stages of the disease. So far, methotrexate (MTX) has shown promising results. In a double-masked trial, 29 limited and diffuse SSc patients were randomized to receive 15 mg ofMTX per week or placebo. 86 Mter 24 weeks, 8 of 17 patients in the MTX group versus 1 of 12 patients in the placebo group .were judged to have improvement in skin scores, creatinine clearance, and general well-being (outcomes were not statistically significant). Similarly, a double-masked, placebo-controlled trial examining the safety and efficacy of low-dose tissue plasminogen activator (t-PA) in the treatment of SSc concluded that low-dose recombinant human t-PA is safe and is accompanied by modest improvelnent in symptoms in a subset of scleroderma patients. 87 Other immunomodulatory therapies that have been used in patients with SSc have included intravenous dexamethasone pulses,88 oral cyclophosphamide,82,89 and plasmapheresis and oral daily 2.5mg/kg cyclophosphamide therapy.9o Several other immunomodulatory agents including thalidomide, an inhibitor of tumor necrosis factor alpha (TNF-a) and oral type 1 collagen 8 are under study.

PROGNOSIS The presence and extent of internal organ involvement are the main determinants of morbidity and Inortality in patients with scleroderma. Those with the diffuse disease are known to have a high incidence of internal organ manifestations and have a slightly worse 1!Irognosis. Scleroderma renal crisis was once regarded as one of the features associated with the worst prognosis. Because of its association with hyperreninemia, ACE inhibitors have been very successful in reversing SRc and improving surviva1,33 Pulmonary complications associated with pulmonary hypertension and interstitial fibrosis have emerged as the most difficult to treat end-organ involvement and are the principal cause of morbidity and mortality in late SSe. Pulmonary hypertension has a particularly poor prognosis,7 with most patients dying within 2 years. The disease is usually detected during the moderate to severe, irreversible stage. None of the current noninvasive studies (chest radiography, pulmonary function test, echocardiography) are sensitive in detecting early, potentially reversible, mild degree of PHTN.29

SSc is a multisystem disorder of connective tissue disease characterized clinically by fibrosis of the skin and internal organs, including the heart, lungs, kidneys, and gastrointestinal tract. Its etiology and pathogenesis are unknown, rendering effective treatment of the systemic cOlnplications difficult. Most of the ocular manifestations do not lead to significant visual impainnent, unlike many other connective tissue diseases, and they can usually be managed symptomatically. It is conceivable that scleroderma choroidopathy, if extensive, can have a deleterious effect on the outer retinal function. We have recommended periodic fluorescein angiography to monitor patients for scleroderma choroidopathy. One may question the relevance

of this test given that no treatment is available if evidence of progressive scleroderma choroidopathy is observed on the angiogram. The real benefits of obtaining periodic angiograms may have to do with learning more about the natural history of this choroidopathy.

References 1. Heron GS, Romero LI: Vascular abnormalities in scleroderma. Semin Cutan Med Surg 1998;17:12. 2. Leroy EC, Silver RM: Systemic sclerosis and related syl1,dromes. In: Schumacher HR, ed: Primer on Rheumatic Diseases, 10th ed. Atlanta, Georgia, Arthritis Foundation, 1993, p 118. 3. Peterson LS, Nelson AM, Su WP: Classification of morphea. Mayo Clin Proc 1995;70:1068. 4. Christiansen HB, Dorsey CS, O'Leary PA, et al. Localized scleroderma: A clinical study of two hundred' and thirty-five cases. Arch Dermatol 1956;74:629. 5. Curtis AC, Jansen TG: The prognosis of localized scleroderma. Arch Dermatol 1958;78:749. 6. Birdi N, Laxer RM, Thorner P, et al: Localized scleroderma, progressing to systemic disease: A case report and review of the literac ture. Arthritis Rheum 1993;36:410. 7. Stupi AM, Steen YD, Owens GR, et al: Pulmonary hypertension in the CREST syndrome variant of multiple sclerosis. Arthritis Rheum 1986;29:515. 8. Leroy EC, Black C, Fleischmajer R, et al: Scleroderma (systemic sclerosis): classifications, onsets and pathogenesis. J Rheumatol 1988;15:202. 9. Curzio C: a) Discussioni anatomico-pratiche di un raro, e stravagante morbo cutaneo in une giovane donna felicemente curato in questo grande Ospedale degl'Incurabili, Giovanni di Simone, Napoli, 1753 10. Dissertation anatomique et pratique sur une malade de la peau, d'une epsece fort rare et fort singulaire, translated by Vandermonde, Vincent, Paris, 1755. 11. Rodnan GP, Benedek TG: An historical account of the study of progressive systemic sclerosis (diffuse scleroderma). Ann Intern Med 1962;57:305. 12. Gintrac E: Note sur la sclerodermie. Rev Med ChiI' 1847:2:263. 13. Raynaud M: De l'asphyxie locale et de la gangrene symetrique des extremites. Paris, Rignoux, 1862. 14. Weber H: Case presentation. Correspondentzlbart Schweiz. Aertze 1878;8:623. 15. Matsui S: -abel' die Pathologie und Pathogenese von Sklerodermia universalis. Mitt Med Fakult Kaiserl Univ Tokyo 1924;31:55. 16. Goetz RH: Pathology of progressive systemic sclerosis (generalized scleroderma! with special reference to changes in the viscera. Clin Proc 1945;4:337. 17. Mayes MD: Classification and epidemiology of scleroderma. Semin Cutan Med Surg 1998;17:22. 18. Steen YD, Conte C, Santoro D, et al: Twenty year incidence survey of systemic sclerosis. (Abstract.) Arthritis Rheum 1988;31 (Suppl) :S57. 19. Mayes MD, Laing TJ, Gillespie BW, et al: Prevalence, incidence and survival rates of systemic sclerosis in Detroit metropolitan area. (Abstract.) Arthritis Rheum 1996;39(suppl):S150. 20. Silman AJ: Scleroderma-demographics and survival. J Rheumatol 1997;24(Suppl 48) :58. 21. Laing TJ, Gillespie BW, Toth MB, et al: Racial differences in scleroderma among women in Michigan. Arthritis Rheum 1997;40:734. 22. Steen YD, Oddis CV, Conte CG, et al: Incidence of systemic sclerosis in Allegheny County, Pennsylvania. A twenty year study of hospital diagnosed cases, 1963-1982. Arthritis Rheum 1997;40:441. 23. Tamaki T, MOli S, Takahara K, et al: Epidemiological study of patients with systemic sclerosis in Tokyo. (Abstract.) Arch Dermatol Res 1991;283:366. 24. Wigley FM, Flavahan NA: Raynaud's phenomenon. Rheum Dis Clin North Am 1996;22:765. 25. Sjogren RW: Gastrointestinal features of scleroderma. Curr Opin Rheumatol1996;8:569. 26. Lock G, Holstege A, Lang B, et al: Gastrointestinal manifestations of progressive systemic sclerosis. Am J Gastroenterol 1997;92:763.

54: 27. Silver RM: Scleroderma: Clinical problems; the lungs. Rheum Dis Clin North Am 1996;22:825. 28. Sullivan WD, Hurst DJ, Harmon CE, et al: A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine 1984;63:92. 29. Ungerer RG, Tashkin DP, Furst D, et al: Prevalence and clinical correlates of pulmonary arterial hypertension on progressive systemic sclerosis. Am J Med 1983;75:65. 30. Silver RM, Miller KS, Kinsella MB, et al: Evaluation and management of scleroderma lung disease using bronchoalveolar lavage. AmJ Med 1990;88:470. 31. Perez MI, Kohn SR: Systemic sclerosis. Am Acad Dermatol 1993;28:525. 32. Deswal A, Follansbee WP: Cardiac involvement in scleroderma. Rheum Dis Clin North Am 1996;22:841. 33. Steen VD, Constantino JP, Shapiro AP, et al: Outcome of renal crisis in systemic sclerosis: Relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 1990;113:352. 34. Steen VD: Scleroderma renal crisis. Rheum Dis Clin North Am 1996;22:861. 35. Tuffanelli DL, Winkelman RK: Systemic scleroderma: A clinical study of 727 cases. Arch Dermatol 1961;84:359. 36. Cerinic MM, Generini S, Pignone A, et al: The nervous system in systemic sclerosis (scleroderma). Rheum Dis Clin North Am 1996;22:879. 37. Gordon MB, Klein L, Dekker A, et al: Thyroid disease in progressive systemic sclerosis: Increased frequency of glandular fibrosis and hypothyroidism. Ann Intern Med 1981;95:431. 38. Nowlin NS, Brick JE, Weaver DJ, et al: Impotence in scleroderma. Ann Intern Med 1986;104:794. 39. Horan EC: Ophthalmic manifestations of progressive systemic sclerosis. Br J Ophthalmol 1969;53:388. 40. Kirkham TH: Scleroderma and Sjogren's syndrome. Br J Ophthalmol 1969;53:131. 41. West RH, Barnett AJ: Ocular involvement in scleroderma. Br J Ophthalmol 1979;63:845. 42. EI-Baba F, Frangieh GT, Iliff V\Cf, e'f al: Morphea of the eyelids. Ophthalmology 1982;89:1285. 43. Long PR, Miller OF 3rd, et al: Linear scleroderma: report of a case presenting as persistent unilateral lid edema. J Am Acad Dermatol 1982;7:541. 44. Stone RA, Scheie HG: Periorbital scleroderma associated with heterochromia iridis. Am J Ophthalmol 1980;90:858. 45. Dorwart BB: Periorbital edema in progressive systemic sclerosis. Ann Intern Med 1974;80:273. 46. Mancel E, Janin A, Gosset D, et al: Conjunctival biopsy in scleroderma and primary Sjogren's syndrome. Am J Ophthalmol 1993;115:792. 47. McWhae JA, Andrews AM: Transient corneal opacification induced by cold in Raynaud's disease. Ophthalmology 1991;98:666. 48. Arnett FC, Michels RG: Inflammatory ocular myopathy in systemic sclerosis (scleroderma). Arch Intern Med 1973;132:740. 49. Serup J, Serup L, Sjo 0, et al: Localized scleroderma "coup de sabre" with external eye muscle involvement at the same line. Clin Exp Dermatol 1984;9:196. 50. Hoang-Xuan T, Foster CS,Jakobiec FA, et al: Romberg's progressive hemifacial atrophy: An association with scleral melting. Cornea 1991 ;10:361. 51. Grennan AM, Forrester J: Involvement of the eye in SLE and scleroderma. A study using fluorescein angiograph in addition to clinical ophthalmic assessment. Ann Rheum Dis 1977;36:152. 52. Serup L, Serup J, Hagdrup H, et al: Fundus fluorescein angiography in generalized scleroderma. Ophthalmic Res 1987;19:303. 53. Hesse RJ, Slagle DF: Scleroderma choroidopathy: Report of an unusual case. Ann Ophthalmol 1982;14:524. 54. Kraus A, Guerra-Bautista G, Espinoza G, et al: Defects of the retinal pigment epithelium in scleroderma: Br J Rheumatol 1991;30:112. 55. Farkas TG, Sylvester V, Archer D, et al: The choroidopathy of progressive systemic sclerosis (scleroderma). Am J Ophthalmol 1972;74:875. 56. Pollack IP, Becker B: Cystoid bodies of the retina in a patient with sclerodenna. Am J Ophthalmol 1962;54:655, 57. Agatston HJ: Scleroderma with retinopathy. Am J Ophthalmol 1953;36:120.

58. Proctor B, Chang T, Hay D, et al: Parafoveal telangiectasia in association with CREST syndrome. Arch Ophthalmol 1998;116:814. 59. Furst DE, Clements PJ: Hypothesis for the pathogenesis of systemic sclerosis. J Rheumatol 1977;24:53. 60. Arnett FC, Reveille JD, Goldstein R, et al: Auto antibodies to fibrillarin in systemic sclerosis (scleroderma). An immunogenetic, serologic, and clinical analysis. Arthritis Rheum 1996;39:1151. 61. Arnett FC: HLA and autoimmunity in scleroderma. Int Rev Ophthalmol 1995;12:107. 62. Haustein UF, Haupt B: Drug-induced scleroderma and scerlodenniform conditions. Clin Dermatol 1998;16:353. 63. Okano Y: Antinuclear antibodies in systemic sclerosis. Rheum Dis Clin North Am 1996;22:709. 64. Spencer-Green G, Alter D, Welch HG, et al: Test performance in systemic sclerosis: Anti-centromere and anti-Scl-70 antibodies. Am J Med 1997;103:242. 65. Prescott RJ, Freemon AJ, Jones q, et al: Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 1992;166:255. 66. Salmon-Her V, Serpier H: Expression of interleukin-4 in scleroderma skin specimens and scleroderma fibroblasts cultures. Potential role in fibrosis. Arch Dermatol 1996;132:802. 67. Gurram M, Pahwa S, Frieri M, et al: Augmented interleukin-6 secretion in collagen stimulated peripheral blood mononuclear cells from patients with systemic sclerosis. Ann Allergy 1994; 73:493. 68. Higley H, Perischitte K, Chu S, et al: Immunocytochemical localization and in situ detection of transforming growth factor beta 1. Association with type 1 procollagen and inflammatory cell markers in diffuse and limited systemic sclerosis, morphea and Raynaud's phenomenon. Arthritis Rheum 1994;37:278. 69. Southcott AM, Jones 1'P, Li D, et al: Interleukin-8 differential expression in lung fibrosing alveolitis and systemic sclerosis. Am J Respir Crit Care Med 1995;151:604. 70. Patrick MR, Kurkham BW, Graham M, et al: Circulating interleukin1 beta and soluble interleukin-2 receptor: Evaluation as markers of disease activity in scleroderma. J Rheumatol 1995;22:654. 71. Belongia EA, Hedberg CW, Gleich GH, et al: An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med 1990;323:357. 72. Cronstein B, \J\Teissman G: The adhesion molecules of inflammation. Arthritis Rheum 1993;36:147. 73. Sfikakis PP, Tesar J, Baraf H, et al: Circulating intercellular adhesion molecule 1 in patients with systemic sclerosis. Clin Immunol Imn1Unopathol 1993;68:88. 74. Carson \J\TE, Beall LD, Hui1der GG, et al: Serum ELAM-1 is increased in vasculitis scleroderma. J Rheumatol 1993;20:809. 75. Grushwitz MS, Hornstein OP, von Den Driesch P, et al: Correlation of soluble adhesion molecules in the peripheral blood of scleroderma patients in their in situ expression and with disease activity. Arthritis Rheum 1995;38:184. 76. Cox D, Earle L, Jiminez SA, et al: Elevation levels of eosinophil m~or protein in the sera of patients with systemic sclerosis. Arthritis Rheum 1995;38:939. 77. Foster CS: Systemic lupus erythematosus, discoid lupus erythematosus, and progressive systemic sclerosis. Int Ophthalmol Clin 1997;37:93. 78. Subcommittee for Scleroderma Criteria of the American Rheumatism Association, Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581. 79. Finch MB, Dawson J, Johnston GD, et al: The peripheral vascular effects of nifedipine in Rayn.aud's syndrome associated with scleroderma. A double-blind crossover study. Clin Rheumatol 1986;5:493. 80. Stone JH, Wigley FM: Management of systemic sclerosis: The art and science. Semin Cutan Med Surg 1998;17:55. 81. Sfikakis PP, Kyriakidis MK, Vergos CG, et al: Cardiopulmonary hemodynamics in systemic sclerosis and response to nifedipine and captopril AnlJ Med 1991;90:541. 82. Siver RM, Warrick JH, Kinsella MB, et al: Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease. J Rheumatol 1993;20:838. 83. Clements PJ, Furst DE, Wong \lV1'., et al: High-dose versus low-dose

CHAPTER 54: SCLERODERMA

84.

85.

86.

87.

D-penicillamine in early diffuse systemic sclerosis. Analysis of a twoyear double-blind, randomized, controlled clinical trial. Arthritis Rheum 1999;42:1194. Silman A, Herrick A, Denton C, et al: Alpha interferon does not improve patient outcome in early diffuse scleroderma. Arthritis Rheum 1997;40:S123. SieboldJR, KornJ, Simms R, et al: Controlled trial of recombinant human relaxin in diffuse scleroderma. Arthritis Rheum 1997;40:S123. van den Hoogen FH, Boerbooms AM, Swaak AJ, et al: Comparison of methotrexate in dle treatment of systemic sclerosis: a 24 week randomized double-blind uial, followed by a 24 week observational trial. Br J Rheumatol 1996;35:364. Wilson D, Edworthy SM, Hart DA, et al: The safety and efficacy of

88.

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low-dose tissue plasminogen activator in the u-eatment of sclerosis. J Dermatol 1995;22:637. Pai BS, Srivas CR, Sabitha L, et al: Efficacy of dexamethasone pulse therapy and progressive systemic sclerosis. Int J Dermatol 1995;34:726. Akesson A, Scheja A, Lundin A, et al: Improve pulmonary nmction in systemic sclerosis after treatment with cyclophosphamide. Arthritis Rheum 1994;37:729. Dau PC, Callahan JP: Immune modulation during the treatment of systemic sclerosis with plasmapheresis and immunosuppressive drugs. Clin Immunol Immunopathol 1994;70:159. McKown KM, Carbone LD, Bustillo JM, et al: Open u-ial of oral type 1 collagen in patients widl systemic sclerosis (SSC). Arthritis Rheum 1997;40:S100.

I Jean Yang and C. Stephen Foster

Giant cell arteritis (GCA), also known as temporal arteritis, is a systemic granulomatous vasculitis that involves medium- and large-sized arteries. The disease has certain characteristic manifestations, including headache, temporal tenderness or reduced pulsation, jaw claudication, and scalp tenderness. Involvement of the ophthahnic and posterior ciliary arteries can lead to permanent partial or complete vision loss. Blindness can be potentially prevented by prompt treatment with corticosteroids.

HISTORY Ali-ibn-Isa of Baghdad first described GCA in the 10th century and made the association between this disease and vision loss. 1 In the English literature, Hutchinson in 1890 described the disease in a man in his 80s who "had red streaks on his head which were painful and prevented him wearing his hat. The red streaks proved, on examination, to be his temporal arteries."2 Horton and colleagues, in 1932, first described the pathologic features of the arteritis. 3 In 1938, Jennings reported loss of vision as a result of the disease. 4 GCA is also known as temporal arteritis,3 cranial arteritis,S and granulomatous arteritis.; In Europe, the disease is sometimes called Horton's giant cell arteritis. Giant cell arteritis is the preferred name for the disease because of its systemic nature.

EPIDEMIOLOGY GCA usually occurs in individuals aged 50 or older, and the incidence of the disease increases with age. Women are two to three times more frequently involved than Inen. 7-9 Most epidemiologic studies have shown the disease to be prevalent predominantly in whites of European origin. The reported incidence is variable, ranging from 0.49 to 33.6 per 100,000 aged 50 and 01der. 7- 26 Comparison of results between studies is difficult because of differences in diagnostic and inclusion criteria. The incidence of biopsy-proven GCA ranges from 0.49 12 to 25.422 per 100,000 aged 50 and older. The incidence is highest in Scandinavia (23.3 to 33.6 per 100,000 over age 50 15 ,18,22) and Minnesota (19.1 to 24.1 per 100,000 over age 50).8,13 A much lower incidence is reported in Israel (0.49 to 0.86 per 100,000 over age 50 12 ) and Tennessee (1.58 per 100,000 over age 50),14 Several studies showed an agespecific incidence rate increasing from 2.1 to 6.6 per 100,000 in the sixth decade, to 48.9 to 70.7 per 100,000 in the ninth decade. 7, 23 ,Significant increases in the annual incidence rate of GCA have been reported in several series from different countries and regions. 8-1o , 21, 23, 26 The reason for this increase is unclear. In some of these studies, the increase in incidence is observed only in women and therefore cannot be explained by increased clinical awareness of physicians and improved diagnostic tests alone. 8,9 Salvarani and colleagues 23 and Elling and coworkers 24 showed

fluctuations of incidence rate in a cyclic pattern with "epidemics" occurring every 6 to 7 years, and they speClllated an infectious cause for this disease~ Elling and colleagues correlated peak incidences of GCA with two epidemics of Mycoplasma pneumoniae infection,24 and Gabriel and associates note that the cycles of GCA epidemic-like peaks mimics that of parvovirus B19 epidemic cycles. 27 Autopsy histopathologic studies found arteritis lesions in the temporal artery or aorta in 1.5 to 1.7 % of autopsies performed. 28 , 29 This suggests that subclinical GCA may be more prevalent than the epidemiologic data indicate.

CLINICAL

Systemic Features The disease often begins insidiously, with constitutional symptoms such as malaise, anorexia, weight loss, night sweats, myalgia, and fever. The prodromal period may las't from several weeks to months. The most common symptom is headache,lO, 11, 30 which is usually temporal or occipital, and can be either unilateral or bilateral. The headache can gradually increase in severity and is usually worse in the evening and with exposure to cold temperatures,31 Other cranial symptoms include scalp and temporal tenderness, jaw claudication, facial pain, earache, toothache, tongue and palate pain, and odynophagia. 30-34 Given the potentially devastating visual consequences of GCA, and the fact that this disease is one of the treatable causes of blindness, it is important to be reminded of what Paulley and Hughes once stated, "When elderly people begin to fail mentally and physically, this should be one of the first disorders to be considered, and not one of the last. "32 It is especially incumbent on clinicians to be vigilant of the "silent" presentation, or the occult form of the disease. In occult GCA, the classic symptoms may be minimal or absent, or they may appear long after the ocular phase of the disease. 35 In 8%7 to 34%35 of cases, patients present with only vague constitutional symptoms, which makes the diagnosis difficult. In one study, atypical, silent presentation of the disease in a group of patients resulted in a mean delay in diagnosis of 21.5 days, in contrast to a delay of 8.5 days in the group with typical presentations. 36 A recent study showed 21 % of 85 patients had ocular involvement without any systemic syInptoms and signs of GCA.37 Many neurologic diseases are associated with GCA. Caselli and colleagues reported neurologic problems occurring in 31 % of 166 patients with GCA.38 Cerebrovascular disease is thought by some to be the most common cause of death in patients with GCA.40,41 It is difficult to assess the frequency of cerebrovascular disease, which has been reported to be 1% to 25% in a number of series. 31 , 38-40 Other associated neurologic diseases include peripheral neuropathies, neuro-otologic syndromes, neuropsychiatric syndromes, seizures, and myopathy.32, 34, 38, 41-45 Neuro-ophthalmic manifestations will be discussed later.

CHAPTER 55: GIANT CEll ARTERITIS

Large vessels such as the aorta and its major branches can be involved. The cardiovascular involvement of GCA may not be readily recognized because the involvement can be asymptomatic, and atherosclerosis often coexists with GCA. Severe involvement can lead to aortic incompetence, aortic aneurysm, aortic arch syndrome, aortic rupture, and myocardial infarction. 32 , 45-50 Involvement of other large vessels can result in claudication of an extremity, paresthesias, and Raynaud's phenomenon. In a study of 248 patients with GCA, 34 had evidence of aortic or: other large vessel disease.46 Other . less common systemic manifestations include pulmonary abnormalities such as cough,51,52 pleural effusion,53 pulmonary thrombosis, and infarction 54, 55; gastroenterologic complications such as intestinal fistula formation and perforation 56, 57; renal vasculitis and renal failure58, 59; and dermatologic diseases such as scalp necrosis,34,60 gangrene, and erythema nodosum-like lesions on the lower extremities. 61 , 62

Relationship to Polymyalgia Rheumatica The relationship between GCA and polymyalgia rheumatica (PMR) is unclear. PMR is a syndrome characterized by morning stiffness, pain and stiffness in pelvic and shoulder girdles, elevated erythrocyte sedimentation rate (ESR), and a rapid response to small doses of corticosteroids. Like GCA, it is a disease of the elderly, involving predominantly whites, and is more common in women by a ratio of 2 or 3 to 1. GCA and PMR are often present in the same patient. Furthermore, arteritis was found in clinically asymptomatic temporal arteries~in patients with PMR.63 It is believed by some that the two diseases are different manifestations of the same underlying pathology.64 The incidence of PMR is reported to be 53.7 per 100,000 aged 50 and older in Olmstead County, Minnesota,13 and 28.6 per 100,000 aged 50 and older in Goteborg, Sweden. 65 In the Minnesota study, GCA was found in 15 of 96 patients (16%) with PMR. In other series, positive temporal artery biopsy in patients with PMR ranges from 0% in New York66 to 41 % in some Scandinavian countries. 45, 67 The low rate of positive biopsy in New York is thought to be a result of the Jewish descent of many of the patients studied, because it corresponds to the low incidenGe of GCA reported in Israel.68 In a large prospective study in Norway, random biopsies of 68 patients with PMR revealed inflammatory changes in only three patients (4:4%) .69 A recent study identified the, best predictors of arteritis in patients with PMR as a new-onset headache, clinically abnormal temporal arteries, jaw claudication, elevated liver enzymes, and age greater than 70 years at disease onset. 70 Among the patients with GCA, approximately half develop PMR.I0 GCA and PMR have different clinical courses that suggest that they are indeed two separate diseases. Unlike GCA, PMR responds to small doses of corticosteroids. Also 'PMR can be chronic and recurrent, while late recurrence of GCA is very uncommon.

Ophthalmic Features Anterior Ischemic Optic Neuropathy The reported rate of ocular involvement in GCA varies greatly, from 14% to 70%.8, 10, 11,22,31,37, 38, 40, 71, 72 Likely

explanations for the differences in reported incidences are differences in diagnostic criteria, and probable selec~ tion bias in favor of cases with ophthalmic involvement in some of the earlier series. More important, the decreasing incidence of ophthalmic involvement in later studies probably should be credited to increased clinical awareness and prompt treatment. The most common and devastating ocular symptom of GCA is vision loss, either partial or complete. The rate of vision loss is difficult to ascertain, with reported incidence wildly ranging from 8% to 65%.8,10,11,30,31,37,38,40,71 The use of corticosteroids and, again, increased clinical awareness may account for the lower rate of vision loss in the later series. The most common etiology of vision loss is anterior ischemic optic neuropathy (AlaN). Other causes include central or branch retinal artery occlusion, cilioretinal artery occlusion, posterior ischemic optic neuropathy (PION), choroidal infarction, and, rarely, anterior segment ischemia and cortical blindness. The vision loss in GCA may be either unilateral or bilateral, and it is usually sudden, painless, and permanent. Often the loss of vision is found on waking up in the morning. Amaurosis fugax is an ominous sign of impending AlaN, which occurs in 10%11,38 to 18%73 of cases. When the second eye is involved, the time interval between vision loss of two eyes is 7 11 to 23 73 days. Fleeting visual blurring with heat or exercise, or Uhthoff's phenomenon, has been described in GCA.74 AlaN results from ischemia of the optic nerve head, which is mainly supplied by the posterior ciliary arteries. AlaN is divided into the arteritic type, caused by GCA, and the nonarteritic type, which has other causes such as hypertension, diabetes mellitus, atherosclerosis, carotid artery disease, and collagen vascular disease. 75 Nonarteritic AlaN also includes those cases with no apparent cause. The majority of AlaN is nonarteritic, accounting for 87.5% to 91 % of cases. 75-77 AlaN presents with sudden painless loss of vision, although visual acuity can range from 20/20 to no light perception. 78 Relative afferent pupillary defect can be found. Fundus examination shows optic disc edema, which may be accompanied by splinter hemorrhages at the disc margin (Fig. 55-1). A chalky white edematous optic disc is highly suggestive of arteritic AlaN, and it is very rare in the nonarteritic type (Fig. 55-2),19 Similarly, the presence of cilioretinal artery occlusion is also almost diagnostic of arteritic AlaN (Fig; 55-3) .79 In nonarteritic AlaN, a small "crowded" optic disc cup is often found in the fellow eye, which is not characteristic of arteritic AlON.80 Visual field perimetry typically shows inferior altitudinal defect, inferior nasal sectoral defect or central scotoma, and a variety of other defects. 73, 78 Fluorescein angiogram reveals filling defects of the .optic disc, peripapillary choroid, and choroidal watershed zones. Extensive choroidal nonfilling is very characteristic of arteritic AlaN (Fig. 55-4) .79 With time, the optic disc edema usually resolves, in about 2 months, and it is followed by sectoral general optic atrophy. Bilateral involvement is more common in arteritic AlaN, by a factor of 1.9 according to one study.77 It is important to distinguish arteritic from nonarteritic AlON. Hayreh described a set of criteria to differentiate the two types. 75 Arteritic AlON can be differentiated from

CHAPTER 55: GIANT CELL ARTERITIS

FIGURE 55-I. Giant cell arteritis, with abrupt loss of vision, left eye, with disc edema and splinter hemorrhages adjacent to the disc. (Courtesy of Simmons Lessell, MD.)

nonarteritic AlON by the previously described classic systemic symptoms, visual symptoms (especially amaurosis fugax and diplopia), elevated ESR and C-reactive protein (CRP) , early massive visual loss; the presence of chalky white optic disc edema, cilioretinal artery occlusion, massive choroidal nonfilling of the choroid on fluorescein angiogram, and positive temporal artery biopsy findings. 75

Posterior Ischemic Optic Neuropathy PION, also referred to as retro""ulbar ischemic optic neuritis, is caused by ischemia of the posterior part of the optic nerve. PION is a less common complication of GCA and is usually a diagnosis of exclusion. The disease is manifested as visual loss with an afferent pupillary defect but with no apparent fundus abnormality.81, 82 The optic nerve head shows atrophic changes 5 to 6 weeks later. A recent color Doppler ultrasonography study showed decreased blood flow in a patient with arteritic PION.83

Central Retinal Artery Occlusion Central retinal artery occlusion (CRAO) is another potential complication of GCA. The incidence of CRAO in

FIGURE 55-2. Giant cell arteritis, in a patient who demonstrates the chalky white form of disc edema. (Courtesy ofJoseph ERizzo III, MD.) (See color insert.)

FIGURE 55-3. Giant cell arteritis with occlusion of a cilioretinal artery, and associated intraretinal hemorrhages. (Courtesy of John 1. Loewenstein, MD.) (See color insert.)

GCA in the literature ranges from 4% to 21 %y, 39, 73, 84 It was shown that central retinal artery and one or more of the posterior ciliary arteries often arise from a common branch from the ophthalmic artery.85 Therefore, it is not surprising that in cases of CRAO in GCA, there is involvement df the posterior ciliary arteries. Hayreh demonstrated, by fluorescein angiogram, that the majority of the CRAO cases in GCA were accompanied by a combined occlusion of the posterior ciliary artery.78 This is also supported by color Doppler ultrasonography findings of decreased flow in the posterior ciliary arteries in a patient with CRAO caused by GCA.83 Another color Doppler study showed significantly reduced flow velocities in central retinal and short posterior ciliary arteries in all the patients with GCA studied. 86 Cilioretinal artery is also a branch of the posterior ciliary artery. Occlusion of the cilioretinal artery is usually associated with AlON, and its occlusion is a differential feature of arteritic AlON from, the nonarteritic type. 75

FIGURE 55-4. Giant cell arteritis, fluorescein angiogram, demonstrating extensive delayed filling of multiple areas of the choroid, which is indicative of choroidal invoivement in this systemic arteritic disease. (Courtesy ofJoseph F. Rizzo III, MD.)

CHAPTER 55: GIANT CELL ARTERITIS

Branch Retinal Artery Occlusion Branch retinal artery occlusion has also been reported in GCA.87 However, Hayreh argued that many cases of branch retinal artery occlusion in GCA are probably Illisdiagnosed cilioretinal artery occlusions, as GCA is not a disease that involves arterioles. 88 Recently, another case of GCA presenting with branch retinal artery occlusion as the initial sign was reported. 89 The authors speculated that the inflammation or thrombosis of the ophthalmic artery or central retinal artery reduces blood flow in retinal arterioles and predisposes the development of branch retinal artery occlusion. This speculation is supported by the observation of cotton-wool spots in GCA, which is a sign of focal retinal ischemia caused by retinal arteriolar obstruction. 90

Choroidal Ischemia Choroidal ischemia is another manifestation of occlusion of the posterior ciliary artery, because the choroid is supplied by the posterior ciliary arteries. Choroidal ischemia is often found only on fluorescein angiogram, and it remains asymptomatic. 79 However, it may lead to decreased vision: It was the cause of vision loss in 6% of cases in one study.73 Choroidal ischemia may not have any obvious retinal findings. When the macula is involved, choroidal ischemia may have the appearance of a whitish lesion involving the peripapillary region, which probably represents degenerated pigment epithelium. 79 Choroidal ischemia may also appear as scattered X,ellow-white lesions at the level of the retinal pigment epithelium. 91 Areas of choroidal infarcts resulting from choroidal ischemia later appear as peripheral chorioretinal degenerative lesions. These areas are often found in the midperipheral region, and they tend to be triangular in shape, with the base toward the equator and the apex toward the posterior pole. 79 ,92

Neuro-ophthalmic Diplopia is a frequently reported finding in GCA, with an incidence of 2% to 17%.10,31,34,38,40,71,93 Diplopia may occur during and after the headache, and it can precede visual 10ss.71, 93 It has been noted that diplopia may be present without any evident extraocular muscle abnormalitiesY' 71, 94 Hollenhorst reported that only 12 of 22 patients with diplopia had demonstrable extraocular muscle abnormalitiesY Hollenhorst also noted that the vertically acting extraocular muscles are more frequently affected. The OculOlllotor nerve appears to be the most commonly involved, usually sparing the pupiJ.93, 95 Other cranial nerves frequently involved are the abducens (CN VI) and the trochlear (CN IV).11' 39, 95, 96 The cause of diplopia is generally thought to be neurogenic in nature. ~owever, some have suggested that the ophthalmoplegia IS due to muscle ischemia. Barricks and colleagues s~owed autopsy findings of muscle ischemia in a patient WIth GCA and ophthalmoplegia. 97 Sibony and Lessell reported transient oculomotor synkinesis in GCA, and argued that this was evidence that the ophthahlloplegia was neurogenic rather than myogenic in nature. 98 In contrast to the visual loss in this disease, which often is permanent, diplopia usually resolves with time, sometimes even without steroid treatment. 11 , 71,93

Other neuro-ophthalmologic abnormalities associated with GCA include ptosis,99 nystagmus,31 and internuclear ophthalmoplegia. 1oo Pupillary abnormalities associated with GCA include, most commonly, a relative afferent pupillary defect, tonic pupil,101, 102 and Horner's syndrome. 103

Uveitis

Anterior segment ischemia104, lOS and uveitis106,107 are less common in GCA. Ocular hypotony,108 corneal edema,109 marginal corneal ulceration,l1O episcleritis and scleritis,111 neovascular glaucoma,112 and orbital pseudotumor113 have all been reported. Cerebral ischemia may rarely produce visual 10ss.39, 114 Charactelistic visual field defects such as homonymous hemianopia probably results from ischemic postchiasmal lesions. 31 Cortical blindness caused by infarction of the occipital lobes and associated with vertebral arteritis has been described.11 s , 116

PATHOLOGY The most commonly involved vessels in GCA are the superficial temporal, occipital, vertebral, ophthalmic, and posterior ciliary arteries. 116 The reason for the frequency of involvement of the cranial vessels is not clear. Other arteries, especially the aorta and coronary arteries, can be involved. 46 It has been noted that intracranial arterial involvement is less frequent, and the vertebral arteries that are severely affected show no evidence of the disease shortly after entering the dura.11 6 It has been postulated that the inflammation in GCA is correlated with the amount of the elastic tissue in the arteries, which would explain why intracranial arteries are less involved, because they contain less elastic fibers.11 7 All three layers of the arterial wall may be involved by granulomatous inflammation, although the inflammation can be located mainly in the media and intima.33, 118 The involved area is infiltrated with epithelioid macrophages, lymphocytes, and multinucleated giant cells. The intima is thickenep. with edema and fibrosis, and the lumen may be markedly narrowed as a result. Fragmentation and destruction of the internal elastic lamina are frequently seen. Multinucleated giant cells are often seen adjacent to the internal elastic lamina. Although giant cells are characteristic of this disease, their presence is not a prerequisite to make the histopathologic diagnosis. Although focal areas of intimal and medial necrosis can be observed, extensive necrosis is unusual and should suggest other diagnoses.11 9 Healed arteritis is characterized by irregular intimal and medial fibrosis, scattered chronic inflammatory cells, and small blood vessel formation in the vessel walls. 120 Skip areas, or segments of normal artery, can be present between the arteritic lesions. 121 Therefore, a negative biopsy cannot sufficiently exclude the diagnosis.

IMMUNOLOGY AND Despite the great interest and extensive immunologic studies on GCA, the etiology of this disease remains unclear. Studies have suggested the role of a humoral immunologic mechanism in the pathogenesis of GCA, but in-

CHAPTER 55: GIANT CELL ARTERITIS

creasing evidence points to its being a cell-mediated disease. An early report speculated that the immune reaction of the disease was directed toward elastin. ll8 This was derived from the observation of the degradation of the internal elastic lamina and associated granulomatous inflammation, especially the concentration of giant cell reaction in the region of the internal elastic lamina. Occasionally, giant cells also appeared to have phagocytosed elastin,ll8 although this was not generally confirmed by electron microscopy. 122, 123 The speculation of elastin being the target of the inflammatory activity is supported by the fact that intracranial arteries, which contain fewer elastic fibers, are less frequently affected,u6 Furthermore, the basal and stimulated elastolytic activity of monocytes was shown to be increased in GCA.124 Deposition of leukocyte elastase was found along the fragmented internal lamina. 125 Elevated serum levels of neutrophil elastase in GCA patients was reported. 126 However, anti-elastin antibodies have not been demonstrated in the serum of GCA patients. 127 A recent study investigated the reaction of peripheral blood mononuclear cells from patients with GCA and controls, to elastase-derived elastin peptides. A proliferative response was found in 12 of 13 patients with GCA, and only in 3 of 34 of controls. 128 Another study found actinic elastotic degeneration in the posteriOI:- ciliary arteries of 68 % of subjects aged 70 to 90 years. Particularly, one of these eyes showed giant cells on degenerate lamina, which was thought to be preclinical GCA.129 Another postulated pathoge'hic mechanism is an immune reaction to degenerated smooth muscle cells, with a secondary degradation of the elasticum and the formation of giant cells. 130 This hypothesis is supported by the finding, by electron microscopy, of macrophages and giant cells closely attached to the smooth muscle cells. 131 In addition, adhesion molecules, such as intercellular adhesion molecule-l (ICAM-l), have been found to be expressed on the smooth muscle cells of the media. 132 There may be a genetic predisposition to GCA, given the observation that the disease predominantly involves the white population. Increased prevalence of human leukocyte antigens HLA-DR3, HLA-DR4, HLA-B8, HLADRBl, and HLA-Cw3 (which is linked to HLA-DR4) have been found in patients with GCA.133-137 There were also reports indicating that HLA-DR4 is increased only in those GCA patients who also have PMR, but not in patients with GCA alone. 138, 139 Of note is that the molecule encoded by HLA-DRBI is intimately involved in antigen presentation to T cells. 140 Earlier reports suggested that humoral autoimmunity may playa role in the pathogenesis of this disease. Elevated serum immunoglobulins and complement were reported. 141 Some reported circulating immune complexes,142 as well as certain. correlation between this finding and clinical disease activity,143, 144 However, others did not corroborate the prevalence of circulating immune complexes in patients with GCA compared to controls. 145 Deposition of immunoglobulins and complement in the arterial wall were demonstrated by some,146-148 although others found the deposition in many fewer biopsy samples.1'19-151 Antibodies against intermediate filaments

were also demonstrated, which was thought to be a supportive finding for an autoimmune process. 152 Cellular immunity is suggested by the infiltrating cell types, consisting of I)'lTIphocytes, monocytes, interdigitating reticulum cells, histiocytes, and giant cells. The majority of the lymphocytes in the arteritic lesions of GCA are T IYJ-TIphocytes, with an absence of or very few B IYJ-TIphocytes. 149 , 152-154 A study of five patients who developed GCA after the onset of chronic IYJ-TIphocytic leukemia found no leukemic B cells, known for their ability to diffusely seed organs, in the arteritic lesions. 155 This finding suggests that B cells are actively excluded in the inflammatory process. Monoclonal antibody studies in most of the reports indicated a predominance of CD4 + helper/inducer subsets over CD8 + cytotoxic/suppressor subset,150, 153, 154 except for one report, in which equal numbers of each were observed. 147 Interdigitating reticulum cells were observed in 41 % of the. patients in one study and were associated with a shorter duration of disease activity.154 Some of the infiltrating macrophages and T IYJ-TIphocytes were shown to express class II major histocompatibility antigen HLA-DR and transferrin receptors, which suggests that these lymphocytes are immunologically activated. 153 , 154, 156 A higher percentage of T IYJ-TIphocytes in the arterial wall expressed HLA-DR than those of the peripheral blood, indicating a high degree of local Tcell activation. 156 Infiltrating T lymphocytes also expressed interleukin-2 (IL-2) receptors. 153 , 154, 156 In one of the stud:" ies, the IL-2 receptor expression decreased from 87.5% to 14% after the treatment with corticosteroids. 154 Most of T lymphocytes expressed the integrin receptors, such as IYJ-TIphocyte function-associated antigens-l (LFA-l) and very late activation molecules (VLA-l). 157 Strong expressions of ICAM-l and LFA-3 were found on macrophages, epithelioid cells, and giant cells in the granulomatous lesion. 132 There is evidence indicating that T cells involved in the disease are of selected clonotypes. T cells of identical T-cell receptor (TCR) V beta chains were isolated from distinct inflammatory foci of the same patient. 158 ,159 When inflamed arteries are implanted into severe combined immunodeficiency (SCID) mice, T cells with identical TCRs were expanded in different mice with the same tissue grafts from the same patient. 160 This selective proliferation suggests that there is a locally expressed antigen that is recognized by a small fraction ofCD4 T cells. In situ production of cytokines, including IL-l beta, IL6, transforming growth factor-beta (TGF-f3), interferongamma (IFN-')'), and IL-2, were detected in the vasculitic lesions of GCA.161 IL-2 was also found in the biopsy specimens from patients with PMR, but TGF-13 was not. 161 In the GCA artery-implanted SCID mice, it was shown that T-cell depletion led to decreased production of IL-l beta and IL-6, and adoptive transfer of tissue-derived T cells enhanced the production of IL-2 and IFN-')' .160 Further studies showed different patterns of cytokine production correlated with different patterns of clinical manifestations. For example, ischemic sYJ-TIptoms, such as jaw claudication and visual sYJ-TIptoms, were associated with higher concentrations of IFN,..')' and IL_l. 162 An elevated serum IL-6 level has been reported in GCA, and higher levels

55: GIANT CELL ARTERITIS

were found to correlate with disease activity. 163, 164 Tumor necrosis factor was demonstrated in the artery walls,and it was localized to giant cells and macrophages. 165 Plateletderived growth factor-A (PDGF-A) and PDGF-B were produced by macrophages, smooth muscle cells, and giant cells at the media-intima border. PDGF expression was associated with concentric intimal hyperplasia. 166 Serum levels of soluble IL-2 receptors and CD23 were found to be elevated during the active phase of the disease. 167 ,168 The effect of corticosteroids on the cytokine production was studied in artery-SCID mice chimeras, which revealed that the treatment reduced tissue concentrations of IL-2, IL-l-beta, and IL-6 mRNA. Synthesis of IFN-')' mRNA was only slightly decreased, and that of TGF-131 was unaffected. 169 The persistent TGF-131 transcription may explain the chronicity of the disease. Macrophages in arterial walls were found to contain proteolytic enzymes, including gelatinases such as matrix metalloproteinases (MMPs), which are type IV collagenases. Specimens from GCA patients showed enhanced immunostaining for MMP-9 and MMP-2 in the media and near internal elastic lamina. l7O , 171 Serum MMP-9 titers were also significantly increased in patients with GCA.172 The detection of MMP-9 suggests that degradation of intercellular matrix, especially elastic fibers, may take place in GCA. A recent study demonstrated that the strongest inflammatory infiltration was in the adventitia, and a higher concentration of macrophages, HLA-DR, ICAM-l, and IL2 were seen in the outer than in the iN.ner half of the intima. This distribution was thought to indicate that the majority of the inflammatory cells enter the arterial wall from adventitial microvessels, migrate through the media, and aggregate at the peripheral intima and internal elastic membrane. 173 In another study, different subsets of macrophages were found at different areas of the arterial wall. The TGF-131-expressing subset exhibited a strong preference for the adventitia, whereas the inducible nitric oxide synthase-expressing subset was almost exclusively found in the intimal layer, and the collagenase-expressing subset preferred the intima-media junction. 174 This finding suggests that the TGF-131-expressing subset may function as a pro-inflammatory mediator, whereas the inducible nitric oxide synthase- and the collagenase-expressing macrophages are involved in tissue destruction in the center of pathology.

CD8 + lymphocytes in the peripheral blood of patients with GCA and PMR have been noted· to be decreased in both absolute numbers and relative percentages.175-177 SOllie studies indicate that the decrease of CD8 + lymphocytes is related to disease activity. 175, 177 Low percentages of CD8 + T cells in the peripheral blood of healthy relatives of patients with GCA suggest that this might be a hereditary characteristic. 178 The peripheral blood CD8 + T cells in patients with GCA were found to have a restricted repertoire with a distinct] beta gene segment usage, indicating that selectively expanded CD8 + cells may be of functional importance in the pathogenesisP9 A recent study detected parvovirus B19 DNA, by polymerase chain reaction, in the temporal artery biopsy tissue from patients with GCA. Parvovirus B19 DNA was detected in 7 of 13 specimens with histologic diagnosis of GCA, but it was not found in 33 of the 37 negative biopsy specimens, therefore suggesting a possible role of parvovirus B19 in the pathogenesis of this disease. 27

DIAGNOSIS The diagnosis of GCA is largely based on clinical impression. The American College of Rheumatology 1990 criteria for the classification of GCA are listed in Table 55_1. 180 The fulfillment of three of the five criteria is associated wj.th a sensitivity of 93.5% and a specificity of 91.2%. Laboratory tests, particularly an elevated ESR, elevated serum fibrinogen, and soluble IL-2 receptor, can strongly support the diagnosis. Histopathologic evidence of GCA is still regarded as definitive.

Hematologic: Tests ESR is the most widely used, and remains the most valuable, laboratory test in the diagnosis of GCA. The Westergren technique is commonly used, as it is more sensitive than the Wintrobe technique, especially to increases in asymmetric macromolecules. l81 It is, for example, directly correlated with serum fibrinogen levels. In most series, ESR is elevated in 90% to 100% of cases. 1O ,31,32 The mean ESR value in the acute phase of GCA ranges from 83 to 107 mm/hour;,lO, 11, 45, 73 However, normal values of ESR in biopsy-proven GCA are well documented,40,182 and ESR values less than 30 or 50 mm/hour have been found in 22.5% to 26% of cases in some series.73, 183 Therefore, a normal ESR value does not exclude the diagnosis of GCA. The ESR level usually correlates well with disease activity

TABLE 55-I. 1990 AMERICAN COLLEGE OF RHEUMATOLOGY CRITERIA FOR THE CLASSIFICATION OF GIANT CELL ARTERITIS (TRADITIONAL FORMAT) CRITERION

DEFINITION

1. Age at disease onset, ::::::50 years 2. New headache 3. Temporal artery abnormality

Development of symptoms or findings beginning at age 50 or older New onset of or new type of localized pain in the head Temporal artery tenderness to palpation or decreased pulsation, unrelated to arteriosclerosis of cervical arteries Erythrocyte sedimentation rate ::::::50 mm/hr by the Westergren method Biopsy specimen with artery showing vasculitis characterized by a predominance of mononuclear cell infiltration or granulomatous inflammation, usually with multinucleated giant cells

4. Elevated erythrocyte sedimentation rate 5. Abnormal artery biopsy

Clinical diagnosis of GCA is made if at least three of these five criteria are present. The presence of any three or more criteria yields a sensitivity of 93.5% and a specificity of 91.2%. From Runder GG, Bloch DA, Michel BA, et al: The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33:1122-1128.

CHAPTER 55: GIANT CELL ARTERITIS

and therefore is useful in monitoring treatment. 184, 185 ESR may be affected by anemia. An inverse relationship between ESR and hematocrit has been reported. 186 CRP is a protein produced by hepatocytes, and it can be elevated in acute inflammatory disorders. Unlike ESR, CRP is not affected by anemia or the concentrations of other plasma proteins. 94, 187 CRP has been reported to be elevated in acute GCA, and its level correlates well with clinical disease activity. 184, 185, 187, 188 Compared with ESR and other hematologic tests, CRP tends to normalize more rapidly following corticosteroid treatment. 184, 187, 189 Opinions differ as to which is a better diagnostic test in GCA. Whereas ESR is regarded by some as a better indicator of clinical disease activity,184, 185, 190 others consider CRP as more sensitive in the diagnosis of GCA191 and in assessing the adequacy of corticosteroid treatment. 187 Other hematologic tests including plasma viscosity, blood count, and various acute-phase reactants may also be helpful in the diagnosis of GCA. Plasma viscosity often is raised in GCA and is found to correlate well with ESR.189, 192 Plasma viscosity combined with ESR may improve the diagnostic accuracy.192 Normochromic normocytic anemia is commonly seen in GCA,13, 193-195 and thrombocytosis is also documented. 195 Serum fibrinogen is typically elevated in GCA, which decreases rapidly following corticosteroid treatment. 184, 189 Von Willebran,d factor can also be raised in GCA, and it may persist after corticosteroid treatment. 196 One study showed raised von Willebrand factor persisted during the first 2 years of treatment but normalized in p~tients in long-term remission. 197 Other proteins that may be raised in GCA include haptoglobin,184, 190 orosomucoid,190 a-l-antichymotrypsin,188 and a-l-antitrypsin. 190 Anticardiolipin antibodies have been found to be prevalent in GCA patients.198-201 The findings of some studies suggested that patients with PMR and/or GCA with elevated levels of anticardiolipin antibodies had increased risk of developing GCA or other major vascular complications. 199 , 200

liver Function Tests Liver function is frequently abnormal in GCA.I0, 13, 195 A common abnormality is an elevated alkaline phosphatase level, although transaminases may also be elevated. 13 , 195, 202 Alkaline phosphatase is usually modestly elevated and tends to normalize with treatment. 203 The etiology of liver dysfunction is unclear. Although hepatic arteritis,204 hepatic granuloma,205 hepatocyte necrosis,206 and intrahep'atic cholestasis, suggesting immune complex deposition,207 have all been reported in association with GCA, many liver biopsies appeared normal or showed nonspecific changes. 203 Radionuclide liver scans showed abnormal uptake in 7 of 29 patients with PMR or GCA, and this persisted even when liver function returned to normal after treatment. 203 Patients with abnormal liver scans were more likely to have raised alkaline phosphatase.

Other Diagnostic Studies Fluorescein Angiogram Fluorescein angiography shows a delay in arm-to-retina circulation time, and massive choroidal nonfilling. 79 This pattern of choroidal nonfilling is considered almost diag-

nostic of arteritic AlON.88 The medial posterior ciliary artery is involved more frequently than the lateral posterior ciliary artery.79

Color Doppler Ultrasonography Color Doppler ultrasonography has been found to be a useful noninvasive tool in the diagnosis of GCA. Using this technique, studies of temporal arteries showed decreased blood flow velocity, thickening of the vessel wall, and stenosis or occlusions of the temporal arteries. 208 ,209 One of the studies revealed a dark halo around the lumen of the temporal arteries in patients with GCA, which was thought to be caused by edema of the artery wall. The dark halo was a specific sign, and it disappeared after corticosteroid treatment. 208 Color Doppler studies of the orbit showed undetectable blood flow, reduced flow velocities in central retinal and short posterior ciliary arteries, high velocity and turbulent flow at presumed focal stenotic lesions, reversal of flow within the ophthalmic artery, and reduced and truncated time-velocity waveforms. 2l0 ,211 Some of these observed changes are unique for, or more frequent in, GCA compared to nonarteritic AlON.

Temporal Artery Biopsy A positive temporal artery biopsy provides the definitive diagnosis of GCA; Because the diagnosis of GCA commits the patient to long-term corticosteroid treatment, which is associated with significant morbidity, a biopsy of the temporal artery is strongly advised to definitively secure the diagnosis. The rate of positive biopsies varies among different series, ranging from 60% to 95% of clinical cases of GCA,31, 44, 212-217 with rates greater than 90% in several seriesY, 45, 212-217 Negative biopsies cannot exclude the diagnosis of GCA, because skip areas, areas in between segments of arteritic lesions that show little or no sign of inflammation, may have been obtained at biopsy.121 Falsenegative biopsies can be decreased by obtaining longer biopsy specimens (2 to 3 cm), and by careful serial sectioning. 88, 94, 121 If the biopsy is negative but there is a strong clinical suspicion, biopsy of the contralateral temporal artery should be performed. 88 Immunofluorescence microscopy studies were compared to light microscopy, and the former was not found to be more sensitive. 218 The treatment with corticosteroids should not be delayed pending the results of temporal artery biopsy, although the biopsy should be. performed within 1 week after the beginning of the treatment. Histopathologic changes may persist for months after the initiation of steroids. 45 , 219 Although some data suggested the positivity rates of biopsy were similar in corticosteroid-treated and untreated patients,212 one study showed the rate of a positive biopsy result falls from 82% in the untreated patients to 60% in patients who were treated for less than 1 week. 213 Various signs and symptoms of GCA have been studied to determine which would best predict the diagnosis. The combination of a recent-onset headache, jaw claudication, and abnormalities of the temporal arteries on physical examination was associated with a specificity of 94.8% with respect to the histologic diagnosis, and 100% with

55: GIANT CEll ARTERITIS

respect to final diagnosis. 217 Another study also indicated that a history ofjaw claudication and a palpably abnormal temporal artery were more common in cases with positive biopsies. 2l5 A more recent study identified jaw claudication, CRP above 2.45 mg!dl, neck pain, and an ESR of 47 or above as the clinical criteria most strongly suggestive of GCA.191

TREATMENT Corticosteroids should be started immediately when there is a high suspicion of GCA. The use of corticosteroids was shown by Birkhead and colleagues in 1957 to be effective in the treatment of GCA, especially in reducing the rate of blindness. 219 In this study, 16 eyes of 55 patients presented with blindness, and two additional eyes became blind following corticosteroids treatment. This outcome was compared to 53 patients who were treated prior to the introduction of steroids, of which 16 eyes were blind at presentation, and eight more eyes became blind during follow-up. Corticosteroids also significantly relieved many other systemic symptoms. The prompt symptomatic relief is so characteristic that it is used by some as a diagnostic criterion. 8, 220 There are no controlled prospective trials addressing the dosage and duration of treatment. Usually, a high initial dosage of corticosteroids, SO to 120 mg! day of prednisone, is given. It has been noted that ophthalmologists tend to use higher dosages than rheumatologists, which probably is a result of different disease characteristics encountered by different subspecialfies. 94 A lower dose of steroids, 40 mg!day of prednisolone, was used by some rheumatologists to achieve adequate control in most patients with GCA.221 A retrospective evaluation studied patients treated with three different dose regimens: 30 to 40 mg! day, 40 to 60 mg!day, and over 60 mg/day, and similar efficacies were found. However, the group treated with over 60 mg! day had fewer flare-ups during the first year. 222 In cases of acute visual loss, highdose intravenous corticosteroids are used by some to prevent the further visual loss or involvement of the felloweye. 88 Although some data suggest high-dose intravenous corticosteroids may diminish the likelihood of fellow-eye involvement,73 cases of severe visual loss in the fellow eye despite this treatment regimen were also reported. 223 It is unclear if visual improvement can be achieved with high-dose intravenous corticosteroids. Reports of visual improvement following high-dose intravenous corticosteroids have been anecdotaP1, 224, 225 and are viewed with skepticism by some. 88 Alternate-day oral corticosteroid therapy has been tried but found to be less effective. 226 There are no generalized rules regarding the rate of steroid reduction once the disease is stabilized. Usually the steroid dose is adjusted based on the clinical response and the decrease in ESR. Other tests such as CRP and color Doppler ultrasonography may also aid in assessing the disease activity. The lowest dose of steroids that achieves disease quiescence and the lowest possible ESR is used as the maintenance dose. The steroid taper should be gradual to prevent exacerbation. Relapses can occur while the patients are on steroids,40 especially when the steroid reduction is too rapid. 10, 45 Relapses usually occur

within the first year or within 3 months after withdrawal of treatment, but they can occur as late asl0 years after. 227 In a majority of cases, the dose of steroid can be decreased to below 7.5 mg! day of prednisone after 1 year of therapy. 227, 228 The duration of therapy should be individualized. A review of literature indicates that in many studies, the treatment is needed for at least 2 years,ll, 45, 229, 230 with 30% to 40% of patients in smne European studies requiring longer or even indefinite treatment. 39, 227 The duration of treatment is somewhat shorter in the American studies. 10 , 13 There are some reports indicating that the percentage of peripheral CDS + lymphocytes remained decreased after 6 months or 1 year of corticosteroid treatment, even when the disease was under control symptomatically, and ESR and CRP were significantly decreased. 175 , 231 One study showed that those patients who had a lower percentage of CDS + at 6 months of treatment required a significantly longer course of corticosteroid treatment and more relapses, suggesting CDS + percentage may be a useful monitoring parameter. 231 Azathioprine has been used in an attempt to reduce the maintenance dose of steroids in patients with PMR and GCA, and in one study it was found to have a modest effect. 232 However, another study found methotrexate to be, superior than azathioprine. 233 There are several reports indicating a steroid-sparing effect of methotrexate. 234,235 However, one controlled study of PMR and GCA, with only six GCA patients included, failed to demonstrate this. 236 There have been some anecdotal reports of cyclosporine being an effective adjuvant therapy,237 and of cases of steroid-resistant GCA that were responsive to cyclophosphamide treatment. 238 If parvovirus B19 is confirmed to be a pathogenic factor, then the treatment with intravenous immunoglobulin (IVIg) may become plausible, as IVIg is effective in controlling chronic parvovirus B19 infection in immunocompromised individuals, and in patients with systemic necrotizing vasculitis possibly related to parvovirus B19 infection. 239

PROGNOSIS

General Prognosis GCA is a systemic vasculitis that can result in serious, life-threatening complications, such as cerebral vascular accidents, aortic rupture, and myocardial infarction. Prior to the introduction of corticosteroids, in one report, three of the seven patients with GCA died. 240 With the use of corticosteroids, several large series with long-tenn follow-up indicate that life expectancy in patients with GCA is the same as that of the general population,lo, ll, 240, 241 with one study showing an even lowered Inortality rate. 227 On the other hand, a study from Sweden showed an increased mortality rate from vascular diseases during the first year, while the overall mortality rate after the first year, and over a 10-year period, was not higher than that in the general population. The increased first-year mortality rate was attributed to inadequate corticosteroid treatment. 242 Another report also considered inadequate treatment as an important contributory factor to the cause of deaths. 243 On the contrary, high maintenance

CHAPTER 55: GIANT CELL ARTERITIS

steroid dose and visual loss were associated with a shortened life span in another study.39 The· authors suggested that the steroid treatment itself contributed to the increased mortality, because the clinical features in this group of patients were not more severe. A Danish study reported a significantly higher mortality rate in GCA patients. 244 Although the maintenance corticosteroid doses used in treating this disease are relatively low, the reported side effects are nonetheless numerous. Common side effects include cushingoid appearance, weight gain, osteoporosis, compression fractures, hypertension, diabetes, peptic ulcer disease, immunosuppression and infections, ischemic necrosis of the femoral head, proximal muscle weakness, elevated intraocular pressure, and cataracts. lO , 11, 227, 245 One study showed that serious corticosteroidrelated complications are significantly more frequent in the group of patients on an average daily maintenance prednisone dose of 26.3 mg, compared with those on a daily dose of 13 mg. 245

Visual Prognosis In the earlier reports, the rate of visual loss was as high as 60%,11, 31, 40, 71, 219 with the rate of bilateral visual loss being 20%.11,71,219 With corticosteroid treatment and increased clinical awareness of the disease, the rate of visual loss in more recent studies ranges from 6% to 22%.8,30,38, 73,8'1 It has been reported that 6% to 13% of patients with visual loss lose vision while on corticosteroids treatment. 73, 84 The visual loss in GCA is uSlially permanent, although there are reports of improved vision, including with highdose intravenous corticosteroid treatment.11' 224, 225

CONCLUSION GCA is a systemic disease of the elderly that may result in profound, irreversible loss of vision. GCA is also a disease for which the treatment with corticosteroids is effective, and therefore loss of vision can be prevented by prompt diagnosis and initiation of treatment. The disease requires long-term corticosteroid treatment, which is associated with significant corticosteroid-related side effects. Alternative treatment with corticosteroidsparing agents remains to be further explored. Although there have been significant new advances in the understanding of the immunopathology of GCA, the exact etiology of the disease remains unclear. Further understanding of the immunopathogenesis of the disease in the future may result in treatment with more diseasespecific immunomodulators.

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174.

and cytochemical studies of temporal arteritis. Arthritis Rheum 1983;26:1201-1207. Gallagher P, Jones Kimmunohistochemical findings in cranial arteritis. Arthritis Rheum 1982;25:75-79. Dasgupta B, Duke 0, Kyle V: Antibodies tointermediate filaments in polymyalgia rheumatica and giant cell arteritis: A sequential study. Ann Rheum Dis 1987;46:746-749. Andersson R, Jonsson R, Tarkowski A, et al: T cell subsets and expression of immunological activation markers in the arterial walls of patients with giant cell arteritis. Ann Rheum Dis 1987;46:915-923. Cid MC, Campo E, Ercilla G, et al: Immunohistochemical analysis of lymphoid and macrophage cell subsets and their immunologic activation markers in temporal arteritis. Influence of corticosteroids treatment. Arthritis Rheum 1989;32:884-893. Martinez-Tabodada V, Brack A, Hunder GG, et al: The inflammatory infiltrate in giant cell arteritis selects against B lymphocytes. J Rheumatol 1996;23:1011-1014. Andersson R, Hansson GK, Soderstrom T, et al: HLA-DR expression in the vascular lesion and circulating T lymphocytes of patients with giant cell arteritis. Clin Exp Immunol 1988;73:82-87. Schaufelberger C, Stemme S, Andersson R, et al: T lymphocytes in giant cell arteritic lesions are polyclonal cells expressing alpha beta type antigen receptors and VLA-1 integrin receptors. Clin Exp Immunol 1993;91:421-428. Weyand CM, Schonberger J, Oppitz U, et al: Distinct vascular lesions in giant cell arteritis share identical T cell clonotypes. J Exp Med 1994;179:951-960. Martinez-Taboada VM, Hunder NN, Hunder GG, et al: Recognition of tissue residing antigen by T cells in vasculitic lesions of giant cell arteritis. J Mol Med 1996;74:695-703. Brack A, Geisler A, Martinez-Taboada VM, et al: Giant cell arteritis is a T cell-dependent disease. Mol Med 1997;3:530-543. Weyand CM, Hicok KC, Hunder GG, et al: Tissue cytokine patterns in patients with polymyalgia rheumatica and giant cell arteritis. Ann Intern Med 1994;121:484-491. Weyand CM, Tetzlaff N, Bjornsson J, et al: 'bisease patterns and tissue cytokine profiles in giant cell arteritis. Arthritis Rheum 1997;40: 19-26. Dasgupta B, Panayi GS: Interleukin-6 in serum of patients with polymyalgia rheumatica and giant cell arteritis. Br J Rheumatol 1990;29:456-458. Roche NE, Fulbright]W, Wagner AD, et al: Correlation ofinterleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum 1993;36:1286-1294. Field M, Cook A, Gallagher G: Immuno-localisation of tumour necrosis factor and its receptors in temporal arteritis. Rheumatol Int 1997;17:113-118. Kaiser M, Weyand CM, Bjornsson J, et al: Platelet-derived growth factOl~ intimal hyperplasia, and ischemic complications in giant cell arteritis. Arthritis Rheum 1998;41:623-633. Salvarani C, Boiardi L, Macchioni P, et al: Role of peripheral CD8 + lymphocytes and soluble IL-2 receptors in predicting the duration of corticosteroids treatment in polymyalgia rheumatica and giant cell arteritis. Ann Rheum Dis 1995;54:640-644. Roblot P, Morel F, Lelievre E, et al: Serum soluble CD23 levels in giant cell arteritis. Immunol Lett 1996;53:41-44. Brack A, Rittner HL, Younge BR, et al: Glucocorticoids-mediated repression of cytokine gene transcription in human arteritis-SCID chimeras. J Clin Invest 1997;99:2842-2850. Nikkari ST, Hoyhtya M, Isola J, et al: Macrophages contain 92-kd gelatinase (MMP-9) at the site of degenerated internal elastic lamina in temporal arteritis. AmJ Pathol 1996;159:1537-1533. Tomita T, Imakawa K Matrix metalloproteinases and tissue inhibitors of metalloproteinases in giant cell arteritis: An immunocytochemical study. Pathology 1998;30:40-50. Sorbi D, French DL, Nuovo GJ, et al: Elevated levels of 92-kd type IV collagenase (matrix metalloproteinase 9) in giant cell arteritis. Arthritis Rheum 1996;39:1747-1753. Nordborg E, Nordborg C: The inflammatory reaction in giant cell arteritis: An immunohistochemical investigation. Clin Exp Rheumatol 1998;16:165-168. Weyand CM, Wagner AD, Bjornsson J, et al: Correlation of the topographical arrangement and the functional pattern of tissueinfiltrating macrophages in giant cell arteritis. J Clin Invest 1996;98:1642-1649.

175. Dasgupta B, Duke 0, Timms AM, et al: Selective depletion and activation of CD8 + lymphocytes from peripheral blood of patients with polymyalgia rheumatica and giant cell arteritis. Ann Rheum Dis 1989;48:307-311. 176. Benlahrache C, Segond P, Auquier L, et al: Decrease of the OKT8 positive T cell subset in polymyalgia rheumatica. Lack of correlation with disease activity. Arthritis Rheum 1983;26:1472-1480. 177. Elling H, Elling P: Decreased level of suppressor/cytotoxic T cells (OKT8 +) in polymyalgia rheumatica and temporal arteritis: relation to disease activity. J Rheumatol 1985;12:306-309. 178. Johansen M, Elling P, Elling H: A genetic approach to the aetiology of giant cell arteritis: Depletion of the CD8 + T-lymphocyte subset in relatives of patients with polymyalgia rheumatica and arteritis temporalis. Clin Exp Rheumatol 1995;13:745-748. 179. Martinez-Taboada VM, Goronzy JJ, Weyand CM: Clonally expanded CD8 + T cells in patients with polymyalgia rheumatica and giant cell arteritis. Clin Immunol Immunopathol1996;79:263-270. 180. Hunder GG, Bloch DA, Michel BA, et al: The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33:1122-1128. 181. Goodman BW: Temporal arteritis. Am J Med 1979;67:839-852. 182. Wong RL, KornJH: Temporal arteritis without an elevated erythrocyte sedimentation rate. AmJ Med 1986;80:959-964. 183. Ellis ME, Ralston S: ESR in the diagnosis and management of polymyalgia rheumatica/giant cell arteritis syndrome. Ann Rheum Dis 1983;42:169-170. 184. Al1.dersson R, Malmvall BE, Bengtsson BA: Acute phase reactants in the initial phase of giant cell arteritis. Acta Med Scand 1986;220:365-367. 185. Kyle V, Cawston TE, Hazleman BL: Erythrocyte sedimentation rate and C reactive protein in the assessment of polymyalgia rheumatica/giant cell arteritis on presentation and during follow up. Ann Rheum Dis 1989;48:667-671. 186. Jacobson DM, Slamovits TL: Erythrocyte sedimentation rate and its relationship to hematocrit in giant cell arteritis. Arch Ophthalmol 1987;105:965-967. 187. Eshaghian J, Goeken JA: C-reactive protein in giant cell (cranial, temporal) arteritis. Ophthalmology 1980;87:1160-1166. 188. Pountain GD, Calvin J, Hazleman BL: Alpha 1-antichymot:rypsin, C-reactive protein and erythrocyte sedimentation rate in polymyalgia rheumatica and giant cell arteritis. Br J Rheumatol 1994;33:550-554. 189. Gudmundsson M, Nordborg E, Bengtsson BA, et al: Plasma viscosity in giant cell arteritis as a predictor of disease activity. Arm Rheum Dis 1993;52:104-109. 190. Park JR, Jones JG, Hazleman BL: Relationship of the erythrocyte sedimentation rate to acute phase proteins in polymyalgia rheumatica and giant cell arteritis. Ann Rheum Dis 1981;40:493-495. 191. Hayreh SS, Podhajsky PA, Raman R, et al: Giant cell arteritis: Validity and reliability of various diagnostic criteria. Anl J Ophthalmol 1997;123:285-296. 192. Brittain GPH, McIlwaine GG, Bell JA, et al: Plasma viscosity or erythrocyte sedimentation rate in the diagnosis of giant cell arteritis? Br J Ophthalmol 1991;75:656-659. 193. Weiss LM,' Gonzales E, Miller SB, et al: Severe anemia as the presenting manifestation of giant cell artelitis. Arthlitis Rheum 1995;38:434-436. 194. Healy LA, Wilske KR: Presentation of occult giant cell artelitis. Arthritis Rheum 1980;23:641-643. 195. Malmvall BE, Bengtsson BA: Giant cell arteritis. Clinical features and involvement of different organs. Scand J Rheumatol 1978;7:154-158. 196. Federici AB, Fox RI, Espinoza LR, et al: Elevation of von Willebrand factor is independent of erythrocyte sedimentation rate and persists after glucocorticoid treatment in giant cell arteritis. Arthritis Rheum 1984;27:1046-1049. 197. Cid MC, Monteagudo J, OristrellJ, et al: Von Willebrand factor in the outcome of temporal arteritis. Ann Rheum Dis 1996;55:927930. 198. Espinoza LR, Jara LJ, Silveira LH: Anticardiolipin antibodies in polymyalgia rheumatica-giant cell arteritis: Associated with severe vascular complications. AmJ Med 1991;90:474-478. 199. McLean RM, Greco TP: Anticardiolipin antibodies in the polymyalgia rheumatica-giant cell arteritis syndromes. Clin Rheumatol 1995;14:191-196.

CHAPTER 55: GiANT CELL ARTERiTIS 200. Chakravarty K, Pountain G, Merry P,et al: A longitudinal study of anticardiolipin antibodies in polymyalgia rheumatica and giant cell arteritis. J Rheumatol 1995;22:1694-1697. 201. Duhart P, Berruyer M, Pinede L, et al: Anticardiolipin antibodies and giant cell arteritis: A prospective, multicenter case-control study. Arthritis Rheum 1998;41:701-709. 202. Kyle V, Wraight EP, Hazleman BL: Liver scan abnormalities in polymyalgia/giant cell arteritis. Clin Rheumatol 1991;10:294-297. 203. Kyle V: Laboratory investigations including liver in polymyalgia rheumatica/giant cell arteritis. Baillieres Clin Rheumatol 1991;5:475-484. 204. Ogilvie AL,James PD, Toghill PJ: Hepatic involvement in polymyalgia arteritica. J Clin Pathol 1981;34:769-772. 205. Litwack KD, Bohan A, Silverman L: Granulomatous liver disease and giant cell arteritis. Case report and literature review. J Rheumatol 1977;4:307-312. 206. Leong AS-Y, Alp MH: Hepatocellular disease in giant cell arteritis/ polymyalgia rheumatica syn.drome. Ann Rheum Dis 1981;40:92-95. 207. MaCormack LR, Astarita RW, FOl'oozan P: Liver involvement in giant cell arteritis. Digest Dis 1978;23:728-745. 208. Schmidt WA, Draft HE, Vorpahl K, et al: Color duplex ultrasonography in the diagnosis of temporal arteritis. N Engl J Med 1997;337:1336-1342. 209. Lauwerys BR, Puttemans T, Houssiau FA, et al: Color Doppler sonography of the temporal arteries in giant cell arteritis and polymyalgia rheumatica. J Rheumatol 1997;24:1570-1574. 210. Ghanchi FD, Williamson TH, Lim CS, et al: Colour Doppler imaging in giant cell (temporal) arteritis: Serial examination and comparison with non-arteritic anterior ischaemic optic neuropathy. Eye 1996;10:459-464. 211. Ho AC, Sergott RC, Regillo CD, et al: Color Doppler hemodyn.amics of giant cell arteritis. Arch Ophthalmol 1994;112:938-945. 212. Achkar AA, Lie JT, Hunder GG, et al: How does previous corticosteroids treatment affect the biopsy findings in giant cell arteritis? Ann Intern Med 1994;120:987-992. 213. Allison MC, Gallagher PJ: Temporal artery biopsy and corticosteroids treatment. Ann Rheum Dis '~984;43:416-417. 214. Allsop q, Gallagher PJ: Temporal artery biopsy in giant cell arteritis. A reappraisal. Am J Surg Pathol 1981;5:317-313. 215. Hall S, Persellin S, Lie JT, et al: The therapeutic impact of temporal artery biopsy. Lancet 1983;2:1217-1220. 216. Hedges TR, Gieger GL, Albert DM: The clinical value of negative temporal artery biopsy specimens. Arch Ophthalmol 1983; 101: 1251-1254. 217. VilasecaJ, Gonzalez A, Cid MC, et al: Clinical usefulness of temporal artery biopsy. Ann Rheum Dis 1987;46:282-285. 218. Cohen DN: Temporal arteritis: Improvement in visual prognosis and management with repeat biopsies. Trans Am Acad Ophthalmol Otolaryngol 1973;77:74-85. 219. Birkhead NC, Wagener HP: Treatment of temporal arteritis with adrenal corticosteroids: Results in fifty-five cases in which lesion was proved at biopsy. JAMA 1957;163:821-827. 220. Jones JG, Hazleman BL: Prognosis and management of polymyalgia rheumatica. Ann Rheum Dis 1981;40:1-5. 221. Kyle V, Hazleman BL: Treatment of polymyalgia rheumatica and giant cell arteritis. I. Steroid regimens in the first two months. Ann Rheum Dis 1989;48:548-551. 222. Nesher G, Rubinow A, Sonnenblick M: Efficacy and adverse effects of different corticosteroid dose regimens in temporal arteritis: A retrospective study. Clin Exp Rheumatol 1997;15:303-306. 223. Cornblath WT, Eggenberger ER: Progressive visual loss from giant cell arteritis despite high-dose intravenous methylprednisolone. Ophthalmology 1997;104:854-858.

224. Rosenfeld SI, Kosmorsky GS, Klingele TG: Treatment of temporal arteritis with ocular involvement. Am J Med 1986;80: 143~145. 225. DiamonJP: Treatable blindness in temporal arteritis. BrJ Ophthalmol 1991;75:432. 226. Hunder GG, Sheps SG, Allen GL, et al: Daily and alternate-day corticosteroid regimens in treatment of giant cell arteritis: Comparison in a prospective study. Ann Intern Med 1975;82:613-618. 227. Bengtsson BA, Malmvall BE: Prognosis of giant cell arteritis including temporal arteritis and polymyalgia rheumatica. Acta Med Scand 1981;209:337-345. 228. Kyle V, Hazleman BL: The clinical and laboratory course of polymyalgia rheumatica/giant cell arteritis. Br J Rheumatol 1988;27 (suppl) :7. 229. Bahlas S, Ramos-Remus C, Davis P: Clinical outcome of 149 patients with polymyalgia rheumatica and giant cell arteritis. J Rheumatol 1998;25:99-104. 230. Fernandez-Herlihy L: Duration of corticosteroid therapy in giant cell arteritis. J Rheumatol 1980;7:361-364. 231. Salvarani C, Boiardi L, Macchioni P, et al: .Role of peripheral CD8 + lymphocytes and soluble IL-2 receptor in predicting the duration of corticosteroid treatment in polymyalgia rheumatica and giant cell arteritis. Ann Rheum Dis 1995;54:640-644. 232. De Silva M, Hazleman BL: Azathioprine in giant cell arteritis/ polymyalgia rheumatica: A double-blind study. Ann Rheum Dis 1986;45:136-138. 233. Settas L, Dimitriadis G, Sfetsios T, et al: Methotrexate versus azathioprine in polymyalgia rheumatica-giant cell arteritis: A double blind, cross over trial. Arthritis Rheum 1991;34(suppl):S72. 234. Hernandez C, Fernandez B, Ramos P, et al: Giant cell arteritis therapy: MTX as steroid-sparing agent. Arthritis Rheum 1991;34(suppl) :S73. 235. Krall PL, Mazanec DJ, Wilke WS: Methotrexate for corticosteroidresistant polymyalgia rheumatica and giant cell arteritis. Cleve Clin J Med 1989;56:253-257. 236. van del' Veen MJ, Dinant HJ, van Booma-Frankfort C, et al: Can methotrexate be used as a steroid sparing agent in the treatment of polymyalgia rheumatica and giant cell arteritis? Ann Rheum Dis 1996;55:218-223. 237. Wendling D, Hory B, Blanc D: Cyclosporine: A .new adjuvant therapy for giant cell arteritis? Ann Rheum Dis 1985;28:1078-1079. 238. Utsinger PD: Treatment of steroid non-responsive giant cell arteritis (GCA) with cytoxan. Arthitis Rheum 1982;25(suppl):S31. 239. Cooke WT, Cloake PCP, Govan ADT, et al: Temporal arteritis: A generalized vascular disease. QJ Med 1946;15:47. 240. Matteson EL, Gold KN, Bloch DA, et al: Long-term survival of patients with giant cell arteritis in the American College of Rheumatology giant cell arteritis classification criteria cohort. An1J Med 1996;100:193-196. 241. Gonzalez-Gay MA, Blanco R, Abraira V: Giant cell arteritis inLugo, Spain, is associated with low longterm mortality. J Rheumatol 1997;24:2171-2176. 242. Nordborg E, Bengtsson BA: Death rates and causes of death in 284 consecutive patients with giant cell arteritis confirmed by biopsy. Br Med J 1989;299:549-550. 243. Soderbergh J, Malmvall BE, Andersson R, et al: Giant cell arteritis as a cause of death. Report of nine cases. JAlVIA 1986;255:493-496. 244. Bisgard C, Sloth H, Keiding N, et al: Excess mortality in giant cell arteritis. J Intern Med 1991;230:119-123. 245. Rubinow A, Brandt KD, Cohen AS, et al: Iatrogenic morbidity accompanying suppression temporal arteritis by adrenal corticosteroids. Ann Ophthalmol 1984;16:258-265. 246. Schneider HA, Weber AA,Ballen PH: The visual prognosis in temporal arteritis. Ann Ophthalmol 1971;3:1215-1228.

Panayotis Zafirakis and C. Stephen Foster

NITION Adamantiades-Beh<;:et disease (ABD) is a chronic, relapsing inflammatory disorder of unknown etiology, historically characterized by the triad of recurrent oral and genital aphthous ulcers, ocular inflammation, and skin lesions such as erythema nodosum and acneiform eruptions. ABD frequently involves the joints, the central nervous system (CNS), and the gastrointestinal tract as well. Furthermore, ABD may be the best example of a disease characterized mainly by retinal vasculitis associated with devastating effects on the patient's visual outcome. There is not a universally accepted diagnostic test for this disorder. Thus, the diagnosis of ABD relies on the identification of several sets, or combinations, 'of its more typical clinical features.

ISTORY The first description of the symptoms of the disease was probably reported by Hippocrates, 5th century Be, in his third book of epidemiology1: There were other forms of fever.... Many developed aphthae, ulcerations. Many ulcerations about the genital parts ... watery ophthalrriies of a chronic character, with painJ'; fungus excretions of the eyelids externally, internally whiCh destroyed the sight of many persons. . . . There were fungous growth on ulcers, and on those localized on the genital organs. Many anthraxes through the summer ... other great affections; many large herpetes.

Since that time, isolated symptoms of the ABD were described during the 19th century, and concomitant symptoms were reported in 1895 and 1906. 2 Isolated symptoms were recognized by Bliithe,3 Planner,4 and Shigeta. 5 In 1930, Benedictos Adamantiades,6 a Greek ophthalmologist, presented at the Medical Society of Athens the case of a 20-year-old man who suffered from recurrent iritis with hypopyon resulting in blindness, associated with phlebitis, mouth ulcers, genital ulcers, and knee arthritis. Synovial fluid from the knee was tested and found to be sterile and transparent. Based on these observations, Adamantiades concluded that "recurrent iritis with hypopyon constitutes a discrete clinical entity."6 One year later, in 1931, he published this case in the Annales d'Oculistique. 7 In 1932, Dascalopoulos, another Greek ophthalmologist, reported a new case with the same symptoms in the Annales d'Oculistique journaLS Six years later in 1937, H. Beh<;:et, a Turkish professor in dermatology, described three patients with this -constellation of findings of oral and genital ulcers and recurrent iritis; the disease is known by his name primarily because of the wider distribution of his paper in the medical literature. 9- 11 Goddejolly,12 Bietti-Bruna,13 and others long ago suggested that the disease should probably more appropriately be called Adamantiades-Beh<;:et disease, to better reflect the important contributions both these physicians

made, and this chapter adopts that attitude and philosophy. Despite the fact that Adamantiades's first patient did suffer from phlebitis with leg ulcer, it was only in 1946 that he described what he named the fourth symptom, "thrombophlebitis" of retinal vessels, the limbs, or both. 14 Later, additional signs were described worldwide regarding other body organs.

EPIDEMIOLOGY Geographic and Ethnic Distribution ABD has a worldwide distribution but is most common in the countries of the Eastern Mediterranean and in the Eastern rim of Asia. The disease is predominately reported between the 30° and 45° north latitudes in Asian and European populations, which corresponds to the old Silk Route used by traders from the East to Europe. 15 The exact incidence, prevalence, and family occurrence of the dis~ase are unknown, but the prevalence of ABD appears to have increased during the last 40 years, the highest prevalence being 80 to 300 cases per 100,000 population in Turkey.16, 17 The prevalence of ABD14 was 8 to 10 cases per 100,000 population in Japan in the late 1970s. 18 It is postulated that there are approximately 15,000 patients in Japan with ABD, 11,000 of them being treated currently.15 ABD was diagnosed in more than 20% of the patients with uveitis examined in the uveitis clinic of the University of Tokyo's Department of Ophthalmology between 1965 and 1977. 18 The annual incidence of ABD in Iran is approximately 345 patients in a population of 60 million,19 and the prevalence is 16 to 100 cases in 100,000. 20 The prevalence of ABD in Greece is 6 cases per 100,000 population. 21 The prevalence of the disease in Germany (West Berlin) was 1.6 cases in 100,000 in 1989, and this has risen to 2.26 cases in 100,000 in 1994. 22 In the United States, the prevalence is 4 patients per 1 million population,23 with ABD representing 0.2 to 0.4 percent of uveitis cases in this country.24 The increased prevalence may be related to a better awareness of the illness, and in some countries to migration (Table 56-1).

Sex Many reports, mainly from the Mediterranean basin and the Far East, have shown a preponderance of males to females. 24-27 More recent evidence, however, suggests a more even distribution of the disease between the sexes. In the series of Colvard and colleagues,28 only 13 of the 32 patients were male. In 1971, in a series of 10 patients from North America, only 3 were male. 29 Sakamoto and colleagues 30 reported a 2:1 male-to-female ratio in Japan. Other data have shown that men predominate in Lebanon (11:1), Greece (7.9:1), Egypt (5.3:1), Israel (3.8:1), Turkey (3.4:1) and Iran (1.2:1), whereas women predominate in Germany (1:0.9), Brazil (1:0.7), and the United States (1:0.2). Although

IAI)E~)-BEHCET

TABLE 56-I. PREVALENCE OF ADAMANTIADESDISEASE PER 100,000 INHABITANTS COUNTRY

Turkey Japan Iran Germany USA

DISEASE

TABLE 56-2. DIAGNOSTIC SYSTEM OF ADAMANTIADES-BEHC;ET DISEASE SUGGESTED BY BEH<;ET'S RESEARCH COMMITTEE OF JAPAN

PREVALENCE

80-300 8-10 16...,.100 2.26 0.4

male-to-female ratios may reflect a change in the· nature of the disease, it is more likely that in previous years, women in many countries were embarrassed to visit a physician with complains related to the cluster of signs and symptoms that make up ABD. The complete type of ABD (see the later section on clinical features) is more frequent in males; the incomplete type has equal frequency in both sexes. Although the disease is believed to have a worse overall prognosis in males than in females 31 in the Mediterranean basin and in the Middle and Far East, no such difference has been noted in Western European and American studies.

Age The age of onset of the first symptom varies in many studies. Most authors consider the onset of the disease to be the age at which the patient fulfilled the diagnostic criteria of the disease. The mean age of onset is 25 to 35 years worldwide, with a range ~f 2 months to 72 years. In Germany the mean age of onset is estimated to be approximately 25 for men and 24.5 for women. 32

Heredity and Sexual Transmission ABD sometimes affects· more than one member In the same family. Although several familial cases33-35 and a pair of monozygotic brothers36 concordant for the disease have been reported, no consistent inheritance pattern has been confirmed. 37, 38 Furthermore, no transmission of the disease from husband to wife or vice versa has been reported.

CLINICAL Diagnostic Criteria and Clinical Types the Disease The diagnosis of ABD is based on the presence of a set of clinical findings, and diagnostic criteria were first suggested in 1969. 39 There followed suggested criteria, published by the Research Committee of japan and by O'Duffy,41 Zhang,42 Dilsen and colleagues,43 james,44 and lately the International Study Group.45 One diagnostic system has been suggested by the Beh~et' s Research Committee ofjapan (Table 56-2).40 In this diagnostic system there are four major and five minor criteria. The major criteria include recurrent aphthous ulcers of oral mucosal, skin lesions (similar to those of erythema nodosum or acne, and a pathergy test), genital ulcers, and ocular inflammatory disease. The minor criteria include arthritis, intestinal ulcer, epididymitis, vascular disease, and neuropsychiatric symptoms. Combinations of these criteria lead to four types of ABD: (1) the complete type (four major symptoms simultaneously or at different

Major criteria Recurrent oral aphthae Skin lesion Recurrent genital ulcers Inflammation of the eye Minor criteria Arthritis Ulceration of the bowel Epididymitis Vasculitis/vasculopathy Neuropsychiatric symptoms Types of ABD Complete (4 major) Incomplete (3 major, or ocular involvement with 1 other major) Suspect (2 major, no eye involvement) Possible (1 major) Modified from Newman NM, Hoyt WF, Spencer WH: Macula-sparing monocular blackouts: Clinical and pathologic investigation of intermittent choroidal vascular insufficiency in a case of periarteritis nodosa. Arch Ophthalmol 1974;91:367370.

times); (2) the incomplete type (three major symptoms simultaneously or at different times, or typical recurrent ocular disease with one other major criterion); (3) the suspect type (two rmajor symptoms excluding ocular); and (4) the possible type (one main symptom). The committee also identified several special clinical types of ABD, depending on the predominant manifestation; namely, neuro-Beh~et, oculo-Beh~et, intestinal-Beh~et or vasculo-Beh~et. Three laboratory tests have also been included in this system: a pathergy (skin-prick) test, human leukocyte antigen (HLA) testing for HLA-B51, and a screening of nonspecific factors indicative of immune system activation (elevated erythrocyte sedimentation rate, positive C-reactive protein, and an increase in peripheral blood leukocytes). The same diagnostic system has been advocated by Nussenblatt and colleagues46 The diagnostic system that has been suggested by the International Study Group for Beh~et's Disease 45 requires the presence of oral ulceration in all patients plus any two of the following: genital ulceration, typically defined eye lesion, typically defined skin lesion, or a positive pathergy test (Table 56-3). Thus, the International Study Group for Beh~et's Disease stresses the importance of oral aphthae in the diagnosis of ABD, whereas the Beh~et's Research Committee classification stresses the importance of ocular symptomatology.

TABLE 56-3. DIAGNOSTIC SYSTEM OF ADAMANTIADES-BEH<;ET DISEASE SUGGESTED BY THE INTERNATIONAL STUDY GROUP FOR BEH<;ET'S DISEASE Recurrent oral aphthae (at least 3 times per year), plus 2 of the following: Recurrent genital ulcers Skin involvement Ocular inflammation Positive pathergy test Modified from Gold DH: Ocular manifestations of connective tissue (collagen) diseases. In: Tasman W, Jaeger AE, eds: DUaIle's Clinical Ophthalmology, vol 5. Philadelphia,].B. Lippincott, 1989, pp 17-19.

CHAPTER 56:

IAIJE!i·BEtiICE:T DISEASE

The International Study Group for Beh~et's Disease suggested that there are· several clinical findings that may be important and may aid in the diagnosis of ABD, but as their frequency is low, they are not included in their criteria. The reason was to simplify the list, thus reducing the chance of subjective error. Undoubtedly, all the diagnostic systems have some degree of uncertainty, as any of the criteria may be manifested at different times during the clinical course of the disease.

Nonocular Manifestations Oral Aphthae Oral aphtha is the most frequent finding in ABD (Fig. 56-1). These ulcers produce a significant amount of discOlnfort and are recurrent. Although the number of individuals with oral aphthae in the general population is quite high, the lesions in ABD may occur in clusters and may be located anywhere in the oral. cavity: the lips, gums, palate, tongue, uvula, and posterior pharynx. They can be slnall and very painful. The characteristic oral lesions are discrete, round or oval, white ulcerations 3 to 15 mm in diameter with a red rim. They may recur every 5 to 10 days, or every month, or even years apart without following any rule. They usually last for approximately 7. to 10 days and may heal without scarring, although they may produce scarring when they are numerous and large. The aphthae of ABD should be differentiated from those seen in Stevensjohnson and Reiter's syndromes,47 in which they are painless, with irreguHfr rims or heapedup edges and they usually occur on the palate, pharynx, and tonsils, structures rarely involved in ABD. Oral aphthae can also be found in some individuals after eating certain type of foods, or they may be provoked by trauma to the oral mucosa.

Skin Lesions Cutaneous involvement is frequent in ABD. Painful, recurrent lesions of erythema nodosum may appear in groups not only over the tibia, which is the most frequent location, but also on the face, neck, buttocks, and elsewhere (Fig. 56-2). The lesion usually disappears, without

FIGURE 56-2. Erythema nodosum-like lesions on anterior tibial surface. (See color insert.)

any scarring, after several weeks, but they may indeed leave scars. It is not uncommon to find hyperpigmented or hypopigmented scars in the wake of erythema nodosum in ABD. This may be a helpful physical sign. Superficial thrombophlebitis can occur in the upper or lower extremities. It can be migratory or it may occur after an il~ection or the drawing of a blood sample. This phenomenon should be·' evaluated carefully, because it may denote a more systemic vascular disorder. Skin eruptions resembling acne vulgaris or folliculitis frequently appear on the upper thorax and face. Approximately 40% of patients with ABD exhibit a cutaneous phenomenon termed pathergy, in which sterile pustules develop at sites of spontaneous or induced trauma (venipuncture, injection of sterile saline).48 This phenomenon is not pathognomonic of ABD, although some investigators believe that it is an important criterion that can be used for the diagnosis. '15 Dermatographia, another dermatologic phenomenon of cutaneous hypersensitivity, can also be found in one third to one half of the patients.

Genital Ulcers The gross appearance of the genital ulcers is similar to that of the oral aphthous ulcers. In male patients they can occur on the scrotum (Fig. 56-3) or penis (Fig. 56-4). In female patients they can appear on the vulva and vaginal mucosa. 49 Such ulcers can also be found on the perianal areas. They may be painless in women. Sometimes, however, they are very painful, leading initially to misdiagnose them as herpetic in origin. Vulvar lesions frequently occur premenstrually.46 Genital lesions can be deep, scarring as they heal. Therefore, examination of the genital area in a patient suspected as having ABD can be helpful, since signs of healed lesions may be present.

Vascular Disorders, Cardiac Involvement

FIGURE 56-I. Aphthous oral ulcer on the inner surface of the inferior lip. (See color insert.)

Although vasculitis as the presenting symptom of ABD is rare, vessels of any size can be affected. Mi'tftCloglou and colleagues50 observed vascular involvement in 24% of the 531 patients with ABD in whom the deep and the superficial thrombophlebites of the leg were the rnost frequent vascular alterations. In other series of patients, thrombo-

CHAPTER 56:

IAI:JE~imBEHICE:T

DISEASE

nary arteritis, and pericarditis. 69 The incidence of heart lesions usually ranges from 5% to 10% of ABD cases. 66 However, in the Japanese autopsy registry, the frequency of heart manifestations was found to be 17%.65

Neurologic Involvement, Psychiatric Disturbances

FIGURE 56-3. ABD lesion on the scrotum.

phlebitis occurred in 10%.43 During the disease course, the frequency ranges from 8%51 to 38%.43 Four types of vascular lesions are recognized: arterial occlusion, aneurysms, venous occlusion, and varices. Vasculitis occurring simultaneously in multiple vessels has been reported. 52 ,53 Not only have both deep and superficial venous thrombosis been reported but also varicose veins, arterial obstruction, aneurysms, and Budd-Chiari syndrome. 54 The frequency of deep arteriovenous thrombosis was found to be 10% in 'a study from India. 5.5 Obstructive vasculitis of veins and arteries have also been documented. 56-59 Aneurysms are not uncommon, and they have a worse prognosis than that of occlusive lesions, with a death rate estimated to reach 60%,60 because aneurysmal rupture leads to severe hemorrhage. 59 Although 14% of ABD patients were documented to have venous manifestations, only 2% had arterial manifestations in one large series. 61 Both arterial and venous involvement have been found in nearly all body vessels. 61 Cardiac involvement includes granulomatous endocarditis,62 recurrent ventricular arrhythmias,63 myocarditis,64 endomyocardial fibrosis,65, 66 myocardial infarction,67 silent myocardial ischemia,68 valvular regurgitation, coro-

FIGURE 56-4. ABD lesion on the penis. (See color insert.)

Nervous system involvement (often termed neuro-ABD) is one of the most serious manifestations of ABD. Although any part of the neuraxis can be involved and CNS involvement is quite well recognized, there is no clear evidence that the associated peripheral nervous system symptoms or signs are a direct result of the ABD process. Therefore, they should be cautiously incorporated into ABD. The nervous system involvement either is caused by primary neural parenchymal lesions (neuro-ABD) or is secondary to major vascular involvement (vasculo-ABD). The reported frequency of CNS involvement in cases of ABD ranges from 3% to 10%,27 and computed tomography (CT) findings have been correlated with clinical variables. 70 The onset of the neurologic picture generally appears 4 to 6 years after the onset of ABD. However, some patients develop neuro-ABD simultaneously with or prior to the full-blown picture of ABD, and this may cause confusion in the diagnosis. Approximately 10% of patients with neuro-ABD show ocular involvement, whereas up to 30% of patients with ocular-ABD have neuro-ABD. However, in a recent study frOlTIJapan,71 only 6.6% of 317 patients with ocular-ABD developed CNS symptoms. In the same study, the incidence of neuroABD in patients who did not take cyclosporine-A (Cs-A) was only 3.3% (9 of 270), but 12 (25.5%) of the 47 patients who were on Cs-A developed neurologic manifestation. The authors concluded that Cs-A may exhibit neurotoxicity in patients with ABD or may accelerate the development of neuro-ABD. The following neuro-ophthalmic changes have been noted in ABD72: (1) palsies (usually transient) of cranial nerves VI and VII; (2) central scotomas caused by papillitis and visual field defects73; and (3) papilledema74 resulting from pseudotumor cerebri caused by thrombosis of the intradural venous sinuses. 75 Neuro-ABD is mainly a disease of the motor compartment of theCNS, frequently accompanied by mental changes. CNS involvement may be acute, with clinical signs suggestive of meningoencephalitis, which may resolve spontaneously.76 Headaches usually are related to widespread vasculitis, which induces brain lesions. 77 The main signs of CNS involvement are pyraniidal brain stem lesions and seizure. The clinical course of CNS involvement is relapsing, with recurrences to be the rule, in 40% of cases, whereas 30% have a secondary progressive course and 16% a primary progressive course. 78 Although the prognosis in older series was poor,79 with death occurring in 10% of cases,78 today the outcome generally is good because of early diagnosis and aggressive treatment with immunosuppressive or immunomodulating drugs. 8o Men are affected more often than women. 78 Sphincter disturbances, pseudobulbar syndrome, intracranial hypertension, and deep sensory abnormalities may be seen, and a few cases of aseptic meningitis have been reported. 78 Psychiatric manifestations include confusion,

CHAPTER 56:

DISEASE

llallucinations, and agitation. Audiovestibular involvement may be seen in patients with ABD and may induce mdden deafness. 81 CT, magnetic resonance imaging (MRI) , single-photon emission computed tomography, brain angiography, and analysis of cerebrospinal fluid (CSF) offer assistance in the diagnosis of CNS involvement in ABD. However, MRI is more sensitive than CT in detecting abnormalities in neuro-ABD.77 The lesions shown by MRI or CT usually show contrast enhancement in the acute period, which usually resolves in the passage of time. 70 , 77 CSF usually has a high protein content and/or pleocytosis with lymphocyte predominance. 78 ,82

Genitourinary Involvement The reported incidence of epididymitis in patients with ABD ranges from 4%83 to 11 %.19 Recurrent episodes of pain and swelling of the area are the cardinal signs of epididymal involvement. Kidney involvement includes acute 'glomerulonephritis,69 IgA nephropathy,84 and amyloidosis. 85 Acute glomerulonephritis has been found in 11 % of ABD cases,19 and amyloidosis has been described in 2% of patients with ABD.85 Renal vein thrombosis, diffuse crescentic, or focal and segmental necrotizing glomerulonephritis have also been reported. 84

been reported in 13% in the series of Kaklamani and colleagues,9'1 in 9% in the series of Gharibdoost and colleagues,95 and in 14% in the series from Germany.32 Peripheral arthritis may be monoarticular, oligoarticular, or polyarticular. It mainly affects the joints of the lower extremities, it recurs occasionally, and it rarely is chronic. The arthritis is usually nonmigrating and nondestructive and may be symmetrical (86%)55 or asymmetrical. 96 However, in rare cases, loss of cartilage and pannus fonnation with erosive damage have been found. 39, 51, 97 Ankylosing spondylitis has been reported in 10%98 and sacroiliitis in 34%99 of ABD cases. Other investigators have found a lower frequency of sacroiliitis. 39 This discrepancy may be attributed to more frequent use of CT today. Joint lesions can be found more often with CT scans than with plain radiographs. 99 Based on these observations, it had been suggested that ABD should be added in the seronegative arthritis group.100

Ocular Manifestations

The onset of ocular involvement, frequently termed ocular-ABD, has extremely serious implications. Recurrences are common and the recurrent attacks of ocular inflammation lead to severe, permanent ocular damage unless effective treatment is instituted. Each attack damages the eye; The involvement of the eye occurs in 43%55 to 72%,83 . and loss of sight occurs in 25% of ABD patients. 101 The Gastrointestinal Involvement reported frequency of ocular involvement in cases of ABD Gastrointestinal lesions include single or multiple ulcers is 83% to 95% in men and 67% to 73% in women. 102 The of the esophagus, stomach, or intestine. ,;;rhe reported disease is more severe in men,22 and bilateral disease frequency varies in different countries, with a low fre- occurs in 80% of patients. Eye involvement as the first quency in Turkey86 and a high frequency in Japan (50%- presenting manifestation of ABD is uncommon, ranging 60% of ABD cases) .51 These patients usually complain of from 10%85 to 13%.95 The time from the onset of buccal diarrhea and hemorrhagesY Intestinal perforation can and genital lesions to ocular involvement is estimated to also be seen. 51 In a large series of ABD patients, digestive be between 3 and 4 years. 103 The initial ocular manifestalesions were found in 16%, whereas ulcerative colitis was tions may be unilateral, but progression to bilateral noted in 1%.87 No difference in frequency of Helicobacter involvement is the rule, occurring in at least two thirds pylori was found between ABD patients and controls. 88 of the cases. 104 Nongranulomatous inflammation with necrotizing Pulmonary Involvement obliterative vasculitis may be found either in the anterior The main pathologic feature of respiratory involvement or the posterior 'segment, or, more commonly, in both. is pulmonary arteritis, which may present as a tuberculosis-like shadow. 89 However, the lungs can also be affected secondary to superior vena caval and/or other mediasti- Anterior Segment nal vascular lesions. The consequences are pulmonary em- Anterior uveitis may be the only ocular manifestation of bolisms, infarctions, or aneurysmal bronchial fistula. 9o ,91 ABD. The classic finding of iridocyclitis with hypopyon Pulmonary hypertension, pleural effusion due to biopsy (Fig. 56-5) is present in only 19% to 31 % of ABD proven vasculitis, and cor pulmonale can also be seen cases. 18,104 Mamo and Baghdassarian26 reported that hypoin patients with pulmonary involvement. 90 ,91 Recurrent pyon has become an uncommon finding in ABD. They hemoptysis, dyspnea, cough, chest pain, and fever are the attributed this apparent decline to the advent of steroid cardinal symptoms. 92 When the hemoptysis is massive, it management, which has resulted in dampening inflamInay require emergency surgery.93 CT or MRI may reveal matory responses. The inflammatory response in the anterior chamber asymptomatic aneurysmal dilatations. The prognosis of patients with aneurysms is poor. The frequency of pulmo- in ABD is nongranulomatous in nature. The patients nary involvement in some studies is estimated to be up often complain of redness, periorbital pain, photophobia, to 18%.85 and blurred vision. Tearing may occur, but ocular discharge is rare. Slit-lamp biomicroscopic examination reJoint Involvement veals conjunctival injection, ciliary flush in the perilimbal At least half of the patients. with ABD manifest arthritis area, cells and flare in the anterior chamber, and fine at some time during the clinical course of the disease, keratic precipitates. The cells can be seen to move freely with the knee being the most common joint affected in the anterior chamber, following the currents of aque(50%).46 Arthritis as a first symptom in ABD patients has ous movement caused by the temperature differential

CHAPTER 56:

FIGURE 56-5. Hypopyon in a patient with ABD. (See color insert.)

between the front and the back portions of the chamber. A typical finding with the hypopyon of ABD is that it may shift with gravity as the patient changes head positions. In eyes with severe iridocyclitis, in which hypopyon is not seen by direct examination with slit-lamp biomicroscopy, a small layering of leukocytes can be observed ilf the angle by gonioscopy. This is termed angle hypopyon. A more common presentation is iridocyclitis without hypopyon, which is found in two thirds of cases. IS The anterior uveitis may res<¥ve spontaneously over 2 to 3 weeks even if therapy is not instituted. Chronic inflammation is not characteristic of this disorder. It is explosive in nature, appearing very rapidly. Some patients with ABD may change from feeling perfect one moment to having very severe inflammation 2 hours later. However, this anterior segment inflammation may not be accompanied by posterior segment involvement. Structural changes of the anterior portion of the eye, including posterior synechiae, iris atrophy, and peripheral anterior synechiae, may develop during the course of repeated ocular inflammatory attacks. The presence of peripheral anterior synechiae or iris bombe from pupillary seclusion may lead to secondary glaucoma. Neovascularization of the iris can occur as a result of posterior segment involvement (see later). It is also an ominous sign, a prognosticator of poor outcome. Other, less frequent anterior segment findings are cataract, episcleritis, scleritis, subconjunctival hemorrhage, filamentary keratitis, conjunctival ulcers, IS and corneal immune ring opacity.l05

found that posterior vitreous detachment occurred at an early stage of ocular involvement, in 92% of the affected eyes. The essential retinal finding is an obliterative, necrotizing vasculitis that affects both the arteries and veins in the posterior pole. l04 , 107 Fundus examination reveals venous and capillary dilation with engorgement. Involvement of the retinal vessels in the form of acute periphlebitis or thromboangiitis obliterans may lead to massive retinal and vitreous hemorrhage. l04 Patchy perivascular sheathing with inflammatory whitish yellow exudates surrounding retinal hemorrhages may be seen (Fig. 56.:...6). They usually accumulate in the deeper retinal layers during acute episodes, while the overlying retina shows turbidity and edema. Retinal edema is present in 10% to 20% of cases, especially in the macula. l04 Retinal atrophy frequently is present after the retinal exudates and hemorrhage resolve, offering stark testimony to the prior ischemia. Sheathing of the veins often precedes sheathing of the arteries. Choroidal vascular involvement occurs as well, and choroidal infarcts are probably more common than is generally appreciated. Severe vasculitis may lead to ischemic retinal changes because of vascular occlusion. This vascular occlusion causes tissue hypoxia, which stimulates the growth -of new vessels at the optic nerve (neovascularization of disc [NVD]) or elsewhere (NVE). Both NVD and NVE can rupture and bleed, causing the vitreous cavity to fill with blood. Bleeding into the vitreous cavity can lead to organization with membrane formation. These membranes may contract and pull the retina, causing retinal tears with subsequent retinal detachment. Neovascular glaucoma occurs in as many as 6% of patients with ABD. This often results in phthisis bulbi, which may occur in the presence or absence of central retinal vein or artery occlusion. Central or branch retinal vein (Fig. 56-7) or artery occlusions may be present. lOS, 109 The optic nerve is affected in at least one fourth of ABD patients. 104 Hyperemia of the optic disc with blurring of the margins (papillitis) is the most frequently observed

Posterior Segment White cell infiltration of the vitreous body, ranging from a moderate number of cells suspended on the vitreous fibrils to a dense plasmoid reaction with sheets of inflammatory cells, is always present during the acute phase. An isolated vitreous inflammatory reaction is not characteristic of ABD. However, Horiuchi and colleagues l06 reported that the most frequent sign of the involvement of the posterior' segment was irreversible changes of the vitreous, and that the most important of these changes was posterior vitreous detachment. They

FIGURE 56-6. Fundus photograph of a retinal lesion with accompanying intraretinal hemorrhages and vasculitis. (See color insert.)

mD

CHAPTER 56: ADAMANTIADES-BEHC;:ET DISEASE

FIGURE 56-7. Fundus photograph with a branch retinal vein occlusion in a patient with ABD.

lesion of the optic disc. Papilledema is not frequent, but it may occur (Fig. 56-8A,B) yo Progressive optic atrophy may occur as a result of microvasculitis of the arterioles supplying the optic nerve. Repeated inflammatory bouts are of major concern, with the most vision-robbing pathology located in the posterior pole, with fibrotic, attenuated retinal arterioles, narrowed and occluded "silver-wired" vessels (Fig. 56-9), a variable degree of chorioretinal sc;;trs (Fig. 56-10), reti~ nal pigment epithelial alternations, ~nd optic nerve atrophy being the consequences of repeated inflammatory assaults (see Fig. 56-9).

ADAMANTIADES..BEH<;ET DISEASE IN CHILDREN Several reports describing ABD in children have been published. 11l- 1l6 ABD in neonates whose mothers had oral and genital ulcers during pregnancy have also been describedY7 Recently, a case of transient neonatal ABD with life-threatening complications was reportedYs The incidence of ABD in childhood in]apan is approximately 1.5% of all reported cases of ABD, and there are some differences in these cases compared to adult cases. Dur-

FIGURE 56-9. End stage of repeated ABD attacks of posterior pole. Note the retinal atrophy associated with vessel attenuation and an optic disc atrophy. (See color insert.)

ing the course of the disease, uveitis and arthritis are seen more frequently in children, whereas genital and oral ulcers are less frequent. The first disease manifestation in children with ABD is oral aphthae in 55%, and uveitis in 31 % of casesYs However, periphlebitis has not been described in childhood ABD yet. In another study from Turkey, children showed lower vascular, neurologic, and ocular manifestations than did adultsY3

ADAMANTIADES..BEH<;ET DISEASE IN PREGNANCY Fetal and pregnancy outcomes were generally considered good in a recent study by Marsal and colleagues, in which 59 pregnancies in 54 women with ABD were analyzedy9 No changes regarding disease activity during pregnancy were noted in 47%, exacerbation of the disease was observed in 34%, and symptomatic improvement was reported in 26%. Mter delivery, stable disease was noted in 43%, improvement was observed in 31 %, and disease deterioration was found in 19%. Ten miscarriages occurred. 1l9 However, in another study, in which 27 WOlnen were enrolled, exacerbation of ABD during pregnancy

FIGURE 56-8. A and B, Bilateral optic disc edema in a patient with ABD. (See color insert.)

CHAPTER 56:

IAI)E~)-BEHICE:T

DISEASE

isolated from patients with ABD. 131 However, the pathogenic role of this protein has not been accepted.

Immune Mechanisms

FIGURE 56-10. Fundus photograph from a patient with repeated attacks of ABD showing a scar in the nasal area of the posterior pole. (See color insert.)

was noted in 18 pregnant women (67%).120 In a recent study, fetal and pregnancy outcomes were generally considered good. In addition, disease manifestations were not worsened, and the frequencies of spontaneous abortions, congenital malformation, and perinatal death in babies born to ABD patients were not significantly different from those of healthy women with recurrent' oral ulcerations. 121 Finally, the first. case of Budd-Chiari syndrome during puerperium was described. 122

PATHOGENESIS AND IMMUNOLOGY OfABD The cause of ABD remains unknown. Environmental factors, infectious agents, immune mechanisms, and genetic factors have been studied intensively. Many environmental factors have been implicated but not proved. 123

Infectious Agents

Epidemiologic data 124 as well as familial incidence incriminate an infectious cause for ABD. However, no microorganism has been reproducibly isolated from lesions of patients with ABD. In a limited number of patients, herpes simplex virus type 1 was found in the peripheral blood by using polymerase chain reaction (PCR). A positive reaction for herpes simplex was detected in biopsy samples from genitaP25 and intestinal ulcers,126 but a large number of patients is needed to confirm such results. Not only herpes simplex virus but also hepatitis C virus has been incriminated as a causative factor for ABD.127 Although parvovirus BIg has been reported to be associated with vasculitis, recent findings do not support a role for parvovirus BIg in the pathogenesis of ABD.128 Elevated serum antibody titers for antistreptococcal antibodies against certain serotypes of Streptococcus sanguis have been found in patients with ABD,129 and ABD patients showed a greater frequency of S. sanguis in their oral flora compared with controls. 130 This observation could explain the decision of some investigators who treat oral ulcers with penicillin. Immunoglobulin A isotype of antibodies specific for Mycobacterium, tuberculosis heat shock protein-65, which can cross-react with certain serotypes of S. sanguis, have been

Although there are disagreements as to whether ABD should be considered an autoimmune disease, autoimmunemechanisms are incriminated in the pathogenesis of ABD.132 However, there are many ways in which ABD differs from a classic autoimmune disease. The most important differences lie in the male preponderance, the lack of association with other autoimmune diseases, the absence of autoantibodies, the lack of association with HLA-alleles usually seen in autoimmune diseases, the hyperactivity of B cells, and the lack of definite T-cell hypofunction in ABD. Since the most popular research interest in ABD is directed toward immunologic mechanisms, Emmi and colleagues 133 recently described the immunologic aspects of ABD. The main microscopic finding at most sites of active ABD is an occlusive vasculitis (see later) .134 At the cellular level, few reports have correlated T-cell changes with ABD disturbances,135 but current observations suggest that during the active stage of ABD, T cells are activated (overexpression of CD25), HLA class II (HLA-DR) expression on T cells is down-regulated, whereas both helper (CD4) and suppressor-c)'totoxic (CD8) Tcells have cytophilic IgA bound to their surfaces. In addition, an increased percentage of T-cell receptor (TCR) "Yo has been found in the circulation of patients with ABD.136, 137 The significance of this increase in "Yo T cells in circulation and their effect in inflammation in ABD is unclear. Nonetheless, recently it has been shown that the ABD-specific heat shock protein peptides predominately stimulate the "Yo Tcell populations. 136 Natural killer cells and neutrophils are also increased in number and activity. Sera from patients with ABD enhanced the adherence of neutrophils to vascular endothelial cell monolayer in vitro. 138 This finding could explain the mechanism responsible for neutrophil accumulation at injury sites. Evidence is emerging that immune response caused by ThI/Th2 (ThO) cells is critical in the development of the pathologic/inflammatory response. 139 However, the role of ThO cell cytokines in human autoimmune diseases has rarely been studied. In ABD, various proinflammatory interleukins (ILs), such as IL-Ia, IL-6, IL-8, tumor necrosis factor-a (TNF-a), and soluble IL-2 receptors have been reported to be elevated in the sera of patients with ABD.140-143 IL-8 has a potent effect on neutrophils,141 and increased chemotactic activity of neutrophils has been observed in ABD disease. 144, 145 It is unclear how antiinflammatory cytokines IL-4, LI-IO, and IL-I3 (the Th2 response) regulate secretion of proinflammatory cytokines IL-Ia, IL-6, IL-8, and TNF-a in ABD.140-143 Recently, it has been shown that the immune system in ABD may be characterized by a divergent cytokine production profile of mixed ThI/Th2 (ThO) cell type, and interferon-"Y (INF-"Y) is critical in modulating the IL-4, IL-IO, and IL12 cytokine network pathway in this disease.1'16 Initial concepts of immune alternations in patients with ABD concerned immune complexes. Circulating immune complexes (Cle) have been associated with uve-

CHAPTER 56:

IAI)E~)-BEHICE:T

DISEASE

itis 147 and found in ocular specimens. 148 Thus, the finding of CIC in ABD patients supports such an association for its ocular complications. 149 Serum levels of immunoglobulins A, E, and M are increased in ABD patients. These antibodies found in patients. with ABD have been used in an attempt to define the disease itself.150-152 Immune complex formation has been detected in the tissues, particularly in active stages of ABD. Furthermore, Rasp and colleagues 153 have reported that patients with elevated levels of CIC had a better visual prognosis than did patients without CIC. They have theorized that CIC may have a protective value, as opposed to a destructive role, inasmuch as they may help to eliminate potentially harmful initiators of the immune reaction. These findings are in agreement with those reported by Charteris and colleagues,l5'1 who suggested that cell-mediated immunity, rather than immune complex deposition was responsible for the perpetuation of the ocular inflammation in ABD and that CD4 T cells played a centra~ role in this. Sera of patients with ABD were examined for the presence of antiphospholipid antibodies. 155 , 156 There was a statistically significant association between these antibodies and the retinal vascular disease in ABD patients. Antibodies against the endothelium have also been detected in the sera of patients with ABD and active thrombophlebitis or retinal vasculitis. Antithrombin III, protein C, and protein S are major natural inhibitors of coagulation, and it is well known that deficiency of those proteins causes thrombotic disorders. However, antithrombin III, protein C, and protein S deficiencies are not a'~probable cause of thrombotic manifestations in ABD.157, 158 Endothelial damage may be induced by increased levels of voh Willebrand factor, which was increased in ABD patients, particularly those with vasculitis. 159

Genetic Factors The fact that certain racial groups appear to be at increased risk for ABD suggests a genetic predisposition to the disease. Indeed, HLA-B5 phenotype and its subtype HLA-Bw5p60 have been found in a significantly higher proportion of patients suffering fromABD than in the general population. This strong association has been confirmed in many different ethnic groups from the Middle East to the Far .East, such as Japan,18, 161 Turkey,162 Germany,22 and Greece,163 but not in whites living in the United States and England. 164, 165 The HLA-B51 gene has recently been identified to comprise seven alleles, B*5101 to B*5107. 166, 167 However, ABD was found to be strongly associated with the HLA-B*5101 alleles in Japan 168 and in Greece. 169 On the other hand, HLA-DRI and HLA-DQwl have been shown to be significantly decreased in patients with ABD. This may indicate that an individual who carries these antigens is resistant to develop the disease. These results suggest that not only disease s'usceptibility but also resistant genes play an important role in the immunogenetic mechanisms of ABD.l7° Specific associations between HLA type and clinical manifestations of ABD have also been found. Thus, HLAB12 is associated with mucocutaneous lesions, HLA-B27 - with arthritis, and HLA-B5 with ocular lesions. l7l Such associations, however, were not found in a study from

Turkey.172 Furthermore, in a Asian report, patients with ABD and refractory ocular lesions were strongly associated with HLA-DQw3, and the onset of the disease was earlier than in the HLA-DQw3-negative patients. 173 The reason for the association between HLA-B51 and ABD is not clear. It is possible that the HLA specificity is a marker for the different immune response gene found in ABD patients, as the genomic region that encodes the HLA antigens is the same as the one that controls the immune response. Another hypothesis suggests that HLA antigens may function as targets themselves, either for exogenous agents or for endogenous autoimmune reactions. Taking into account these findings, a model explaining the etiopathogenesis of ABD was proposed by Emmi and associates. 133 An exogenous factor (e.g., a microbe) is internalized by antigen-presenting cells (APC) (e.g., macrophages, dendritic cells), where it undergoes processing in an acidic vesicular compartment. Processing ensures that portions of a protein (the immunodominant peptides) will bind to class II major histocompatibility complex (MHC) molecules, forming an immunogenic complex that is then expressed on the surface of the APC, where it is recognized by CD4 + T cells. Activated Thl cells produce ILs (IL-2, INF-')', and TNF-(3) and induce B cell proliferation. INF-')' activates macrophages and they release TNF-a, IL-l, and IL·.g, These cytokines are responsible for the expression of adhesion molecules on the endothelial cells. IL-8 also induces chemotaxis and activates neutrophils. Both factors are necessary for the increased vascular permeability and the passage of neutrophils and activated T cells through the endothelium to the inflammatory area. Genetic factors may also be responsible for the expression and perpetuation of the illness. 174 Thus, inflammation and B-cell proliferation in a genetically susceptible individual can lead to ABD.

PATHOLOGY Even though ABD can cause blindness, few reports on the ocular immunohistopathology of ABD have been published. 152 , 154, 175, 176 In contrast, many histopathologic studies have been performed on other tissues involved with ABD. It is primarily an inflammatory disorder involving small blood vessels, particularly venules. The early lesions resemble a delayed type hypersensitivity reaction, whereas the late lesions resemble an immune complex type reaction. The role of immune complexes in causing venulitis is, however, questionable, as immunoglobulins are not routinely found in vessel walls.

Histopathology The common underlying histopathologic lesion in all affected organs is both leukocytoclastic and monocytic occlusive vasculitis that is responsible for organ failure. However, the level of occlusion may reflect the age of the lesion and the type of cells that participate in such a lesion. 177 The principal pathologic features are perivascular infiltrates of lymphocytes and mononuclear cells, swelling and proliferation of small vessels, and fibrinoid degeneration. In postmortem examination of the brain, demyelination is the most common finding, followed by encephalomalacia at multiple sites, accompanied by peri-

IAl)I:~)·BI:HIC:lE:T

vascular cell infiltration in the brain stem, spinal cord, cerebrum; and cerebellum.55 The histologic characteristics of erythema nodosum are areas that are infiltrated by lymphocytes and a few histiocytesPS Histopathology of the mucocutaneous lesions in ABD are characterized by the presence of neutrophils, fibrinoid necrosis, and a mixed perivascular infiltrate. 179 Increased numbers of mast cells have also been reported in the cellular infiltrates of the recurrent mucocutaneous ulcers. ISO Ocular histopathologic changes are similar to those found in other organs, as was described previously. During the acute inflammation, the iris, ciliary body, and choroid show diffuse infiltration with neutrophils, and later with l}'lnphocytes, monocytes, and mast cells. In the more chronic stage, with many recurrences, increased collagen is present, which can lead to iris atrophy and posterior synechiae, cyclitic membrane formation, and thickening of the choroid and sometimes hypotony and phthisis bulbi. In the retina, vasculitis with marked infiltration of leukocytes, and 'plasma cells in and around blood vessels and into retinal tissue is the most prominent finding. Veins are more affected than arteries. During the inflammatory process, the retinal vascular endothelial cells become swollen, neutrophils migrate, and thrombus formation begins. Rods and cones in areas of involvement are destroyed, and fibrosis of the inner nuclear lay,er is present. Retinal pigment epithelium destruction is minimal. In more advanced cases, there is fibrosis of the blood vessels and sometimes complete vascular obliteration. The optic nerve vessels can also'ifbe affected by the vasculitic process, which can lead to optic neuritis, ischemia, and, in more severe chronic cases, optic atrophy.

Immunopathology

DISEASE

well as no visual complains. lS3 .Fundus FA is 1nandatory in the study and longitudinal care of patients with ocular ABD. It should be used to monitor the extent of damage to the vasculature of the retina and the optic nerve 1S4 so that therapy can be adjusted on the basis of these subclinical signs rather than solely on vision loss, clearly an irreversible clinical finding. During acute inflammation, there is diffuse fluorescein leakage from the retinal capillaries (Fig. 56-11), the larger engorged vessels, and the optic disc. Persistent, diffuse dye leakage is seen even with resolution of inflammatory episodes. In addition, FA may show late staining of the vasculature, evidence of large zones of capillary nonperfusion, collateral vascular formation, secondary retinal telangiectasia,and retinal neovascularization. Macular alterations (macular ischemia, cystoid Inacular edema [Fig. 56-12J, macular hole, and epiretinal membrane), which may be responsible for poor vision, can be seen by FA.1s5 Evidence of retinal pigment. epithelial involvement is rarely seen in this disorder. However, Matsuo and colleagues 1S5 reported that patients with ABD have choroidal abnormalities that were revealed only with indocyanine green angiography (ICG), and not with funduscopy or FA. Thus, simultaneous ICG and FA would be useful for examining choroidal lesions in ABD. FAand/ or ICG, together with slit-lamp fundus biomicroscopy should be used td.evaluate the response to medical treatment.

Electrophysiology Flash electroretinography together with pattern visually evoked potentials may be good indicators for monitoring posterior segment changes as well as for predicting visual prognosis. 1S7

Immunopathology of the affected organs has shown that the T cell is the predominant inflammatory cell type, suggesting that cell-mediated immunity plays a central role in ABD.135, 154, lSI Immunohistologic study of the pathergy test site shows infiltration similar to that observed in a delayed-type hypersensitivity reaction. 1S2 Furthermore, immunopathology of the conjunctival biopsy of patients with inactive ABD has revealed that both neutrophils and T cells are involved in response to surgical trauma, along with overexpression of E-selectin and intracellular adhesion molecule-I, suggesting a hyperreaction in areas that are not primarily involved during the disease process. 175

DIAGNOSIS Diagnosis of ABD is based on clinical observations only. Therefore, the criteria defined either by the International Study Group of Beh<;:et's disease or the Japanese Research Committee of Beh<;:et's disease should be applied. Although there are no laboratory tests that are specific for the diagnosis of ABD, some are helpful for evaluation.

Fluorescein Angiography and Indocyanine Green Angiography Fluoresceiri angiography (FA) demonstrates marked dilation and occlusion of the retinal capillaries in patients with ABD. In a recent study from Turkey, FA disclosed incipient fundus changes in 6.3% of patients with ABD who had no abnormal finding on fundus examination as

FIGURE 56-II. Fluorescein angiography (same patient of Figure 5610) revealing substantial leakage of dye from peripheral retinal vessels due to peripheral retinal vasculitis.

DISEASE

FIGURE 56-12. Fluorescein angiography with the characteristic angiographic pattern of prominent cystoid macular edema. Note the accumulation of fluorescein in the cystoid spaces of Henle's layer.

Serologic Studies The erythrocyte sedimentation rate, C~eactive protein, and other acute-phase reactants, such as properdin factor band <Xcacid glycoprotein, may be elevated dltring the acute phase of ABD.188 Additionally, longitudinal monitoring of soluble CD25 molecules in the serum (soluble IL2 receptor [sIL-2rJ) along with these acute-phase reactants, to be quite useful, since a rise in these markers often precedes· the development of a clinically obvious recurrence, thereby providing the clinician the opportunity for a preemptive therapeutic strike. The levels of ILs and adhesion molecules, and the role of the imaging techniques have already been discussed in the relevant sections. Hence, diagnosis and assessment of disease activity are based on clinical findings on examination. Decreased fluorescein leakage indicates a favorable response to therapy. The longitudinal assessment strategy and the treatment philosophy described here are extremely important, because ABD is categorically a blinding disease, and usually bilateral. 18, 189, 190 The second eye is generally affected within 1 year of disease onset in the first eye, although this may not occur for as long as 7 years.

DIFFERENTIAL DIAGNOSIS

Reiter's syndrome can resemble the incomplete form of ABD. However, Reiter's syndrome is generally not associated with vasculitis, and the oral ulcers are usually painless. Although sarcoidosis may have posterior segment lesions similar to those found in ABD, the uveitis in ABD has an explosive nature. Even though vasculitis can be found in sarcoidosis, it is usually not occlusive, and it more frequently affects veins in a sectional manner, in contrast to ABD, which affects both arteries and veins in a diffuse manner. Other forms of vasculitis such as systelnic lupus erythematosus (SLE) , polyarteritis nodosa (PAN), and Wegener's granulomatosis (WG) should also be included in the differential diagnosis of ABD. In the evaluation of a patient with multisystem illness and possible vasculitis, it is useful to take an organized system approach to the history and examination. The specific pattern of tissue involvement can be used to focus on potential diagnoses and subsequent diagnostic tests. For example, the presence of oral ulcers in the setting of a systemic process may suggest ABD but also WG, Crohn's disease, Reiter's syndrome, or SLE. Specific eye findings may help to focus the diagnostic evaluation. SLE, like ABD, produces multisystem involvement, and definitive criteria are available with the detection of extractable antinuclear antibodies, and in particular antiDNA antibodies. The retinal features of SLE are caused by arterial occlusion, and the characteristic findings are cotton-wool spots, larger retinal infarcts, and optic disc infarction. Thus, unlike ABD, in which arteries and veins can both be involved, veins are not involved in SLE, and there ar~ no inflammatory changes in the anterior chamber or vitreous. PAN is a necrotizing vasculitis that involves mediumsized macular arteries and smaller arterioles. Retinal vasculitis of PAN resembles the vasculitis found in ABD, but vitritis is not so prominent. In addition, nephropathy is commonly found in PAN but is very rare in ABD. Retinal vasculitis can also be found in WG. However, the presence 'of upper and lower respiratory involvement, the concomitant glomerulonephritis, and a positive antineutrophil cytoplasmic antibody test are highly specific for WG. In contrast to the occlusive vasculitis found in ABD, the vasculitis of WG is a necrotizing granulomatous vasculitis. Finally, the retinitis of ABD can be suggestive of a viral retinitis. Acute retinal necrosis mimics the rapid progression and severity of ABD. However, the lesions of ABD rarely begin as uniformly in the periphery and are often associated with systemic symptoms and signs.

It is important to consider other types of uveitis in the

TREATMENT

differential diagnosis of ABD, particularly when the presentation is incomplete or atypical, since other illness may have ocular manifestations similar to those found in ABD. Severe recurrent iridocyclitis with hypopyon can be found in HLA-B27-associated anterior uveitis. In contrast to ABD, this uveitis is usually unilateral and the hypopyon is less mobile.

The goal of therapy is to treat the acute disease, but, perhaps even more important, to prevent or at least to decrease the number of repetitive ocular inflammatory episodes of the posterior pole (Figs. 56-13 and 56-14). The choice of medication is based on the severity of the disease. In general, treatment should be more aggressive whenever the following are present: complete ABD, involvement of the CNS, vascular involvement, retinal

CHAPTER 56:

IAI)E~i-BEHCET

DISEASE

FIGURE 56-13. Fundus photographs of posterior pole (A) and periphery (B) of OD, and posterior pole of OS (C) from a patient with active ABD. Retinal lesion located in the inferior quadrant accompanied by some degree of vitritis is noted in OD (A). Snow bank lesion is revealed in the periphery of OD (B). Extensive vitritis that obscures fundus details is shown in OS (C). (See color insert.)

and bilateral involvement, male sex,18 and a geographic origin in the Mediterranean basin or Far East. 18 Many treatment modalities have been tried in ocular ABD with varying claims of success. Evaluation of all these treatment modalities is very difficult because of the unpredictable and intermittent course of the symptoms. The frequency of exacerbations can be influenced by drugs for various periods of time, but systematic study of the influence of these treatment modalities on the final outcome and the final visual acuity has been very limited. The most commonly used agents today are corticosteroids, cytotoxic drugs, colchicine, Cs-A, and tacrolimus (FK-506) .

Corticosteroids Although many forms of uveitis are initially treated with corticosteroids, ABD usually becomes "resistant" to corticosteroid therapy. 191 Systemic or topical corticosteroids have a beneficial effect on the acute ocular inflammation. Despite the fact that corticosteroids alone have failed to prevent vision loss in patients with ABD,18, 24, 26, 104, 191, 192 systemic corticosteroids (1 to 1.5 mg/kg of prednisone per day) are especially useful in quickly controlling acute inflammation, but they appear to have little effect, if any, on the late sequelae. The addition of corticosteroid to a therapeutic regimen for treatment of the ocular manifestations of ABD is not well accepted in Japan. However, it is appropriate to use systemic corticosteroids for patients being treated with immunosuppressive drugs for acute

posterior segment inflammation, because their immediate anti-inflammatory action is of benefit while waiting for the full effect of the cytotoxic drugs. Then the corticosteroids are gradually tapered. Intravenous administration of a high dose of corticosteroids may be beneficial in selected case of acute severe inflammation. 193 In select cases, low-dose corticosteroids (15 to 30 mg/day) may be required chronically in combination with immunosuppressive agents for controlling the uveitis. This combination is beneficial for reducing the adverse effects of either drug. 194 More will be said later about the art of the polypharmacologic approach to treating ABD. In anterior segment inflammation, topical corticosteroids, with or without periocular corticosteroids, are required.

Cytotoxic Agents Immunosuppressive treatment is required for severe uveitis with retinal involvement. Several reports from the Mediterranean area have underlined the efficacy of cytotoxic agents in controlling ABD ocular inflammation.195-197 Immunosuppressive drugs that are currently used in the treatment of ocular ABD include azathioprine, chlorambucil, cyclophosphamide, methotrexate, cyclosporine, tacrolimus, and mycophenolate mofetil.

Azathioprine Azathioprine is an immunosuppressive drug that interferes with purine incorporation into DNA, and hence it affects rapidly proliferating cells such as activated lymphocytes.

CHAPTER 56: ADAMANTIADES-BEH<;:ET DISEASE

FIGURE 56-14. Fundus photographs (same patient of Figure 56-12) 15 days after treatment revealing OD with a smaller area of retinitis (A) and without snow bank lesion (B), and OS totally quiet (C). (See color insert.)

Although earlier reports of treatment with azathioprine (2.5 mg/kg/day) gave inconclusive results,1°4, 198 a doubleblind study from Turkey showed that azathioprine was useless in restoring compromised vision, but it was superior to placebo in preserving visual acuity in those with established eye disease. 189 Azathioprine was also effective in treating oral and genital ulcers, and arthritis. 189 My results with azathioprine alone are less impressive. Indeed, as will be emphasized later, I rarely, if ever, rely on any single agent for patients with ABD posterior segment manifestations at the Massachusetts Eye and Ear Infirmary.

Chlorambucil Chlorambucil, a slow-acting alkylating agent, was the first immunosuppressive drug to be used in patients with ocular ABD; It was employed in 1970 by Mamo and Azzam because corticosteroids failed to prevent visual deterioration in their patients with ABD in Lebanon. 199 Although its side effects are essentially the same as those of cyclophosphamide, the rationale behind its use was that it was slower acting than cyclophosphamide and could be administered more safely on an outpatient basis. Godfrey and colleagues 200 as well as Pivetti-Pezzi and colleagues 201 also reported on the effectiveness of chlorambucil in the treatment of ABD, and Tessler and Jennings 202 reported that high-dose,< short-term chlorambucil treatment for ABD also produced favorable results. However, Tabbara203 reported long-term results with chlorambucil that were disappointing, with 75% of eyes

in patients treated with chlorambucil as monotherapy having visual acuity of 20/200 or less. These results could be explained by the fact that chlorambucil, a slow-acting agent, suppresses the immune system slowly, which would be a disadvantage, as rapid immunosuppression is usually desirable for patients with ABD. To understand Tabbara's results, it would be helpful to have comparative data on the vigor of therapy and the level of immunosuppression of the patients. The usual starting dose of chlorambucil is 0.1 mg/kg/ day. One to 3 months of therapy is usually required before its immunosuppressive action is apparent. The drug dose is adjusted to maintain clinical remission for approximately 1 year. Proper hematologic monitoring can be complex and must be done by a chemotherapist experienced in chlorambucil therapy. Azoospermia in men cannot be avoided, and therefore sperm banking, when available, should be offered. Amenorrhea in women can often be avoided by induction of menopause during the course of treatment through the use of leuprolide acetate (Lupron).

Cyclophosphamide Cyclophosphamide, a fast-acting alkylating agent, has been utilized widely in Japan with favorable results in controlling uveitis, preventing ocular attacks, and maintaining good visual acuity for long periods in patients with ABD. 19 7 It has been shown that cyclophosphamide is superior to steroids in suppressing ocular inflammation

CHAPTER 56:

in patients with ABD.204 Silnilarly, oral cyclophosphamide produced ocular and systemic iInprovement in patients with ABD who had been previously unresponsive to systemic corticosteroids. 205 Although chlorambucil may be the single most efficacious agent in management of ABD, capable of inducing long-term disease remission, intl-avenous cyclophosphamide may be a highly attractive alternative. Intravenous cyclophosphamide (750 to 1000 mg/ sq m every 4 weeks) has been used by Baer and colleagues 104 in cases refractory to chlorambucil and in severe vasculitis with favorable results. Foster and colleagues 206 as well as Fain and colleagues 207 have shown both cyclophosphamide and chlorambucil to be superior to Cs-A in management of the posterior segment manifestations of ABD. However, in a study from Turkey in which intravenous cyclophosphamide was compared with oral Cs-A, cyclophosphamide was found to be less effective, especially during the first 6 months of the treatment. 208

Cyc/osporine...A The mechanisms by which Cs-A acts are not completely understood, attesting to the enormous complexity underlying T-cell activation. It is believed that Cs-A disrupts the transmission of signals from the T-cell receptor to genes that encode for multiple lymphokines and enzymes necessary for activation of resting T cells and cytoaggre~sion while leaving the T-cell priming reaction unaffected. 209 Nussenblatt and colleagues of the National Eye Institute were first to report the efficacy of Cs-A at doses of 10 mg/kg/day in patients with intr;Jl-ctable uveitis of various etiologies, including ABD refractory to corticosteroid and cytotoxic agents.210-214 This observation was subsequently corroborated by other investigators in treatment of ABD.215 However, a dose of 10 mg/kg/day that was initially used is now known to be associated with a 100% incidence of renal toxicity, and it has been suggested that the more prudent dose should be 5 mg/kg/day.216 Later studies have shown that combination of a low dose of CsA with corticosteroids was more effective in improving visual acuity than the higher dose of Cs-A alone.217-220 A very slow tapering of the medication is usually advisable since a rebound phenomenon has been observed in some cases when discontinuation of Cs-A was abrupt. 22o Nevertheless, Foster and colleagues206 as well as Chavis and colleagues 221 have shown that less toxic doses of Cs-A are distinctly inferior to cytotoxic agents (azathioprine, cyclophosphamide, and chlorambucil) in management of the posterior segment manifestations and inflammatory recurrences in patients with ABD. I have successfully employed Cs-A at low doses in combination with azathioprine as a steroid-sparing strategy in the treatment of ABD. However, it is extremely difficult to wean patients off Cs-A without recurrent disease, even when they have been on this medication for over 2 years. The definitive efficacy and long-term outcome of combined Cs-A regimens with prednisone and other immunosuppressive agents (e.g., azathioprine) in ABD await critical evaluation in prospective, randomized trials.

Tacrolimus Tacrolimus (FK-506) is a newly developed immunosuppressive drug. Its action is very similar to that of Cs-A: It

IA[)E~~.B.EHCET

DISEASE

selectively suppresses CD4 + T lymphocytes. The Japanese FK-506 Study Group on Refractory Uveitis reported favorable results in 75% of 53 patients with refractory uveitis, including 41 patients with ABD.79 The therapy was switched to FK-506 (0.10 to 0.15 mg/kg/day) because of therapeutic failures and adverse side effects with systemic corticosteroids, colchicine, cyclophosphamide, and Cs-A. However, FK-506 is associated with not infrequent occurrence of disconcerting side effects such as renal, gastrointestinal, and neurologic problems. 222 On the other hand, hirsutism, gingival hypertrophy, and coarsening of facial features have not been reported in patients treated with FK-506.

Colchicine Colchicine exhibits both anti-inflammatory and antimitotic properties, mediated mainly through its inhibition of microtubular formation. 223 Because enhanced neutrophil migration is a characteristic feature of ABD, colchicine (0.6 mg/day) is most useful in prophylaxis of recurrent inflammatory episodes (rather than in ti-eatlnent of active disease) or in the rare patients with mild, unilateral involvement in whom the clinician wishes to defer immunosuppressive therapy.224 Colchicine can also be used in combination with other drugs in treating all forms of ocular and systemic manifestations of ABD.144, 197, 225 It is not effective as I)1onotherapy in treating ocular symptoms, but it may form part of a polypharmacologic "recipe" for patients with ABD.

Mycophenolate MofetU Mycophenolate mofetil is a novel immunosuppressive agent that blocks DNA synthesis by the' inhibition of the enzyme inosine monophosphate dehydrogenase. 226 Mycophenolate mofetil, unlike Cs-A and FK-506, does not inhibit the early production of interleukin-2 or the production of cytokines of T-helper-cell clones belonging to the ThO and Th2 subsets. 227 Because mycophenolate mofetil works at a later stage in the T-cell cycle, it acts synergistically with other immunosuppressives. 228 More recently; Larkin and Lightman 229 successfully treated two' ABD patients by adding mycophenolate mofetil to their therapeutic regiments. These patients responded inadequately to steroids used concomitantly with Cs-A.

Other Treatment Modalities Other treatment modalities that have been tried in ocular ABD with some benefit include interferons,230-233 plasmapheresis,161, 234 pentoxyphilline,235 penicillin,236 thalidomide,237 and interferon-a2b. ABD is a complex disorder for which no best therapeutic agent has yet been described. Although one patient may respond well to combination low-dose prednisone and cyclosporin, another, with seemingly identical ABD manifestations, may not. Azathioprine may be just the right additional ingredient in the nonresponding patient's therapeutic recipe to result in stability and freedom from relapses, or it may not. The patient may need to be advanced to alkylating therapy with chlorambucil' or cyclophosphamide to induce disease remission. The following case description, contributed by Dr. C. Stephen Foster of Boston, is an example of the complexities and

·CHAPTER 56:

difficult decisions that the physician and patient may need to make throughout the course of ABD.

CASE REPORT A 22-year-old white man presented to the Ocular Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary in November, 1997, referred from his local ophthalmologist with a 6-week history of bilateral uveitis, treated with topical and systemic steroids. The presenting visual acuity was 20/80 in each eye (aU). Review of systems disclosed a history of recurrent aphthous mouth ulcers, seasonal allergies, and acneiform skin lesions. The ophthalmic examination disclosed panuveitis, with posterior segment involvement much greater than anterior segment manifestations, with papillitis string-ofpearls vitreal exudates, and substantial narrowing of the arterioles. FA disclosed late disc and arteriolar staining; areas of nonperfusion with infarction were present. Serologic studies disclosed a white count of 14,000 with a hemoglobin of 15, lymphopenia, with atypical lymphocytes, and both IgM and IgA serologic titers for positive for antibodies directed against Toxocara. The patient had significant dog and puppy contact. Because of treatment resistance and the unusual appearance, as well as progression to hand-movement acuity inthe left eye (OS), a diagnostic pars planavitrectomy was performed. Results of an HLA-B51 test, received after the vitrectomy, were positive. Because the cytology of the harvested vitreal cells were not indicative of a malignant process, and because PCR analysis did not indicate an infectious etiology, therapy was begun with combination prednisone, cyclosporin, and azathioprine. Visual acuity of the right eye improved to 20/ 25, and that of the left eye improved to 20/ I00. With prednisone tapering, however, the patient's Adamantiades-Beh~et's disease, with primarily retinal manifestations, recurred abruptly over a period of 36 hours, diminishing the acuity of the right eye to 20/ I00 and diminishing hand-movement acuity in the left. The cyclosporin and azathioprine therapy was stopped. Regional steroid injection, intravenous pulse steroid therapy (250 mg of methylprednisolone intravenously 5 times a day), and pulse cyclophosphamide therapy were instituted. This combination was associated with a complete abrogation of the active inflammation and recovery of vision to 20/25 00 and 20/200 as. Noncompliance for appointments for repeated cyclophosphamide infusions resulted in an additional hypopyon uveitis with retinal vaso-occlusive vasculitis and loss of acuities to hand movements 00 and counting fingers as. Hospitalization once more, with emergency intravenous cyclophosphamide and steroid therapy, along with intraocular dexamethasone 400 /-Lg and plasmapheresis, was associated with recovery of visual acuities of 20/40 00 and 20/70 as. The patient was then maintained (with relative stable visual acuity and freedom from such explosive episodes) over the next 8 months with intermittent cyclophosphamide infusions, approximately every 3 to 6 weeks. Two more episodes of recurrence were managed in the same way, with plasmapheresis employed urgently. An additional recurrence in June of

j

1999 appeared to have slightly different characteristics from previous ones, with unusual areas of peripheral retinitis. Urgent diagnostic pars plana vitrectomy with PCR and culture analysis of the harvested material disclosed herpes simplex virus; the intraoperative appearance of the right eye was that of peripheral acute retinal necrosis. Intravitreal and high-dose intravenous acyclovir therapy was employed. Because of this new turn of events, we did not feel comfortable with the idea of continued control of the ABO with intravenous pulse cyclophosphamide therapy. Therefore, we began subcutaneous interferon-a2b, 3 million units subcutaneously 3 times weekly. For 4 months, the patient was maintained on this therapeutic technique without evidence of relapse. The visual acuities as of the date of this report, February, 200 I, were 20/80 00 and 20/60 as. This case report illustrates some of. the challenges faced by the physician caring for a patient with ABD. There is no best treatment. There is as much art as science involved in discovering a recipe that induces long-lasting remission in each individual patient. Those physicians most experienced with such patients may be best prepared, by virtue of that experience, to deal with the intricacies of ocular ABO cases, adapting to the changing characteristics of the case as it evolves, adjusting the therapeutic recipe based on the characteristics of the patient and knowledge of new and evolving technology and medications. Finding such physicians in regions where ABO is uncommon is especially difficult.

MANAGEMENT COMPLICATIONS Ophthalmic complications such as cataract, cystoid macular edema, glaucoma, neovascularization, and vitreous hemorrhage are not rare in patients with ABD, and they produce vision loss if not treated correctly. Cataract formation is especially common, both because of the recurrent inflammation and as a consequence of the steroid tn;atment. Cataract removal should be performed in the quieted eye for two reasons. The first is for visual acuity improvement. The second is so that the physician can observe the posterior segment of the eye to monitor disease activity and treatment effect, and the cataract may obscure that view. Successful cataract surgery with minimal postoperative inflammation will be most likely if the uveitis has been inactive for 3 months, prophylactic perioperative treatment with corticosteroids is employed, immunosuppressive drugs are continued, complete removal of cortical material is performed, and a posterior chamber intraocular lens is placed into the capsular bag if an intraocular lens is implanted.238-240 Systemic and topical corticosteroids should be administered 1 week prior to any surgical intervention and should continue postoperatively.238 It is important to remember that even if one understands and abides by the principles of operating only on quiet eyes, the visual prognosis may be extremely guarded, regardless of surgical skills and elegance, if posterior segment complications of ABD have already occurred prior to surgery.241,242 Yoshikawa and colleagues 243 reported that uveitic cystoid macular edema resolved with periocular injections

CHAPTER 56:

of corticosteroids in approximately 50% of the cases. However, management of pseudophakiccystoid macular edema associated with ABD is more difficult than management of uveitic cystoid macular edema in general. Secondary and neovascular glaucoma may be responsible for profound loss of vision in patients with ABD. Initial medical therapy with topical and systemic antiglaucoma medications may not suffice. Treatment decisions require consideration of the status of the optic nerve and the visual field. Evaluation of the visual fields can be difficult. The coexistence of neuro-ABD or other ocular complications such as cataract and posterior segment disease can cause visual field defects that are difficult to distinguish from those seen because of glaucoma. If medical treatment is inadequate to control the intraocular pressure and stabilize the visual field, surgical intervention must be considered. Trabeculectomy with localized antimitotic therapy or use of a drainage tube such as the Ahmed or Molteno valve tube shunt are the most reasonable options. Vitreous hemorrhages are very frequent in ABD cases with severe retinal disease. Hemorrhages may resolve spontaneously, but in some cases vitrectomy is required. Visual outcome after vitrectomy may be disappointing because of coexisting macular damage. In patients with multiple episodes of retinal disease, areas of atrop,hic retina are present. Retinal detachments are therefore common in the later stages of the disease. Phthisis bulbi with or without iris neovascularization usually follows retinal detachment. Development of retinal and/or optic disc neovascularization is a major complication of the repeated attacks on the retinal vasculature. This neovascularization is attributed to the ABD vasculopathy leading to retinal hypoxia. Thus, meticulous evaluation of the retina is very important for the early diagnosis of neovascularization and treatment with laser photocoagulation. 244 However, concerns about the efficacy of such treatment. exist: Some investigators believe that laser photocoagulation may release antigens from the retina, which can be responsible for systemic sensitization and exacerbation of the ABD. Therefore, patients with signs of recurrence should be aggressively treated. Cataract surgery and other operations such as vitrectomy and scleral buckling procedure are well tolerated in patients with inactive ABD.1S, 104, 239, 240, 245

PROGNOSIS FOR VISION Visual prognosis in ABD is a subject of much controversy. Some authors have reported loss of vision in many of their patients and others have reported little loss of vision.l9l, 246 The use of immunosuppressive drugs as well as genetic predisposition for severe ABD may explain such discrepancies. Today, no definitive prognostic factors for visual outcome have been identified, although Sakamoto and colleagues 30 did try to determine such prognostic factors. They concluded that skin lesions, arthritis, and posterior uveitis attacks were linked to loss of vision, whereas female sex, disease free interval, and anterior attacks were related to retention of vision. Accurate prognostic factors for visual outcome could be valuable for deciding the most appropriate type of treatment. Thus,

IA[)E~)-BEHICE:T

DISEASE

if the patient with ABDis at high risk for visual loss, very aggressive treatment should be instituted. On the other hand, if the patient is at low risk, a mild treatment with few potential side effects should be recommended. In addition, Demiroglu and colleagues 247 reported that age of 30 years or less, male sex, vascular thrombosis, and CNS involvement were risk factors for ocular disease. It is clear that the key to preserving good vision is prompt and aggressive treatment with very close surveillance and monitoring, as ABD is a chronic disease with exacerbations after long periods of remissions.

CONCLUSION ABD is a chronic, recurrent, multisystem inflammatory disorder, mainly characterized by the classic triad of recurrent ocular inflammation, skin lesions, and recurrent oral and genital ulcers. It frequently involves the joints, the CNS, and the gastrointestinal tract. It is most common in Turkey and the Far East, and in countries along the old Silk Route connecting the Far East with the Mediterranean basin. Children are rarely affected. Infectious agents, immune mechanisms, and genetic factors are implicated in the etiopathogenesis of the disease, which remains to be elucidated. The pathology of the lesions consists of widespread vasculitis. There is not a universally accepted diagnostic test for this disorder. Thus, the diagnosis of ABD relies.on the identification of several combinations of its more typical clinical features. The prognosis of the disease has improved, even when vital organs are involved, because of early diagnosis and treatment. However, untreated, the natural history of ocular ABD for useful vision appears' to be very poor. Therapy with cytotoxic medications such as cyclophosphamide and chlorambucil has been shown to be efficacious in treating ABD. In fact, chlorambucil is the only medication that has resulted in complete remission and "cure" of ABD. On the other hand, Cs-A showed promising results in preserving good vision in patients with ABD, but the initial work was performed with doses that are now known to be associated with 100% incidence of nephrotoxicity, and subsequent results with slualler doses have been disappointing. Treatment is a complicated issue and needs to be individualized to the patient, balancing the risks of therapy with the putative efficacy of a given approach.

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CHAPTER 56: 173. Matsuki K, Tuji T, Tokunago K, et al: HLA antigens in Behc;et's disease with refractory ocular attacks. Tissue Antigens 1987;29:208-213. 174. Mizuki N, Ohno S: Immunogenetic studies of Behc;et's disease. In: YIlth International Conference on Behc;et's Disease. Rev Rhum Engl Ed 1996;63:520-527. 175. Charteris DG, Champ C, Rosenthal AR, et al: Behc;et's disease: Activated T lymphocytes in retinal perivasculitis. Br J Ophthalmol 1992;76:499-501. 176. Tugal-Tutkun I, Urgancioglu M, Foster CS: Immunopathologic study of the conjunctiva in patients with Behc;et's disease. Ophthalmology 1995;102:1660-1668. 177. Inoue C, Itoh R, Kawa Y, et al: Pathogenesis of mucocutaneous lesions in Behc;et's disease. J Dermatol 1994;21:474-480. 178. Su WPD, Chun S, Lee S, Rogers RS III: Histopathological spectrum of erythema nodosum lesions in Behc;et's disease. In: o 'Duffy JD, Kohnen E, eds. Behc;et's Disease. New York, Marcel Dekker, 1991, pp 229-240. 179. Kienbaum S, Zouboulis CC, Waibel M, Orfanos CE: Chemotactic neutrophilic vasculitis: A new histopathological pattern of vasculitis found in mucocutaneous lesions of patients with AdamantiadesBehc;et's disease. In: Godeau 0, Wechsler B, eds. Behc;et's Disease. New York, Elsevier Science, 1993, pp 337-341. 180. Shikano S: Ocular pathology of Behc;et's syndrome. In: Moracelli M, Nazzaro P, eds. International Symposium on Behc;et's Disease. Karger, Basel, 1966, pp 111-136. 181. Yamana S, Jones SL, Aoi K, et al: Lymphocytic subset in erythema no do sum-like lesions from patients with Behc;et's disease. In: Lecher T, Barnes CG, eds. Recent Advances in Behc;et's Disease. London, Royal Society of Medicine, 1986, pp 117-121. 182. Gul A, Esin S, Dilsen N, et al: Immunopathology of skin pathergy reaction in Behc;et's disease. Br J Dermatol 1995;132:901-907,. 183. Atmaca LS: Fundus changes associated with Behc;et's disease. Graefes Arch Clin Exp Ophthalmol 1989;227:340-344. 184. Matsuo N, Ojima M, Kumashiro 0, et al: Fluorescein angiographic disorders of the retina and the optic disc in Behc;et's disease. In: Inaba G, ed. Behc;et's Disease: Patho~enic Mechanism and Clinical Future. Proceedings of the International Conference on Behc;et's Disease. Tokyo, October 23-24, 1981. Tokyo, University of Tokyo Press, 1982;161-170. 185. Bentley CR, Stanfort MR, Shilling JS, et al: Macular ischemia in posterior uveitis. Eye 1993;7:411-414. 186. Matsuo T, Sato Y, Shiraga F, et al: Choroidal abnormalities in Behc;et's disease observed by simultaneous indocyanine green and fluorescein angiography with scanning laser ophthalmoscopy. Ophthalmology 1999;106:295-300. 187. Cruz CD, Adachi-Usami E, Kakisu Y: Flash electroretinograms and pattern visually evoked cortical potentials in Behc;et's disease. Jpn J Ophthalmol 1990;34:142-148. 188. Ozoran K, Duzgun N, Tutkak H, et al: Fibronectin and circulating immune complexes in Behc;:et's disease. Rheumatol Int 1996;15:221-224. 189. Yazici H, pazarli H, Barnes C, et al: A controlled trial of azatllioprine in Behc;et's syndrome. N EnglJ Med 1990;322:281-285. 190. Michelson JB, Dhisari FV: Behc;et's disease. Surv Ophthalmol 1982;26:190-203. . 191. BenEzra D, Cohen E: Treatment and visual prognosis in Behc;et's disease. Br J Ophtllalmol 1986;70:589-592. 192. pazarli H, Ozyazgan Y, Actunc T: Clinical observations on hypoyon attacks of Behc;et's disease in Turkey. In: YIlth International Conference on Behc;et's Disease. [Abstracts], Rochester MN, September 14-15, 1979. 193. Reed BJ, Morse LS, Schwab IR: High-dose intravenous pulse methylprednisolone hemisuccinated in acute Behc;et's retinitis. Am J OphthalmoI1998;125:410-411. 194. Santamaria]: Steroidal agents: The systemic and ocular complications. Ocul Inflamm Ther 1988;1:19-25. 195. Mamo JD: Treatment of Behc;et'~ disease with chlorambucil. A follow-up report. Arch Ophthalmol 1976;94:580-583. 196. Trichoulis D: Treatment of Behc;et's disease with chlorambucil. Br OphthalmoI1976;60:55-57. 197. Hijikata K, Masuda K: Visual prognosis in Behc;et's disease: Effects of cyclophosphamide and colchicine. Jpn J Ophthalmol 1978;22:506-519. 198. Nussenblatt RB, Palestine AG: Cyclosporine: Immunology, pharmacology and tllerapeutic uses. Surv Ophthalmol 1986;31:159-169.

IAI'}II:~S-II:SII:HCII:

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199. Mamo JG, Azzam SA: Treatment of Behc;et's disease with chlorambucil. Arch Ophthalmol 1970;84:446-450. 200. Godfrey WA, Epstein WV, O'Connor GR, et al: The use of chlorambucil in intractable idiopathic uveitis. Am J Ophthalmol 1974;78:415-428. 201. Pivetti-Pezzi P, Gasparri V, De Liso P, et al: Prognosis in Behc;et's disease. Ann Ophthalmol 1985;17:20-25. 202. Tessler HH, Jennings T: High-dose short term chlorambucil for intractable sympathetic ophthalmia and Behc;et's disease. BrJ Ophthalmol 1990;74:353-357. 203. Tabbara KF: Chlorambucil in Behc;et's disease. A reappraisal. Ophthalmology 1983;90:906-908. 204. Oniki S, Kurakazu K, I\awata K: Immunosuppressive treatment of Behc;et's disease with cyclophosphamide. Jpn J Ophthalmol 1976;20:32-40. 205. Gills JP, Buckley CE: Cyclophosphamide tllerapy of Behc;et's disease. Ann OphthalmoI1970;2:399-405. 206. Foster CS, Baer JC, Raizman MB: Therapeutic responses to systemic immunosuppressive chemotherapy agents in patients with Behc;et's syndrome affecting the eyes. In: o 'Duffy JD, Kokmen E, eds. Behc;et's disease: Basic and clinical aspects. New York, Marcel Dekker, 1991, pp 581-588. 207. Fain 0, Du LTH, Wechsler B: Pulse cyclophosphamide in Behc;et's disease. In: O'Duffy JD, Kokmen E, eds. Behc;:et's disease: Basic and clinical aspects. New York, Marcel Dekker, 1991, pp 569-573. 208. Ozyazgan Y, Yurdakul S, Yazici H, et al: Low dose cyclosporin A versus pulsed cyclophosphamide in Behc;:et's syndrome: A single masked trial. BrJ OphthalmoI1992;76:241-243. 209. Sigal NH, Dumont F]: Cyclosporine A, FK-506, and rapamycin: Pharmacologic probes of lymphocyte signal transduction. Ann Rev Immunol 1992;10:519-560. 210. Nussenblatt RB, Palestine AG, Chan CC, et al: Effectiveness of cyclosporin therapy for Behc;et's disease. Arthritis Rheum 1985;28:671-679. 211. Nussenblatt RB, Palestine AG, Rook AH, et al: Treatment of intraocular inflammation Witll cyclosporine A. Lancet 1983;1:235-238. 212. Nussenblatt RB, Palestine AG, Chan CC: Cyclosporin A in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents. Am J Ophthalmol 1983;96:275-282. 213. Nussenblatt RB, Palestine AG, Chan CC, et al: Improvement of uveitis and optic nerve disease by cyclosporin in a patient with multiple sclerosis. AmJ OphtllalmolI984;97:790-:-791. 214. Nussenblatt RB, Palestine AG, Chan CC: Cyclosporin therapy for uveitis: Long-term follow up. J Ocul Pharmacol 1985;1:369-382. 215. Binder AI, Graham EM, Sanders MD, et al: Cyclosporine A in the treatment of severe Behc;:et's uveitis. Br J Rheumatol 1987;76:285291. 216. BenEzra D, Nussenblatt RB, Timonen P: Optimal use of Sandimmline in endogenous uveitis. Berlin, Springer-Verlag, 1988. 217. Whitcup SM, Salvo EC, Nussenblatt RB: Combined cyclosporine and corticosteroid therapy for sight-threatening uveitis in Behc;et's disease. AmJ OphthalmoI1994;118:39-45. 218. Sajjadi H, Soheilian M, Ahmadieh H, et al: Low dose cyclosporinA tllerapy in Behc;et's disease. J Ocul Pharmacol 1994;10:553-560. 219. Atinaca LS, Batioglu F: The efficacy of cyclosporin-A in the treatment of Behc;et's disease. Ophthalmic Surg 1994;25:321-327. 220. Hayasaka S, I\awamoto K, Noda S, et al: Visual prognosis in patients with Behc;et's disease receiving colchicine, systemic corticosteroid or cyclosporin. Ophthalmologica 1994;208:210-213. 221. Chavis PS, Antonios SR, Tabbara KF: Cyclosporine effect on optic nerve and retinal vasculitis in Behc;et's disease. Doc Ophthalmol 1992;80:133-142. 222. Martin DF, DeBarge LR, Nussenblatt RB, et al: Synergistic effect of rapamycin and cyclosporine A on tlle inhibition of experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci 1993; 34:S1476. 223. Insel PA: Analgesic-antipyretics and antiinflammatory agents: Drugs employed in the treatment of rheumatoid arthritis and gout. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. New York, Pergamon Press, 1990, pp 674-676. 224. Nussenblatt RB, Plestin AG: Uveitis, Fundamentals and Clinical Practice. Chicago, Year Book Medical, 1989, pp 116-144. 225. Raynor A, A1<.ari AD: Behc;et's disease and treatment with colchicine. J Am Acad Dermatol 1980;2:396-400.

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226. Allison AC, Eugui EM: Mycophenolate mofetil (RS-61443): Mode of action and effects on graft rejection. In: Thompson AW, Starzl TE, eds. Immunosuppressive Drugs: Developments in Anti-rejection Therapy. Boston, E Arnold, 1994, 141-159. 227. Allison AC, Eugui EM: Immunosuppressive and other effects of mycophenolic acid and an ester prodrug mycophenolate mofetil. Immunol Rev 1993;136:5-28. 228. Siconolfi L: Mycophenolate mofetil (CellCept): Immunosuppression on the cutting edge. AACN Clin Issues 1996;7:390-402. 229. Larkin G, Lightman S: Mycophenolate mofetil: A useful immunosuppressive in inflammatory eye diseases. Ophthalmology 1999;106:370-374. 230. Alpsoy E, Yilmaz E, Basaran E, et al: Interferon therapy for Beh\=et's disease. JAm Acad Dermatol 1994;31:617-619. 231. o 'Duffy JD, Calamia K, Cohen S, et al: Interferon-')' treatment of Beh\=et's disease. J Rheumatol 1998;25:1938-1944. 232. Zouboulis CC, Orfanos CE: Treatment of Adamantiades-Belwet's disease with systemic interferon-')'. Arch Dermatol 1998;134:10101016. 233. Kotter I, Eckstein AK, Stubiger N, Zierhut M: Treatment of ocular symptoms of Beh\=et's disease with interferon alpha 2a: A pilot study. Br J Ophthalmol 1998;82:488-494. 234. Wizemann AI, Wizemann v: Therapeutic effects of short-term plasma exchange in endogenous· uveitis. Am J Ophthalmol 1984;97:565-572. 235. Yasui K, Ohta K, Kobayashi M, et al: Successful treatment of Beh\=et's disease with pentoxifylline. Ann Intern Med 1996; 124:891-893. 236. Calguneri M, Kiraz S, Ertenli I, et al: The effect of prophylactic penicillin treatment on the course of arthritis episodes in patients with Beh\=et's disease. A randomized clinical trial. Arthritis Rheum 1996;39:2062-2065.

237. Gardner-Medwin JM, Smith NJ, Powell RJ: Clil~ical experience with thalidomide in the management of severe oral and genital ulceration in conditions such as Beh\=et's disease: Use of neurophysiological studies to detect thalidomide neuropathy. Ann Rheum Dis 1994;53:828-832. 238. Rojas B, Zafirakis P, Foster CS: Cataract surgery in patients with uveitis. Curl' Opin Ophthalmol 1997;8:6-12. 239. Foster CS, Fong LP, Singh G: Cataract surgery and intraocular lens implantation in patients with uveitis. Ophthalmology 1988;96:281-288. 240. Tabbara I\F, Chavis PS: Cataract extraction in Beh\=et's disease. Ocul Immunol Inflamm 1997;5:27-32. 241. Ciftci OU, Ozdemir 0: Cataract extraction in Beh\=et's disease. Acta Ophthalmol Scand 1996;74:74-76. 242. Yazici H, Tuzun YU, pazarli H: Influence of age of onset and patient's sex on the prevalence and severity of manifestations of Beh\=et's syndrome. Ann Rheum Dis 1984;43:783-789. 243. Yoshikawa K, Ichiishi A, Kotake S, et al: Posterior sub-Tenon's space injection of repository corticosteroids in uveitis patients with cystoid macular edema. Nippon Ganka Gakkai Zasshi 1993; 97:1070-1074. 244. Atmaca LS: Experience with photocoagulation in Belwet's disease. Ophthalmic Surg 1990;21:571-576. 245. Minura Y: Surgical results of complicated cataract in Belwet's disease. In: Reports of the Beh\=et's Disease Research Committee. Japan, Ministry of Health and Welfare, 1976, pp 152-159. 246. Mamo JG: The rate of visual loss in Beh\=et's disease. Arch Ophthalmol 1970;84:451-452. 247. Demiroglu H, Batista I, Dii.ndar S: Risk factor assessment and prognosis of eye involvement in Beh\=et's disease in Turkey. Ophthalmology 1997;104:701-705.

Masoud Soheilian

DEFINITION Polyarteritis nodosa (PAN) (also called periarteritis and polyangiitis) is a group of rare multisystemic diseases with necrotizing vasculitis but without granulomatous features (as in Wegener's granulomatosis). They are characterized by patchy but widespread involvement of small to medium-sized muscular arteries and sometimes even small vessels such as arterioles, capillaries, and venules. Involvement leads to focal signs that result from local circulatory disturbances and ischemia, caused by thrombosis, embolism, or rupture of the vessel wall. There are two forms of systemic PAN: macroscopic PAN (MaPAN) and microscopic PAN (MiPAN).

HISTORY AND CLASSIFICATION The term nodosa in PAN reflects the characteristic.nodular appearance of the diseased vessels. It was first described by Kussmaul and Maier in 1866. 1 They described a 27-year-old tailor's apprentice with nephritis, mononeuritis multiplex, and abdominal pain, and they named this condition periarteritis nodosa,l1.oting extensive inflammation, thrombosis, and fibrosis of small and mediumsized arteries resulting in aneurysmal thickening of arteries, resembling a string of knots.1>eriarteritis nodosa was renamed polyarteritis nodosa in 1903 by Ferrari, who emphasized the transmural and multifocll nature of the inflammation. 2 A number of different clinical and pathologic types of vasculitis were described over the next 50 years. In 1948, Zeek and colleagues 3 were the first to propose a classification scheme for vasculitis. They categorized five types of necrotizing vasculitis based on clinical and pathologic features and size and type of vessel involvement. The American College of Rheumatology Subcommittee on Classification of Vasculitis developed a standard vasculitis classification and selected seven forms of vascuIitis. 4 Subsequently the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis set out to correct the problem of a lack of standardized diagnostic terms and definitions. 5 According to the Chapel Hill classification, PAN is a disease affecting all arteries and therefore all systems. However, because involvement of small vessels such as arterioles and venules has been described in PAN, the 19th century classification of PAN needed to be revised and reclassified. The classification system proposed by this group limits the definition to exclude involvement of small vessels and glomerulonephritis. These cases are designated as microscopic polyangiitis or polyarteritis (MiPAN). However, some authorities argue that this distinction is unwarranted because there is no clear biologic evidence to support the existence of two different disease entities.

as women. 6 Exact appreCIatIOn of the incidence of systemic PAN is difficult to achieve. Estimates of the annual incidence of PAN-type systemic vasculitis in a general population range from 4.6 per million in England,? to 9.0 per million in Minnesota,S to 77 per million in a hepatitis B hyperendemic Alaskan Eskimo population. 9 Another published study has shown a prevalence rate of 7 per million. 10 The estimated annual mortality rate for PAN in New York City in 1950 was 1.2 to 1.5 per millionY It should be emphasized that most studies of PAN in the past were likely to include both Inicroscopic and macroscopic forms.

CLINICAL CHARACTERISTICS

Systemic Manifestations Polyarteritis nodosa is a systemic illness that can. affect almost any organ. The onset is variable depending on the organ system affected. The general signs and sYInptoms of serum sickness may occur, including fever, malaise, weight loss, myalgias, and arthralgias. Certain main clinical presentations have been distinguished: 12 1. A nonspecific subacute or chronic pyrexial wasting illness 2. An atypical abdominal illness 3. A primary renal disorder 4. A combination of polyneuritic and polymyositic features The order and progress of system involvement are variable. Sometimes, only one organ or system may be involved for a long period. More commonly, multisystem involvement occurs early.

Renal Involvement Renal manifestations l3 , 14 are eventually present in three of every four patients with PAN. Vascular lesions such as microaneurysms with vessel stenosis and thrombosis may lead to cortical infarction. These pathologic findings may preclude renal biopsy because of the risk of vessel ruptureY Kidney involvement with or without hypertension is a primary cause of death in patients with systemic PAN".

Cardiovascular Involvement Cardiovascular manifestations are as frequent as renal involvement and are the second leading cause of death in patients with PAN.12 Hypertension, a consequence of renal involvement, is an almost constant accompanying feature. Coronary thrombosis, pericarditis, intrapericardial hemorrhage, and acute aortitis can occur. Myocardial involvement may lead to dysrhythmias, heart failure, and infarction.

EPIDEMIOLOGY

Cutaneous Involvement

PAN is an uncommon disease that affects mostly 40- to 60-year-old adults; men are twice as likely to be affected

Approximately one fifth to one half of patients with systemic PAN have cutaneous manifestations. 12 The most

CHAPTER 57: POLYARTERITIS NODOSA

significant clinical sign is the presence of cutaneous or subcutaneous nodules, which occur in groups along the course of superficial arteries. They are found around the knee,anterior lower leg, and dorsum of the foot (Fig. 57-1}.16 They are the result of local necrosis of the arterial wall at points of bifurcation. Pulsatile aneurysms result from healing by fibrosis. Local rupture may give rise to a local intracutaneous hematoma or ecchymosis. Peripheral embolization of thrombi causes infarction of the tissues, and the fingers and toes in particular may be affected by small infarcts, splinter hemorrhage, Osler's nodes, and gangreneP Infarcts in the skin may present as tender nodules, purpuric plaques, or hemorrhagic bullae. A cutaneous localized form of PAN characterized by cutaneous nodules and livedo reticularis exists; however, patients with systemic disease usually do not manifest this type of lesion. 17

FIGURE 57-2. Abdominal aortic angiogram in a patient with recurrent scleritis and episodic abdominal pain. Note the sacular aneurysms of the mesenteric artery, nearly a pathognomonic feature of polyarteritis nodosa. (Courtesy of C. Stephen Foster, M.D.)

Gastrointestinal Involvement Abdominal pain is caused by polyarteritic lesions in the submucous and muscular layers of the intestine, or by mesenteric thrombosis (Fig. 57-2) or infarcts in the liver and spleen, giving rise to perihepatitis and perisplenitis. Gangrene of the bowel, peritonitis, perforation, and intra-abdominal hemorrhage are other features. Steatorrhea may occur as a result of the scarred bowel. 18 Acute pancreatitis and pancreatic fibrosis may occur.

Musculoskeletal Involvement Nondeforming and nonerosive arthritis and arthralgia, resembling that in rheumatic fever, may occur without gross physical signs. Bony changes in the form of periosteal thickening of the tibia and fibula may also occur. A true myopathy may occur in PAN. In some cases, the disorder may be confined to the skin and muscle, presenting with pain in the legs. 19

I

plex is a symptom complex of pain, paresthesia, or paresis of a single peripheral nerve occurring secondary to interruption of the blood supply to that nerve. Other manifestations of neurologic involvement vary widely, from a Guillain-Barre-like syn.drome to hemiplegia, convulsion, or multiple sclerosis-like features. 15

Genitourinary Involvement Epididymal pain is an extremely suggestive clinical feature and is virtually pathognomonic of polyarteritis nodosa in the appropriate clinical context. Biopsy of the involved epididymis unequivocally establishes the diagnosis in cases where other tissue is unavailable for sampling or the diagnosis is uncertain.

Neurologic Involvement

Ocular Manifestations

Neurologic manifestations are usually the result of involvement of the arteries of the vasa nervorum and are usually limited to the peripheral nervous system. Both motor and sensory changes occur. Mononeuritis multi-

PAN can involve almost every tissue of the eye, depending on which vessels are affected by the vasculitic process. Ocular manifestations appear in 10% to 20% of PAN patients, and it can be the first manifestation of the disease. 2o-22 The ophthalmologist may play an important role in the diagnosis and management of a patient with this potentially lethal vasculitic disease.

Anterior Segment Manifestations

FIGURE 57-I. Subcutaneous nodule, dorsal aspect of the foot of a patient who subsequently was biopsied (see Figure 57-7), with histopathologically proven polyarteritis nodosa. (Courtesy of C. Stephen Foster, M.D.) (See color insert.)

The conjunctiva may be hyperemic and edematous, with occasional subconjunctival hemorrhages. Sjogren's syndrome with keratoconjunctivitis sicca has been described in association with PAN. Conjunctival infarction may produce pale yellow, raised, and friable conjunctival lesions with subconjunctival hemorrhages. 23 Vascular inflammation of episcleral, scleral, and limbal vessels may lead to episcleritis, scleritis, and sclerokeratitis. 24-27 The incidence of PAN in patients with scleritis ranges from 0.68 to 6.45. 28-30 Necrotizing anterior scleritis, often associated with peripheral ulcerative keratitis (PUK) , is the most frequent type of scleritis in patients with PAN.21, 26, 27 The scleritis becomes extremely painful and is highly destructive unless the correct diagnosis is made and control of the underlying systemic disease is

CHAPTER 57: POLYARTERITIS ..........,...........""

achieved (Fig. 57-3). The PUK corneal ulceration is pro~ gressive, both circumferentially and centrally, with undermining of the central edge of the ulcer that results in an overhanging lip of the cornea. However, scleral involvement helps to distinguish classic Mooren's ulcer from the sclerokeratitis-associated vasculitic diseases such as PAN. On occasion, episcleritis may be seen in patients with PAN, but it is less common or ominous than scleritis. 24, 29, 31 In most cases, sclerokeratitis presents after PAN has been diagnosed, but it occasionally may be the presenting manifestation of the disease. 20-22 Cogan's syndrome (nonluetic interstitial keratitis with audiovestibular disease) has been described in association with PAN.32

Uveoretinal Manifestations Involvement of iris vasculature Inay produce acute, nongranulomatous iritis with leakage of protein into the anterior chamber. 23 ,25 A vitritis may also be noted. 33 Diffuse bilateral nongranulomatous panuveitis associated with retinal vasculitis has also been described in PAN.34 The most common ocular findings in PAN are choroidal and retinal vasculitis24 (Figs. 57-4 and 57-5). Choroidal vasculitis is the most frequent histologic abnormality,35-37 but the presence of yellow subretinal patches is less often appreciated clinically. Involvement of the posterior ciliary arteries and choroidal vessels may manifest as choroIdal infarcts and exudative retinal detachments. 38 The retinopathy of PAN is sometimes secondary to coexistent hypertension, but it may occur as a re&J;1lt of retinal vasculitis. Subhyaloid hemorrhage, retinal hemorrhages, edema, lipid exudate, cotton-wool spots, marked irregularity of the caliber of retinal vessels, and exudative retinal detachment have all been described. Vascular occlusion, particularly central retinal artery occlusion, is not uncommon. 25 ,39 Fluorescein angiography has shown a normal retinal circulation with delayed choroidal filling,40 and an arteritis with staining of involved arterial segments, dilated and tortuous capillaries both in the peripapillary region and

FIGURE 57-3. Left eye of patient described in Figure 57-2, with resolving scleritis but now with the onset of peripheral ulcerative keratitis prior to the institution of adequate doses of cyclophosphamide therapy. (Courtesy of C. Stephen Foster, M.D.) (See color insert.)

FIGURE 57-4. Retinal vasculitis, right eye, in a patient with polyarteritis nodosa. Note the slightly hazy view of tlle fundus, because of tlle presence of vitreal cells. Frank arteritis is clinically obvious, and fluorescein angiogram confirmed tllis (see Figure 57-6). (Courtesy of C. Stephen Foster, M.D.)

in the vicinity of the diseased arteries, and thrombosis of the retinal vein, usually without evidence of a retinal periphlebitis 41 (Fig. 57-6). However, Morgan and colleagues reported a case of biopsy-proven PAN in which the patient presented with bilateral iritis, vitritis, and retinal vasculitis involving both the retinal arteries and veins, demonstrated clinically and by fluorescein angiography.38 Leakage through diseased vessel walls may also be noted. 41

Neurophthalmic Manifestations Optic nerve involvement takes several different forms. Papilledema or papillitis due to optic nerve vasculitis may occur. In one study, papilledema was present in 10% of patients. 39 Orbital involvement may produce exophthalmos or a pseudotumor condition as a result of inflammation of orbital vessels 39; 42-45 and sometimes assumes the picture of an orbital neoplasm. 44

FIGURE 57-5. Fluorescein angiogram of the same patient as shown in Figure 57-4, illustrating tlle focal areas of delayed choroidal filling, which are indicative of choroidal involvementfrom the arteritic process. (Courtesy of C. Stephen Foster, M.D.)

·CHAPTER 57: POLYARTERITIS NODOSA

FIGURE 57-6. Fluorescein angiogram of the same patient as shown in Figure 57-4, late phase, demonstrating the extensive leakage from the inflamed retinal arterioles. (Courtesy of C. Stephen Foster, M.D.)

Arteritis of the posterior ciliary vessels with intermittent choroidal vascular insufficiency may be responsible for recurrent episodes of monocular constriction of the visual field with sparing of central vision. 40 Vasculitic involvement of central and peripheral nervous system may produce third, fifth, sixth, and seventh nerve palsies, hemianopia, nystagmus, amaurosis fugax, diplopia,45 and Horner's syndrome. 39

PATHOGENESIS AND ETIOLOGY The etiology of polyarteritis nodosa and the cause of the arteritis are unknown. Some evidence supports a role for immune complex-mediated vessel daluage, because circulating immune complexes are found frequentl y 46 and (less commonly) serum complement is also diminished. 47 However, immune deposits of immunoglobulins and complement are seldom found in involved tissue in PAN.48 It is likely that various antigens may trigger a circulating immune complex-mediated vasculitis. Viruses may contribute to the pathogenesis of arteritis, with the most commonly associated virus being hepatitis B. Between 30% and 70% of patients with PAN have antihepatitis B antibodies. 49 Recently other viruses such as human immunodeficiency virus (HIV) ,50 cytomegalovirus,51 hepatitis A and C,52 human T-cell leukemia-lymphoma virus,53 and parvovirus 54 have been associated with PAN. Viruses can infect endothelial cells and alter their functions, including induction of receptors for the Fe portion of IgG, induction of receptors for C3B, and promotion of leukocyte adherence. 55 Infected endothelial cells express class 2 antigens and are capable of producing interleukin1 (IL-l) .56 Finally, as a result of viral infection, the biology of endothelial cells is altered, permitting the endothelial cells to participate in a chronic inflammatory process. Other known factors associated with PAN include drug abuse,57 hyposensitization treatment,58 B-cell neoplasm,59 and acute otitis media. 60 Antiendothelial cell antibodies may have a pathogenic role in PAN in the presence of factors such as tumor necrosis factor (TNF), IL-l, and interferon-gamma (IFN-'Y) .61 It is possible that PAN could be a result of several

etiologic agents' having a final common pathway of inducing necrotizing vasculitis. Inflammation of the arterial wall, induced by immune complexes, direct organism invasion, or antibodies toward endothelial cells, injures and perturbs the endothelial cells, resulting in an elevation of Von Willebrand factor and factor VIII in the blood of patients, just as in other systemic vasculitis diseases. The injured endothelial cells may release platelet-activating factor, which may influence the chemotaxis of neutrophils and eosinophils plus the release of other cytokines. 62 IL-l and TNF that may. be released from endothelial cells can convert a normally anticoagulant endothelial cell surface to a procoagulant surface. Finally, adherence of endothelial cells by neutrophils, monocytes, and lymphocytes increases. Consequently, the injured endothelial cells, by release of a variety of cytokines, become the promoter and the focus of an immune response, clot formation, and cellular proliferation. Injury to the endothelium of blood vessels also diminishes its modulating effect on underlying smooth muscle tone that is usually mediated by the production of a dilator substance-endothelially derived relaxing factor (which may be nitric oxide) 63, 64-and ultimately alters blood vessel contractility. Consequently, although in the healthy state, the endothelium produces factors that relax the underlying smooth muscle in response to numerous mediators and physiologic conditions; in the diseased endothelium, vasoconstrictive events may dominate. Coagulation abnormalities such as hyperfibrinogenemia, thrombocytosis, and diminished fibrinolytic activity may occur in systemic vasculitic disorders, such as PAN, which result in arterial occlusive changes. 61 In summary, the effect of inflammation on the blood vessels, and specifically on the endothelium, is a net increase in vasoconstriction, platelet aggregation, clot formation, and release of growth factors that may result in luminal occlusion. The proliferation of endothelial and smooth ,muscle cells triggered by inflammation may be as important as the inflammation itself in determining the outcome of the pathologic changes in the artery.

MaPAN is a necrotizing segmental vasculitis involving small and medium-sized arteries, principally at branching and bifurcation points. The involvement may be so focal that only a solitary microscopic lesion is found in a large tissue section. The segmental necrotizing vasculitis is characterized by fibrinoid changes of the media with destruction of the internal elastic lamina, accompanied by infiltration of the media and adventitia, initially by neutrophils and later by mononuclear cells, the latter imparting a frankly granulomatous morphology to some of more chronic vascular lesions (Fig. 57-7). Fibroblastic proliferation ensues, with secondary thrombosis and resultant organ infarction. A subsequent reparative medial response occurs, characterized by replacement of the medial wall by granulation tissue and intimal fibrosis. A disruption of normal architecture of the entire vessel wall results in the typical aneurysmal dilations that give the disease its name. It must be appreciated that in PAN, diagnostic histopathology will not be obtained from su-

CHAPTER 57: POLYARTERITIS

III.H,....,lF"II>r.c

tion in renal, hepatic, and gastrointestinal vessels may be helpful in establishing the diagnosis, although they may be found in systemic lupus erythematosus 74 and fibromuscular dysplasia. 75

FIGURE 57-7. Histopathology, H & E section, 800 X, from the biopsy of the subcutaneous nodule of the patient shown in Figure 57-1. Note the neutrophil invasion of the media of this artery, with fibrinoid necrosis of the vessel wall. (Courtesy of C. Stephen Foster, M.D.) (See color insert.)

perficial biopsies of the cutaneous lesions. Diagnostic changes in muscular arteries are usually seen in tissue from muscle, kidney, or even testes or occasionally from deep incisional skin biopsies. 17, 55

DIAGNOSIS The diagnosis of systemic PAN is generally based on clinical and histopathologic grou'1.ds. General laboratory evaluation is nonspecific and only supportive of clinical diagnosis. Any patient with· PUK, scleritis, or occlusive retinal vasculitis should be reviewed for systemic evidence of PAN. A tissue diagnosis is usually necessary for confirmation. Muscle, renal, skin, peripheral nerve, testicular, or epididymal tissue is often required. 55,57 Biopsy of involved tissue may demonstrate a hemorrhagic vasculitis and fibrinoid necrosis, which establishes the diagnosis. 58 Testicular and skin biopsy can confirm the diagnosis in 50% to 80% of patients.59, 70 Autopsy studies have shown vascular inflammation in the testes in 86% of patients when the entire testis is sectioned and examined thoroughly.70 Blind biopsy of asymptomatic organs rarely establishes the diagnosis. 31 , 71

Laboratory Findings Most laboratory tests are nonspecific and reflect only the systemic nature of the disease. The erythrocyte sedimentation rate (ESR), neutrophil count, and serum globulin levels are usually elevated. Eosinophilia may be present. When the urinary sediment reveals red cells, red cell casts, or proteinuria, renal disease must be suspected. Hypocomplementemia may reflect a more active disease. Approximately one third of patients with PAN have hepatitis-B antigenemia. 72 Cryoglobulins may be present, and circulating immune complexes may be detected. Rheumatoid factor and antinuclear antibody are usually negative, but antineutrophil cytoplasmic antibody (ANCA) may be positive. In a review of published studies, the average diagnostic sensitivity of c-ANCA for MaPAN was 5%, and of p-ANCA it was 15%.73 The angiographic finding of small, aneurysmal dila-

Important entities to exclude in the differential diagnosis of polyarteritis nodosa include obvious systemic diseases associated with retinal vasculitis, such as AdamantiadesBeh~et's disease, systemic lupus erythematosus, mixed connective tissue disease, dermatomyositis, and progressive systemic sclerosis. Dermatomyositis and progressive systemic sclerosis can usually be differentiated on the basis of systemic features.. The clinical picture and serologic abnormalities are distinct for systemic lupus erythematosus and for mixed connective tissue diseases. While both entities may manifest buccal mucosal ulcerations, the aphthous lesions of Adamantiades-Beh~et's disease are distinct, they may also appear on the external genitalia, and these patients frequently have associated arthralgias and erythema nodosum.

This group of disorders is potentially fatap4, 58 and yet there is no completely satisfactory treatment for either the systemic or the ocular components. As in other vasculitic diseases, the ocular manifestations of PAN are reliable signs of systemic vasculitis and represent a clear indication for immunosuppressive therapy. These patients must be treated with systemic cyclophosphamide and corticosteroids, and it is important to treat the patient rather than the laboratory abnormalities, although the ESR is a useful indication of activity. The combination of prednisolone (60 to 120 mg) with cyclophosphamide (1 to 2 mg/ kg/day) results in an 80% to 96% 5-year survival rate. 75 , 77 If the patient is intolerant to cyclophosphamide, other immunosuppressants should be used in an effort to save not only the patient's eye but the patient's life as well. Such alternatives include azathioprine, methotrexate, cyclosporine A, and, recently, tacrolimus. 78 Sulfapyridine therapy has also been shown to induce remissions in patients with predominantly cutaneous disease. 79 The use of antiplatelet drugs concomitantly with the initiation of corticosteroid treatment might modify the potential vasospastic and platelet-aggregation effects of the disease. Comorbid diseases, such as hypertension, diabetes mellitus, and hyperlipidemia, must be vigorously treated. Agents inhibiting cytokines, growth factors, and cellular proliferation may play a therapeutic role in the future. Intravenous gamma globulins and lllonoclonal antibody therapy have been helpful in some patients. IFN-a has been effective in patients with PAN associated with hepatitis B.80

PROGNOSIS Prior to the advent of new immunosuppressive chemotherapies, systemic PAN was usually fatal and was associated with a progressive course, leading to death from renal or cardiac complications. Without therapy, classic PAN carries an 80% to 90% 5-year mortality rate. COl-ticQsteroids have reduced this rate to 50%, and the addition of cyclophosphamide has profoundly improved survivaP6

CHAPTER. 57: POLYARTERITIS NODOSA

are older age and renal failure. The usual treatment for patients with MiPAN and renal involvement or significant lung involvement is prednisone (60 mg/day) and cyclophosphamide (1 to 2 mg/kg/day). Intravenous gamma globulin has been successfully used in the treatment of cyclophosphamide-resistant MiPAN. 68

Poor prognostic factors at the time of diagnosis include gastrointestinal vasculitis and older age (over 50 years) at diagnosis. 7, 31, 81 Other identified factors indicative of a poor prognosis include renal, cardiac, and neuropathic involvement.7, 81, 82

Microscopic Polyarteritis Nodosa MiPAN, also called polyangiitis, is now distinguishable from MaPAN by the criteria established at the Chapel Hill Conference on Nomenclature (Table 57-1).5 Based on this recent classification of vasculitis syndromes, MiPAN histologically refers to a necrotizing vasculitis involv~ ing capillaries, venules, and arterioles along with a focal segmental necrotizing glomerulonephritis and sometimes crescent formation. Pulmonary involvement can occur as a result of capillaritis and is characterized clinically by hemoptysis and histologically by a neutrophilic capillaritis. This combination of renal and pulmonary disease often suggests the diagnosis of Go~dpasture'ssyn.drome. 83 Nasopharyngeal involvement is frequent, with oral ulcers, sinusitis, and epistaxis among the more common manifestations. Skin involvement is also frequent. Involvement of small and medium-sized arteries does not exclude the diagnosis of MiPAN. The p-ANCA (antibody to myeloperoxidase) autoantibody pattern, a marker for MiPAN, is found in 50% to 80% of affected patients; about 40% have the c-ANCA (antibody to proteinase-3) autoantibody pattern,84 with few or no immune deposits in involved vessels. Positive ANCA and negative serologic tests for hepatitis B help differential MiPAN from MaPAN. MiPAN differs histopathologically from Wegener's granulomatosis by the absence of extravascular inflammation. Ocular manifestations in MiPAN are UnCOmlTIOn but may include conjunctival injection, nodular lesions of the conjunctiva, peripheral corneal thinning or ulceration, scleritis, PUK, sicca syndrome, eyelid edema, and nodular lesions of the skin of the eyelid margin with an ulcerative surface. 85 Review of the literature after the Chapel Hill classification on Nomenclature of Systemic Vasculitis disclosed only one case of uveitis with retinal vasculitis and vitreous hemorrhage reported in pure MiPAN.78 The 5-year survival of MiPAN is approximately 60%. Death is caused by uncontrolled active disease or superimposed infection. Factors contributing to early demise

TABLE 57-I. CLINICAL fORMS Of SYSTEMIC POLYARTERITIS NODOSA (PAN) ADOPTED BY THE CHAPEL HILL CONSENSUS CONfERENCE ON THE NOMENCLATURE Of SYSTEMIC VASCULITIS Macroscopic polyarteritis nodosa (MaPAN)

Microscopic polyarteritis nodosa (MiPAN)

Necrotizing inflammation of mediumsized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Necrotizing vasculitis with few or no immune deposits affecting small vessels (capillaries, venules, or arterioles). Necrotizing arteritis involving small and medium-sized arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs.

CONCLUSIONS

l

The classification system of patients suspected of having PAN has changed recently. MaPAN is diagnosed when necrotizing inflammation of medium-sized or small arteries is observed without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Whenever necrotizing vasculitis, affecting small vessels (i.e., capillaries, venules, or arterioles) with few or no immune deposits, is found, MiPAN is diagnosed, even if concurrent small and medium~sized artery involvement exists. Ocular involvement is seen in 10% to 20% of patients with PAN but is less commonly observed in MiPAN. Both c-ANCA and p-ANCA patterns are serologically demonstrable in nearly half of the patients with MiPAN, whereas they have low diagnostic sensitivities and specificities for MaPAN. Several inflammatory conditions can be mistaken for either MaPAN and MiPAN: Wegener's granulomatosis, Adamantiades-Beh<;et's disease, systemic lupus erythematosus (including some forms of rheumatoid arthritis with widespread arterial changes), and other forms of systemic vasculitis. The clinical features and tissue biopsy can help differentiate PAN from other entities. The current therapy for PAN involves a combination of oral cyclophosphamide and corticosteroids. Systemic corticosteroids alone are not effective in controlling ocular inflammation in PAN. Ophthalmologists should be familiar with the clinical features of this rare disease, as this potentially fatal disorder may present initially with ocular involvement. A close collaboration with a team of other treating physicians (such as a rheumatologist, dermatologist, nephrologist,hematologist, or pulmonary physician), especially in the comanagement of immuno=-suppressive therapy, ensures the best possible care for these patients.

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POLYARTERITIS ...II .....'LP ...'..""..

Oph42. Friedenwald JS, Rones B: Ocular lesions in septicemia. t.halmol 1931;5:175. . 43. Gaynon IE, Asbury MK: Ocular findings in a case of .~=,,;~.hpr,,1 nodosa. AmJ Opht.halmol 1943;23:1072. 44. Van Wien S, Merz EH: Exopht.halmos secondary to periart.erit.is nodosa. Am J Opht.halmol 1963;56:204. 45. Gold DH: Ocular manifest.at.ions of connective tissue (collagen) diseases. In: Tasman W, Jaeger AE, eds: Duane's Clinical Opht.halmology, vol. 5. Philadelphia,].B. Lippincott, 1989, pp17-19. 46. Leib ES, Hibrawi H, Chia D, et. al: Correlation of disease act.ivity in syst.emic necrot.izing vasculitis wit.h immune complexes. J Rheumat.ol 1981;8:258. 47. Conn DL, McDuffie FC, Holley KE, et al: Immunologic mechanisms in syst.emic vasculitis. Mayo Clin Proc 1976;51 :511. 48. Ronco P, Verroust. P, Mignon F, et. al: Immunopat.hological st.udies of polyarteritis nodosa and Wegener's granulomatosis: A report. of 43 patient.s wit.h 51 renal biopsies. QJ Med 1983;52:212. 49. Gocke DJ, Hsu K, Morgan C, et al: Association between polyart.eritis nodosa and Aust.ralia antigen. Lancet. 1970;2:1149. 50. Calabrese LH, Est.es M, Yen-Leieberman B, et. al: Syst.emic vasculitis in association wit.h human immunodeficiency virus infect.ion. Art.hrit.is Rheum 1989;32:569. 51. Curtis JL, Egbert. BM: Cut.aneous cyt.omegalovirus vasculitis: An unusual clinical present.at.ion of a common opport.unistic pat.hogen. Hum Pat.hol 1982;13:1138. 52. Inman RD, Hodge M, Johnson MEA, et. al: Art.hritis, vasculitis, and cryoglobulinemia associated with relapsing hepat.itis A virus infection. Ann Int.ern Med 1986;105:700. 53. Haynes BF, Miller SE, Palker TJ, et. al: Identificat.ion of human Tcell leukemia virus in aJapanese pat.ient. wit.h adult. T-cell leukemia and cut.aneous lymphomat.ous vasculit.is. Proc Natl Acad Sci USA 1983;80:2054. 54. Li Loong TC, Coyle.PV, Anderson MJ, et. al: Human serum parvovirus associat.ed vasculitis. Post.grad Med J 1986;62:493. 55. Friedman HM: Infect.ion of endot.helial cells by common human viruses. Rev Infect. Dis 1989;2 (suppl 4) :700. 56. Bielke MA: Vascular endot.helium in immunology and infect.ious disease. Rev Infect. Dis 1989;2:273. 57. Cit.ron BP, Halpern M, McCarron M, et al: Necrot.izing angiitis associat.ed witll drug abuse. N EnglJ Med 1970;283:1003-1011. 58. Phanuphak P, Kohler PF, Stanford RE, et. al: Onset. of polyarteritis nodosa during allergic hyposensit.izat.ion t.reat.ment.. Am J Med 1980;68:479-485. 59. Elkon KB, Hughs GRV, Catovsky CJP, et. al: Hairy cell leukemia with polyarteritis nodosa. Lancet. 1979;2:280-282. 60. Sargent. JS, Christian CL: Necrotizing vasculitis aft.er acut.e serous ot.it.is media. Ann Int.ern Med 1974;81:195-199. 61. Conn DL: Polyart.eritis. In: Rheumat.ic Disease Clinics of Nortll America, vol 16. Philadelphia, W.B. Saunders, 1990, pp 341-362. 62. Brag'uet. P, Hosford D, Braquet M, et. al: Role ofcyt.okines and plat.elet-act.ivat.ing fact.or in microvascular immune injury. Int Arch Allergy Appl Immunol 1989;88:88. 63. Palmer RMJ, Ashton DS, Moncada S: Vascularendotllelial cells synt.hesize nit.ric oxide from L-arginine. Nat.ure 1988;333:664. 64. Vanhoutte PM: The endot.helium-modulat.or of vascular smoot.hmuscle t.one (edit.orial). N EnglJ Med 1988;319:512. 65. Patalano V], Sommers SC: Biopsy diagnosis of polyart.eritis nodosa. Arch Pat.hol 1961;72:1-7. 66. Diaz-Perez JL, Winkelmann RK: Cut.aneous periart.erit.is nodosa. Arch Dermat.ol 1974;110:407. 67. Dyck PJ, Conn DL, Okazaki H: Necrot.izing angiopat.hic neuropathy: Three-dimensional morphology of fiber degenerat.ion relat.ed to sit.es of occluded vessels. Mayo Clin Proc 1972;47:461. 68. Valent.e RM, Hall S, O'Duffy JD, Conn DL: Vasculitic syndromes. In: Kelly WN, Harris ED Jr, Ruddy S, Sledge CB, eds: Text.book of Rheumat.ology, 5t.h ed, vol. 2, Philadelphia, W.B. Saunders, 1997, pp 1079-1122. 69. Maxeiner SR Jr, McDonald JR, Kirklin JW: Muscle biopsy in t.he diagnosis of periart.eritis nodosa: An evaluation. Surg Clin Nort.h Am 1952;10:1225. 70. Dahl EV, Baggenst.oss AH, DeWeerdJH: Testicular lesions of periart.erit.is nodosa, wit.h special reference t.o diagnosis. Am J Med 1960;28:222. 71. Sizeland PC, Bailey RR, Lynn KI, Robson RA: Wegener's granulomat.osis wit.h renal involvement.: A 14-year experience. N Z Med J 1990;103:366-367.

CHAPTER 57:

NODOSA

72. Duffy j, Lidsky MD, Sharp jT, et al: Polyarthritis, polyarteritis, and hepatitis B. Medicine 1976;55:19-37. 73. Kallenberg CG, Brouwer E, Weening lJ, Cohen Tervaert JW: An.tineutrophil cytoplasmic antibodies: Current diagnostic and pathophysiological potential. Kidney Int 1994;46:1-15. 74. Longstreth PL, Lorobkin M, Palubinskas AJ: Renal microaneurysms in a patient with systemic lupus erythematosus. Radiology 1974;113:65. 75. McKusick VA: Buerger's disease: A distinct clinical and pathologic entity. JAMA 1962;181:93. 76. Fauci AS, Doppman jL, Wolff SM: Cyclophosphamide-induced remission in advanced polyarteritis nodosa. Am j Med 1978;64:890. 77. McCauley RL, johnston MR, Fauci AS: Surgical aspects of necrotizing vasculitis. Surgery 1985;97:104-110. 78. Sloper CM, Powell Rj, Dua HS: Tacrolimus (FK506) in the treatment of posterior uveitis refractory to cyclosporine. Ophthalmology 1999;106:723-728. 79. Diaz-Perez jL, Winkelmann RK: Cutaneous periarteritis nodosa: A

80.

81.

82. 83. 84.

85.

study of 33 cases. In: Wolff K, Winkelmann RK, eds: Major Problems in Dermatology. Philadelphia: WB Saunders Co., 1980, pp 273-284. Guillevin L, Lhote F, Leon A, et al: Treatment of polyarteritis nodosa related to hepatitis B virus with short-term steroid therapy associated with antiviral agents and plasma exchanges: A prospective trial in 33 patients. j Rheumatol 1993;20:289-298. Guillevin L, Du LTH, Godeau P, et al: Clinical findings and prognosis of polyarteritis nodosa, and Churg-Strauss angiitis: A study in 165 patients. Br j Rheumatol 1988;27:258. Sack M, Cassidy jT, Bole GG: Prognostic factors in polyarteritis. j Rheumatol 1975;2:411. Harman LE, Margo CE: Wegener's granulomatosis. Surv Ophthalmol 1998;42:458-480. Geffriaud-Ricouard C, Noel LH, Chauveau D, et al: Clinical spectrum associated with ANCA of defined antigen specificities in 98 selected patients. Clin Nephrol 1993;39:125-136. Caster jC, Shetlar Dj, Pappolla M.A, Yee RW: Microscopic polyangiitis with ocular involvement. Arch Ophthalmol 1996;114:346-348.

Sarkis H. Soukiasian

DEFINITION Wegener's granulomatosis is a distinct systemic clinicopathologic entity characterized by granulomatous vasculitis of the upper and lower respiratory tract with frequent involvement of the kidneys, the latter being a major determinant of poor outcome. l -4 Ocular involvement is seen in about 50% of cases. 5 - 8 Wegener's granulomatosis is usually classified within the spectrum of systemic necrotizing vasculitis (of the small arteries and veins), a group of disorders that may exhibit nonspecific features in the early stages but may evolve over time to more clinically recognizable patterns. 9-11 A number of classification systems for systemic vasculitis have been proposed and modified, each with limitations, as an understanding of the pathogenicity of most of the clinically recognized entities has been lacking, and tissue sampling errors, chronicity of disease, and partial therapy can greatly impact the pathologic features. 12- 17 Nonetheless, a useful classification has been formulated by Lie,18 which is partly based on the size of the involved blood vessels (Table 58-1); The classic diagnostic criteria for Wegener's granulomatosis was based on the initial detailed clinicaP9 and pathologic 20 findings presented'¥by Godman and Churg in 1954, which included the triad of necrotizing granulomas of the upper and lower respiratory· system, systemic TABLE 58-I. CLASSifiCATION Of VASCULITIS Primary vasculitides Affecting large-, medium-, and small-sized vessels Takayasu's arteritis Giant cell arteritis Isolated angiitis of the central nervous system Affecting predominantly medium- and small-sized blood vessels Polyarteritis nodosa Churg-Strauss syndrome Wegener's granulomatosis Affecting predominantly small-sized blood vessels Microscopic angiitis Sch6nlein-Henoch syndrome Cutaneous leukocytoclastic angiitis Miscellaneous conditions Beh«;;:et's syndrome Beurger's disease Cogan's syndrome Kawasaki disease Secondary vasculitides Infection-related vasculitis Vasculitis secondary to connective tissue disease Drug hypersensitivity-related vasculitis Vasculitis secondary to essential mixed cryoglobulinemia Malignancy-related vasculitis Hypocomplementemic urticarial vasculitis Post-organ transplant vasculitis Pseudovasculitic syndromes (antiphospholipid syndrome, atrial myxoma, endocarditis, Sneddon's syndrome) Modified from Lie JT: Illustrated histopathologic classification Clitelia for selected vasculitis syndromes: American College of Rheumatology Subcommittee on Classification of Vasculitis. Arthritis Rheum 1990;33:1074-1087, with permission.

vasculitis, and necrotizing glomerulonephritis. These classic criteria correlate with a complete and fulminant form of the disease, which historically had been nearly always fatal. However, it is apparent that Wegener's granulomatosis is a continuum of disease, where various combinations of the three major anatomic sites (the upper and lower respiratory tract and the kidney) can produce a spectrum ofdisease,21 and that in many patients some features of the disease may be absent. In the incomplete or limited form of Wegener's granulomatosis,22 the kidneys are usually spared (Table 58-2) .23-26 Although any organ systelll may be involved in limited Wegener's granulomatosis, the upper or lower respiratory system is the most common. A very limited form of the disease, with clinical involvement of a single organ such as the eye, has also been described. 27 Ophthalmic involvement can manifest as orbitopathy, conjunctivitis, episcleritis, scleritis, keratitis, uveitis, and vasculitis.

HISTORY Klinger was the first to describe this disease as a form of polyarteritis nodosa. 28 However, Frederich Wegener, a German pathologist, recognized the unique nature of the condition and established Wegener's granulomatosis as a distinct clinicopathologic entity with his description of three patients with necrotizing granulomatous arteritis of the upper and lower respiratory tract, including the sinuses, middle ear, and nasopharynx. 29 , 30 The classic diagnostic criteria for Wegener's granulomatosis were based on the detailed clinicopathologic description of Godman and Churg in their 1954 publication and included the triad of (1) necrotizing granulomatous vasculitis of the upper and lower respiratory tract, (2) focal necrotizing glomerulonephritis, and (3) systemic necrotizing vasculitis involving both arteries and veins. 20 This classic form of the disease was almost always fatal prior to introduction of cytotoxic immunosuppressive therapy. 19, 31 The use of systemic cytotoxic immunosuppressive agents heralded a new era in the treatment of Wegel1.er's granulomatosis. The effectiveness of combined cyclophosphamide and corticosteroid therapy in producing partial and complete remissions was demonstrated prospectively at the National Institutes of Health (NIH) TABLE 58-2. WEGENER'S GRANULOMATOSISDIAGNOSTIC CRITERIA Classic triad or complete form Necrotizing granuloma of the upper and lower respiratory tract Systemic vasculitis Focal necrotizing glomerulonephritis Incomplete or limited form Common Localized, cavitary necrotic pneumonitis 'with sparing of the kidneys, with or witl10ut other organ involvement Less Common Isolated organ involvement sparing both tl1e lungs and kidneys

58: WEGENER'S GRANULOMATOSIS

Systemic

nasal discharge, epistaxis resulting from chronic sinusitis and rhinitis, nasal ulceration, and serous otitis media. These can result in suppurative otitis, mastoiditis, a saddle-nose defect, and hearing 10ssl, 3, 21, 35, 37 (Fig. 58-1). If a physician discovers that a patient has ulceration of the nasal mucosa, palatal ulcers, or destructive sinusitis, Wegener's granulomatosis should be strongly considered. 26 Ultimately, over 90% of patients have upper respiratory involvement. 35 Secondary bacterial infections often develop in the sinuses and are usually caused by Staphylococcus aureus. It has been proposed that relapse is lTIOre common in patients who are chronic nasal carriers of S. aureus. 42 Some laboratory evidence suggests that chronic stimulation of phagocytes by infectious agents may result in the generation of a humoral response against phagocyte cytoplasmic components. 43 A significant proportion of patients present with pulmonary findings. 37, 44 Symptoms include cough, hemoptysis, dyspnea, and, less commonly, pleuritic chest pain and tracheal obstruction. Unilateral or bilateral pulmonary infiltrates, nodules, or both, which are the most characteristic features, are present in nearly 50% of patients initially, 35, 45 with lung disease eventually developing in 85% of patients 35 (Fig. 58-2). Pleural effusion may be found in 12% of cases. 45 However, about one third of patients will have radiographs showing infiltrates and nodules but no clinical symptoms. 35 One of the most frequent causes of diffuse pulmonary hemorrhage is Wegener's granulomatosis, and this is associated with significant morbidity.13 Although renal involvement is clinically evident in only 11 % to 20% of cases at presentation, glomerulonephritis eventually develops in 77% to 85% of patients, usually within the first 2 years of disease onset. 35 , 37 Thus, it is important for the physician not to have a false sense of security that the patient has a limited form of disease,

The clinicopathologic criteria for the classic or complete form of Wegener's granulomatosis was detailed by Godman and Churg in 195420 and included the triad of necrotizing granuloma of upper and lower respiratory system, systemic vasculitis, and necrotizing glomerulonephritis. However, the limited form of Wegener's granulomatosis is more common,25 can be more indolent, may at times have a protracted clinical course,40 and may also have a better prognosis than the complete form. 22 The disease can begin with limited organ involvement and then evolve with variable speed to a more generalized form with nose, lung, and kidney involvementY Because increased awareness of the disease has made earlier diagnosis possible, the limited form may be even more common than first suspected. Although no specific criteria are established for the limited form, and any organ can be involved, the most common clinically recognized presentation is that of upper or lower respiratory system involvement, with sparing of the kidneys, with or without systemic vasculitis (see Table 58-2). The clinical presentation of patients with Wegener's granulomatosis often includes nonspecific signs and symptoms of a systemic illness, such as fever, malaise, weight loss, arthralgias, and myalgias. 37 The earliest complaints and the most common reason for seeking medical care are usually referable to the upper respiratory tract and may include symptoms such as sinus pain, purulent

FIGURE 58-I. Sinus x-ray study showing complete opacification of the maxillary sinus on the right, and partial opacification with some bony destruction in the maxillary sinus on the left in this patient with Wegener's granulomatosis.

in 1973,32 and it has profoundly changed the outlook for this previously universally fatal disease. More recently, the demonstration of antibodies directed against neutrophil and monocyte cytoplasmic target antigens (antineutrophil cytoplasmic antibodies [ANCAs]) (see Diagnosis section, later) has resulted in a highly specific and sensitive laboratory test for active Wegener's granulomatosis, which has facilitated its earlier diagnosis, especially in anatomically limited cases, thus favorably impacting morbidity.

EPIDEMIOLOGY Wegener's granulomatosis is a rare inflammatory disease and the exact incidence is unclear. A preliminary estimate from Rochester, Minnesota, was 0.4 cases per 100,000. 33 Although it has been suggested that the· incidence of Wegener's granulomatosis is increasing, this may simply represent the availability of ANCA testing, enabling more frequent diagnosis. 34 The peak inci~ence is typically in the fourth and fifth decades of life,7' 19, 31, 35 although the disease has been observed across the whole spectrum of life, with patients as young as 3 months 22 and as old as their eighties. 36 A slight male predominance has been reported in some series,31,37 but a recent large study of 158 patients found an equal number of men and women. 35 Wegener's granulomatosis can be seen in any racial group, although the disease is most frequently reported in white patients. 35 , 37 Although a seasonal association has been reported (the most frequent onset beginning in the winter months) ,38 a more rect'!'nt study found no seasonal differences. 39

CLINICAL CHARACTERISTICS

CHAPTER 58: WE:GE:NER'S GRANULOMATOSIS

FIGURE 58-2. Chest x-ray study demonstrating pulmonary infiltrates, which is a characteristic presenting feature in a significant percentage of patients with Wegener's granulomatosis.

but rather to monitor the patient closely for more ominous renal signs. Findings ultimately include proteinuria, hematuria, red blood cell casts, and renal insuffic~ency. Hypertension is relatively uncommon. Dermatologic involvement is seen in about half of the patients, although at presentation only about 13% have such findings. 35 The most co~mon finding is purpura involving the lower extremities, with trunk and upper extremities involved infrequently. Less commonly, ulcers, vesicles, papules, subcutaneous nodules, and lesions resembling those of pyoderma may be seen. The lesions mayor may not be pruritic. 46 Arthralgias and myalgias, which occur early in the course of the disease, are common and may be seen in as many as 70% of patients. 35 They resolve without residual effects. Joint swelling and nondeforming arthritis are less commonly seen. An incorrect diagnosis of rheumatoid arthritis may be made in the presence of a false-positive rheumatoid factor (seen in 60% of patients) .35 Nervous system involvement is seen in about one third of patients. Peripheral neuropathies, such as mononeuritis multiplex, are the most commonY Cranial neuropathies (most commonly of cranial nerves II, VI, and VII), external ophthalmoplegia, seizures, cerebritis, and stroke syndromes are important findings. Diabetes insipidus may occur when granulomas extend from the sinuses into the pituitary glandY Cardiac involvement is rare, with pericarditis being the most frequent (6%). Myocarditis or arteritis is relatively rare. Other infrequently involved organs are the parotid gland, breast, urethra, cervix, vagina, and gut. 35 Pediatric patients have clinical features similar to those of adult-onset disease but with subglottic stenosis and nasal deformities being more frequent. 48- 5o

Ophthalmic Straatsma's review of the literature was the first large series of autopsy-confirmed cases of Wegener's granulomatosis published, in which ocular involvement was noted

in 43% (19 of 44) of these cases. 5 Subsequent studies report similar findings, with ophthalmic involvement ultimately present in about half of the patients (29% to 79%) (Table 58-3) ,6,7,35,51 although ocular abnormalities may have been noted in only 13% to 15% at presentation. 7, 35 Ocular disease can be a presenting or even the only clinically apparent manifestation .of Wegener's granulomatosis. 52- 61 A very limited form of the disease, with clinically apparent involvement of a single organ such as the eye, has been reported. 27 Eye and systemic disease can follow a parallel course. The ocular manifestations of Wegener's granulomatosis are diverse and essentially any ocular tissue may be involved (see Table 58-3). Straatsma classified the ocular findings as contiguous if there was direct extension from the adjacent involved sinuses, or primary (noncontiguous) when there was lack of continuity.5 Contiguous orbital disease may result in severe orbital pseudotumor, abscess, or cellulitis. Noncontiguous or focal disease results from a focal vasculitis, which may involve both the anterior and posterior segments of the eye and occasionally the orbit. Multiple ocular structures may simultaneously be involved. Severe ocular morbidity with vision loss or total blindness may be seen in 8% to 37% of patients, especially if the disease has been longstanding or inadequately treated, or when there has been a delay in diagnosis. 36 , 51 The,' ocular symptoms or findings may be the presenting feature or even the only clinically apparent findings, especially in limited Wegener's granulomatosis.7, 27, 53, 54, 56-61 Orbital involvement is one of the most frequently reported ocular finding of Wegener's granulomatosis5-7, 35, 51 and is usually secondary to contiguous sinus or nasal disease (Fig. 58-3). Damage may result from mass compression, vascular occlusion, or spread of an orbital cellulitis. 6 Proptosis, which is frequently painful, is a common ocular manifestation in up to one third of cases involving the eye or orbit. 35 Pseudotumor of the orbit or an orbital mass are common findings, with cranial nerve involvement and entrapment of extraocular muscle resulting in diplopia. 62 Orbital involvement can frequently result in vision loss or blindness, usually from a compressive ischemic optic neuropathy.5, 6, 19, 20, 35 In the most recent published experience from the NIH, in a group of 158 patients with Wegener's granulomatosis, about one half of the patients with retro-orbital pseudotumors lost vision (8% of the total) .35 Nasolacrimal duct obstruction, which is seen less frequently, is a late finding and is usually associated with nasal involvement. 7,58 Although most findings may be relatively nonspecific, proptosis in the setting of upper or lower airway disease or glomerulonephritis is strongly suggestive of Wegener's granulomatosis. 35 Although recurrent conjunctivitis and episcleritis are frequent ocular findings in patients with Wegener's granulomatosis, they are relatively benign. In contrast, scleritis and peripheral ulcerative keratitis can lead to significant ocular morbidity, with vision loss and even blindness, if treatment is inadequate. The globe can perforate and may require enucleation. Scleritis may be nodular, diffuse, or necrotizing (Fig. 58-4). Keratitis, which is sometimes associated with scleritis, can begin as peripheral

TABLE 58-3. OPHTHALMIC INVOLVEMENT IN WEGENER'S GRANULOMATOSIS

STUDY

Straatsma5 Haynes et al. 6 Haynes et al. 6 (review of lit) Spalton et al. 53 Bullen et al. 7 Pinching et al. 8

TOTAL (N)

OCULAR INVOLVEMENT

44 29 342

19 (43)b 14 (4S) 131 (3S)

S 140 lSI

40 (2S.6) 14 (7S)

CONJUNCTIVAa

6 (32) 5 (3S)

3 (3S) 6 (15) 7 (39)

EPISCLERITISI SCLERITIS

KERATITISI PUK

UVEITIS

3 (16) 4 (29) 46 (35)c

2 (11)

3 (16)

NA

NA -

NA

4 (29)

3 (3S) 15 (3S) Sg (44)

4 (50)

NA NA

6 (5) 3 (3S)" "4 (10) 2 (11)

OPTIC NERVE

1 (13) 9 (22) 2 (l1)h

RETINAL ARTERYIVEIN OCCLUSION ± VASCULITIS OR RETINITIS

ORBITAL

NLD OBSTRUCTION

1 (5) 1 (5) 23 (1S)d

6 (32) 7 (50) 52 (40)

2(14) .9(7)

1 (13) 7 (1S) Retinal vasculitis (clinical) 10 (71)i

3 (3S) IS (45)

10 (25)

NA

"Coruunctivitis and conjunctival hemorrhages. "The number of eyes is followed by the percent of eyes in parentheses. "Combined conjunctivitis, episcleritis; scleritis, and corneoscleral ulcer. dPresented as retinal and optic nerve vasculitis. "2 of 3 patients had associated marginal keratitis or scleritis. [Study reviewed patients with severe retinal disease. gNoted only episcleritis. hPapilledema was the type of optic nerve involvement. iClinically diagllosed as vasculitis. Patients had hemorrhages and exudates, and fluorescein angiography showed leaking vessels. Some of the patients were hypertensive and probably had hypertensive retinopathy. PUK, peripheral ulcerative keratitis; NLD, nasolacrimal duct.

CHAPTER 58: WEGENER'S GRANULOMATOSIS

FIGURE 58-3. Orbital involvement in a patient with Wegener's granulomatosis with proptosis and limitation of extraocular movement.

FIGURE 58-4. Necrotizing scleritis with associated peripheral keratitis in a patient with Wegener's granulomatosis. (See color insert.)

intrastromal infiltrates, ultimately ulcerating, and progressing circumferentially and centrally. Scleritis, with or without peripheral ulcerative keratitis, can be a presenting, or at times the only apparent, clinical feature of Wegener's granulomatosis. 5, 27, 51-53, 58-61, 63 It has been proposed that necrotizing scleritis with peripheral ulcerative keratitis may characterize systemic vasculitis. 64,65 Interestingly, a recent study has reported that the sera of 46% of Wegener's granulomatosis patients had autoantibodies to one of two corneal antigens.6~Wegener'sgranulomatosis-associated necrotizing scleritis appears to correlate best with systemic involvement,63 and the onset of scleritis may portend the development of systemic diseaseY Lid edema and granuloma, as well as sicca syn.drome with positive SS-A/SS-B antibodies, have also been reported.51, 67, 68 The uveitis associated with Wegener's granulomatosis is nonspecific, is unilateral or bilateral, and can be anterior, intermediate, or posterior, with or without vitritis5, 7, 24, 51, 69-71 (Fig. 58-5). Although about 10% of

patients with Wegener's granulomatosis and ocular involvement have been reported to have uveitis (the majority having a nonspecific anterior uveitis), many have undoubtedly been associated with scleritis or keratitis. 6, 51, 59,60,71,72 Foster and Sainz de la Maza reported that 42% of their 14 patients with Wegener's granulomatosisassociated scleritis had anterior uveitis. 60 However, the incidence was no different than in 158 scleritis patients without Wegener's granulomatosis, thus leading them to conclude that there was no association, per se, between Wegener's granulomatosis and anterior uveitis. 60 In contrast to scleritis, uveitis has usually not been the presenting manifestation of Wegener's granulomatosis, as most patients had established disease or had previously presented with other symptoms and signs attributable to Wegener's granulomatosis. Intermediate uveitis with "peripheral snowballs" has been reported, although one of two cases also had diffuse scleritis. 7 Choroidal folds with uveal thickening 73 and chor~oretinal ischemia with infarction presenting clini-

FIGURE 58-5. A, Posterior uveitis, with retinal vasculitis and frank retinal infarct in a patient with Wegener's granulomatosis. Note in particular the hazy view as a consequence of cells in the vitreous. B, Same patient as in Figure 58-SA, with partial resolution after institution of cyclophosphamide therapy. Note the clearing of the vitreous and a clearer view of the area of retina, which has now been destroyed through infarction. (See color insert.)

CHAPTER 58: WEGENER'S GRANULOMATOSIS

cally as single or multiple, white or creamy lesions at the agents, such as parvovirus B19 78 , 79 and Staphylococcus level of the retinal pigment epithelium have also been aureus, may playa role by providing an antigenic prilner, reported. 74 especially because some relapses are associated with a Retinal involvement is a relatively uncommon ophthal- preceding or concurrent infection. 8, 43, 80 The role of sumic manifestation of Wegener's granulomatosis (5% to perantigens in the pathogenesis of vasculitis has been 12%), with retinal hemorrhages in the posterior or pe- considered, because superantigen-producing microorganripheral retina being the most common finding. 5-8, 24, 51 isms have regularly been found in patients with Wegener's Vitreous hemorrhage may result. 24 Both central retinal granulomatosis. 81 However, the evidence for an infectious artery and vein occlusions have been reported6-8,51; how- contribution to. the pathogenesis of Wegener's granuloever, the exact etiology, whether vasculitic, embolic, matosis is speculative and some studies have not found thrombotic, or a retro-orbital process, has not always been an association. 32 To date, no offending antigen, microbe, clearly defined. Retinal vasculitis, in the form of arteritis chemical, or noxious agent has been isolated. or periphlebitis, is an uncommon but often-reported Circulating immune complexes and glomerular subefinding 7, 24, 51 and may, at times, be seen with associated pithelial immune deposits have infrequently been rescleritis. 24, 73 Bullen and colleagues identified four patients ported, thus being termed pauci-immune, and cryoglowith retinal vasculitis manifesting as retinal hemorrhages bulin levels are seldom elevated. 82-84 The presence of and edema, cotton-wool exudates, and choroidal thick- granulomas suggests a delayed-type hypersensitivity reacening. 7 One of the four had hypertensive renal failure. tion and involvement of T cells. Activated T cells, preOf the 10 patients reported by Pinching and colleagues dominantly CD4, are found in biopsy specimens,8;:; and to have clinical retinal vasculitis,' all had severe renal soluble interleukin-2 (IL-2)-receptor levels are elevated disease and some were hypertensive, with six of six fluo- during active Wegener's granulomatosis, even when other rescein angiograms revealing only "vascular leakage."8 markers of disease activity such as C-reactive protein Thus! some reported cases may be the result of hyperten- (CRP) are norma1. 86 ,87 Circulating T cells obtained from sive retinopathy. Other reported findings have included patients with Wegener's granulomatosis seem to have a pigment epithelial atrophy with disc edema,51 unilateral predominantly Th1-type profile 88 ,89 with conserved T-cellor bilateral choroidal detachments,51 and a case of com- ,receptor-beta motifs. 90 A recent study has shown that bined detachment of the choroid and retina in conjulic- CD4+ T cells from active Wegener's granulomatosis pation with scleritis and vitritis. 71 tients overproduce interferon-gamma and tissue necrosis Retinitis with retinal vasculitis, exudates, and retinal factor-alpha, thus resulting in an unbalanced TH1-type necrosis have been reported in an 'J>ccasional patient profile, probably as a result of dysregulated IL-12 secrebeing treated with cytotoxic agents and prednisone for tion. 91 The dose-dependent inhibition of interferonsystemic Wegener's granulomatosis. 7o,75 Both patients in gamma by exogenous IL-10 may have therapeutic implicathese two reports had concomitant systemic cytomegalovi- tions for this disease.91 rus (CMV) infection. One was treated with ganciclovir Wegener's granulomatosis has been observed in sibwith resolution of the retinitis. 75 Later, a retinal biopsy lings. 92 A higher frequency of certain human leukocyte was obtained (to differentiate CMV from Wegener's gran- antigen markers (B2, B8, DR1, DR2, and DqW7) than in ulomatosis vasculitis) at the time of repair of a complete control subjects has been reported, without a consistent rhegmatogenous retinal detachment. 75 The biopsy dis- relationship to disease. 93 ,94 closed perivascular immune complex deposition without cellular infiltration and with no cytomegalic cells or viral Wegener's inclusions. 75 These two cases most likely represented CMV Role of Granulomatosis retinitis, although vasculitis secondary to Wegener's granulomatosis cannot be excluded. These cases also highlight It is unclear whether ANCAs playa pathologic role in the importance of considering an infectious cause for Wegener's granulomatosis. The majority of the target anthe uveitis. Secondary iris neovascularization from severe tigens for ANCA have proteolytic activities. Studies of the uveitis or retinal vascular occlusions may result in neovas- interactions between ANCA and its target antigens have produced mixed results (i.e. agonistic, antagonistic, or ollar glaucoma.2 4, 51 nil [reviewed in Hoffman and Specks95 ]). Because all patients with Wegener's granulomatosis are not ANCA PATHOGENESIS/IMMUNOPATHOLOGY The cause of Wegener's granulomatosis is unknown. A positive, it is unlikely that ANCAs are essential for disease hypersensitivity phenomenon has been proposed by some pathogenesis. However, evidence suggests that they may because the pathologic reaction manifested by granulo- still play an important role by enhanced neutrophil oxidamatous vasculitis and glomerulonephritis is character- tive bursts and degranulation, enhanced neutrophil adheistic of hypersensitivity states described in animals and sion to endothelial cells, and synthesis and release of man. 5, 19, 31, 76 Because respiratory tract disease usually IL-1[3 from neutrophils and IL-8 from monocytes, thus precedes renal and systemic involvement, it has been enhancing the recruitment of more inflammatory cells postulated that the upper and lower airways are the initial to the site of active inflammation (reviewed in Hoffman sites of stimulation in an individual susceptible to certain and Specks95 ). The increased surface expression of proairborne substances. Various allergies, including allergic teinase-3 (PR3) on neutrophils, which was reported to skin reactions, allergic rhinitis, asthma, and drug aller- correlate with disease activity, suggests that the interacgies, are reported to be more common in patients with tion of ANCA with expressed PR3 may have a role in the Wegener's granulomatosis. 77 It is possible that infectious disease. 96

CHAPTER 58:

FGFNFR'~

GRANULOMATOSIS

appropriate cultures. The clinical features are important for differentiating other diseases with similar histopathologic changes, such as Churg-Strauss granulomas, rheumatoid nodules, and tuberculous granulomas.

Eye Pathology

FIGURE 58-6. Lung biopsy demonstrating granulomatous inflammation in a patient with Wegener's granulomatosis. (See color insert.)

PATHOLOGY

General Wegener, in his original report,30 emphasized that Wegener's granulomatosis is not only a vasculitis but also a necrotizing granulomatosis. The earliest lesion of the condition in the lung has been shown to be a focus of injury and necrosis evolving into a necrotizing, palisading granuloma without the involvement of vessels. 97 Arteries, veins, and capillaries can all l'!>e affected. 98 Arteritis is typically characterized by chronic inflammation, although acute inflammation with fibrinoid necrosis may be seen in 11 %. Venulitis is seen in 76% and tissue eosinophilia is seen in 63% of cases. 98 In open lung biopsies, about 90% of specimens have been found to have combination of granulomas and vasculitis, or vasculitis, necrosis, and granulomatous inflammation 98 (Fig. 58-6). In contrast, in only 7% of transbronchial biopsies is vasculitis identified. 98 Vasculitis, although present in most cases, is not necessary for the diagnosis of Wegener's granulomatosis and may not be central to the disease pathogenesis. 41 ,99,100 The pathology of head and neck tissue differs from that of the lung, possibly because of sampling errors resulting from the small amount of tissue available from biopsies. The combination of vasculitis, necrosis, and granulomatous inflammation is found in only 16%.101 The presence of all three features establishes the diagnosis of Wegener's granulomatosis. However, when less than the three features are present, clinical correlation is required. 102 The most common renal lesion in Wegener's granulomatosis is focal necrotizing glomerulonephritis, with the spectrum extending from diffuse proliferative glomerulonephritis and interstitial nephritis to hyalinization of glomeruli. 35 , 103, 104 Granulomatous inflammation around glomeruli and necrotizing vasculitis of small renal arteries are not common, being seen in only about 5% of cases,11, 35-37 thus emphasizing the lack of diagnostic usefulness of a percutaneous renal biopsy. It is imperative to exclude infectious etiologies such as Mycobacterium, Nocardia, and fungi, which may have similar histopathologic features, by using special stains and

Orbital tissue demonstrates evidence of acute and chromic inflammation, with or without granulomatous vasculitis. 37,54 Limited ocular tissue, especially of the retina and choroid (which usually becomes available after enucleation or postmortem), may be available for systematic histopathologic evaluation. The majority of tissue is from the sclera and conjunctiva, with the latter being less specific. Necrotizing granuloma with or without inflammatory Inicroangiopathy is very suggestive of Wegener's granulomatosis,60 even if the classic necrotizing, granulomatous vasculitis is rarely seen 105 (Fig. 58-7). Although a recent study was able to differentiate between necrotizing scleritis that was associated with systemic autoimmune disease from those that were not by identifying the presence of zonal necrotizing granulomatous inflammation, the investigators could not differentiate between rheumatoid arthritis (the most common disease) and other systemic conditions including Wegener's granulomatosis.10 6 This study was limited by the fact that, for Wegener's granulomatosis and other systemic autoimmune diseases, only a single case of each was included. Hence, the possibility remains that other differentiating features might have been detected if additional specimens had been studiyd. The histopathologic findings in uveitis cases show evidence of nonspecific vasculitis and granulomatosis. 5, 52 Chronic necrotizing granulomatous reaction of the uvea and peripheral retina; perivascular leukocytoclastic infiltration of the episclera, sclera, and retinal vessels; and chronic choroiditis have been reported.51, 59~ 107 In severe cases, necrosis of the ciliary body and the iris root may be seen. 59

DIAGNOSIS Establishing the diagnosis of Wegener's granulomatosis is essential, because therapy with cyclophosphamide is

FIGURE 58-7. Photomicrograph of scleral tissue from a patient with limited Wegener's granulomatosis demonstrating granulomatous foci with collagen necrosis. (See color insert.)

CHAPTER 58: WEGENER'S GRANULOMATOSIS

required for this entity, whereas some other forms of vasculitis may be treated with corticosteroids alone. The diagnosis of Wegener's granulomatosis has historically been made using the clinicopathologic criteria of granulomatous involvement of the upper and lower respiratory tract, glomerulonephritis, and varying degrees of systemic vasculitis. 2o Various diagnostic criteria have been proposed and continue to evolve. 37, 13,21, lOS Given the wide range of clinical presentations, including those patients with mild and indolent disease, diagnosis may be delayed. In the NIH cases, the median and mean tilnes from the onset of symptoms to the diagnosis of Wegener's granulomatosis were 4.5 and 15 months, respectively, with 8% of the patients being diagnosed 5 to 16 years later. 35 Mter reviewing their data, Fauci and colleagues at the NIH recommended that to establish a definitive diagnosis of Wegener's granulomatosis, a patient should have clinical evidence of disease in at least two of three areas (upper airways, lung, and kidney), and biopsy results that show disease in at least one and -preferably two of these organ systems. 37 The American College of Rheumatology has established the following criteria for the diagnosis of the Wegener's granulomatosis and to distinguish it from other vasculitides: (1) a urinary sediment containing red blood cell casts or more than five red blood cells per high-power field, (2) abnormal findings on the chest radiograph (e.g., nodules, cavities, or fixed infiltrates), (3) oral ulcers or nasal discharge, anq. (4) granulomatous inflammation on biopsy.13 The presence of two or more of these four criteria was associated ~th an 88 % sensitivity and a 92% specificity. These criteria were based on cases that had demonstrated vasculitis. However, the earliest lesion of the condition has been shown to be a focus of injury and necrosis evolving into a necrotizing, palisading granuloma without the participation of vessels. 97 Thus, cases in the granulomatous phase without vasculitis could be misclassified. The ELK classification system proposed by DeRemee and colleagues (E = ears, nose, and throat, or upper respiratory tract; L = lung; and K = kidney) utilizes

ANCA results. 2l , 116 Under this system, any typical manifestation in the L, or K supported by typical histopathology or a positive c-ANCA test (see next section) qualifies for the diagnosis of Wegener's granulomatosis. lOS Most laboratory findings are generally nonspecific and indicate a systemic inflammatory illness (such as normochromic, normocytic anemia; moderate leukocytosis without eosinophilia; thrombocytosis; hypergammaglobulinemia; elevated erythrocyte sedimentation rate [ESRJ; and elevated CRP) .35, 37 ESR correlates better with disease activity than does CRP.35 Levels of all immunoglobulins may be elevated, especially IgE.l09 Rheulnatoid factor has been reported to be elevated in more than 50% of patients, being present most often in patients with extensive disease. s,35 However, antinuclear antibodies and cryoglobulins are usually absent, with complement C3 levels usually being normal. Abnormal urinary sediment, proteinuria, and creatinine clearance may denote glomerular involvement.

Antineutrophil Cytoplasmic Antibody Testing

I

Until the mid 1980s, there was no specific laboratory test for Wegener's granulomatosis. Mter the first reports of ANCAs in the early 1980s in patients with necrotizing glomerulonephritis 11o and systemic vasculitis with pulmonary symptoms,11 1 ANCAs have been recognized to be both sensitive and specific for Wegener's granulomatosis.112-115 ANCAs are antibodies directed against cytoplasmic azurophil granules of neutrophils and monocytes. The original and still most widely used method of detection is by indirect immunofluorescence (IIF) , which demonstrates two fluorescence patterns of staining on ethanolfixed neutrophils: a granular, centrally accentuated, cytoplasmic pattern termed c-ANCA, and a perinuclear staining pattern termed p-ANCA (Fig. 58-8). The specific target antigens for ANCA responsible for each pattern of staining have been identified (Table 58-4). Enzymelinked immunosorbent assay (ELISA) is currently used

FIGURE 58-8. A, Photomicrograph showing a positive cANCA pattern of staining on ethanol fixed neutrophils by indirect immunofluorescence. This centrally accentuated cytoplasmic pattern of staining is characteristic for patients with Wegener's granulomatosis and is almost always due to antibodies directed against proteinase 9 (PR3). B, This photomicrograph demonstrates a pANCA (paranuclear) pattern of staining by indirect immunofluorescence. A variety of target antigens can produce this pattern of staining including those that are nonspecific. Myeloperoxidase (MPO) is the target antigen (as demonstrated by ELISA) with the most utility, because it is frequently associated witl1Wegener's granulomatosis, microscopic polyangiitis, and pauci-immune glomerulonephritis. (See color insert.)

CHAPTER 58: WEGENER'S GRANULOMATOSIS TABLE 58-4. TARGET ANTIGENS FOR ANCA AND DISEASE ASSOCIATION IMMUNOFLUORESCENCE PATTERN

c-ANCA p-ANCA

DISEASE ASSOCIATION

TARGET ANTIGEN

WG (very rarely CSS) WG, microscopic polyarteritis l95 , 196 (very rarely CSS) Systemic vasculitis-unspecified Rheumatic autoimmune disease (RA [16%-35%], SLE, SS, polymyositis and dermatomyositis, RP, APAS, juvenile chronic arthritis, etc) IBD Ulcerative colitis (40%-83%) Crohn's disease (10%-40%) Other autoimmune disease Primary sclerosing cholangitis (64%-87%) Autoimmune hepatitis (type I) Drugs Hydralazine-induced lupus Hydralazine-induced vasculitis Minocycline-induced arthritis, fever, livedo reticularis Propylthiouracil- vasculitis Infectiona HIV (or atypical cANCA) Bacterial infection in CF Chromomycosisa Malariab

PR3 MPO Azurocidin, BPI Lactoferrin, elastase, lysozyme, cathepsin G, MPO (rare), elastase, unidentified antigens Cathepsin G, LF, elastase, lysozyme, and BPI Not identified

MPO, elastase MPO,lactoferrin MPO PR3, MPO, elastase Undefined BPI Undefined PR3

"Some with atypical c-ANCA pattern. "Included here for categOlization reasons. ANCA, antineutrophil cytoplasmic antibodies; PR3, proteinase 3; c-ANCA, classic cytoplasmic ANCA; p-ANCA, perinuclear ANCA; MPG, myeloperoxidase; BPI, bactericidal/permeability-increasing protein; CSS, Churg-Strauss syndrome;,RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; PR, relapsing polychondritis; APAS, antiphospholipid antibody syndrome; SS, Sjogren's syndrome; IBD, inflammatory bowel disease; CF, cystic fibrosis; WG, Wegener's granulomatosis. Modified from Hoffman GS, Specks U: Aritineutrophil cytoplasmic antibodies. Arthritis Rheum 1998;41:1521-1537, with permission.

for antigen-specific ANCA dete~mination. The c-ANCA pattern is almost always produced by antibodies against PR3 11 6-118 and very rarely by antibodies to other antigens (see review by Hoffman and Specks 95 ), and this makes it both sensitive and specific for Wegener's granulomatosis. However, antibodies against a variety of target antigens can produce the p-ANCA fluorescence pattern, including antibodies directed against myeloperoxidase (MPO) , elastase, cathepsin G, azurocidin, lactoferrin, lysozyme, and bactericidal/permeability-increasing protein, with the target antigen being elusive in many cases. 95 MPO is the target antigen with the greatest clinical utility because of its frequent association with Wegener's granulomatosis, microscopic polyangiitis, and pauci-immune glomerulonephritis.ll 9, 120 A p-ANCA staining result needs to be further evaluated by ELISA to assess whether the target antigen is MPO or another nonspecific antigen. Because testing methodology and titer readings differ from laboratory to laboratory, with no international standards, values from one laboratory cannot always be compared to those from another, and thus serial titer determinations for any given patient should be performed at a single laboratory. Ideally, the IIF results should be corroborated with antigen-specific testing for PR3 and MPO (although c-ANCA by'IIF is nearly always due to antiPR3). The identification of other target antigens is of unclear clinical significance at this time. Between 80% and 95% of all ANCA found in Wegener's granulomatosis is c-ANCA; the remainder is p-ANCA directed against MPO.120-123 ANCA specificity is about 98%, but the sensitivity depends on disease activity and extent. 124 For patients with active generalized disease, it is about 95% sensitive, but this decreases to 41 % when

the disease is in remission. The sensitivity for active limited disease is about 65%, but it is only 35% when the disease is in remission. 124 Numerous studies have reported a relationship between ANCA titers and disease activity,112, 114, 115, 124, 125. with the disappearance of ANCA being associated with clinical remission. 114, 125 However, this association has not been universal and cannot be relied on solely.127-129 Despite clinical remission, elevated ANCA titers may persist in up to 40% of patients, and ANCA titer changes with disease activity in only 64% of patients. 35 , 124, 126-130 Because of the time differential of months and possibly years between serologic and clinical relapse in some patients, the direct cause-and-effect relationship of ANCA titer to disease activity becomes less certain. 128 , 131, 132 The lack of reversion of ANCA titers in clinical remission may be a prognosticator for early relapse as reported by Power and associates in cases of Wegener's granulomatosis-associated scleritis. 129 Thus, an ANCA titer is more predictive of activity in the serial follow-up of an individual patient than in the general comparison of groups of patients.

ANCA in Ocular Inflammation There have been numerous studies published on the use of ANCA in patients with ocular inflammation, with either type of ANCA being present. 58 , 51, 72, 73,129,133-135 A positive ANCA appears to be very sensitive and specific for Wegener's granulomatosis-associated scleritis.51 Of IllY study of 24 patients with scleritis in whom ANCA titers were obtained, all seven with a positive ANCA had clinical and pathologic evidence of Wegener's granulOlllatosis. However, in none of the patients who were ANCA negative could the diagnosis of Wegener's granulomatosis eventu-

CHAPTER 58: WEGENER'S GRANULOMATOSIS

ally be established. Nolle and colleagues also found cANCA testing to be very specific in 72 patients with Wegener's granulomatosis and various forms of ocular inflammation. 135 The sensitivity or specificity in patients with uveitis alone is unclear. Young found a positive ANCA by IIF in 11 of 98 cases with uveitis. 133 Of the three patients who had a positive c-ANCA, two had retinal vasculitis but neither of these had Wegener's granulomatosis (one had Behc;:et's disease, the other had "mild colitis").133 The remaining eight were p-ANCA positive, but the specific target antigen was not determined, and the specific clinical diagnosis was not specified. These results, from nearly a decade ago, employing IIF testing rather than ELISA, are of uncertain significance. ANCA testing in patients with contiguous orbital involvement may have a sensitivity and specificity profile similar to that reported for limited Wegener's granulomatosis. Thus, ANCA testing is a useful adjunct for establishing the clinical diagnosis and in the management of Wegener's granulomatosis, but there are certain limitations. Therefore, neither a positive nor a negative ANCA result can be solely relied on. Patients presenting with scleritis or proptosis with associated respiratory or renal symptoms and a positive ANCA with antibodies to PR3 or MPO must be considered to have Wegener's granulomatosis, most likely, even in the absence of tissue diagnosis. The specificity of a positive ANCA is less clear inpatients with isolated uveitis or retinal vasculitis, so other clinical findings and a supportive biopsy are required for the diagnosis to be established. 'I(

Evaluation of Patients The evaluation of patients suspected to have Wegener's granulomatosis should include a complete, meticulous review of systems, laboratory testing (ANCA, ESR, CRP, complete blood count, blood urea nitrogen, creatinine, and urine analysis), a chest radiograph, and a radiograph or computed tomography scan of the sinus. Referral to a medical subspecialist and otolaryngology consultant may be required based on the ophthalmologic evaluation. Histopathologic tissue should be sought whenever possible.

Historically, a variety of treatment modalities, including antibiotics,31 chelating agents,136 and local irradiation,31, 137 were tried without success. The prognosis for most patients with generalized Wegener's granulomatosis, untreated or ineffectively treated with corticosteroids alone, was dismal, particularly after the recognition of functional renal impairment. 8, 31, 138 The average life expectancy for a patient with Wegener's granulomatosis without treatment was only 5 months,31 with a I-year survival rate of less than 20%.10,11,35,37 Steroids alone only slightly more than doubled the life expectancy to about 12 months,138 with a I-year survival of 34%Y Alternative therapies using nitrogen mustard, chlorambucil, and other cytotoxic agents suggested a better outcome. 19 , 138-143 The introduction of combination treatment 'with lowdose cyclophosphamide and corticosteroids dramatically altered the prognosis for this fatal disease. 1o , 11,32,35,37, 144 The landmark prospective study and long-term follow-up

of Wegener's granulomatosis patients at the NIH has delTIonstrated long-term remission rates of 93%, lasting from 7 months to 13.2 years (mean, 48 months), with a median time to remission of 12 months. 32 , 35, 37 However, nearly half the patients who have achieved remission later .experience at least one relapse,35 reinforcing the importance of careful long-term follow-up. The classic regimen from the NIH,35, 37 which is not unlike that currently used, consists of daily oral therapy with cyclophosphamide, 2 mg/kg body weight, and prednisone, 1 mg/kg body weight. Higher doses may be used in patients with fulminant and rapidly progressive disease. The daily prednisone dose is continued for 4 weeks and changed to an alternate day regimen. The prednisone dosage is gradually tapered according to individual response to therapy. Cyclophosphamide is continued for at least 1 year after the patient has achieved complete remission. Cyclophosphamide is then tapered by 25-mg decrements every 2 to 3 months until discontinuation, or until disease recurrence requires a dose increase. The cyclophosphamide dosage may need to be adjusted to maintain acceptable blood counts (particularly a leukocyte count above 3000/mm3). Both oral and intravenous cyclophosphamide have been used successfully,126, 145-149 with equal effectiveness, ,in combination with corticosteroids. 126 Although intermittent pulse cyclophosphamide is less toxic than daily oral cyclophosphamide and the overall monthly dose may be less, relapse may occur more frequently with the intravenous routeY' 35,126 The intravenous pulse cyclophosphamide dose is 15 mg/kg given in a single intravenous pulse every 4 to 6 weeks. Because of the rarity of Wegener's granulomatosis and the sllfficiently compelling results of cyclophosphamide therapy compared with the predictable natural history of the disease, no controlled randomized comparative drug trials have been conducted. However, the significant lTIOrbidity associated with cyclophosphamide therapy (see later) has prompted the use of alternative therapies, although they are still considered second-line. Azathioprine has shown some success, but it is less effective than cyclophosphamide and should not be used as first-line therapy. It should only be considered in patients experiencing adverse side effects or when fertility concerns arise. 38 , 150-154 Disease relapse has occurred when therapy has been converted from cyclophosphamide to azathioprine. Methotrexate has also been used for the treatment of Wegener's granulomatosis without significant side effects.155-160 Low-dose weekly methotrexate, with or without concomitant corticosteroids, has been used successfully for the maintenance of cyclophosphamide-induced remission (about 90% of the cases were successfully maintained in remission) .158 Low-dose weekly methotrexate has also been used successfully for non-life-threatening Wegener's granulomatosis, as either primary therapy or when cyclophosphamide therapy was not effective or had caused significant toxicity, with remission rates of 59% to 74%.35, 155, 158-160 However, Stone and colleagues found a high rate of disease relapse with methotrexate, and a need to maintain patients on long-term chronic therapy.160 Other therapies that show promise include cycloIII

sporine, monoclonal antibody, intravenous ilTImunoglobulin, and protein A immunoadsorption.151-155 Trimethoprim-sulfamethoxazole (TIS) has been reported to be of benefit157-172 in patients with the limited form of Wegener's granulomatosis where there is no renal involvement. The mechanism of action is unclear, and both an antimicrobial effect (which would prevent infections that would trigger relapses) and an anti-inflammatorylimmunosuppressive effect are theorized. A case of very limited Wegener's granulomatosis, with a positive conjunctival biopsy, MPO-positive p-ANCA, and presenting with scleritis as the only clinically apparent manifestation, was successfully treated with oral TIS with clinical improvement and normalization of serial p-ANCA titers. 172 The anecdotal nature of such reports, the questionable diagnosis, the failure to rule out infections, and the use of concurrent immunosuppressive therapy do not provide convincing evidence of the efficacy of TIS in Wegener's, so the use of this therapy should be approached with caution. 35 , 173 Patients should be treated and appropriately monitored for myelosuppression and the potential complications of corticosteroid and cyclophosphamide or other cytotoxic agent therapy by individuals with training and experience in the use of chemotherapeutic agents. Therapy of patients with limited disease and ophthalmic involvement should be approached with the same philosophy as patients with the complete form of the disease. Because the onset of ocular inflammation may herald systemic disease, careful <1(review of systems and appropriate referral to a medical subspecialist to carefully assess systemic involvement is critical. Conjunctivitis and episcleritis, which are usually not vision threatening, may be treated with local corticosteroid therapy with careful monitoring for the development of more severe ophthalmic disease. TIS may be considered, with the reservations noted. However, the frequent failure of localized, severe, vision-threatening ophthalmic disease (orbital disease, scleritis [especially necrotizing], peripheral ulcerative keratitis, uveitis, and retinal and optic nerve vasculitis) to respond to local therapy alone 5s, 59, 73, 174 and the not infrequent progression to other organ involvement with its associated morbidity require the use of systemic cytotoxic immunosuppressive therapy, as for any patient with Wegener's granulomatosis. l 4'1 Systemic prednisone alone is not effective. 53 Thus, a systemic regimen of cyclophosphamide with the adjunctive use of systemic and local or regional corticosteroids, using the guidelines noted, should be used. Surgical intervention may be required in patients with orbital disease (e.g., decompression and drainage), and appropriate consultation should be obtained. Tectonic scleral grafting may be required in patients with impending globe perforation from necrotizing scleritis. Although some investigators feel that a rise in an ANCA titer in a patient with stable disease portends a clinical exacerbation132 and justifies immunosuppressive therapy, this is not universally accepted. 35 Patients in clinical remission whose ANCA titers do not revert to normal may also be at increased risk of recurrence. 129 Power and colleagues reported on eight patients with scleritis; •


disease relapse occurred in four of the five patients in whom ANCA titers had not normalized" None of the three patients whose ANCA titers normalized had a relapse. 129 Thus, close monitoring of clinically inactive patients with persistently high or rising ANCA titers is imperative.

Complications Disease and Systemic Cytotoxic Therapy Disease-related morbidity was seen in 86% of patients at the NIH. These complications included chronic renal insufficiency (42%), hearing loss (usually partial unilateral or bilateral) (35%), cosmetic and functional nasal deformities usually associated with chronic sinus disease (28%), tracheal stenosis (13%), and vision loss (8%) .35 Disease- and therapy-related morbidity included chronic sinus dysfunction (47%) and pulmonary insufficiency (17%) .35 Cyclophosphamide is associated with the potential for side effects and complications. Opportunistic infections (particularly herpes zoster) may occur, as can sterility (57%), cyclophosphamide-induced cystitis (43%), bladder cancer (2.8%), and myelodysplasia (2%). Glucocorticosteroid-induced cataracts (21 %), fractures (11 %), aseptic necrosis of the femoral head (3 %), infection, hair loss, diabetes mellitus, hypertension, Cushing's syndrome, and peptic ulcer disease may arise as a consequence of corticosteroid therapy. There is a 2.4-fold overall increase in malignancies in patients with Wegener's granulomatosis. A 33-fold increase in bladder cancer is noted, with a latency of 7 months. to 10 years after discontinuing cyclophosphamide. Thus, serial urinalyses should be obtained even after discontinuation of cyclophosphamide therapy, and the presence of hematuria warrants cystoscopy. An 11fold increase of lymphomas is also noted. Neoplasms such as lymphocytic leukemias have been observed in patients with Wegener's granulomatosis who were treated for long periods with cytotoxic agents.175-17S

The outcome of Wegener's granulomatosis had dramatically improved with the introduction of daily cyclophosphamide combined with glucocorticosteroids. The prognosis for limited Wegener's granulomatosis is better than for the complete form. 22 Patients with severe renal disease, even with cytotoxic immunosuppressive therapy, have a guarded prognosis with a higher mortality.s, 179 In the study by Pinching and colleagues of 18 patients with severe renal disease, 11 (61 %) had died at 5 years, highlighting the importance for early diagnosis. s In the NIH series of 158 patients who had been followed from 6 months to 24 years, 91 % experienced a marked improvement, and 75% achieved a complete remission. 35 Although 50% of patients in remission may have orie or more relapses, 44% of patients do have remissions of greater than 5 years. 35 However, there is significant associated lTIorbidity from the disease (86%) or side effects from the therapy (42%) .35 The socioeconomic and qualityof-life impacts of Wegener's granulomatosis are also significant. 1so The visual prognosis depends on the severity and chro-

CHAPTER 58: WEGENER'S GRANULOMATOSIS

nlClty of the eye disease and, in general, is good when treated appropriately with systemic cytotoxic therapy. Vision loss or total blindness may be seen in 8% to 37% of patients, especially if the disease has been longstanding or inadequately treated, or when there has been a delay in diagnosis. 35 ,51 Frequently, the causes are compressive optic neuropathy, retinal and optic nerve vasculitis, and globe perforation from necrotizing scleritis and peripheral ulcerative keratitis. Complications of chronic uveitis, such as cystoid macular edema, can also permanently affect vision. These findings emphasize the importance of rapid diagnosis and the institution of appropriate therapy.

CONCLUSION Wegener's granulomatosis is no longer a universally fatal disease; rather, it is eminently treatable, with a very high chance of remission and long-term survival. Despite this dramatic improvement in prognosis, there can still be significant morbidity and even death from delays in diagnosis and from the systemic cytotoxic therapy. The importance of rapid diagnosis prior to the onset of renal disease and the initiation of appropriate therapy by a trained expert cannot be overstated. Better understanding of the immunopathogenesis of Wegener's granulomatosis, such as the role of T cells and dysregulated IL-12 secretion, may lead to more novel and selective treatment strategies, including the use of monoclonal antibodies and cytokines. The utility of ANCA as a very serl~itive diagnostic laboratory test, especially in patients with very limited disease, has greatly facilitated earlier diagnosis and may help in the clinical management of Wegener's granulomatosis, including the ocular inflammation. The ophthalmologist must be exceedingly familiar with Wegener's granulomatosis, not only because of the diversity of ocular inflammatory manifestations present in about 50% of affected patients, but also because ocular involvement can be the only or the predominant presenting feature of the disease. The presence of corneoscleral disease may be an indicator of systemic vasculitis, so a careful systemic evaluation and timely therapy may reduce not only ocular morbidity but also systemic morbidity. Although uveitis and retinal vasculitis are less frequently encountered than scleritis or orbital disease, and they are often found in association with scleral inflammation, they can cause significant vision loss. The treatment of ocular inflammation should be similar to the approach used in other clinical variants of limited or generalized Wegener's granulomatosis. Local therapy is not effective for vision-threatening disease, nor is the use of systemic corticosteroids alone. Cytotoxic immunosuppressive agents, such as cyclophosphamide, are mandatory. The visual prognosis with appropriate therapy remains good.

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tion of disease reactivation in relapsing ANCA-associated vasculitis. Nephrol Dial Transplant 1998;13:2074-2076. jayne DRW, Davies Mj, Fox CJV, et al: Treatment of systemic vasculitis with pooled intravenous immunoglobulin. Lancet 1991;337:1137-1139. Tuso P, Moudgil A, Hay j, et al: Treatment of antineutrophil cytoplasmic autoantibody positive systemic vasculitis and glomerulonephritis with pooled intravenous gammaglobulin. Am j Kidney Dis 1992;20:504. Rossi F,jayne DRW, Lockwood CM, Kazatchkine MD: Antiidiotypes against anti-neutrophil cytoplasmic antigen autoantibodies in normal human polyspecific IgG for therapeutic use and in the remission sera of patients with systemic vasculitis. Clin Exp Immunol 1991;83:298-303. Lockwood CM, Thiru S, Isaacs HO, et al: Long-term remission of intractable systemic vasculitis with monoclonal antibody tl1erapy. Lancet 1993;341:1620-1622. Lockwood CM: Refractory Wegener's granulomatosis: A modelfor shorter immunotherapy of autoimmune disease. j R ColI Physicians Lond 1998;32:473-478. De Remee RA, McDonald Tj, Weiland LH: WG: Observations on treatment witl1 antimicrobial agents. Mayo Clin Proc 1985;60:2732. West BC, Todd HR, KingJW: WG and trimethoprim-sulfamethoxazole. Ann Intern Med 1987;106:840-842. Yuasa K, Tokitsu M, Goto H, et al: WG: Diagnosis by transbronchial lung biopsy, evaluation by gallium scintigraphy and treatment with sulfamethoxazole/trimethoprim. Am j Med 1988;84:371-372. De Remee RA: The treatment of WG witl1 trimethoprim/sulfamethoxazole: Illusion or vision? Arthritis Rheum 1988;31:10681072. Israel HL: SulfametllOxazole-trimethoprim therapy for WG. Arch Intern Med 1988;148:2293-2295. Soukiasian SH,jakobiec FA, NilesjL, Pavan-Langston D: Trimethoprim-sulfamethoxazole for scleritis associated witl1 limited Wegener's granulomatosis: Use of histopathology and anti-neutrophil cytoplasmic antibody (ANCA) test. Cornea 1993;12:174-180. Leavitt TY, Hoffman GS, Fauci AS: Response: The role of trimethoprim/sulfamethoxazole in the treatment of WG. Arthritis Rheum 1988;31:1073-1074. Brady HR, Israel MR, Lewin WH: WG and corneo-scleral ulcer. JAMA 1965;193:248. Wheeler GE: Cytoxan-associatedleukemia in WG. Ann Intern Med 1991;94:361. Westberg NS, Swolin B: Acute myelogenous leukemia appearing in two patients after prolonged continuous chlorambucil therapy for WG. Acta Med Scand 1976;199:373. Chang H, Geary CB: Therapy-linked leukemia (letter). Lancet 1997;1:97. Sant GR, Ucci A.A, Meared EM: Renal immunoblastic sarcoma complicating immunosuppressive therapy for WG. Urology 1983;21:632-634. Brandwein S, Esdaile j, Danoff D, et al: Wegener's granulomatosis. Clinical features and outcome in 13 patients. Arch Intern Med 1983;143:476. Hoffman GS, Drucker Y, Cotch MF, et al: Wegener's granulomatosis: Patient-reported effects of disease on health, function, and income. Arthritis Rheum 1998;41:2257-2262.

I I

IS Richard Paul Wetzig

DEFINITION Relapsing polychondritis (RP) is a rare autoimmune disease with protean manifestations. It frequently affects the eye, typically with episcleritis, scleritis, uveitis, vasculitis, or some related pathology. Although certain laboratory parameters may be abnormal, none are diagnostic of the disease; The diagnosis is therefore based on clinical grounds. The most distinguishing features include inflammatory episodes of auricular, nasal, or laryngotracheal cartilage and an inflammatoTy arthritis. Isolated findings arecnot sufficient to make the diagnosis of RP and can often be associated with other distinct syndromes; Rather, a particular array of signs and symptoms defines the disease, often presenting in a staggered relapsing and remitting pattern over time. It can run a relatively benign course, or it can be fatal. The criterion of McAdam and colleagues 1 for RP, as revised by Damiani and Levine 2 and later by Isaak and colleagues,3 is the presentation of three or more of the following six signs: recurrent chondritis ,,of both auricles, chondritis of nasal cartilage, nonerosi~e inflammatory polyarthritis, inflammation of ocular structures, chondritis of the respiratory tract, or cochlear or vestibular damage. Any of these signs and a positive biopsy is also considered diagnostic. Finally, the diagnosis can be made based on chondritis in two or more separate anatomic locations, with response to corticosteroids or dapsone.

HISTORY RP was first described by Jaksch-Wartenhorst in 1923. He called it polychondropathia. 4 In subsequent years, the disease was called polychondritis, perichondritis, chondritis, and eventually relapsing polychondritis for the first time by Pearson and coworkers in 1960. 5 The first reported ocular histologic findings were described by Verity and colleagues in an episcleritis specimen. They included a decrease in basophilia and fragmentation of elastic tissue with an accumulation of mast cells, plasma cells, and lymphocytes around episcleral vessels. 6 It has been noted that phylogenetically the sclera has associations with cartilage, as cartilaginous plates have been found in the sclera of lower vertebrates but not of humans. Because cartilage appears to be a primary target of the destructive immune response in RP, it has been postulated that scleral components sharing antigenicity with cartilage are the targets in ocular disease. 7 Sequestration of these ocular antigens could play a part in the pathology ofRP as proposed by Magargal and coworkers. 8 Various experimental models for the immunologic privilege of the eye have been studied. 9- 12 Because of the wide variety of its clinical manifesta-

tions, an understanding of RP requires a multidisciplinary approach. Over 550 cases of RP have been reported in a broad spectrum of specialties throughout the worldwide literature.13

EPIDEMIOLOGY Most series reporting findings in RP indicate an equal male-to-female ratio, a predilection for white persons, an average age of onset in the fourth decade, and multisystem involvement at the time of presentation. 3, 14, 15 In one series, the mean delay between the onset of symptoms and diagnosis was 2.9 years. 16

CLINICAL In a retrospective study of 112 patients with RP attending the Mayo Clinic, 21 had ocular symptoms at onset and 57 developed ocular symptoms during the course of the disease. 3 The authors describe ocular findings of episcleritis, scleritis, iridocyclitis, corneal infiltrates and thinning, proptosis, lid edema, retinopathy, and optic neuritis. Consistent with other investigators, they reported characteristic features of otorhinolaryngeal, respiratory, arthritic, renal, cardiovascular, dermatologic, and neurologic findings. In a study of 62 patients with RP, Zeuner and coworkers reported that 85.1 % showed intermittent inflammatory episodes, and 12.9% had symptoms that persisted during follow-upY Auricular chondritis presents initially in roughly half the patients with RP and eventually develops in 80% to 90%, whereas saddle-nose deformity presents in about 20% to 25% and subsequently evolves in 30% to 60% (Fig. 59-1) .3, 17 Patients with these s}'lnptoms are seen initially by the otolaryngologist. 1s Auricular and nasal chondritis are painful, with inflammation of cartilage in ear and nose; some patients may develop epistaxis. 16 Approximately 30% of patients with RP develop laryngotracheal involvement. Beginning with hoarseness or aphonia and local tenderness, this is the result of inflammation of cartilage, with inflammatory edema and narrowing or collapse of the airway (Fig. 59-2) .3, 16, 17 Iatrogenic airway obstruction has been reported with attempted bronchoscope, intubation, and tracheostomy.19 Hughes and coworkers reported that, overall, 50% of deaths resulting from complications of RP were related to airway lesions. 15 Impairment of lower airway mucociliary function and a poor cough reflex may also occur as a result of inflammation of bronchial cartilage, leading to bronchitis or pneumonia. 16, 20 General constitutional symptoms and signs, including fever, weight loss, fatigue, night sweats, and enlarged inguinal lymph nodes occur in 20% to 35% of patients with RP at disease onset; eventually, 45% to 60% are

CHAPTER 59: EYE DISEASE AND SYSTEMIC CORRELATES IN RELAPSING POLYCHONDRITIS

affected. 3, 17 Nondeforming, nonerosive rheuIllatoid factor-negative oligoarthritis or polyarthritis can occur periodically over the course of RP.21 Virtually any joint can be involved. Anterior flail chest has resulted frOlll joint dissolution caused by costochondritis. 16 Both sensorineural and conductive hearing loss occur in roughly 20% to 30% of RP patients. 3, 17 Cardiovascular disease is the second leading cause of death in patients with RP, although a causative link is not always found. Regurgitation resulting from involvement of the aortic ring, mitral regurgitation, aortic aneurysms, conduction defects, myocarditis, pelicarditis, and myocardial infarction are reported. 16 , 17, 22 Skin lesions can be associated with RP, at times in the form of a nonspecific dermatitis and at other times in the form of a more characteristic leukocytoclastic vasculitis.3, 17, 23 Renal complications can be lethal in RP, with deaths due to glomerulonephritis reported. 3 Associations with inflammatory bowel disease,24 autoimmune hemolytic anemia,25 myeloproliferative syndrome,26 autoimmune thyroiditis,27,28 and insulin-dependent diabetes mellitus 27,28 have rarely been reported. Of particular note is the occasional association between RP and collagen vascular diseases such as rheumatoid arthritis, confusing the differenti;:tl diagnosis at times, yet adding valuable insights into dIe pathologyp I

CLINICAL MANifESTATIONS Of OCULAR INVOLVEMENT Numerous case reports of ocular inflammation in patients with RP have appeared in the literature. 29-31 Ocular mani-

fiGURE 59-I. Active chondritis of the external ear, with 'floppiness' of that same ear as a consequence of prior episodes of chondritis with loss of cartilage. (Courtesy of C. Stephen Foster, MD.) (See color insert.)

fiGURE 59-2. Relapsing' polychondritis with obvious destruction of nasal cartilage, with collapse and saddle nose deformity. Note also that the patient has developed tracheal involvement as a consequence of undertreatment, with resultant need for permanent tracheostomy. (Courtesy of C. Stephen Foster, MD.) (See color insert.)

festations in 11 patients with RP and scleritis treated on the Immunology Service at the Massachusetts Eye and Ear Infirmary included necrotizing scleritis, nodular scleritis, diffuse inflammation, peripheral ulcerative keratitis, descemetocele, iritis, vitritis, retinopathy, papilledema, muscle palsy, ptosis, peripheral corneal infiltrates, and episcleritis. 32 In one large series, nonspecific ocular involvement was the first manifestation of RP in 19% of cases, whereas most patients with inflaIllmatory eye disease tended to develop multiple systemic manifestations. 3 The data obtained by Isaak and colleagues 3 and by Zeuner and coworkers 17 are in approximate agreement, with 20% to 30% of patients with RP reported to have ocular symptoms at the time of RP onset, and around 50% ultimately developing ocular SYlllptOlllS during the course of the disease. The most common eye presentations are conjunctivitis, episcleritis, and scleritis, each appearing in more than 10% of involved eyes. In addition, 5% to 10% had iritis, retinopathy, muscle paresis, or peripheral corneal thinning. Less common were lid edema, orbital inflammation, peripheral corneal infiltrates, keratitis sicca, and papilledema. 3 Overlap syndromes and ocular manifestations are too nonspecific to be used alone to make the diagnosis of RP. Scleritis can be a sight-threatening manifestation of RP. It is either diffuse, nodular, or necrotizing. 8, 32 Scleral thinning or scleromalacia can occur, but posterior scleritis is infrequent. 33, 34 Sainz de la Maza reported, in a series of 113 eyes with scleritis, that 47.7% of the patients had

CHAPTER 59: EYE DISEASE AND SYSTEMIC CORRELATES IN RELAPSING POLYCHONDRITIS

associated systemic vasculitic disease, including 32 with rheumatoid arthritis, 14 with Wegener's granulomatosis, 11 with RP, 7 with arthritis and inflammatory bowel disease, and 7 with systemic lupus erythematosus (SLE) .35 It was observed that diffuse scleritis tended to occur without systemic vasculitis and that necrotizing scleritis tended to accompany systemic vasculitis. The occurrence of nodular scleritis did liot correlate with the presence or absence of systemic vasculitis. Some investigators have noticed a parallel between scleritis or episcleritis and disease activity in RP elsewhere, most commonly the nose and joints. 3 Iridocyclitis may be recurrent and may occur in up to 30% of RP patients, often in association with inflammation of the cornea or sclera.1, 3, 31 Isaak and coworkers found 10 patients with iritis, 1 with choroiditis, and 9 with "retinopathy" in a cohort of 112 patients with relapsing polychodritis,3 and Matoba and colleagues reported on another 10 patients with uveitis, 5 of whom did not have scleritis. 3o Three of the patients in the latter study developed uveitis prior to the development of any other symptoms of RP, and in nearly all of the patients the diagnosis of RP had not been established prior to the onset of uveitis, emphasizing the importance of the ophthalmologist in establishing the diagnosis. Conjunctival inflammation in the form of nonspecific bilateral redness, irritation, and itching occurred in 3 of 112 patients with RP in the Mayo Clinic series, and 2 of 112 had nonspecific conjunctival hemQrrhage. The same series reported mild keratoconjunctivitis sicca in several patients, with severe dry eyes in two patients with SjogI:en's syndrome. 3 Corneal thinning and ulceration have been associated with relapsing polychondritis. 3, 36-38 In addition, focal peripheral epithelial or stromal corneal infiltrates associated with ulceration, pannus, peripheral corneal thinning, perforation, or corneal edema can occur. 3, 29, 30, 36, 39 N eurosensory or exudative retinal detachments as well as retinal infiltrates and chorioretinitis with uveitis are reported in patients with RP.l, 3, 8, 33 Isolated reports of retinal artery occlusion have appeared. 4o ,41 Rarely, retinal pigment epithelial defects or retinal vein occlusion is seen. 3,8 Cataracts, most frequently posterior subcapsular, often occur in patients with RP.l, 3,16 They may be caused either by the disease itself or by the corticosteroids used in its treatment. Variousneuro-ophthalmologic presentations infrequently appear with relapsing polychondritis. Extraocular muscle paresis, perhaps caused by an underlying vasculitis, are the most common and can cause ophthalmoplegia and diplopia. 13 , 16, 33, 42 RP has been seen with ptosis 43 and Horner's syndrome. 15 ,44 Optic neuritis and ischemic optic neuropathy sometimes occur. 13 , 33, 45, 46 Optic atrophy has been reportedY Also, visual field defects, perhaps caused by cerebral vasculitis, may occur. 3 Other neurologic symptoms that may present include headaches, encephalopathy, ataxia, hemiplegia, seizures, and a temporal arteritis vasculitisP Papilledema may be observed. 3,48 Proptosis and chemosis, possibly caused by posterior orbital inflammation of cartilage, are the most common ocular adnexal findings in RP and can mimic pseudotumor. 3, 16, 33, 49-51 Other adnexal findings include lid edema

that can mimic cellulitis, as well as tarsitis and dacryocystitis. 3 Secondary glaucoma sometimes occurs in the setting of keratitis or iridocyclitis.30, 52 End-stage eye disease in RP can unfortunately result in panophthalmitis. and blindness. 36, 53

No histopathologic pattern is pathognomonic for RP, and unless perichondral tissue at marginal sites of involvement is sampled, only nonspecific granulation tissue is found. 16 Any cartilage, including the elastic cartilage of the ears and nose, the hyaline cartilage of peripheral joints, the fibrocartilage at axial sites, and the cartilage of the tracheobronchial tree together with other proteoglycan-rich structures in the eye, heart, blood vessels, and inner ear may be inflammed. 16 Histologically, there is loss of basophilic staining of the cartilage matrix, perichondral inflammation at the cartilage-soft tissue interface, fibrocytic and capillary endothelial cell proliferation, perivascular mononuclear and neutrophil infiltrates, and vacuolated necrotic chondrocytes with replacement by fibrous tissue. 15 , 54, 55 Biopsy of cartilage may produce structural damage and cosmetic deformity; a posterior auricular approach is the least destructive. 16 Conjunctival biopsy in a patient with RP and scleritis ~howed mast cells and chr,onic inflammatory cells such as plasma cells and lymphocytes in the substantia propria. Additionally, there was a vasculitis defined by conjunctival vessel wall invasion with neutrophils and deposition of IgG, IgM, and complement component C3 in the vessel walls on immunofluorescent study.32 In an eye obtained at autopsy from a patient with RP and iridocyclitis, chronic inflammatory cells and fibroblasts were found in the anterior segment,forming a cyclitic membrane. 56 In a blind eye enucleated following hypopyon uveitis, marginal keratitis and perforation, and inflammatory cellular infiltration of the corneal stroma and iris were found. 36 Additional regional findings have been perivascular lymphocytic cuffing in a biopsy of inflamed conjunctiva from one patient with episcleritis, and granulomatous inflammation of the sclera and choroid with vasculitis of the conjunctiva in another. 57 In another globe obtained at autopsy, mononuclear inflammatory cells and plasma cells were scattered about episcleral vessels. 55 Vasculitis affects a wide range of organ systems and vessels of all sizes in patients with relapsing polychondritis, from aortitis with aortic rupture to microscopic angiitis of dermatologic, renal, neural, audiovestibular, and episcleral tissue. 58 Several lines of evidence indicate that RP might be an autoimmune disease. 59 Autoantibodies to native collagens type 1160- 63 and types IX and XI64 have been reported. Immunofluorescence microassays show granular immunoglobulin G (IgG) , IgA, IgM, and complement at the junction of fibrous and cartilaginous tissue, suggesting the presence of immune complexes. 3, 65-67 Additionally, cell-mediated immune response to collagen has been reported. 68 ,69 Five of 11 patients with scleritis and RP had circulating immune complexes, 5 of 11 had antinuclear antibodies, and 3 of 11 had abnormal serum complement levels in one series. 32 Patients have been reported with low

CHAPTER 59: EYE DISEASE AND SYSTEMIC CORRELATES IN

titers of cytoplasmic antibody or perinuclear cytoplasmic antibody that are sometimes correlated with coexisting vasculitis. 70 In one study, cellular infiltrates were predominantly human lymphocyte antigen (HLA)-DR-positive antigen-presenting cells, with a significant number of CD4 + T lymphocytes. 71 One study of RP patients reported 8 of 21 patients with elevated anticardiolipitl antibodies, 1 of 21 with elevated antiphosphatidylserine antibodies, and none with elevated anti-beta-2-glycoprotein I antibodies; the investigators suggested that, when high levels of antiphospholipid do exist, they are more likely to reflect SLE because RP patients showed no clinical signs or symptoms of antiphospholipid syndrome. 72 Circulating antibodies to corneal epithelium have been detected by immunofluorescence before and after treatment in a RP patient. 73 It has been suggested by some that immune complex deposition in the eye could explain aspects of inflammatory eye disease in patients with RP.8 A highly significant association between RP and the major histocompatibility locus HLA-DR4 has been found, with no statistically significant link to any of its DRB1 *04 subtype allelesY' 18, 74 No significant association between HLA-DR4 and any specific manifestations of RP was found, and HLA-DR1 was not statistically linked to patients even when they were HLA-DR4 negativeY Furthermore, the extent of organ involvement was negatively correlated with HLA-DR6 in this series. The frequency of HLA-DR4 is also quite high in rheumatoid arthritis patients, although Gregerson and coworkers implicate a different role for this than for RP.17, 75 To date, mo association between RP and either the HLA-A or HLA-B loci has been detected. 74 , 76 In animal models, rats or mice immunized with native type II collagen developed auricular chondritis with arthritis and positive findings on immunofluorescence, similar to those seen in humans with RP.77,78 The response occurs in some strains of rats or mice but not in others, suggesting immunogenetic restriction. 79 , 80 Altogether, strong evidence supports the hypothesis that RP is an autoimmune disease with vasculitis as the cause of ocular, cardiovascular, dermatologic, neurologic, and audiovestibular inflammation. 3, 17

Trentham and Le enumerated various aspects of the differential diagnosis in RP.16 The initial presentation of a painful, tender, and swollen ear in isolation is usually misdiagnosed as infectious perichondritis and needs to be distinguished from trauma, insect bite, or exposure to excessive heat or cold. 16. The ears can become floppy and soft with internal calcific deposits detectable on radiographs after repeated episodes of RP.16 Nasal pain, hoarseness, throat pain, and difficulty talking are common presenting symptoms, as are joint pain with or without swelling caused by a seronegative nondeforming arthritis of virtually any synovial joint. 1, 2, 16 Conductive hearing loss can occur when chondritis causes closure of the external auditory canal from collapse or edema, whereas sensorineural hearing loss can result from vasculitis occurring in the vestibular or cochlear branch of the internal auditory artery. 1, 2, 16 As presenting signs in RP, the abrupt onset of hearing loss, dizziness, ataxia, nausea, and vomiting can mimic a posterior circulation stroke. 16

1I'(~ILAH"'~HINh

Acute vestibular symptoms usually improve, but hearing loss is often permanent. 16 Recurring episcleritis or scleritis may occur early in RP but are not diagnostic in isolation and may even mistakenly suggest a reactive arthritis or spondyloarthropathy when coincident with joint sYInptoms. 16 Included in the differential diagnosis for RP are rheumatoid arthritis, Sjogren's sYIldrome, Reiter's SYI1drome, sarcoidosis, polyarteritis nodosa, AdamantiadesBeh~et disease (ABD) , Still's disease, solitary scleritis, Cogan's syndrome with interstitial keratitis plus audiovestibular symptoms, and Wegener's granulomatosis, which is distinguishable through its early involvement of noncartilaginous tissue and granulomas on biopsy.1-3, 16 Although biopsy and laboratory tests are nondiagnostic, nearly all patients with RP have increased nonspecific inflammatory activity as manifested by elevated erythrocyte sedimentation rate (ESR) , C-reactive protein, and serum protein electrophoresis. 3, 16, 17 When rheumatoid factor or antinuclear antibodies are positive, there is usually a collagen vascular disease such as rheumatoid arthritis or SLE associated with RP.16, 17 Out of 61 patients with RP, including two with glomerulonephritis in Zeuner's series, all had a creatinine level below 1.5 lng/dl. 17 The diagnosis of RP continues to rest on clinical findings. Magnetic resonance imaging, computed tomography, and roentgenograms can be useful in following the course of RP, particularly with respect to laryngotracheal function.3, 81-83 Imaging studies have also been useful in detecting abnormalities in lobar and segmental bronchi 84 and cerebral arteritis 85 in the setting of RP. Pulmonary function tests may be useful in following lower airway involvement.20 Roughly 25 % of patients in recent large series of RP have associated collagen vascular disease such as SLE, rheumatoid arthritis, ABD, Sjogren's syndrome, or mixed connective tissue disease, whereas some are hypothyroid or have myelodysplastic syndromes. 16, 17

Topical steroids do little to alleviate ocular symptoms in RP; systemic steroids are necessary at the very least, and immunosuppressives are used in refractory cases. 16 Dapsone is felt to be efficacious in treating extraocular manifestations of moderately severe RP.86, 87 Azathioprine and penicillamine also have been used. 88 , 89 RP has been treated with plasma exchange 90 and anti-CD4monoclonal antibody.91,92 Investigators using methotrexate in RP found a steroid-sparing effect, ilnprovement in symptoms, and increased longevity.16, 93 One patient who developed toxicity to methotrexate improved on oral minocycline, which is sometimes used in rheumatoid arthritis. 94 RP with ocular involvement has responded to cyclosporin A.95,96 Cyclophosphamide has been a mainstay in the treatment of severe refractory RP.1, 97 With respect to ocular manifestations of RP, Hoang-Xuan reported that diffuse scleritis was controlled by either indomethacin, dapsone, or cyclophosphamide, nodular scleritis was controlled by either steroids or azathioprine, and necrotizing scleritis responded only to cyclophosphamide. 32 Mortality is low with systemic chemotherapy.98 Lamellar keratectomy and keratoepithelioplasty are surgical approaches reported to be effective in preventing

59: EYE

UI::~II:J.l~~1I:

AND SYSTEMIC CORRELATES IN RELAPSING

recurrence of a corneal marginal ulcers in patients with

RP.3S; 99

PROGNOSIS It has been reported that the average duration of RP is 8

years. 16 Its course may be relatively indolent and benign, or rapidly fatal. Recent series seem to indicate a trend toward more favorable outcomes than earlier studies, perhaps because of a combination of less referral bias and ilnproved modern treatment modalities. 14, 27 A recent series reported a survival rate of 94% over an average disease duration of 8 years,16 whereas an earlier series reported a 5-year survival of 74%, with the most common cause of death being infection, usually in the form of pneumonia. 3 At final follow-up, Michet and colleagues 27 did not find that most patients still had symptoms requiring steroids, in contrast to Hughes and coworkers. 15 The former group noted that anemia at diagnosis was overall a bad prognostic sign for all, whik saddle-nose deformity and systemic vasculitis were the worst prognostic signs for patients under 51 years of age. 27 The prognosis in RP worsens with delay in diagnosis. 3,27 Sainz de la Maza and colleagues reported that, in their series of patients with scleritis, the outcome of scleritis with systemic vascular disease was worse than the outcome of scleritis without systemic vasculitis. 35 It was found that' scleritis associated with Wegener's granulomatosis was the most severe, scleritis with SLE or spondyloarthropathies was usually benign and self limiting, and scleritis with rheumatoid arthritis or RP was of intt!rmediate severity. Mortality from vascular-related events is higher when necrotizing scleritis occurs in the setting of rheumatoid arthritis. 100, 101 It might be inferred that outcomes in RP with severe ocular disease would be improved with aggressive immunosuppressive therapy.

CONCLUSIONS Chronic debilitating diseases such as RP can extract a devastating emotional and physical toll on patients. Goldsmith notes that this is particularly true in patients with immunologic and collagen vascular diseases or cancer, motivating them to spend more time than most treating physicians will ever have to investigate their particular illness on the internet. 102 One website for uveitis in RP reads: fever, inflamlnatory episodes of cartilage (ear, nose, trachea, costochondritis) with arthritis (McAdam's criteria), and cardiac, renal, and skin vasculitis (http://www. uicedu/ com/ eye/ department/ guptabook/ emuveitis6. htm). Patients have access to information beyond the scientific database as well. The result is a concerted distillation of information through the internet with respect to a disease process, leading to "virtual communities" of patients. lOl Instead of being steered by managed care, patients are flooded with information regarding where they should go for treatment. Physicians need not see increased patient activism as an adversarial trend. A future symbiosis between patient advocacy and provider leadership might influence free market forces in America to evolve into a kinder and gentler health care system. Perhaps it would not even be too much to hope for better education, stronger research and development, and an approach toward universal coverage as a result.

The author gratefully appreciates the help of the staff at the Webb medical library at Penrose Hospital in Colorado Springs and the staff at the Dennison medical library at the University of Colorado Health Sciences Center in Denver for valuable assistance in performing the literature search for this chapter. I also thank my wife Melissa for help with the word processing in preparation of the manuscript.

References 1. McAdam LP, O'Hanlan "NLA, Bluestone R, et al: Relapsing polychondritis: Prospective study of 23 patients and a review of the literature. Medicine 1976;55:193-215. 2. Damiani JM, Levine HL: Relapsing polychondritis-Report of ten cases. Laryngoscope 1979;89:929-946. 3. Isaak BL, Liesgang TJ, Michet CJ Jr: Ocular and systemic findings in relapsing polychondritis. Ophthalmology 1986;93:681-689. _4. Jaksch-Wartenhorst R: Polychondropathia. Wien Arch Intern Med 1923;6:93-100. 5. Pearson CM, Kline HM, Newcomer VD: Relapsing polychondritis. New EnglJ Med 1960;263:51-58. 6. Verity MA, Larson WM, Madden SC: Relapsing polychondritis. Report of two necropsied cases with histochemical investigation of the cartilage lesion. AmJ Pathol 1963;42:251-269. 7. Anderson B: XXIII Edward Jackson Memorial Lecture. Ocular lesions in relapsing polychondritis and other rheumatoid syndromes. Trans Am Acad Ophthalmol Otol 1967;71:227-242. 8. Magargal LE, Donoso LA, Goldberg RE, et al: Ocular manifestations of relapsing polychondritis. Retina 1981;1:96-97. 9. Wacker WB, Donoso LA, Kalsow CM, et al: Experimental allergic uveitis, isolation, characterization and localization of a soluble uveito-pathogenic antigen from bovine retina. J Immunol 1978;19:1949-1958. 10. Wetzig RP, Foster CS, Greene MI: Ocular immune responses. Priming of A/J mice in the anterior chamber with azobenzene arsonatederivatized cells induces second-order-like suppressor T-cells. J Immunol 1982;128:1753. 11. Foster CS, Monroe JG, Campbell R, et al: Ocular immune responses. II. Priming of A/J mice in the vitreous· induces either enhancement or suppression of subsequent hapten-specific DTH responses. J Immunol 1986;36:2787. 12. Holland EJ, Chan CC, Wetzig RP, et al: Clinical and immunohistologic studies of corneal graft rejection in the rat keratoplasty model. Cornea 1991;7:809. 13. Myasaka LS, de Andrade A, Bueno CE, et al: Relapsing polychondritis. Rev Paul Med 1998;116:1637-1642. 14. Dolan DL, Lemmon GB, Teitelbaum SL: Relapsing Polychondritis; analytical literature review and studies of pathogenesis. Anl J Med 1966;41:285-299. 15. Hughes RA, Berry CL, Seifert M, et al: Relapsing polychondritis; Three cases with a clinico-pathological study and literature review. QJ Med1972;41:363-380. 16. Trentham DE, Le CH: Relapsing polychondritis: Clinical review. Ann Intern Med 1998;129:114-122. 17. Zeuner M, Straub RH, Rauh G, et al: Relapsing polychondritis: Clinical and immunogenetic analyses of 62 patients. J Rheumatol 1997;24:96-101. 18. McCaffrey TV, McDonald TJ, McCaffrey LA: Head and neck manifestations of relapsing polychondlitis: Review of 29 cases. Otolaryngology 1978;86:473-478. 19. Purcelli FM, Nahum A, Monell C: Relapsing polychondritis with tracheal collapse. Ann Otol Rhinol Laryngol 1962;71:1120-1129. 20. Mohsenifar Z, Taskin DP, Carson SA, et al: Pulmonary function in patients with relapsing polychondritis. Chest 1982;81:711-717. 21. O'Hanlan M, McAdam L, Bluestone R, et al: The arthropathy of relapsing polychondritis. Arthritis Rheum 1976;19:191-194. 22. Cipriano PR, Alonso DR, Baltaxe HA, et al: Multiple aortic aneurysms in relapsing polychondritis. Anl J Cardiol 1976;37:10971102. 23. Maestres CA, Igual A, Botey A, et al: Relapsing polychondritis with glomerulonephritis and severe aortic insufficiency surgically treated with success. Thorac Cardiovasc Surg 1983;31:307~309.

CHAPTER 59: EYE DISEASE AND SYSTEMIC CORRELATES IN RELAPSING 24. Asuncion AM, Federman DG, Kirshner RS: Swelling of the ear in a patient with ulcerative colitis. Arthritis Rheum 1994;37:432-434. 25. Itabashi H, Hishinuma A, Yoshida K, et al: A case of relapsing polychondritis associated with hemolytic anemia. Jpn J Med Sci BioI 1990;29:91-93. 26. Diebold J, Rauh G, Jaeger K, et al: Bone marrow pathology in relapsing polychondritis: High frequency of myelodysplastic syndromes. Br J Haemotol 1995;89:820-830. 27. Michet q, McKenna CH, Harvinder S, et al: Relapsing polychondritis. Survival role of early disease manifestations. Ann Intern Med 1986;104:74-78. 28. Takamatsu K, Nishiyama T, Nkauchi Y, et al: A case of insulin dependan.t diabetes mellitus associated with relapsing polychondritis, Hashimoto's thyroiditis, and pituitary adrenocortical insufficiency in succession. Jpn J Med Sci BioI 1989;28:232-236. 29. Bergaust B, Abrahamsen A: Relapsing polychondritis. Report of a case presenting multiple ocular complications. ACTA Ophthalmol 1969;47:174-181. 30. Matoba A, Plager S, Barber J, et al: Keratitis in relapsing polychondritis. Ann Ophthalmol 1984;16:367-370. 31. Zierhut M, Foster CS: Uveitis and relapsing polychondritis. In: Dernouchamps JP, Verougstraete C, Caspers-Velu L, Tassighin MJ, eds: Recent Advances in Uveitis. Amsterdam, Kugler, 1993, pp 487489. . 32. Hoang-Xuan T, Foster C, Rice B: Scleritis in relapsing polychondritis. Response to therapy. Ophthalmology 1990;97:892-898. 33. McCay DA, Watson PG, Lyne AJ: Relapsing polychondritis and eye disease. Br J Ophthalmol 1974;58:600-605. 34. Turut P, Malthieu D, LerouxJL: Scleromalacia in a case of chronic atrophic polychondritis. Bull Soc Ophthalmol Fr 1981;81:589-592. 35. Sainz de la Maza M, Foster CS, Jabbur NS: Scleritis associated wip1 systemic vasculitic diseases. Ophthalmol 1995;102:687-692. 36. Barth WF, Berson EL: Relapsing chOlldritis, rheumatoid arthritis and blindness. Am J Ophthalmol 1968;66:890-896. 37. Zion VM, Brakup AH, Weingeist S: Relapsing polychondritis, erythema nodosum and sclerouveitis. A'~case report with anterior segment angiography. Surv Ophthalmol 1974;19:107-114. 38. Martin NF, Stark V\Q", Maumenee AE: Treatment of Mooren's and MOOl'en-like ulcer by lamellar keratectomy: Report of six eyes and literature review. Ophthalmic Surg 1987;18:564-569. 39. MichelsonJB: Melting corneas with collapsing nose. Surv Ophthalmol 1984;29:148-154. 40. Hemry DA, Moss AJ, Jacox RF: Relapsing polychondritis, a "floppy" valve and migratory polytendinitis. Ann Intern Med 1972;77:576-580. 41. Ridgway HB, Hansotia PL, Schorr WP: Relapsing polychondritis. Arch Dermatol 1979;115:43-45. 42. Rucker CW, Ferguson RH: Ocular manifestations of relapsing polychondritis. Arch Ophthalmol 1965;73:46-48. 43. DupondJL, Humbert P, Mallet H: Chronic atrophic polychondritis and exophthalmos. Ann Med Interne (Paris) 1989;140:64-65. 44. Lang H: Recurrent iridocyclitis purulenta with secondary glaucoma and recurring chondritis of the external ear, nasal cartilage and larynx. Bel' Zusammenkunft Dtsch Ophthalmol Ges 1974;72:521-525. 45. Killian PJ, Susae J, Lawless OJ: Optic neuropathy in relapsing polychondritis. JAMA 1978;239:49-50. 46. Sundoram MB, Rajput AH: Nervous system complications of relapsing polychondritis. Neurology 1983;33:513-515. 47. Eckardt CE: Seltene form del' Augenbeteiligung bei rezidivierender Polychondritis. Klin Monatsbl Augenheilkd 1981;178:368372. 48. Stiles MC, Khan JA: Relapsing polychondritis. Arch Ophthalmol 1989;107:277. 49. Crovato F, Nigro A, De Marchi R, et al: Exophthalmos in relapsing polychondritis. Arch Ophthalmol 1965;73:46-48. 50. Rucker CW, Ferguson RH: Ocular manifestations of relapsing polychondritis. Arch Ophthalmol 1965;73:46-48. 51. Rosen SW, MacKenzie MR, Cohen PJ, et al: A syndrome resembling polychondritis in a patient with ulcerative colitis. Gastroenterology 1969;56:323-330. 52. Neild GH, CameronJS, Lessof MH: Relapsing polychondritis with crescentic glomerulonephritis. BrJ Med 1978;1:743-745. 53. Czarnowski J: Systemic cartilage disease. Otolaryngol Pol 1986;40:59-64.

54. Herman JH: Polychondritis. In: Kelly WN, Harrid ED, Ruddy S, et aI, eds: Textbook of Rheumatology, 3rd ed. Philadelphia, W.B. Saunders, 1993, pp 134-138. 55. Trentham DE: Relapsing polychondritis. In: McCarty DJ, Koopman V\Q", eds: Arthritis and allied conditions: A Textbook of Rheumatology, 12th ed. Philadelphia, Lea & Febiger, 1993, pp 1369-1375. 56. Matas BR: Iridocyclitis associated with relapsing polychondritis. Arch Ophthalmol 1970;84:474-476. 57. Anderson B: Ocular lesions in relapsing polychondritis and other rheumatoid syndromes. AmJ Ophthalmol 1967;64:35-50. 58. Michet CJ: Vasculitis and relapsing polychondritis. Rheum Dis Clin North Am 1990;16:441-444. 59. Giroux L, Paquin F, Guerard-Desjardins MJ, et al: Relapsing polychondritis: An autoimmune disease. Semin Arthritis Rheum 1983;13:182-187. 60. FoidartJM, Abe S, Martin GR, et al: Antibodies to type II collagen in relapsing polychondritis. N Engl J Med 1978;299:1203-1207. 61. Meyer 0, Cyna J, Dryll A, et al: Relapsing polychondritisPathogenic role of anti-native collagen type II antibodies: A case report with immunological and pathological studies. J Rheumatol 1981 ;8:820-824. 62. Terako K, Shimozuru Y, Katayama K, et al: Specificities to antibodies to type II collagen in rheumatoid arthritis. Arthritis Rheum 1990;33:1493-1500. 63. Yang CL, Brinkman J, Rui HF, et al: Autoantibodies to collagens in relapsing polychondritis. Arch Dermatol Res 1993;285:245-249. 64. Alsalemeh S, Mollenhauer J, Scheuplein F, et al: Preferential cellular and humoral immune reactivities to native and denatured collagen types IX and XI in a patient with fatal relapsing polychondritis. J Rheumatol 1993;20:1419-1424. 65. Dolan DL, Lemmon GB, Teitelbaum SL: Relapsing polychondritis. Analytical literature r~view and studies on pathogenesis. Am J Med 1966;41:285-298. 66. Kindblom LJ, Dalen P, Edmar G, et al: Relapsing polychondritis: A clinical pathologic-anatomic and histochemical study of 2 cases. Acta Pathol Microbiol Immunol Scand 1974;85:656-664. 67. Valenzuela R, Cooperrider PA, Gogate P: Relapsing polychondritis: Immunomicroscopic findings in cartilage ear biopsy specimens. Hum Pathol 1980;11:19-22. 68. Herman JH, Dennis MY: Immunopathologic studies in relapsing polychondritis. J Clin Invest 1973;52:549-558. 69. Rajapake DA, Bywaters EG: Cell-mediated immunity to cartilage proteoglycan in relapsing polychondritis. Clin Exp Immunol 1974;16:497-502. 70. Papo T, Piette JC, Le Thi Huong Du, et al: Antineutrophil cytoplasmic antibodies in polychondritis [letter]. Ann Rheum Dis 1993;52:384-385. 71. Svenson KG, Holmdahl R, Klareskog L, et al: Cyclosporin A treatment in a case of relapsing polychondritis. Scand J Rheumatol 1984;13:329-333. 72. Zeuner M, Straub RH, Schlosser U: Anti-phospholipid antibodies in patients with relapsing polychondritis. Lupus 1998;7:12-14. 73. Albers FW, Majoor MH, Vander Gaag R: Corneal autoimmunity in a patient with relapsing polychondritis. Eur Arch Otorhinolaryngol 1992;249:296-299. 74. Lang B, Rothenfusser A, Lauchbury JS, et al: Susceptibility to relapsing polychondritis is associated with HLA-DR4. Arthritis Rheum 1993;36:660-664. 75. Gregerson PK, Silver J, Winchester RJ: The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1988;30:1205-1213. 76. Luthra HS, McKenna CH, Terasaki PI: Lack of association of HLA-A and B locus antigens with relapsing polychondritis. Tissue Antigens 1981;17:442-443. 77. Cremer M.A, Pitcock JA, Stuart JM, et al: Auricular chondritis in rats: An experimental model of relapsing polychondritis induced with type II collagen. J Exp Med 1981;154:535-540. 78. McCune V\Q", Schiller AL, Dynesius-Trentham RA, et al: Type II collagen-induced auricular chondritis. Arthritis Rheum 1982;25:266-273. 79. Wooley PH, Dillon MI, Luthra HS, et al: Genetic control of type II collagen-induced arthritis in mice: Factors influencing disease susceptibility and evidence for multiple MHC-associated gene control. Transplant Proc 1983;15:180-185.

CHAPTER 59: EYE DISEASE AND SYSTEMIC CORRELATES IN RELAPSING POLYCHONDRITIS 80. Griffiths MM: Immunogenetics of collagen-induced arthritis in rats. Int Rev Immunol 1988;4:1-15. 81. Eng J, Sabanathan S: Airway complications in relapsing polychondritis. Ann Thorac Surg 1991;51:686-692. 82. Fornadley JA, Seibert DJ, Ost:rov BE, et al: The role of MRI when relapsing polychondritis is suspected but not proven. IntJ Pediatr Otorhinolaryn.gol 1995;31:101-107. 83. Cossu ML, Rovasios S, Iannucelli A, et al: A case of relapsing polychoridritis presenting as mediastinal syndrome, diagnosed by CT scans of the trachea and head. Panminerva Med 1997;39:233236. 84. Davis SD, Berkmen YM, King T: Peripheral bronchial involvement in relapsing polychondritis: Demonstration by thin-section CT. Am J Radiol 1989;153:953-954. 85. Massry GG, Chung SM, Selhorst JB: Optic neuropathy, headache, and diplopia with MRI suggestive of cerebral arteritis in relapsing polychondritis. J Neuroophthalmol 1995;15:171-175. 86. Ridgway HB, Hansotia PL, Schorr WF: Relapsing polychondritis: Unusual neurological findings and therapeutic efficacy of dapsone. Arch Dermatol 1979;115:43-45. 87. Barranco VP, Minor DB, Soloman H: Treatment of relapsing polychondritis with dapsone. Arch Dermatol 1976;112:1286-1288. 88. Mohnesifar Z, Taskin DP, Carson SA, et al: Pulmonary function in patients with relapsing polychondritis. Chest 1982;81 :711-717. 89. Crockford MP, Kerr IH: Relapsing polychondritis. Clin Radiol 1988;39:386-390. 90. Neilly JB, Winter JH, Stevensen RD: Progressive tracheobronchial polychondritis: Need for early diagnoses. Thorax 1985;40:78-79. 91. Choy EH, Chikanza IC, Kingsley GH, et al: Chimeric anti-CD4 monoclonal antibody for relapsing polychondritis [Letter]. Lancet 1991;338:450.

92. Van del' Lubbe PA, Mittenburg AM, Breedveld FC: Arlti-CD4 monoclonal antibody for relapsing polychondritis [Letter]. Lancet 1991;337:349. 93. Park J, Gowin KM, Schumacher HR: Steroid sparing effect of methotrexate in relapsing polychondritis. J Rheumatol 1996;23:937-938. 94. Trentham DE, Dynesius-Trentham RA: Antibiotic therapy for rheumatoid arthritis. Scientific and anecdotal appraisals. Rheum Dis Clin North Am 1995;21:817-834. 95. Priori R, Pardi MP, Luan FL, et al: Cyclosporin A in the treatment of relapsing polychondritis with severe recurrent eye involvement. Br J Rheumatol 1992;32:352. 96. Kung AW, Lau CS, Wu PC: Grave's ophthalmopathy and relapsing polychondritis. Clin Exp Rheumatol 1995;13:501-503. 97. Ruhlen JL, Huston KA, Wood WG: Relapsing polychondritis with glomerulonephritis. Improvement with prednisone and cyclophosphamide. JAMA 1981;245:847-848. 98. Foster CS, Forstot SL, Wilson LA: Mortality rate in rheumatoid arthritis patients developing necrotizing scleritis or peripheral ulcerative keratitis: Effects of systemic immunosuppression. Ophthalmology 1984;91:1253-1263. 99. Kato T, Yamaguchi T, Hamanaka T, et al: Corneal marginal ulcer in relapsing polychondritis: Treatment with keratoepithelioplasty. Ophthalmic Surg Lasers 1998;29:767-769. 100. Foster CS: Immunosuppressive therapy for external ocular inflammatory disease. Ophthalmology 1980;87:140-150. 101. Tuft SJ, Watson PG: Progression of scleral disease. Ophthalmology 1991;98:467-471. 102. Goldsmith J: The future of medicine. Colorado Medical Society Interim Conference, Denver, CO, Feburary 26-27, 1996.

Elisabetta Miserocchi and C. Stephen Foster

Antiphospholipid syndrome (APS) is a hypercoagulable disorder with highly variable symptoms that include ocular manifestations. It is characterized by recurrent venous and arterial thrombosis, fetal losses, and thrombocytopenia associated with raised levels of antiphospholipid antibodies (aPL) , which are the serologic markers of this clinical entity. Clinically, the most important aPL are anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC). The presence of this heterogeneous group of antibodies was first reported in patients affected by systemic lupus erythematosus (SLE) , but aPL were subsequently detected in patients without any clinical or laboratory evidence of SLE. This led investigators to define primary antiphospholipid syndrome (PAPS) as occurring in subjects without any associated medical disorder,I-'l as opposed to secondary APS, which is associated with SLE and other collagen diseases,5 or with certain therapeutic drugs 6,7 and infections. 6

HISTORY Current concepts about aPL date to the first part of this century with the development of the nontreponemal serologic tests for syphilis. Syphilis and other infections caused by Treponema jJallidum induce antibodies that give a highly positive serologic test for syphilis. 8 But it later became clear that two types of biologic false-positive serologic tests for syphilis could occur: acute, most frequently associated with viral or other infections, and chronic, often associated with the presence of collagen vascular disease. 6,9 In the early 1940s, Mary Pangborn 9a identified the antigenic component of the tissue used in these tests as an anionic phospholipid, which she named cardiolipin. 10 Subsequent studies characterized cardiolipin structure and found that the antibodies present in patients with syphilis have a cross reactivity with synthetic cardiolipin analogues and anionic phospholipids. 11 In 1952, Conley and Hartmann 12 reported the occurrence of a circulating anticoagulant (synonym: inhibitor) in the setting of SLE. They also concluded that the anticoagulant was associated with clinical bleeding. Subsequently, a number of reports appeared describing no association of this inhibitor with bleeding cOlnplications, but rather a paradoxical association with thrombosis. 13 The term lupus anticoagulant was given to this inhibitor by Feinstein and Rapaport in 1972. 14 It was then determined that patients with LAC may also have a false-positive result on a serologic tests for syphilis, with the association between SLE and the biologic false-positive serologic test for syphilis being so strong that this latter test was included in the diagnostic criteria for SLE.15 This phenomenon was explained with the development of a radioimmunoassay that detected antibodies against the cardiolipin substrate of the syphilis test. Finally, in 1993, G. R. Hughes 16 demonstrated a corre-

lation between elevated anticardiolipin antibody levels and the presence of LAC in patients with venous and arterial thromboses, recurrent pregnancy loss, and thrombocytopenia. The association of these signs and symptoms was called antiphospholipid antibody syndrome or Hughes' syndrome. 1

The epidemiology of APS is still unclear because of the relatively low incidence of the disease and the poor standardization of diagnostic tests to identify the antibodies. The aPL are not specific for APS. The prevalence of aCL in the general population ranges from 0% to 14%,17-19 with a prevalence of less than 5%.20 The prevalence of aCL increases with age, which may reflect a normal phenomenon of aging rather than an increased· risk of disease. In SLE patients, Love and Santoro found the frequency of LAC and aCL to be 34% and 44%, respectively.21 Occasionally, aPL may be present, although in low titers, in various autoimmune disorders other than SLE, such as Sjogren's syndrome, Adamantiades-Beh<;;:et disease (ABD) , and rheumatoid arthritis. Positive levels of IgG or IgM aCL6 in patients with rheumatoid arthritis ranged from 8% to 33%, and 13 of 70 patients with ABD were positive for aCL in a study by Sammaritano and colleagues. 6 Other conditions that can be associated with the presence of aPL include common viral infections, such as adenovirus, rubella, chicken pox, mumps, and mycoplasma, and nonviral infections, such as syphilis, Lyme disease, Q fever, angina or adenoid vegetation treated with penicillin, and typhoid fever. 6, 22, 23 Infection with the human immunodeficiency virus has been associated with aPL; the incidence of aPL in this population ranges from 20% to 42%.6 In addition, some authors found a correlation between chronic hepatitis C and APS.24 The presence of aPL has also been reported in cases of lymphoma and dysglobulinemia. 22 The prevalence of PAPS is still unknown. 1 The frequent correlation between vascular complications such as stroke and myocardial infarction and the presence of aPL gave rise to many studies in patients with arteriosclerotic cardiovascular disease. The prevalence of aPL is higher in patients with stroke and myocardial infarction than in normal controls, ranging from 10% to 20%6; this suggest a causal role of aPL in arteriosclerotic cardiovascular disease. In addition patients with aPL have a higher frequency of recurrent stroke. In a 1989 study of 70 patients with APS, the ratio of women to men was about 2: 1 for the primary form and 9:1 for cases associated with SLE.25 However, when patients with recurrent fetal loss were excluded, distribution between women and men was fairly equal,6' 26 APS occurs most often in relatively young patients; the median age in most series is between 35 and 45 years. 6, 27 Familial

CHAPTER 60: ANTI PHOSPHOLIPID SYNDROME

occurrence of elevated levels of aPL as well as an association with human lymphocyte antigen (HLA) DR4, DR7, DQw7, and DQw53 types have been reported. 28

CLINICAL CHARACTERISTICS

Systemic features The primary clinical features of APS are thrombosis, fetal loss, and thrombocytopenia, although this disease is a multisystemic disorder involving any organ system (Table 60-1). The presentation varies from the subacute (recurrent migraine, visual disturbance, and occasional dysarthria with a possible history of chorea, deep vein thrombosis, or recurrent early miscarriage) to the acute (accelerated cardiac valve failure, thrombocytopenia, major stroke, and widespread thrombosis) .16

tions. Lechemer and Pabinger-Fashing reported the prevalence of cerebral thrombosis to be 25% and that of peripheral arterial thrombosis to be 16%.29 Some cerebral arterial events in APS, however, are probably embolic, with mitral valve vegetation being the leading cause. 31 Rarer arterial lesions that have been described include digital and extremity gangrene and cardiac, intestinal, hepatic, and adrenal thrombosis. 6, 26

Cardiac

Angina and myocardial infarction due to thrombosis have been reported in APS patients with aPL. The frequency of myocardial infarction is unknown, although one study found that a fifth of all young patients with myocardial infarction had aPL.32 Verrucous endocarditis (similar to that found in Libman-Sacks endocarditis), particularly involving the mitral valve, has been detected in patients with APS and someThrombotic The main associated feature is thrombosis, both venous times requires valvular replacement. Khamashta and coland arterial, the latter distinguishing it from many other leagues found that 38% of patients with aPL had valve hypercoagulable disorders, and with the majority of symp- abnormalities. 33 Pulmonary hypertension and pulmonary toms being related to the location of the thrombosis. emboli are also a feature of APS.16 In addition, intracarVessels of any size can be involved: the aortic arch, the diac thrombi that can mimic atrial myxoma, and diffuse carotid artery, pulmonary vessels, and smaller skin vessels. cardiomyopathy have been reported in these patients.31 The most common site of venous thrombosis in APS is A screening echocardiography should be performed in deep vel1ou:s thrombosis of the lower extremities. Other , all APS patients with arterial thrombosis, especially those sites of venous thrombosis include· retinal· vein, renal with lesions in the cereQral or ocular distribution, because vein,and hepatic veins. Lechemer and Pabinger-Fashing29 these patients seem more likely to have valvular abnorfound that venous thrombosis accounted for 71 % of malities than do patients with venous thrombosis. 6, 26 Also, thrombosis in APS. In a study of 100 ~tients with verified a potential role for aPL in atherosclerosis was suggested venous thrombosis, 24% had aCL and 4% had LAC. 30 by a study that showed cross reaction between aPL and Arterial thrombosis is less prevalent than venous oxidized low-density lipoprotein antibodies. 34 thrombosis in patients with APS,26 with one notable exception: The central nervous system has a special predi- Neurologic lection for arterial thrombosis in patients with APS. Although the most common neurologic findings of APS Strokes and transient ischemic attacks are the most com- are ischemic strokes and transient ischemic attacks due mon thrombotic central nervous system (CNS) manifesta- to vascular thrombosis, or secondary to embolic events, some other neurologic conditions have been desClibed not necessarily related to the thrombosis. Chorea is a classic neurologic manifestation of APS.35, 36 TABLE 60-1. SYSTEMIC MANIFESTATIONS OF THE ANTI PHOSPHOLIPID SYNDROME In addition, transverse myelopathy is associated with APS; it is the result of cord infarcts that are detectable by Rheumatology SLE, discoid lupus, Sjogren's syndrome, RA, magnetic resonance imaging. 26, 37 vasculitis, Adamantiades-Belwet disease Migraine headache is a common finding in patients Neurology Cerebral ischemia, stroke, migraine, epilepsy, chorea, transverse myelopathy, multiple with APS and often precedes the diagnosis of APS by sclerosis, dementia, epilepsy, psychiatric many years. Other manifestations include epilepsy, psychifeatures atric features, and cognitive function deficit. In some Cardiology Angina, myocardial infarction, intracardiac untreated patients, recurrent cerebral ischemia leads to thrombi, verrucous endocarditis, multi-infarct dementia. 16 pulmonary hypertension, atherosclerosis Nephrology Renal vein-arterial thrombosis, glomerular An association between multiple sclerosis and aPL has thrombosis, thrombotic microangiopathy, also been reported. In one study,38 22% of patients with renal vasculitis, malignant hypertension definite or probable multiple sclerosis had a positive Dennatology Livedo re1:icularis, leg ulcers, Sneddon's anticardiolipin antibody test. syndrome, skin nodules Endocrinology Gastroenterology Hematology

Obstetrics Intensive care

Addison's disease from adrenal thrombosis Gut ischemia, hematemesis, liver vein thrombosis, Budd-Chiari syndrome Thrombocytopenia, hemolytic anemia Coombs' positive, idiopathic thrombocytopenic purpura Recurrent fetal losses ARDS, acute collapse, jaundice, death

SLE,systemic lupus erythematosus; RA, rheumatoid arthritis; ARDS, acute respiratory distress syndrome.

Renal Different mechanisms of renal involvement in patients with APS can lead to a variety of clinical patterns ranging from isolated hypertension to malignant hypertension, severe proteinuria, and renal failure, including cortical necrosis. Renal vein and arterial thromboses are most common features in patients with APS associated with SLE.16 Gluek and colleagues found a higher prevalence

CHAPTER. 60: ANTIPHOSPHOUPID SYNDROME

of glomerular thrombosis in patients with aPL than in those without these antibodies. 39 Aluigo and coworkers found renal disease in 25% of patients with primary APS, and the biopsy findings were consistent with thrombotic microangiopathy characterized by different degrees of severity. Thrombosis and ischemia, rather than inflammatory vasculitis, seem to have been the pathogenic mechanisms. 40

Dermato/ogic About 25% to 40% of patients with APS have cutaneous lesions. A common (if not the hallmark) cutaneous sign is livedo reticularis, occurring in 20% to 30% of patients. 27 This purple lacelike rash, most prominent on the extremities, is probably secondary to thrombosis in superficial capillaries and venulae. Other common cutaneous signs include superficial thrombophlebitis, skin nodules, and chronic leg ulcers. 16, 26 Early recognition. of these relatively benign signs is important because they can be the precursor of later' major thrombotic events in patients. Patients with Sneddon-Wilkinson syndrome, which comprises the triad of livedo reticularis, cerebrovascular disease, and labile hypertension, may represent a subset of the APS.6

E.ndocrine There has been an increasing nu.mber of reports of Addison's disease in association with aPL in recent years. The mechanism is uncertain bUc,.fluay involve suprarenal hemorrhage or thrombosis.4l .

Hematologic Thrombocytopenia is a common manifestation, found in about 15% to 20% of APS patients. However, the deficit in platelet counts is often transient, and paradoxically these patients are at risk of thrombosis. 6 Hemolytic anemia and leukopenia with a positive Coombs test have been described in patients with APS.6, 16, 26

Gastroentero/ogic ThrOlubosis of the hepatic circulation can occur in patients with APS and can lead to Budd-Chiari syndrome. Recent studies report that APS is the second most common cause of this hepatic disease. 16 , 42

TABLE 60-2. OCULAR. ANTIPHOSPHOUPID COV"I"- ......... ,...1I>.A1I"" Ocular symptoms

Conjunctiva Cornea Anterior chamber Vitreous Retina

Optic nerve

Of

Transient blurry vision, decreased vision, transient diplopia, amaurosis fuga.x, transient visual field loss, headache, asymptomatic photopsia Telangiectasias, aneurysm, episcleritis Keratoprecipitates, limbal keratitis Mild flare, few cells in anterior chamber Vitritis, vitreous hemorrhages Arterial and venous thrombosis (BRVO, BRAO, CRVO, CRAO) , venous tortuosity, aneurysms, cotton-wool spots, vasculitis, vascular sheathing, macular serous detachment, acute retinal necrosis, peripheral drusen, retinal ischemia, retinal neovascularization Optic disc edema, anterior ischemic optic neuropathy

BRVO, branch retinal vein occlusion; BRAO, branch retinal artery occlusion; CRVO, central retinal vein occlusion; CRAO, central retinal artery occlusion.

involvement with acute collapse, thrombocytopenia, adult respiratory distress syndrome, jaundice, and death.

Ocular Features In recent years, numerous research groups have devoted much interest to ocular APS findings. Only a few cases have been reported in the ophthalmologic literature, because the pathogenetic mechanism of aPL is still unclear and it is difficult to make an exact correlation between ocular features and the presence of aPL antibodies. Ocular manifestations occurring during the course of primary and secondary APS include a broad clinical picture. Vaso-occlusive retinopathy and neuro-ophthalmologic symptoms are considered the hallmarks (Table 602) .2

Al1.terior segment involvement is usually mild and relatively uncommon. It includes conjunctival telangiectasia or conjunctival microaneurysms, simple episcleritis, limbal keratitis, and keratoprecipitates with mild anterior chamber inflammation 45 (Fig. 60:..-1). In addition, some authors have described a correlation

Obstetric Fetal loss can occur at any stage of pregnancy, although in late stages it is more specific for APS. Diagnosis of APS as a cause of first trimester loss requires a high index of suspicion, as first trimester losses from other causes are common, occurring in about 10% of clinically recognized pregnancies.26, 43

Musculoskeletal A small number of patients with primary APS develop avascular necrosis of bone. This was primarily observed in patients following orthopedic surgery.44

Intensive Care Occasionally, APS occurs dramatically as "catastrophic" APS of unknown etiology.16 There is multiple organ

FIGURE 60-1. Anterior uveitis with pupillary membrane and posterior synechia in a patient with antiphospholipidsyndrome.

CHAPTER 60: ANTIPHOSPHOUPID SYNDROME

between the presence of aCL and several uveitis entities. These include SLE with retinal vasculitis, acute retinal necrosis, idiopathic retinal vasculitis, and syphilis with posteriOl~ uveitis. 46 Some patients may be symptomatic, but most patients with ocular involvement in APS present with visual symptoms such as transient blurring of vision, decreased vision, transient diplopia, amaurosis fugax, and transient field loss associated with headache and photopsia. 22 , 45 In a study of 17 patients with high titers of IgG aCL antibodies, 59% presented visual symptoms. 45 In the same study, posterior segment abnormalities were found in 88% of the patients, and these included vitreous hemorrhage, vitreous cells, and swelling of the optic disc. Retinal abnormalities included venous tortuosity, vascular inflammation, pigment abnormalities, flame-shaped hemorrhages, cotton-wool spots (Fig. 60-2), microaneurysms, serous macular detachment, intraretinal microvascular abnormalities, and peripheral drusen. 45

Vaso-occlusive Retinopathy Many authors have reported the development of retinal vascular thrombosis in patients affected by APS. Retinal artery occlusion, venous occlusion, and capillary nonperfusion, in particular, have been described in patients suffering from primary or secondary APS.2, 3, 22 Retinal vaso-occlusive entities reported in the literature include central retinal vein occlusion,47,48 branch retinal vein occlusion,49 central retinal arte~y occlusion,50 branch retinal artery occlusion,51 and cilibretinal artery occlusion. 23 Retinal fluorescein angiography demonstrates a variety of patterns of vaso-occlusive retinopathy, including window defects and blocked fluorescence in the choroidal phase, areas of capillary nonperfusion, vascular obstruction, leakage, retinal neovascularization, and vascular caliber alterations such as microaneurysms, capillary ectasia, and tortuosity. Optic disc leakage may also be evident on the fluorescein angiography. 49 The prevalence of vasculopathic eye disease involving

FiGURE 60-2. Posterior segment involvement in a patient with antiphospholipid syn.drome. The arrows show presence of retinal cottonwool spots. (See color insert.)

retinal and choroidal vessels in patients with PAPS is high, around 17%,45 whereas patients with secondary APS associated with SLE are more likely to have retinal thrombotic complications. 45 In contrast to these results, Glacet-Bernard and colleagues, in a prospective study of 75 patients, concluded that aPL antibodies are present in only 5% of patients with retinal vein occlusion, without significant difference from the control group. But, when present, especially in young patients with features· of APS or SLE, aPL luay constitute a contributory factor for the occlusive phenomenon. 22 Others studies reported that vaso-occlusive retinopathy in the course of APS occurs rarely, with an incidence ranging from 0.5% to 8%.52 Although this retinal vascular abnormality cannot be included among the classic clinical manifestations of the syndrome, its presence in association with significant serum levels of aPL, and in the absence of well-recognized risk factors, may be considered diagnostic for APS.53 It is also possible that a classic clinical manifestation of APS does not occur in patients with vaso-occlusive retinopathy and aPL. Nevertheless, these patients should be considered to be affected by APS, since retinal thrombosis could be the first clinical manifestation of the syndrome. 2 It is also possible that these patients will- develop other thrombotic events later, such as pulmonary emboli or cerebral stroke, if correct therapy has not been implemented. Interestingly, some studies have documented an association between occlusive retinal vascular disease and cerebrovascular disease in SLE patients with raised levels of aCL.52

Neuro-ophthalmologk Manifestations Central nervous system involvement in the course of the APS is not uncommon. Both visual sensory symptoms (such as monocular or bilateral transient visual loss or transient visual field loss) and visual sensory lesions (such as ischemic optic neuropathy or progressive optic atrophy) may be observed. 2,45 APS should be included in the differential diagnosis of optic atrophy. Support for the diagnosis of primary APS includes the insidious onset of pallor and visual loss, which would not be expected in optic neuropathy associated with temporal arteritis, ischemic optic neuropathy, or collagen vascular disease, and the lack of any other positive tests supporting alternative diagnoses. 54 The presence of IgG aCL antibodies in patients suffering from arteritic anterior ischemic optic neuropathy, and their absence in patients with nonarteritic forms of the disease, raised questions as to their possible involvement in the pathogenesis of giant cell arteritis. It may be that antibodies deposited on the walls of arteries affected by giant cell arteritis initiate a microvascular thrombosis in the posterior ciliary arteries and peripapillary choroidal vasculature.54, 55 In addition, aPL might interact with nervous system phospholipids, causing spinal cord disease, such as transverse myelitis (TM).2 Interestingly, TM is the most frequently found neurologic disease in SLE patients affected by optic neuropathy. Devic's syndrome is the name used to describe TM with optic neuritis in SLE patients. Jabs

CHAPTER 60:

and colleagues reported that TM is the most common disorder occurring in SLE patients with optic neuropathy, reported in 54% of cases. 56

I The aPL antibodies are a family of immunoglobulins (IgG, IgM, and IgA, or a mixture thereof) with varying affinities for phospholipid-protein complexes. Included in this family are LAC, aCL, and antibodies causing a biologic false-positive serologic test for syphilis. 57 LAC antibodies are recognized by their ability to interfere with phospholipid-dependent coagulation reactions, whereas aCL antibodies are known for their ability to interact with negatively charged phospholipid such as cardiolipin and phosphatidylinositol in solid-phase iIuluunoassays.58 In addition, different autoantibodies have been described in patients with APS.10 These include antinuclear, antissDNA, antimitochondrial, antiplatelet, antierythrocyte, antiprothrombin, anti-protein C, anti-protein S, antiendothelial cell,59 and anti-132-glycoprotein I (GPI) antibodies. This has led some investigators to suggest that APS is a complex autoimmune disorder in which several autoantibodies coexist with aPL.

LAC LACs are immunoglobulins (IgG, IgM, IgA, or a mixture) that interfere with one or more of the in vitro phospholipid-dependent coagulation tests·( e.g., activated partial thromboplastin time [APTT] , dilute prothrombin time [dPT], kaolin clotting time [KCT] ;v'Textarin tiIue), causing a prolongation of coagulation. 14 Several protein targets for LAC have been identified, including 132-GPI, human prothrombin, annexin V, high- and low-molecular-weight kininogens, and other vitamin K-dependent proteins, including protein C and protein S.14 Although the presence of an anticoagulant suggests a bleeding diathesis, only a small minority of patients with LAC experience hemorrhagic difficulties. 12 In these patients, the bleeding complications are associated with thrombocytopenia or an acquired deficiency of prothrombin. 14 The paradoxical association between the presence of antibodies prolonging phospholipid-dependent clotting tests in vitro (LAC) and the occurrence of thrombotic complications in vivo has not been elucidated. One hypothesis 60 that may· explain this LAC in vitro phenomenon is an antibody-mediated agglutination of phospholipid in suspension, which would limit the surface available for coagulation reactions. When a more physiologic surface such as endothelial cells is used for the assembly of the prothrombinase complex, the agglutination of phospholipid cannot take place. In addition, the antibodies that inhibit the prothrombinase activity exert their action via binding to phospholipid-bound prothrombin. This limits the amount of prothrombin available for the prothrombinase and leads to thrombotic events. 60 LAC has been found in patients with a variety of benign conditions, as well in healthy persons with no known systemic disease. It has also been found in patients with autoimmune diseases or infections, and after the use of certain drugs (Table 60-3).H In most cases, drug-induced LAC is not associated with thromboembolic complica-

TABLE 60-3. PRINCIPAL ANTICOAGULANT ACTIVITY Antibiotics Antiarrhythmics Antihypertensives

Antipsychotics

SYNDROME LUPUS

Penicillin Streptomycin Procainamide Quinidine Acebutolol Hydralazine Propranolol Chlorpromazine Halopelidol Fluphenazine

tions. There are, however, some exceptions, including chlorpromazine, phenytoin (Dilantin), quinidine, and alpha-interferon. 14 In the pediatric population, the presence of LAC is most often a result of intercurrent infections. 61 In the young adult and middle-aged population, LAC antibodies are most frequently identified in women, reflecting the greater incidence of autoimmune disease in this population,14 whereas in the geriatlic population many cases of LAC are drug related. 14

The aCL Antibodies Although aCL antibopies are so named because they bind to immobilized cardiolipin in an enzyme-linked immunosOl'bent assay (ELISA), they cross-react with a variety of negatively charged phospholipids besides cardiolipin, including phosphatidylserine, phosphatidylinositol, and phosphatic acid. 62 The association of aCL with the thrombotic predisposition in APS has been considered causal because of the effect of these antibodies on different components within the circulation. Thus aCL antibodies have been shown to activate cultured endothelial cells,63 promote platelet aggregation and activation, induce tissue factor expression, and affect various coagulation pathways.62 The conceivable targets of aCL were thought to be negatively charged phospholipids. However, several authors recently reported that the binding of autoimmune aCL to phospholipid depended on the presence of a plasma cofactor, 132-GPI. 6'1 Nonautoimmune aCL antibodies also exist, binding to negativeiy charged phospholipid and not depending on 132-GPI for binding. These nonautoimmune antibodies explain the aCL detected in patients with infections, and they, unlike those with APS, carry little risk of thrOlubosis. 26

The (32..GPI Cofactor In 1990, several authors found that the antigen for the antibodies detected by the ELISA test was not cardiolipin but rather a plasma protein, 132:.GPI (also termed apolipoprotein H), captllred on cardiolipin. 64 This finding was based on the observation that following pu.rification of aPL autoantibodies, these antibodies do not bind tophospholipid unless incubated with human plasma or human serum.lO, 65, 66 132-GPI is a 50-kD glycoprotein that is present in normal plasma at a concentration of 100 to 300 IJug/ml. The

CHAPTER 60: ANTIPHOSPHOUPID SYNDROME

amino acid sequence of 132-GPI was determined by Lozier volved in APS, some of the most remarkable involve inhiand colleagues,52 and its complementary DNA was cloned. bition of the protein C pathway, an important anticoaguIts physiologic function is not known. Structurally, 132-GPI lant protein. Also, autoantibodies to 132-GPI, protein S, is a member of the complement control protein family, and thrombomodulin have all been implicated in the with five of the consensus repeats ("sushi" domains) that inhibition of this pathway. 1, 25, 72 characterize this group of molecules. 55,57 A fraction of 132Increased platelet aggregation is another potential GPI circulates in association with lipoproteins, which is mechanism for thromboembolism in APS.25 The aPL antiwhy it has also been termed apolipoprotein H. 132-GPI bodies have a direct stimulatory effect on platelets, and binds to anionic phospholipids, and lysine-rich segments they promote the synthesis of the inducible form of in the fifth domain have been implicated as a phospho- cyclooxygenase in endothelial cells. 74 In addition, these lipid-binding region. There is evidence that 132-GPI un- antibodies can induce the expression of adhesion moledergoes a conformational change upon binding to an- cules on endothelial surfaces and enhance monocyte adionic phospholipid, and the resulting presentation of hesion to endothelial cells. 75 neoepitopes has been thought to be responsible for the aCL binding.55 Fetal losses In vitro, I3-GPI inhibits prothrombinase activity, contact The most credible hypothesis for spontaneous abortion pathway activation, ADP-induced platelet aggregation, in APS is placental thrombosis. The immediate cause of and factor Xa generation by platelets.57, 58 Although these fetal death is hypoxia due to insufficient uteroplacental data suggest that 132-GPI functions as a natural anticoagu- blood. Histologic studies reveal that a vasculopathy of the lant, deficiency of this protein is' not clearly associated maternal spiral artery is the most important cause of with an increased risk of thrombosis. 59 Recent data indi- placental infarction. 25 Autoantibodies reactive with trocate that 132-GPI binding to membranes containing physi- phoblast cells have also been implicated. 75 ologic concentrations of anionic phospholipid is relatively weak; thus, normal plasma levels of 132-GPI probably have Thrombocytopenia little effect on hemostatic reactions in vivo. 70 Most aPL The pathogenesis of thrombocytopenia in APS is not antibodies associated with APS are directed against epi- . understood; aPL may interact directly with surface protopes expressed on 132-GPI, not on cardiolipin, and the teins like 132-GPI and CD36, a membrane glycoprotein anti-132-GPI antibodies have been reported by several expressed on platelets and endothelial cells. This interacauthors to be a more specific serologic marker for throm- tion may lead to increased platelet uptake and aggregabotic events than aCL in patients with:,;>APS.71 tion. lo .

IMMUNOPATHOGENESIS Despite the remarkable interest in this syndrome in the last few years, there is no sufficient explanation for the immune response that leads to the development of aPL. The most credible hypothesis is that T lymphocytes play an important role in autoantibody production and disease pathogenesis. 10 Also, aPL antibodies are directed against antigens involved in the maintenance of normal hemostasis. 25 Many of these antigens circulate in the plasma or are associated in enzYIne-cofactor complexes assembled on phospholipid membranes (e.g.,protein C and protein S), and therefore they can be attached by the antibodies. 1, 25 Such complexes can be in vivo immunogens and lead to the autoimmune response in APS. The mechanisms by which such complexes become immunogenic are not known. 1, 10

Thrombosis The pathophysiology of thrombosis in APS is also unclear. Research supports the hypothesis that the implicated autoantibodies not only are an important marker of the disease 72 but also playa direct role in the development of thrombosis, fetal losses,and thrombocytopenia. lO Observations that support this hypothesis 73 include the facts that many of the antigens targeted by aPL are involved in thrombosis and hemostasis, that the autoantibodies and antigens are accessible to one another in circulating plasma or on cell surfaces exposed to circulating plasma (blood cells, vascular endothelium, placental trophoblast), and that antibody levels correlate with clinical risk. 10 Among the many thrombogenic mechanisms in-

DIAGNOSIS

laboratory Investigations The LAC and anticardiolipin tests are generally accepted confirmatory tests for APS.77 The aPL, aCL, and LAC antibodies can be detected by a variety of tests, and their identification is one of the most controversial points in the management of APS because of the lack of standardization in the laboratory test and because of the numerous assays used for diagnosis. Detection of aCL is done by ELISA; most kits use cardiolipin as the target antigen. 78 , 79 This test presents a number of advantages: First, it is relatively easy to perform and also identifies the titer and isotype of the antibodies. 80 ASsay results are usually reported as anticardiolipin antibody units. Values are reported in standardized units: GPL for IgG aCL and MPL for IgM aCL; aCL values are classified as low (10 to 20 units), medium (>20 to 80 units), or high (>80 units). Values below 10 units are considered negative. 81 The anticardiolipin test is positive in more than 80% to 90% of patients with APS when performed appropriately. However, it is not specific: It may be positive in a number of disorders other than APS.81 Therefore, new, more specific tests have been developed. Several authors have reported that the anti-132-GPI test is more specific for detection of APS.77 Its sensitivity varies from 40% to 90%.77 Other investigators have found that an ELISA kit utilizing a mixture of phospholipids as antigen (APhL ELISA Kit, QUANTA LITE@ ELISA, Specialty Laboratories, Inc., Santa Monica, CA) has enabled more specific detection

CHAPTER 60: ANTIPHOSPHOUPID SYNDROME

of patients with APS.82 The specificity of this test is 99% (versus 96% of the standard ELISA), and its sensitivity is 90%.81 The LAC is less frequently positive for APS and it is regarded as the more specific test. 82 The most sensitive assays for LAC detection seems to be the KCT and the Russell viper venom time. The APTT, probably the most commonly used test in clinical studies, is less sensitive than either of the former. 14, 78

Diagnostic: Criteria Preliminary classification criteria for the APS were established during an international workshop in October 1998 in Sapporo, Japan. 83 ,84 Definite aPL antibody syndrome is considered if at least one of the clinical criteria is present, and one of the laboratory criteria in the following steps.

Clinkal Criteria 1. Vascular thrombosis: One'or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ. Thrombosis must be confirmed by ilnaging or Doppler studies or histopathology, with the exception of superficial venous thrombosis. For histopathologic confirmation, thrombosis should be present without significant evidence of vessels wall, inflammation. 2. Pregnancy morbidity: a. One or more unexplained deaths of a morphologically normal fetus at or b~yond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or b. One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe preeclampsia or eclampsia, or severe placental insufficiency, or c. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.

Laboratory Criteria 1. Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer, on two or more occasions, at least 6 weeks apart, Ineasured by a standardized ELISA for f32-GPI-dependent aCL. 2. LAC present in plasma on two or more occasions at least 6 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis, in the following steps: a. Prolonged phospholipid-dependent coagulation demonstrated on a screening test (e.g., APTT, KCT, DVVT [dilute viper venom time], dPT, Textarin time). b. Failure to correct the prolonged coagulation time on the screening test by mixing with normal,platelet-poor plasma. c. Shortening or correction of the prolonged coagulation time on the screening test by the addition of excess phospholipid.

d. Exclusion of other coagulopathies (e.g. factor VIII inhibitor or heparin, as appropriate).

Many aspects of treatment of APS remain controversial. Current management varies significantly and is based on disease manifestations. The most cOlnmonly used drugs in the different trials are anticoagulants, antiplatelet agents, and immunosuppressants.

Primary Prophylaxis Patients who are positive for the presence of aPL but who do not have a history of thrombosis or other manifestations of APS should not be treated. But it is important for these asymptomatic patients to reduce other risk factors for thrombosis, such as lowering elevated cholesterol levels, maintaining ideal weight and well-controlled blood pressure levels, avoiding oral contraception and discontinuing smoking. 26 ,85 Hydroxychloroquin has been used as a prophylactic agent against deep venous thrombosis in hip surgery26,86 and also in symptomatic SLE patients with high titers of aPL antibodies, in the latter case with successful results in controlling both risk of thrombosis and. cutaneous and musculoskeletal manifestations of SLE.26 Different opinions have been expressed about the prophylactic treatment with daily low-dose (80 mg) aspirin and nonste,. roidal anti-inflammatory agents, but the majority of studies did not show benefits from the use of these drugs. 87

Secondary Prophylaxis-Treatment of Thrombotic: Event The most recent and largest retrospective study for the treatment of APS patients after a venous or arterial thrombotic event is that of Khamashta and colleagues. 87 In this series, treatment with intensive warfarin to maintain an international normalization ratio (INR) greater than 3, with or without low-dose aspirin, was more effective than low-intensity warfarin (INR, 2 to 3) in the prevention of recurrent thrombosis. 87 Aspirin is often used in secondary prophyl~"'{is of APS patients, but there is inadequate evidence to support its use. 1 The optimal degree and duration of anticoagulation is controversial. Both the Rosove and Brewer88 and the Khamashta and colleagues series 87 recommended lifelong warfarin therapy, and concluded that the high risk of recurrent thrombosis outweighed the risk of major, even life-threatening bleeding incurred with high-dose warfarin treatment. The use of heparin in APS patients is limited to acute anticoagulation after the thrombotic event, but long-term anticoagulatiop with heparin should be avoided because of the high risk of osteoporosis.1, 26

Treatment of Thrombocytopenia Paradoxically, thrombocytopenic patients with APS remain at risk for thrombosis. Patients whose platelet count falls below 50,000 (or especially below 35,000) are also at increased risk for bleeding. The current opinion 87 is to treat patients who have profound thrombocytopenia with corticosteroids and, if necessary, intravenous immunoglobulins to achieve a platelet count of greater than 50,000.

CHAPTER 60: ANTIPHOSPHOUPID SYNDROME

Treatment

Pregnancy

A pregnant patient in whom aCL or LAC is found, and who does not have a history of miscarriages, does not require· treatment; these women can have a successful pregnancy even in the presence of aPL. 89 Warfarin is contraindicated in pregnancy because of its teratogenic potential. High doses of prednisone should be avoided given the risk of high incidence maternal complications such as preeclampsia, diabetes, infections, and osteoporosis. The most common protocol for APS pregnant patients suggests the use of a combination of subcutaneous heparin and aspirin~lO to help prevent thrOlubosis and decidual vasculopathy.

Treatment of Ocular Complications Given the severity of the thrombotic complications in many patients with aPL, the ophthalmologist must be alert to their presence and start prompt therapeutic intervention. Once the vaso-occlusive event has occurred, anticoagulant therapy must begin as soon as possible, consisting of intravenous heparin followed by oral warfarin, and in most cases given for a prolonged period of time. 91 The duration of the anticoagulant therapy with or without the combination of low-dose aspirin are still controversial. In some patients, the retinopathy appeared to worsen when the anticoagulant therapy was decreased, whereas it stabilized when full anticoagulation was reinstituted. 91 Therefore, it is probably prudent to continue the anticoagulant therapy for many years after the occurrence of the vaso-occlusive retinopathy, IJerhaps for patient's lifetime. The role of corticosteroids is unclear. Conley and Hartmann 12 observed that steroids can suppress the LAC activity. However, retinal thrombosis has occurred or recurred in LAC patients on steroid therapy. If the diagnosis of retinal artery or vein thrombosis excludes a vasculitis cause, medical therapy should not include corticosteroids. Conversely, corticosteroids and immunosuppressants, such as cyclophosphamide or azathioprine, should be given to any patient who might continue to have active retinal thrombosis despite adequate anticoagulation and antiplatelet therapy.91,92 Besides the medical therapy, modalities employed in the treatment of complications arising from vaso-occlusive retinopathy are similar to the approach used in the treatment of other ischemic ocular disorders, including panretinal photocoagulation and vitreous surgery. Mild degrees of nonprogressive peripheral preretinal neovascularization without marked vitreous hemorrhage or traction do not require laser therapy and can be managed by periodic assessement. 93 In eyes with extensive peripheral neovascularization and vitreous hemorrhage, peripheral scatter photocoagulation is usually effective in causing regression of the new vessels. 93 With regard to the treatment of optic neuropathy, Giorgi and colleagues 2 believe that visual improvement after intravenous administration ·of cyclophosphamide could be caused by a vasculitic component in its pathogenesis. Conversely, if the optic neuropathy is caused by severe thrombotic occlusion of the ciliary vessels in relation to aPL, the ischemia may be so acute that it leads to irreversible axonal necrosis, despite the administration of immunosuppressant agents: In these patients, ah anticoagulant therapy is required to achieve visual improvement.

The treatment for optic neuritis in patients with secondary APS associated with SLE is oral corticosteroids. Most patients respond to this treatment, but in smue patients, the response is partial, transitory, or unsuccessful, with progression to permanent blindness; in these patients, immunosuppressive therapy with intravenous cyclophosphamide has been effective. 9'1

PROGNOSIS The natural history of APS is related to the severity of its major clinical manifestation, in particular the risk and the rate of recurrences of thrombotic events. In a prospective study of 360 patients, Finazzi and colleagues85 found a total incidence of thrombotic complications of 9.4%. Thromboses were spontaneous, triggered by infections, pregnancy or immobilization; 73% of these thromboses were recurrences, 68% of which occurred in the same vascular district. In accordance with others authors, Finazzi and colleagues85 found a correlation between the levels and isotypes of aPL and the severity of clinical manifestations. 6, 26, 85, 95 Generally, patients with moderate to high levels of IgG aCL are more susceptible to thrombotic complications than are those with IgM or IgA isotypes. In addition, a history of previous thrombosis associated with high levels of aPL carries an increased risk for thrombosis; therefore these patients require long-term therapy. Conversely, asymptomatic subjects with aPL have a low incidence of thrombosis. 26 ,85 The incidence of major bleeding ranges from 1.7% to 1.8% and included menometrorrhagia, macrohematuria, muscle hematoma, gastrointestinal and retroperitoneal hematoma, and fatal cerebral bleeding. 85 The causes of bleeding were both thrombocytopenia and anticoagulant therapy.85 Although cancer is not usually considered a characteristic feature of APS patients, neoplastic disorders, in particular hematologic neoplasias such as leukemias and non-Hodgkin's lymphoma, have been found as important causes of morbidity and mortality.85 With respect to pregnancy losses, the risk factors identified as significant predictors are elevated levels of IgG aCL, a history of miscarriages, and underlying SLE or lupus-like syndrome. 16 , 85 Today, fetal survival for APS women is approximately 80%, although the prematurity rate of successful pregnancies and the rate of intrauterine growth retardation are still high. 76 In addition, the risk of arterial or venous thrombosis and fetal losses is higher in patients that present three isotypes of aCL and LAC antibodies together. 95

CONCLUSIONS The APS is a rare disorder characterized by the presence of arterial and venous thrombosis, fetal losses, and thrombocytopenia. LAC and aCL are the serologic markers of the syndrome. The exact pathogenesis of thrombosis is not completely understood, but it may involve 132-GPI (a natural anticoagulant), platelet aggregation, the protein C pathway, or endothelial cell function. The multisystemic presentation of APS lUOStly depends on the site of thrombosis and may also include striking ocular features. Vaso-occlusive retinopathy and neuroophthalmologic disorders are the most important ocular

CHAPTER 60: ANTIPHOSPHOUPID SYNDROME

manifestations. Therefore, in the presence of a venous or arterial thrombosis, it is important for the ophthalmologist to include APS in the differential diagnosis of the hypei'coagulable disorders, and to rule out other conditions that display the same clinical manifestations or laboratory finding. The diagnosis of APS is based on clinical characteristics and on the laboratory evidence of the aPL. The difficulty in laboratory technique standardization is probably one of the important causes of misdiagnosis of APSpatients. The early recognition of patients with APS allows appropriate therapy to be instituted, reducing the risk of future thrombosis. The treatment following a thrombotic event includes intravenous heparin for the acute phase, followed by long-term high-dose warfarin with or without aspirin, maintaining an INR greater than 3. The duration of the anticoagulation treatment is still controversial. Corticosteroids and intravenous im-rnunoglobulins can be used for thrombocytopenia. Pregnant women with APS can be treated with subcutaneous heparin and aspirin. The prognosis of patients with APS is mostly related to the site of thrombosis, the rate of recurrences of thrombotic events, and the potential side effects of anticoagulant therapy.

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Charalampos Livir-Rallatos

DEFINITION Fuchs' heterochromic iridocyclitis (FHI) is a low-grade, chronic, nongranulomatous uveitis of unknown origin. This mostly unilateral disease is characterized by a relative absence of redness of the external eye, small stellate keratic precipitates scattered on the entire corneal endothelium, iris atrophy with or without heterochromia, abnormal angle vessels, and a lack of posterior synechiae. Cataract and glaucoma are considered to be the major complications. This limited, classic description of FHI has been challenged recently. More recent reviews have suggested that the clinical spectrum of FHI is wider than what has been previously defined, and that the clinical course is more variable. Some authors use the term Fuchs' uveitis syndrome, as the term heterochromic does not apply to all patients with the disease and the disease may affect other parts of the eye as well.

HISTORY

On several occasions, more than one member of a family have been noted to have FHI,15, 16 and the disease has been described in a pair of monozygotic twins. 17 But familial reports of FHI account for only a tiny minority of the large number of patients now reported, and recently discordance has been· described in proven monozygotic twins. IS Although several types of uveitis have been associated with human lymphocyte antigens (HLA), none have been associated with FHI. An association with HLA-B18 has been reported in one series,19 but this has not been substantiated by others. 20 , 21 A decreased. frequency of both HLA-Cw3 and HLA-DRw53 has been found in some studies,2o,21 but a larger number of patients is required to confirm such association. Recently, the HLA-A2 antigen was found to have a statistically significant negative association with FHI.22

CLINICAL MANIFESTATIONS A review of the medicalliteratu~reS'Llggests that Lawrence 1 was the first to describe some components of this entity, COMPLICATIONS reporting on four patients with cataract and hetero- Most patients with FHI present in early adlllthood, al-' chromia in 1843. Other comp'&nents of this condition though the disease may commence in childhood. The were published later by Weil12 in 1904. It was Ernst Fuchs,3 condition is customarily unilateral but bilateral involveprofessor of ophthalmology at the University of Vienna, ment can be seen. Many patients are unaware of. their however, who expanded on the work of Weill to describe disease, which is discovered during the course of a rouboth the clinical and pathologic features of the disease tine eye examination. The most common symptoms rewith an accuracy remarkable for 1906, a time prior to the ported are floaters caused by vitreous opacities, and visual availability of the slit-lamp biomicroscope. His group of deterioration caused by cataract. Pain and perilimbal in38 patients was very large, considering the paucity of eyes jection are rare. Awareness of heterochrOlnia prior to in the previous reports. The constellation of signs, which diagnosis is seen in the minority of patients. Some pawas originally named complicated heterochromia by tieJ?ts may complain of symptoms associated with recurFuchs, now bears his name and has provoked the interest rent hyphema (blurred vision, floaters) or symptoms .conof many ophthalmologists in the succeeding years. Kim- sistent with elevated intraocular pressure (mild pain, ura and colleagues,4 in their description of 23 patients blurred vision, colored haloes around lights). Classical teaching seems to stress the pararnount imwith FHI, were one of the first groups to recognize other portance of heterochromia in FHI. This emphasis is imfeatures of the disease and the fact that multiple portions of the eye can be affected by this inflammatory process. prudent and can lead to underdiagnosis of the disease. Franceschetti 5 expanded the criteria of FHI and de- Heterochromia can be subtle or absent in25 darkly pigscribed them in more detail, based on a series of 62 mented irides (in blacks,23 whites,24 or Asians ) and when patients. Loewenfeld and Thompson,6, 7 in 1973, reviewed there is bilateral involvement. Typically, heterochromia is by atrophy of the anterior border layer of the FHI, referring to over 700 publications. From 1973 to caused l3 ,26 (Figs. 61-1 and 61-2). This progressive atrophy iris 2000, additional series of patients have been reported, will make the brown iris appear less brown, whereas in expanding the clinical spectrum of the disease. the light blue iris it will cause an apparent deepening of the blue color because of the revealing of the underlying EPIDEMIOLOGY The prevalence of FHI in uveitis populations varies from iris pigmented epithelium. 13 Sometimes stromal atrophy 1.2% to 4.5% in several reported series. s- u The true may become so severe that the iris pigmented epithelium prevalence is probably higher, given the fact that hetero- can be observed directly. The result is a paradoxical or chromia can be absent or very subtle and therefore diffi- "reverse heterochromia" with the involved eye becoming cult to detect, especially in patients with brown irides. the darker eye. FHI causes. atrophy and depigmentation of all iris layThe disease has no racial or sexual predilection and can affect patients at all ages. 12- 14 Although the condition is ers: anterior border layer, stroma proper, and pigmented mostly unilateral, bilateral cases are seen in approxi- epithelium. However, the vast majority of patients have a significant loss of anterior border layer, usually seen early mately 10% of patients. 13 , 14

CHAPTER 61: FUCHS' HETEROCHROMIC IRIDOCYCLITIS

FIGURE 61-1. Right and left eye of a patient with Fuchs' heterochromic iridocyclitis (right eye, A; left eye, B). Note the difference in apparent color of the irides. The left eye is the eye with the iridocyclitis. (Courtesy of C. Stephen Foster, MD.) (See color insert.)

in the course of the disease. Stromal atrophy results in a not. 12 , 28 These nodules are small and transparent and somewhat moth-eaten appearance resulting from blunt- therefore may be overlooked, or when noted they may ing of the surface rugae. Advanced atrophy may lead lead to a misdiagnosis of other types of chronic granuloto the exposure of deeper structures such as the iris matous iridocyclitis, especially in black patients. 29 Other vasculature, the sphincter pupillae, and the underlying minute, crystalline, highly refractile deposits on the surpigmented epithelium. Atrophy of the latter can be dem- face of the iris (termed Russell bodies) are a rare biomionstrated only when it has advanced far enough to result . croscopic finding in eyes with FHI.30, 31 These crystals in transillumination defects which al~e usually noted in probably represent plasma cells filled with immunoglobuthe area adjacent to the pupil. However, sector atrophy, lin.. such as that seen in herpes infection, fl/'does not occur in Posterior synechiae do not generally form in patients FHI.26, 27 The pupillary ruff is particularly vulnerable, hav- with FHI. However, posterior synechiae can occur after ing gaps in the majority of patients. Atrophy of the anterior segment surgery.12, 13, 32 Moreover, transient sysphincter and dilator pupillae may cause anisocoria, with nechiae may occur in association with Koeppe nodules, the affected pupil being larger or smaller than the unaf- but they are evanescent and leave radial residual pigment fected side. In general, FHI causes atrophy of the iris, on the anterior lens capsule. 28 which highlights rather than hides its architecture. This The incidence of iris and anterior chamber angle neois appreciated when comparison with the fellow eye is vascularization in FHI has been a subject of debate. This performed at the slit-lamp biomicroscope. 26 is because it is difficult to interpret normal variations of Iris nodules in FHI can be either pupillary (Koeppe) iris vasculature and because iris atrophy may increase the or stromal (Busacca). Iris nodules are quite common visibility of pre-existing, although possibly altered, iris in FHI in some series,14, 23 whereas in others they are vessels. Such vessels may become straighter, narrower, and infarcted, as demonstrated with fluorescein angiography.6, 7,33-3:3 Although uncommon, frank rubeosis over the anterior chamber angle and iris surface has been reported by several authors. 12 , 13, 23, 24, 33, 36 The fragile blood vessels in the iridocorneal angle (Fig. 61-3) and iris Inay be responsible for the occurrence of hyphema after anterior chamber paracentesis 37 (Amsler's sign). Hyphema in FHI, which has been termed filiform hemorrhage, may also occur spontaneously, or after trivial nonpenetrating eye injury. It has been described after the use of Honan balloon 38 prior to cataract surgery, after applanation tonometry,13 after gonioscopy, and perioperatively in patients undergoing cataract surgery.39-4:3 Not all patients with FHI have signs of active inflammation. Anterior chamber inflammation when present is mild and is characterized by the presence of a moderate number of cells and little flare. The keratic precipitates in FHI are virtually pathognomonic of this condition. FIGURE 61-2. Higher magnification of the left eye shown in Figure They are small and stellate, with fibrillary extensions and 51-lB. Note the loss ofiris substance in the anterior layers of the iris, tiny interspersed fibrils (Figs. 61-4 and 61-5). They are allowing the pigment epithelium to be more apparent. (Courtesy of C. Stephen Foster, MD.) (See color insert.) translucent, nonpigmented, and scattered over the entire

CHAPTER 61: fUCHS' HETEROCHROMIC IRIDOCYCLITIS

FIGURE 61-3. Gonioscopic photograph of a patient with Fuchs' heterochromic iridocyclitis. Note the very subtle vascular anomalies in the angle. (Courtesy of C. Stephen Foster, MD.) (See color insert.)

FIGURE 61-5. Same eye as shown in Figure 61-4; retroillumination photo, which allows one to see slightly more clearly the small fibrils that connect adjacent KPs. (Courtesy of C. Stephen Foster, MD.) (See color insert.)

corneal endothelium. The distribution of keratic precipitates in the upper part of the cornea is also pathognomonic of FHI. However, they can have a triangular distribution in the inferior cornea in some patients. The cellular activity in the anterior chamber varies over time. Some authors have noted that-intraocular inflammation may disappear after cataract surgery.5. 13 It is not known whether this is because the disease may go into remission after lens removal or because it
lytic glaucoma,47, 48 trabeculitis,36, 49 and corticosteroidinduced glaucoma 5o have been described as possible causes of secondary glaucoma in FHI. Vitreous opacification is seen in the majority of patients with FHI.13, 14 In general, profound cellular activity in the vitreous is.not a feature of the disease, but there are exceptions, and severe inflammation With snowball formation can be seen. I3 , 1'1 In contrast to intermediate uveitis, macular edema is never seen in FHI.4, 12,13,23,24 Peripheral inflammatory choriOl~etinal scars resembling those caused in Toxoplasma retinochoroiditis are seen in a few patients with FHI. The prevalence of such scars varies from 7.2% to 65% according to various reports. I3 ,51, 52 These lesions are usually small (one-half disc diameter) atrophic scars with hyperpigmented borders, often located in the periphery. They can. be seen in the affected eye, in the unaffected contralateral eye, or in both eyes. Chorioretinal scars consistent with ocular histoplasmosis have also been noted in patients with FHI. However, a causal relationship with infectious agents is still unproved.

FIGURE 61-4. Typical keratic precipitate (KP) distribution and configuration in a patient with Fuchs' heterochromic iridocyclitis. Note that tl1e KPs are distributed throughout the entire extent of the corneal endothelium and that many have a fibrillar or stellate character to them. (Courtesy of C. Stephen Foster, MD.) (See color insert.)

Fuchs first described the histopathologic findings in specimens obtained from six patients. He reported anterior stromal depigmentation of the iris, hyalinization and endothelial cell proliferation of the blood vessel walls, and cellular infiltration with lymphocytes, plasma cells and Russell bodies. 3 These findings have been confirmed by others.6, 53 Electron microscopy studies demonstrate endoplasmic reticulum damage, a decreased number of melanocytes with no dendritic processes and with melanosomes that are smaller and irregular in size and shape, and degenerationof adrenergic nerve fibers. 26, 54, 55 It is not known whether the structural changes in nerve endings and melanocytes are caused by chronic inflammation or by a primary defect of adrenergic innervation leading to defective production of melanin granules. There is a paucity of light- and electron-microscopic studies on the trabecular meshwork of Fuchs' patients with secondary glaucoma, and these are controversial. An.

CHAPTER 61: FUCHS' HETEROCHROMIC IRIDOCYCLITIS

increased outflow resistance with sclerosis of the trabecular meshwork was reported by Huber,56 whereas Benedict and colleagues·57 noted a collapse of the canal of Schlemm with atrophy of its wall. The overall histopathologic appearance of FHI is that of chronic mononuclear inflammation, which does not differentiate it from other types of chronic iridocyclitis.

ETIOLOGY AND PATHOGENESIS The etiology of the disease remains elusive. Ernst Fuchs assumed that the syndrome was caused by a noxious factor of unknown origin, which was present from fetal or early postnatal life. 3 Since then, many theories concerning the cause of FHI have been proposed, including genetic, sympathetic, infectious, and immunologic-inflammatory theories. Nevertheless, at present there is no adequate evidence to formulate a pathophysiologic mechanism that can explain all features of the disease. Genetic theories emerged from the fact that other types of heterochromia, namely "siinple" uncomplicated heterochromia and heterochromia in Waardenburg's syndrome, are dominantly inherited. Loewenfeld and Thompson, in their review of 1500 cases with FHI, found only five families with two cases of FHI. 7 In another review of 550 cases, Dernouchamps found six familial cases with FHI.lO Although the disease has been reported to occur in monozygotic twinsp there is no strong familial association to provide adequate proof for the·.hereditary theory in FHI. Furthermore, studies on HLA typing have not shown any strong association of FHI with human leukocyte antigens. At present, neither familial concurrence nor HLA association supports the hypothesis of a genetic basis of the disease, although the concept of genetic predisposition remains open. The association of peripheral chorioretinal scars with FHI has raised the hypothesis of an infectious agent causing FHI. Such scars were described both by Fuchs 3 and Kimura and coworkers4 but were noticeably absent in a large number of patients reported by Loewenfeld and Thompson. 6, 7 Liesegang, in his review of 54 patients with FHI, found only two patients with chorioretinal scars. 12 In 1982, de Abreu and coworkers58 reported a high incidence (56.5%) of chorioretinal scars consistent with ocular toxoplasmosis and confirmed serologic evidence for Toxoplasma gondii infection. He suggested that T. gondii could be a possible cause of FHI. Other investigators have also reported an association of toxoplasmosislike scars and seropositivity for T. gondii infection with FHI.23, 59-62 There are various possible reasons for the variation in the reported prevalence of toxoplasmosis-like scars in FHI: methods of examinations, diagnostic criteria both for FHI and toxoplasmosis-like scars, and prevalence of toxoplasmosis in different populations. Therefore, it was of paramount importance that a control group of the same population be studied simultaneously under the same methods. When that was done, a significantly higher prevalence of chorioretinal scarring was observed in FHI patients than in control groups.51, 52, 62, 63 In a recent study, La Hey and associates 51 analyzed the association between FHI and toxoplasmosis by studying humoral and cellmediated immunity against T. gondii in blood and aqueous humor of patients with FHI, other types of uveitis,

and controls. They concluded that there is no association between FHI and toxoplasmosis, although there is an association between FHI and toxoplasmosis-like chorioretinal scars. However, the authors acknowledged that there were no active chorioretinal lesions in patients with FHI at the time of blood sampling or at the time when the aqueous humor was obtained. Until now, few sporadic cases of FHI with an active Toxoplasma lesion or with a well-documented history of congenital toxoplasmosis have been reported. 52, 58, 59, 63-65 These case reports support the hypothesis that infection with T. gondii may lead to FHI, but this may concern only a small number of patients with FHI. It is also possible that ocular toxoplasmosis can create a chronic condition that resembles FHI, as suggested by Schwab. 52 Theories that relate FHI to the sympathetic nervous system arise from the fact that damage to the adrenergic innervation of the iris may lead to iris hypochromia. Bistis was the first to propose that some "trophic" defect in the sympathetic nervous system could inhibit the process of iris pigmentation. 65 Thus, congenital Horner's syndrome was initially thought to be the cause of FHI.66 In 1973, Loewenfeld and Thompson 7 reviewed 1746 cases with FHI and found only 25 cases (1.4%) with Horner's syndrome. This figure was considered to be too low to implicate a causal relation between FHI and Horner's syndrome.However, since 1973, additional cases of FHI and ipsilateral Horner's syndrome have been published. 67 Furthermore, FHI and Horner's syn.drome developed in the same eye after stellate ganglionectomy.68 Two other conditions, the Parry-Romberg syndrome of progressive hemifacial atrophy and the "status dysraphicus," the unilateral syndrome of dysmorphism and asymmetry, have been associated with FHI and sympathetic defect.13, 69-71 Finally, electron microscopic studies have suggested that defective production of melanin granules resulting from inadequate function of adrenergic nerves may cause iris hypochromia. 55 Furthermore, defective adrenergic innervation of blood vessels in FHI may increase vascular permeability (as has been demonstrated with iris fluorescein angiography) with subsequent leakage of proteins and inflammatory mediators into the anterior chamber. Various immunologic abnormalities have been noted in patients with FBI. Cellular and humoral immune responses to a corneal antigen (54 kD) have been found with high frequency in patients with FHI.72, 73 This finding, in combination with the fact that corneal endothelial cells have immunomodulating capacities (ability to express major histocompatibility complex class II antigens and immune adhesion molecules)14,75 may explain the diffuse distribution of keratic precipitates and the endothelial abnormalities demonstrated on specular microscopy in some patients. 76 Arffa and Schlaegel have described patients with toxoplasmosis-like scars and negative titers for toxoplasmosis in undiluted serum. 62 They proposed that chorioretinal lesions could result from autoimmunity against retinal or choroidal antigens. 62 In accordance with this hypothesis, La Hey and colleagues found that a significantly higher percentage of patients with FHI had a positive cellular autoimmune response to S-retinal antigen than healthy controls and other patients with anterior uveitis. 77 How-

CHAPTER 61: FUCHS' HETEIROCHIRQIMIC IRIDOCYCLITIS

ever, they also found patients with no chorioretinal scars but with positive immune response to S-retinal antigen. 77 It is unknown whether the ilTImUne sensitization against corneal and retinal antigens observed in FHI is the cause of the disease or represents a secondary autoimmune epiphenomenon. No autoantibodies to iris components were found in the sera of patients with FHI.77 In a recent study, the cellular phenotypes and the cytokine profile in the aqueous humor in patients with FHI and idiopathic anterior uveitis (IAU) were com-. pared. 78 CDS + T cells were higher in FHI, whereas CD4 + T cells were higher in IAU. INF-)' and interleukin (IL)-10 levels were higher and IL-12 levels were lower in FHI than in IAU. The authors suggest that the predominance of CDS + T cells and the lower levels of IL-12 in FHI may account for the low-grade inflammation and the better outcome of this disease in comparison with IAU. In another study, an increased level of soluble IL-2 receptor, a marker of T-cell activation was found in peripheral blood of FHI patients. 79 . Intraocular production of immunoglobulin G (IgG), mainly the IgG1 subclass, has been found in approximately 60% of patients with FHI.80-82 However, an antigenic stimulus for this oligoclonal B-cell response has not yet been identified. This increased B-Iymphocyte activity may be caused by the local production of IL-6 in the aqueous humor, as it has been demonstrated In 63% of patients with FHI.82 Although deposits of immunoglobulins and complement have been found in the vascular wall of iris biopsy specimens o1'Jtained from patients with FHI, there is still no adequate evidence to support the concept of immune complex vasculitis as the cause of the disease. 83 The many pathogenetic mechanisms that have been proposed, in addition to the fact that the disease has been reported in combination with toxoplasmosis, Horner's syndrome, Parry-Romberg syndrome, a retinitis pigmentosa-like picture,84, 85 ocular trauma,59, 86 subclavian steal syndrome,87 and Mobius' syndrome,88 make it difficult to believe that FHI has a single etiology. It is therefore possible that various stimuli (e.g., infectious, immunologic, and neurogenic) trigger the eye to a particular pathway, the clinical end result of which is FHI.

The diagnosis of FHI is important to make for the following reasons: (1) Patients with FHI are at a significant risk for developing glaucoma and need to be followed regularly for early glaucoma detection. (2) Although corticosteroids can reduce the clinical signs of inflammation, they do not produce any change in the clinical course and on a long-term basis can hasten the formation of cataract and induce glaucoma in steroid responders. (3) As a relatively mild form of chronic uveitis, FHI has a fairly good prognosis for the patient. There are no laboratory tests to confirm the diagnosis of FHI. The diagnosis is essentially a clinical one, based on a thorough ophthalmic examination. Although there are no universally established diagnostic criteria for FHI, I suggest that the following are sufficient to make the diagnosis (Table 61-1): (1) the absence of acute symptoms of severe pain, redness, photophobia, (2) the pres-

TABLE 61-1. DIAGNOSTIC CRITERIA FOR FUCHS' HETEROCHROMiC IRIDOCYCLITIS Absence of acute symptoms of severe pain, redness, photophobia Presence of small, white, stellate keratic precipitates distributed across the endothelium Low-grade anterior chamber inflammation Diffuse iris stromal atrophy with or without heterochromia Absence of posterior synechiae prior to cataract surgery Presence of cells and opacities in the anterior vitreous

ence of characteristic small, white, stellate, keratic precipitates distributed widely across the endothelium, (3) low-grade anterior chamber inflammation, (4) diffuse iris stromal atrophy with or without heterochromia, (5) the absence of posterior synechiae prior to cataract surgery, and (6) the presence of cells and opacities in the anterior vitreous. Cataract and glaucoma can be present but are not essential criteria for the diagnosis of FHI. In a typical case of FHI, the diagnosis of the· disease is usually straightforward. However, in atypical cases the differential diagnosis includes disorders that produce iris heterochromia. Hypopigmentary causes of heterochromia such as "simple" uncomplicated heterochromia, heterochromia in association with Horner's syndrome, Duane's syndrome, and Waardenberg's syndrome do not generally produce a problem because they are not accompanied by inflammation. 89 , 90 Iris heterochromia can be seen in chronic anterior uveitis caused by herpes zoster infection, but the pattern of iris atrophy, the patient's history, and the laboratory work-up will help to make the correct diagnosis. Hyperchromic causes of heterochromia, such as ocular melanosis, iris nevus syndrOlTIe, iris melanoma, siderosis bulbi, and xanthochromia, have typical features that can exclude them from the differential diagnosis. Posner-Schlossmann syndrome and neovascular glaucoma can cause ocular disease that resembles FHI complicated by secondary glaucoma. In addition, glaucomatocyclitic crisis can also cause iris heterochromia. 91 However, the intraocular pressure rise in Posner-Schlossmann syndrome dramatically responds to topical steroids, something that is not seen in FHI. Intermediate uveitis frequently presents with symptoms of floaters and blurred vision,. often unilaterally in an age group similar to that for FHI. Furthermore, nongranulomatous anterior chamber inflammation and inflammatory aggregates in the anterior vitreous and peripheral retina are the hallmark of the disease. However, neither the pars plana exudates nor macular edema has been noted in FHI, whereas in intermediate uveitis these features are quite common.

TREATMENT AND PROGNOSIS In the vast majority of patients with FHI, the inflammatory activity in the anterior chamber is mild and can fluctuate over time. Assuming that minimal inflammatory activity in FHI is not harmful for the intraocular structures, and taking into account the. side effects of the long-term use of topical steroids, therapy is usually not indicated. However, FHI can be associated with pain and floaters and an increase in anterior segment inflamma-

CHAPTER 61: FUCHS' HETEROCHROMIC IRIDOCYCLITIS

tion that may contribute to the development of glau- bag is probably most appropriate. 97 The long-tenn efficoma. 92 These cases may warrant treatment with topical cacy and safety of foldable intraocular lenses in the era steroid for a short period. We know of no studies to of phacoemulsification in patients with FHI have yet to support the use of oral anti-inflammatory medication be addressed. Secondary glaucoma remains the major in FHI. complication of cataract surgery in FHI because of its' Cataract formation is a virtually constant feature of high frequency and uncertain prognosis. Preoperative the disease. Several studies have addressed the problems markers should alert the surgeon for increased vigilance encountered during and after cataract surgery in FHI in detecting and treating both secondary glaucOlna and patients. Some have suggested that cataract surgery is recurrent uveitis. typically uneventful, whereas others have found a higher Treatment of glaucoma is the most difficult aspect in incidence of operative and postoperative complications. the management of FHI. When the intraocular pressure The early encouraging results of Franceschetti5 and Ki- rise is intermittent and associated with increased intramura and colleagues4 during the era of intracapsular ocular inflammation, as may happen in the early stages cataract surgery were disputed by Ward and Hart,39 who of the disease, topical steroids are beneficial. However, reported patients having extensive complications with in- antiglaucoma medications are required later in the tracapsular surgery, including vitreous loss, hyphema, vit- course of the disease. The reported success rate of maxireous hemorrhage, uveitis, and progressive glaucoma. mal medical treatment of glaucoma in FHI varies among Corneal decompensation with peripheral and central bul- authors. Jones93 reported that 63% of glaucomatous palous keratopathy with intracapsular surgery has also been tients with FHI responded to topical medication alone described. 12 Although many eyes With FHI have tolerated over a follow-up period of 10.2 years, a figure that does iris-fixated or anterior chamber intraocular lenses for not significantly differ from that encountered in prilnary many years, there were patients in whom enucleation was open-angle glaucoma. However, La Hey and colleagues lOl performed for intractable glaucoma. Most experts today noted that maximal medical treatment was unsuccessful would agree that iris touch with an intraocular lens is in 73% of glaucOlnatous patients with FHI. undesirable in patients with a history of uveitis. Glaucoma filtration surgery is unavoidable in patients Cataract surgery in eyes with FHI has evolved concur. unresponsive to topical ,medication. Such surgery carries rently with cataract surgery in generaL Several papers all the attendant risks associated with glaucoma surgery have been published on extracapsular. cataract extraction in uveitis patients, including bleb failure. However the with posterior chamber intraocular lens implantation in FHI patients.'10,93-98 Although the incid~nce of postopera- use of fibrosis-inhibiting drugs (5-fluorouracil, mitomycin tive complications may differ in these studies, the visual C) seems to have improved the success rate of filtration as outcome is excellent for a high proportion of patients in surgery in FHI patients and is currently recOlnmended 92 most of them. According to these reports, the most com- an adjunct to the first surgical procedure. , 100 Patients mon complications in eyes undergoing modern extracap- who do not respond to filtration surgery Inay require sular cataract extraction with intraocular lens implanta- shunt implantation. Rarely, patients have undergone enu46 tion are hyphema, glaucoma, pigment deposits on the cleation for absolute or rubeotic glaucoma. , 93 The prognosis of FHI is variable and depends on the lens surface, vitreous opacities, and posterior capsule opacification. Intraocular hemorrhage is rarely significant clinical spectrum of the disease. With prolonged follow enough to interfere with surgery. Although glaucoma is up, 40% of patients maintain a visual acuity of 20/40 or part of the natural history of the disease, cataract surgery better. 12 Cataract formation is the most common cause of may provoke its onset or worsen its course. Vitreous opaci- decreased vision in FHI, and of course this is potentially ties are an integral part of the syndrome and, in some restorable. Glaucoma development is the most COlnmon instances, these may be so profound as to necessitate cause of permanent visual loss in a significant number of vitrectomy.99 Advanced cataract at presentation can ob- patients, with prognosis less favorable than that of priscure the detection of vitreous opacities, so the high mary open-angle glaucoma. frequency of vitreous opacification after cataract surgery is probably not related to the surgery itself. Posterior capsule opacification in FHI is felt to be higher than in CONCLUSIONS the normal cataract population, and glaucoma precipi- FHI is a chronic low-grade uveitis, the diagnosis of which tated by both surgical and yttrium-ahuninum-garnet cap- is entirely clinical. It is underdiagnosed because of its sulotorriy has occurred. 99 Severe iris atrophy with substan- variable clinical spectrum. Although it can mimic various tial transillumination defects, abnormalities of iris forms of uveitis, it is important to make the correct vasculature, and glaucoma are considered preoperative diagnosis because both management and prognosis differ markers of guarded prognosis according to Jones. 43 These from those of other uveitides. While its etiology remains markers are indicators of severe disease and are associ- unknown, it is possible that the disease has multiple causes that lead through different pathogenetic Inechaated with increased postoperative inflammation. nisms to the same clinical entity. Although many patients In conclusion, cataract surgery in patients with FHl is usually uneventful, although occasionally it may have a do not require treatment, it is not a benign condition as compromised outcome. Preoperative and postoperative often perceived. The high incidence of glaucoma makes control of inflammation with topical steroids is of para- it mandatory that all patients should be screened at regumount importance for a successful surgical outcome. A lar intervals, even if they are not being actively treated posterior chamber intraocular lens placed in the capsular and are relative asymptomatic.

CHAPTER 61: FUCHS' HETEROCHROMIC IRIDOCYCLITIS

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99. 100.

Fuchs' heterochromic cyclitis, herpetic uveItIs and toxoplasmic chorioretinitis. Int Ophthalmol 1997;21:187-194. Murray PI, Hoekzema R, Luyendijk L, et al: Analysis of aqueous humour immunoglobulin G in uveitis by enzyme-linked immunosorbent assay, isoelectric focusing, and immunoblotting. Invest Ophthalmol Vis Sci 1990;31:2129-2135. Murray PI, Hoekzema R, van Haren MA, et al: Aqueous humour analysis in Fuchs' heterochromic cyclitis. Curr Eye Res 1990;9 (suppl) :53-57. La Hey E, Mooy CM, Baarsma GS, et al: Immune deposits in iris biopsy specimens from patients with Fuchs' heterochromic iridocyclitis. Am] Ophthalmol 1992;113:75-80. VOUlTe I, Saari M, Tilikainen I, et al: Fuchs' heterochromic cyclitis associated with retinitis pigmentosa: A family study. Can] Ophthalmol 1979;14:10-16. van der Born LI, van Schooneveld]M, delong TVM, et al: Fuchs' heterochromic uveitis associated with retinitis pigmentosa in a father and son. Br] Ophthalmol 1994;78:504-505. Vadot E: Cyclite heterochromique de Fuchs post-traumatique. Bull Soc Ophthalmol Fr 1981;81:665-667. Donoso LA, Eiferman RA, Magargal LE: Fuchs' heterochromic cyclitis associated with subclavian steal syndrome. Ann Ophthalmol 1981;13:1153-1155. Huber A, Kraus-Mackiw E: Heterochromiezyklitis Fuchs bei Mobius Syndrom. Klin Monatsbl Augenheilkd 1981;178:182-185. Pietruschka G, Priesz G: Clinical problems of different forms of heterochromia. Klin Monatsbl Augenheilkd 1975;166:494-498. Raab EL: Clinical features of Duane's syndrome.] Pediatr Ophthalmol Strabismus 1986;23:64-68. Posner A, Schlossmann A: Syndrome of unilateral recurrent attacks of glaucoma with cyclitis symptoms. Arch Ophthalmol 1948;39:517. ] ones NP: Glaucoma in Fuchs heterochromic uveitis: Aetiology, management, outcome. Eye 1991;5:662-667. Razzak A, Al-Samarrai A: Intraocular lens implantation following cataract extraction in Fuchs' heterochromic uveitis. Ophthalmic Res 1990;22:134-136. Chung YM, Yeh TS: Intraocular lens implantation following cataract extraction in uveitis. Ophthalmic Res 1990;21:272-276. ]akeman CM, Jordan K, Keast-Butler], et al: Cataract surgery with intraocular lens implantation in Fuchs' heterochromic cyclitis. Eye 1990;4:543-547. Swewood DR, Rosentl1al AR: Cataract surgery in Fuchs' heterochromic iridocyclitis. Br] Ophtl1almol 1992;76:238-240. Jones NP: Cataract surgery using heparin surface-modified intraocular lenses in Fuchs' heterochromic uveitis. Ophthalmic Surg 1995;26:49-52. Foster RE, Lowder CY, Meisler DM, et al: Extracapsular cataract extraction and posterior chamber intraocular lens implantation in uveitis patients. Ophtl1almology 1992;99:1234-1241. Jones NP: Cataract surgery in Fuchs' heterochromic uveitis: Past, present and future.] Cataract Refract Surg 1996;22:261-268. La Hey E, de Vries], Langerhorst CT, et al: Treatment and prognosis of secondary glaucoma in Fuchs' heterochromic iridocyclitis. Am] Ophtl1almol 1993;116:327-340.

Nikos N. Markomichelakis

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) mostly affecting young adults. The hallmark of the disease is dissemination in time and space (i.e., multiple episodes of dysfunction and multiple areas of involvement within the CNS), although the homogeneity of MS as a disease entity has been a long-debated issue. 1 The disease is divided into benign, relapsing-remitting, and chronic progressive (primary and secondary) forms. 2, 3 The clinical picture is determined by the location of foci of demyelination within the CNS. Classic features include fatigue, cognitive dysfunction, dysarthria, decreased perception of vibration and position sense, ataxia and intention tremor, weakness or paralysis of one or more limbs, spasticity, bladder problems, sexual dysfunction, and pain. The eyes are frequently affected, with optic neuritis, extraocular muscle disturbances, uveitis, and retinal periphlebitis among the ophthalmic signs of the disease. Although the etiology of MS remains unknown, two types of disease processes have been postulated: direct infection of the CNS with a neurotropic agent, and autoimmunity.

HISTORY Although the word sclerosis is derived from the Greek word scleros (hard), Greek or Roman physicians did not describe MS. Sir Augustus d'Esti, grandson of King George III of England, clearly described MS in 1822 in his diary.4 In the mid 1800s, Carswell in London and Cruveilhier and Charcot in Paris published detailed illustrations of MS plaques and sclerosis (in the French literature the disease was called sclerose en plaques). These observers documented the intermittent and seelningly random neurologic symptoms and the variable evolution of the disease. 5 In 1835, Charcot reported a woman with MS and "feebleness of vision," illustrating a link between optic neuritis and MS. Later, in 1866, Vulpian and Charcot emphasized the importance of ocular signs in MS, and in 1885, Uhthoff and Parinaud associated optic neuritis with MS. Sequin published the first American reports of "disseminated cerebrospinal sclerosis," including cases of optic neuritis with subacute transverse myelitis. 5 Adie, DennyBrown, and McAlpine 6 all stated that unilateral retrobulbar neuritis was a symptom of MS. Retinal venous sheathing in patients with MS was first described clinically by Rucker7 in 1944. In 1965, Archambau and colleagues8 mentioned patients with MS who had associated uveitis. Breger and Leopold9 reported that ocular inflammation in patients with MS has the form of intermediate uveitis.

The first episode of MS usually occurs between ages 20 and 40 years. Onset of the disease before age 14 or beyond age 60 is uncommon. Women outnumber men by about 1.8 to 1. 10 There is a striking geographic varia-

tion in the prevalence of MS. The disease is rare in equatorial regions and becomes increasingly more common in higher latitudes in either hemisphere. The prevalence in northern Europe, Canada, New Zealand, and southern Australia is more than 30 cases in 100,000 population. l l In the Mediterranean basin and southern South America, the prevalence is moderate (5 to 29 in 100,000).u In Asia, India, Mrica, the Caribbean, Central America, Mexico, and northern South America, MS is rare (less than five new cases each year per 100,000 persons).u It is estimated that over 100,000 persons in the United States are afflicted with MS.12 However, northern states have a prevalence of over 100 in 100,000, in contrast to southern states, where it is only 20 in 100,000. 10 Several investigators have shown that the number of cases in some locales may be increasing. 13- 15 Optic neuritis is a common manifestation of MS; it may be the initial expression or it may occur later in the course of the disease. Approximately 15% to 25% of cases of definite MS present with optic neuritis, and an additional 40% to 73% will suffer an attack of optic neuritis at some point. 16--18 Conversely, 30% of patients with optic neuritis will develop clinically definite MS, as reported by the Optic Neuritis Study Group.19 The longer patients with optic neuritis are followed, the greater the prevalence of subsequent demyelinative signs and symptoms. In a population-based study in Olmsted County, Minnesota, the life-table analysis showed that of 95 patients with isolated optic neuritis in the prevale~ce cohort, 39% had progressed to clinically definite MS by 10 yeal's of follow-up, 49% had done so by 20 years, 54% by 30 years, and 60% by 40 years. 20 The same study reported equal risks of developing MS in men and women, in contrast to a study in New England,21 in which the risk rate was 3.4 times greater for women. The reported frequency of uveitis among patients with MS varies widely, from 0.4% to 26.9%.8,9,21-24 These extreme differences may reflect the variations in patient populations, diagnostic criteria, and examination techniques. As uveitis may develop as late as 17 years after the onset of MS,25 it is apparent that the longer the followup, the higher the prevalence. The prevalence of MS in the total uveitic population has been reported to be 1% to 2%,23,24,26,27 with a higher prevalence among patients with intermediate uveitis, ranging from 7.8% to 14.8%.25, 28-30 The prevalence of MS in patients with uveitis at the Massachusetts Eye and Ear Infirmary is 1.3%, and 8% in the subgroup of patients with intermediate uveitis. 31

CLINICAL FEATURES

Systemic Manifestations MS lesions in the brain and spinal cord can potentially damage every function of the CNS.

Fatigue This is the most common symptom in MS and is seen in all stages of the condition. 32 Fatigue is sometimes unpro-

CHAPTER 62: MULTIPLE SCLEROSIS

voked (lassitude), or it can develop rapidly after only minimal activity. It is usually worse in high temperature or high humidity or in the afternoon; the body telnperature is slightly higher in all of these situations. This extreme sensitivity to heat is called Uhthoff's phenomenon.

Sensory Disturbance Sensory symptoms are common and are characteristically difficult for the patient to describe. Tingling, numbness, a tight band, pins and needles, a dead feeling, ice inside the leg, standing on broken glass, and something "not right" are common descriptions patients employ in their attempts to describe the sensory symptoms. Paresthesias typically begin in a hand or foot, progress over several days to involve the entire limb, and then resolve over several weeks. One third of MS patients experience Lhermitte's sign, described as the feeling of an electric shock or vibration running from the neck down the spine, especially if the examiner exerts pressure on the patient's inion at the back of the skull or with flexion of the neck. 33

Manifestations Diplopia or Nystagmus Diplopia may occur because the third or sixth cranial nerve pathways are damaged along their course within the CNS. Medial rectus weakness is usually part of an internuclear ophthalmoplegia (INa) that is caused by medial longitudinal fasciculus lesions. INa is paresis or weakness of adduction ipsilateral to the medial longitudinal fasciculus lesion and dissociated nystagmus of the abducting eye. Bilateral INa in a young patient is nearly pathognomonic of MS.39 Nystagmus is common but usually inconsequential. 40 Horner's syndrome is also occasionally present.

Optic Neuritis

The optic nerves are frequently involved, especially in younger patientsY Optic neuritis is considered a forme fruste of MS and a harbinger of underlying neurologic disease. Optic neuritis typically begins with rapid loss of vision, partial or total, usually in one eye. Although central scotoma is more common, virtually any field defect Pain can be seen. Color perception and contrast sensitivity Pain is only recently recognized as a frequent symptom disturbance is seen in virtually all patients and is often in patients with MS. Up to two thirds of patients with MS out of proportion to the reduction in visual acuity. Pain complain of pain at some time during the course of their . in or behind the eye accompanies optic neuritis and disease. Pain may be acute or chronic. The spectrum of sometimes precedes the visual loss. The pain is present pain is broad and includes trigeminal neuralgia, head- at rest, on voluntary movement, and with pressure on the aches, radicular pain, musculoskeletal pain, dysesthesias, globe. A unilateral afferent pupil defect is usually seen. tonic seizures, spasms, and clonus. The fundus is normal in cases with retrobulbar neuritis. Fewer than half of optic neuritis patients show papilliPoor Mobility tis. Slitlike defects in the peripapillary nerve fiber layer Weakness often affects the legs and sometimes the arms. have been described in patients with MS with and without Patients complain of weakness, stiffness, a foot-drop, or a history of acute optic neuritis. Retinal nerve fiber layer tripping. On examination, the hip flexors are often weak. defects can best be seen with red-free light. Retinal veHyperreflexia, spasticity, and the Babinski sign are com- nous sheathing may accompany optic neuritis. mon. Visual acuity usually begins to improve 2 weeks after the onset of optic neuritis, and resolution continues over several months. Complete recovery of visual acuity is comBladder/Bowel/Sexual Dysfunction Bladder dysfunction, including hesitancy, urgency, fre- mon, but other disturbances of vision may persist, such quency, and incontinence, is common; it is the initial as visual blurring, drab colors, and red or blue desaturasymptom in 5% and develops later in 90% of patients. 34 tion. The reduction of apparent light intensity is often Equally common is bowel dysfunction, particularly consti- associated with an ipsilateral Marcus Gunn pupillary repation. 35 Women are more likely to complain of loss of sponse. Bright lights cause a prolonged afterimage, a "flight of colors." Eye movements sometimes cause fleetgenital sensation and occasionally develop anorgaslnia. 36 ing flashes of light (movement phosphenes), which may correspond to Lhermitte's sign. Depth perception is imCognitive Dysfunction paired and is worse with moving objects (Pulfrich pheThis is well established as a common problem in MS nomenon). Increased body temperature can amplify all patients. A recent study has demonstrated that the impairof these symptoms and may diminish visual acuity ment of memory is a factor for poor prognosis. 37 (Uhthoff's phenomenon). Mter the neuritis resolves, the disc is usually pale (optic pallor), commonly in its tempoSpeech or Swallowing Disturbance ral aspect. The cerebellum or its pathways are damaged in 50% of patients with MS. Intention tremor of the limbs, head or Uveitis trunk titubation, and dysarthria can be totally disabling. Intermediate uveitis is the form of ocular inflammation

Psychiatric The incidence of depression is increased in MS patients and their families. 38 Euphoria, when it occurs, indicates widespread cerebral disease and is often associated with dementia.

most commonly encountered in patients with MS. The differences from the idiopathic form of pars planitis (PP) are minimal. Nussenblatt and colleagues 42 note that patients with MS typically develop a granulomatous anterior uveitis with formation of mutton-fat keratic precipitates, in contrast to patients with idiopathic intermediate uve-

CHAPTER 62: MULTIPLE SCLEROSIS

ItIS, who have minimal anterior segment inflammation. According to Bamford and coworkers,43 special signs in MS patients have been observed: vascular sheathing in the posterior pole (and not near the affected pars plana) and absence of macular edema (in contrast to idiopathic PP). In my experience at the Massachusetts Eye and Ear Infirmary and the General Hospital of Athens, there are similarities in clinical findings, course, and outcome of patients with PP with no evidence of an underlying systemic disease and those with MS (unpublished data). Posterior synechiae formation tends to be more common among patients with MS (29% versus 14%). Periphlebitis in MS can be found either in the posterior pole or in the retinal periphery. Although the incidence of periphlebitis in intermediate uveitis is independent of the coexistence of MS, the involvement of vessels in the posterior pole is more common in MS (41 % versus 26%). I have not observed any difference in the incidence of macular edema or epiretinal membr<:!-ne among PP patients with or without MS. In my experience, retinal vasculitis in MS ranges from mild venous sheathing to severe retinal involvement with vascular occlusion, neovascularization, and vitreous hemorrhage. Similar findings have been reported by Graham and colleagues. 44 Optic neuritis may either precede or follow the onset of intermediate uveitis. 27 ,29 Anterior uveitis is rare in patients with MS.45-47 When present, it takes the form of granulomatous iridocyclitis with iris nodule formation. 48 Posterior uveitis associated with MS has been reported only sporadically, 8 although pathologic reports showed increased incidences of choroiditis (11.5% )49 and retinitis (6.4%) .50 Retinal venous sheathing has been described in MS patients with and without concomitant uveitis,43, 44, 51 as well as in patients with optic neuritis. 29 , 52

The most common ocular complication of MS is atrophy of the optic nerve and inner retinal layers. The disc is usually pale (optic pallor), commonly in its temporal aspect. Clinical detection of retinal nerve fiber layer atrophy is possible only after a 50% loss of neural tissue in a given area. The varying degrees of atrophy are secondary to retrograde degeneration ofaxons in plaques of the pregeniculate pathways in MS. 49 Several authors have reported disc pallor in upwards of 50% of cases (Fig. 621).53,54 Complications of intermediate uveitis, as shown in many large series of patients, include, in decreasing order of frequency, cataract formation, cystoid macular edema, epiretinal membrane formation, glaucoma, retinal detachment, and neovascularization with and without vitreous hemorrhage. Whether these complications occur differently in intermediate uveitis associated with MS has been, until recently, unclear. Breger and Leopold,9 in a series of 14 patients, reported only one patient with lenticular opacities, and three patients with possible macular edema (absent foveal reflex). Chester and coworkers,28 using fluorescein angiograms (FA), found three of seven patients with central leakage. At the Massachusetts Eye and Ear Infirmary and the General Hospital of Athens, in a series of 17 patients (34 eyes) with intermediate uveitis and definite MS, the following complications were

FIGURE 62-1. Optic nerve pallor following optic neuritis. (See color insert.)

found: cataract formation (44%), chronic cystoid macular edema (28%), optic pallor (23%), severe epiretinal membrane (12%), elevated intraocular pressure (12%), retinal schisis (6%), and vitreous hemorrhage (3%). With the exception of optic disc atrophy due to optic neuritis, the frequencies of complications are comparable with those in idiopathic PP and sarcoidosis.

The cause of MS remains unknown despite decades of intense research. Hundreds of epidemiologic and genetic studies, pathologic analyses, and animal models have suggested several etiologies, but none are universally accepted. There appears to be an autoimmune attack against myelin and myelin-forming cells in the brain and spinal cord. MS, however, has been difficult to definitively classify as a true autoimmune disease. 55 T-cell and antibody reactivity have been tested against nUlnerous brain antigens, but no target antigen has been clearly and consistently demonstrated. Cloned T cells from MS patients show excessive reactions to myelin antigens in some studies but not in others. It is possible that the imInll11e response evolves through epitope spreading, generating responses to a number of CNS antigens. The lack of a causative antigen suggests that regulation of immune responses may be abnormal and that oligodendroglia are innocent bystanders that are damaged by unregulated inflammation. The heterogeneity of the disease suggests that a variety of causes may be involved in the etiology. Migration, ethnic, and twin studies suggest that both genes and environment affect the development of MS. Many viruses have been implicated as the cause of MS. The list includes rabies virus, measles virus, rubella virus, mumps virus, coronaviruses, canine distemper virus, herpesvirus (herpes simplex virus, varicella-zoster virus, Epstein-Barr virus), simian-virus-5, Marek's virus, ]C virus, and tick-borne encephalitis virus. 56 The most recent candidates are human herpesvirus-6 (a member of the 13-herpes virus family) and MS-associated retrovirus (a member of the endogenous retrovirus-9 family) .56 Unfortunately, none of these claims has withstood intense scrutiny and the test of time. The questIon remains as to

CHAPTER 62: MULTIPLE SCLEROSIS

whether a virus, directly or indirectly, triggers the im- vated levels of tissue necrosis factor (TNF)-a and granulomune reaction seen inMS, or whether this arises from cyte-macrophage colony-stimulating factor (GM-CSF) are auto antigenic stimulus independent of viral infection, observed in the active phase. 72 Expressions of TNF-a, interferon (INF)-')', and IL-10 mRNA are higher in the whetherit be systemic or local. Bacteria also have been implicated in the etiology of CSF and white blood cells of MS patients. 73-75 VanderMS.57 Experimental allergic encephalomyelitis (EAE) , the vyner and colleagues found that TNF-a and INF-')' mRNA experimental analogue of MS, is induced by mixing tissue levels are significantly elevated among myelin basic procells with adjuvant that contains Mycobacterium tuberculosis. tein reactive T-cell clones derived from HLA-DR2-positive Additionally, clinical studies show that there is a three- MS patients. 75 The role of apoptosis in MS has been investigated with fold increase in exacerbations after bacterial infections. 58 Environmental causes have been suggested, but none regard to the oligodendrocyte, the myelinating cell and is clearly a direct cause of MS. Seasonal variations· in MS the CNS, and the lymphocyte. The issue is still controverfrequency differ in various locales. 59 Other putative en- sial in MS. However, with EAE, modulation of apoptosis vironmental etiologies include nutrition, high consump- in transgenic animals has been shown to influence the tion of animal fat and low intake offish products,50,51 course of the disease. 77 latitude,52 sunlight,53 exposure to wool or sheep, and high Taken together, these data suggest that, more likely socioeconomic status. 50 than not, MS develops in the genetically susceptible indiThere are multiple genetic influences on the develop- vidual who is exposed to some trigger (e.g., a microbe), ment of MS. First-degree relatives have a 10- to 70-fold with subsequent T-cell activation or loss of self-tolerance. increased risk of developing MS compared to the general Several different mechanisms may playa role in the initiapopulation. 54 Although this could be interpreted as re- tion and perpetuation of the inflammation through Tflecting an environmental exposure rather than a genetic cell activation. A myelin basic protein (MBP) peptide or predisposition, the monozygotic concordance rate is 30% superantigens can activate T cells. Exogenous antigens, and the dizygotic rate is 5%, indicating that there is a and even self-antigens, sharing sequence similarities with genetic component to MS.55 Familial cases do not follow MBP peptide can activate MBP-specific T cells (molecular Mendelian genetics. Chataway and colleagues suggest tllat . mimicry). Superantigens, which are microbial proteins, MS depends on independent or epistatic·effects of several can also activate T cells expressing a given V13 family genes, each with small individual effects. 55 The most prev- member. Another potential mechanism is the activation alent human leukocyte antigen (HLA) determinants of autoreactive T cells, which can be triggered either found in the MS population of northel"l1. European origin through the T-cell antigen receptor or through an antiare DR15 (the subtype ofDR2 that expresses DRB1*1501) gen-independent mechanism during the course of an and DQ6. 57 Weinshenker and colleagues, in Olmsted inflammatory reaction. 77 County, Minnesota, found a positive association between The nature of the relation between PP and MS is not MS susceptibility and the DR15-DQ6 and DR13-DQ7 hap- clear. Many questions arise from the association: Do PP lotypes; however, they did not find any association with and MS have a common pathogenetic mechanism? Or disease severity.58 Barcellos and colleagues found a sig- does the coexistence of PP with MS represent the tennificant effect of a single locus on chromosome 19q13.2 dency of more than one disease of immune etiology in Caucasian patients with MS.59 The consensus view is to occur in certain individuals? Edelsten and colleagues that it is polygenetic-the major histocompatibility com- reported an increased prevalence of HLA-B7 in patients plex being the most important but not the only genetic with MS and symptomatic uveitis. 78 Malinowski and colfactor. leagues found an association with HLA-B8, B51, and DR2 in their group of PP patients. 79 Most recently, Tang and coworkers 80 and Raja and colleagues81 demonstrated a An MS plaque is formed after activated peripheral T cells strong association of HLA-DR15 and intermediate uveitis, adhere to CNS postcapillary venules. The T cells pass and they mentioned the lack of any association between through the endothelial cells and migrate into the peri- HLA-DR16 (the other "split" epitope of HLA-DR2) and ventricular parenchyma. An equivalent number of mono- expression of the PP phenotype. cytes are also present at this early stage. The inflammaUveitis has been observed in EAE produced by immution is associated with destruction of the inner myelin nization with CNS homogenates. 82 ,83 EAE has been oblamellae and dysfunction of oligodendroglia. served by immunizing with uveal tissue, although uveitis Immune activation in the periphery may precede neu- was not produced. 82 Thus, similar antigens may exist in. rologic problems and possibly magnetic resonance im- the CNS and uvea or retina, and these findings could be aging (MRI) abnormalities. A complex ilnbalance in both explained by an autoimmune response to a common cytokine and the Fas-FasL system is present in MS.70 In factor in MS. Ohguro and coworkers 84 found serum antiactive MS, lymphocytes express excessive levels of activa- bodies to arrestin (retinal S-antigen) in 8 of 14 patients tion proteins (HLA-DR, CD71, SLAM +) and costimula- with MS without any evidence of uveitis. The antibody tory molecules (B7-1 and B7-2) .70, 71 The data from several titers were higher during relapses than during remissions, studies indicate that different cytokine profiles may be and the authors suggest that antibodies reactive with arobserved in patients with acute or stable disease. High restin may be related to the clinical course of MS. These levels of interleukin (IL)-10 and transforming growth findings could also explain the development of uveitis in factor (TGF)-13 are present in the cerebrospinal fluid some patients with MS. (CSF) of patients in a stable phase of MS, whereas eleLucchinetti and colleagues described at least five dis-

CHAPTER. 62: MULTIPLE SCLER.OSIS

tinct patterns of MS pathology, based mainly on the preservation or loss of 01igodendrocytes. 85 In pathologic studies of eyes from patients with MS, observation of uveal tract inflammation has been rare, in contrast to studies of vascular inflammation. 49 , 50 According to Arnold and colleagues,50 retinal phlebitis is not a secondary response to uveitis or a passive extension of a CNS infiltrate but a concurrent part of a multifocal process in neural tissue.

DIAGNOSIS The established clinical criteria for the diagnosis of MS depend on the clinical demonstration of lesions disseminated in both time and space in separate portions of the white matter of the CNS. Patients are also expected to have clinically appropriate MS-like symptoms. Criteria that must be satisfied to establish a diagnosis of clinically definite MS include a reliable history of at least two episodes of neurologic deficit and objective clinical signs of lesions at more than one site within the CNS.86 Demonstration of a second lesion by paraclinical and laboratory tests, in concert with one objective clinical lesion, also fulfills the criteria. 87 An MRI, examination of the CSF, and evaluation of evoked potentials are performed to establish a diagnosis of MS. Other ancillary testing, such as FA, is useful in evaluating ocular signs or detecting subclinical ocular manifestations.

FIGURE 62-2. MRI abnormalities.

Magnetic Resonance Imaging MRI abnormalities can clearly s'f!\pport the diagnosis of MS. The plaques typically appear as areas of increased signal intensity on T2-weighted and proton density images, and sometimes as areas of decreased signal intensity on T1-weighted images (Fig. 62-2). The current feeling is that for an MRI to be strongly suggestive of MS there should be three lesions, at least one periventricular, or four or more lesions. Lesions larger than 6 mm in diameter are more specific for MS than smaller lesions. Lesions that arise from the corpus callosum and infratentorial lesions or oval-shaped lesions have high specificity for the diagnosis of MS. If a lesion of a specific type or location suggestive of MS is found, in addition to the three or four lesions just indicated, the specificity for MS probably increases. 88

Fluorescein Angiography FA is helpful in delineating the presence of vasculitis. Dye leakage or staining of vessel walls corresponding to areas of sheathing indicates active periphlebitis. Sheathing without fluorescein abnormality was observed in patients with venous sclerosis. 43 The most prominent finding on angiography is dye leakage frOlll the retinal venules and capillaries late in the study, which results in cystoid macular and retinal edema.

Ancillary

Electrophysiology

Visual field testing is helpful in detecting optic neuritis. Perimetry shows scotomata that are usually diffuse or central but sometimes are peripheral. Contrast sensitivity tests, flight of colors tests, and color vision tests are useful to detect subclinical optic tract lesions in patients with MS and normal visual acuity but no history of optic neuritis. 91 Color vision abnormalities are traditionally most pronounced with red light; acutely, blue/yellow defects may be more common. 92 A diagnosis of MS should be questioned, judiciously, when there are (l) no eye findings, (2) no remissions, (3) localized disease, (4) no sensory or bladder symptoms, and (5) normal CSF.93

Evoked potentials are occasionally helpful (e.g., when the MRI and CSF are normal), but they should not be used for the routine diagnosis of MS. The frequency of abnormal evoked potentials in definite MS is as follows: visual = 90%, auditory = 80%, and somatosensory = 70%. In patients with optic neuritis, visual evoked potentials are always abnormal in the affected eye, but 35% of patients return to normal within 2 years. 90

Other diseases that may mimic MS must be excluded (Table 61-1). Inflammatory systemic diseases that produce encephalomyelopathy, optic neuritis, ophthalmoplegia, retinal vasculitis, and uveitis include neurosyphilis, neuroborreliosis, viral infections, Adamantiades-Beh<;;:et disease (ABD) , and sarcoidosis.

laboratory Testing The CSF shows elevated protein; a moderate increase in white blood cells (often containing occasional blasts in active disease); increased immunoglobulin G (IgG) , IgG/ albumin index, and IgG synthesis rate; and oligoclonal bands. An index ratio of CSF antibodies to measles, rubella, and herpes zoster may improve sensitivity.89

DIAGNOSIS

CHAPTER 62: MULTIPLE SCLEROSIS TABLE 62-1. DISEASES THAT MAY MIMIC MULTIPLE SCLEROSIS Central nervous system (CNS) lymphoma CNS vasculitis Syphilis Lyme disease Sarcoidosis

Neurosyphilis, both the meningovascular type and tabes dorsalis, lTIay mimic MS. The classic ocular finding is the Argyll Robertson pupil. Also, disc edema or optic atrophy, and oculomotor palsies are frequently found. However, uveitis and retinal vasculitis are rare. 94 Moreover, the clinical history, together with positive serology for syphilis, reactive CSF Venereal Disease Research Laboratory (VDRL) test, and MRI evidence, serve to distinguish this entity from MS. Lyme neuroborreliosis may mimic. MS clinically and on MRI. Intermediate uveitis, vasculitis, and optic neuritis have been reported in Lyme disease. 95 The presence of erythema migrans is a single pathognomonic criterion. Serum and intrathecal production of anti-Borrelia burgdorferi antibody occurs frequently. A positive enzymelinked immunosorbent assay is suggestive for Lyme disease, but this should be confirmed by Western blotting. Herpes family viruses may produce encephalitis. Uveitis (acute retinal necrosis syndrome 96 ,97 or frosted branch angiitis 9S ) may occur at the same time, or following infection as a result of reactivation of virus. These disorders are monophasic, in contrast with MS. Detection of virus in ocular fluids or in CSF by polymerase chain reaction could confirm the diagnosis of a viral infection. Human T-cell leukemia/lymphoma virus (HTLV)-1 has been implicated in the etiology of MS, and this virus has been associated with intermediate uveitis. 99 Therefore, in endemic areas HTLV-l may be included in the differential diagnosis. ABD can cause episodic, multifocal CNS lesions that can be confused with MS clinically and on MRI. However, ABD is associated with genital and oral ulcers and meningoencephalitis. Uveitis is anterior with hypopyon, or posterior with areas of retinal infraction with hemorrhage and edematous retina. Patients experience multiple explosive inflammatory episodes. PP has been reported in ABD,30 but this is relatively rare. Optic neuropathy may be seen, but it has the form of papillitis. loo Sarcoidosis may involve all components of the nervous system. IOI Rarely, multiple lesions that mimic MS, spinal cord abnormalities, and peripheral neuropathy can occur. Optic neuritis,102 intermediate uveitis,25 and periphlebitis l03 are common manifestations of sarcoidosis. Sarcoidosis must be excluded in the evaluation of patients with uveitis who are suspected of having MS.

COURSE AND PROGNOSIS The course of MS varies. The Advisory Committee on Clinical Trials of New Agents in MS of the National Multiple Sclerosis Society has specified consensus definitions of the clinical course of MS.l04 The recommended course labels are relapsing-remitting, primary progressive, secondary progressive, and progressive-relapsing MS.

These categories are not immutable; patients frequently drift from one type of MS to another, become stable, or suddenly develop active disease. The clinical prognosis of optic neuritis in patients with MS is surprisingly good. The Optic Neuritis Study Group 105 has recently reported the visual changes and frequency of recurrent optic neuritis in the first 5 years after enrollment in the Optic Neuritis Treatment Trial. According to these results, contrast sensitivity is more often abnormal than is visual acuity, visual field, or color vision. Visual acuity is generally well preserved even if it is severely reduced at presentation. In large populations, 20% to 40% have "benign disease," defined as having less than moderate disability after 10 years. Half will develop progressive MS within 10 years. Patients with the greatest risk of disability are those with primary progressive disease, and relapsing-remitting patients who are older at onset. 106 The prognosis of intermediate uveitis associated with MS is not well documented. In a series of nine patients,23 visual acuity was 6/9 or better in all 17 eyes, color vision was impaired in only 1 of 17 eyes, and optic atrophy was present in 6 of 17 eyes. Malinowski and colleagues 29 found an overall favorable visual prognosis in 54 patients with PP, among them S patients with definite MS. In myexperience, the course and the final outcome of intermediate uveitis associated with MS are comparable with those of idiopathic intermediate uveitis. Among our 17 PP patients with MS, and with a follow-up ranging from 3 to 15 years, the average number of exacerbations per year was 0.65. More than half of our patients experienced final visual acuity better than 20/40, and one fourth had 20/20. Poor visual outcome was attributed to recurrent attacks of retrobulbar neuritis, leading to optic atrophy.

Many approaches to the treatment of MS have been employed, but no treatment completely halts the disease. 107 Glucocorticoids, such as oral prednisone and adrenocorticotropic hormone, temporarily ameliorate many of the symptoms of MS by reducing edema and inflammation, but they do not alter the course of the disease. lOS High-dose intravenous methylprednisolone lessens recurrences of optic neuritis and prevents the development of MS only durinK the first 2 years. I09 Azathioprine produces modest benefits with respect to relapse rates and disease progression after 2 or more years of treatment. uo Cyclophosphamide, because of its modest impact on disease progression and its potentially severe side effects, is generally reserved for patients with aggressive relapsing/relTIitting or chronic progressive disease in whom other treatments have failed. lll Methotrexate causes slight improvement on a composite score of neurologic function. In patients with rapidly progressive disease, it might be worth considering,u2 Cladribine, a nucleoside drug, targets both resting and dividing lymphocytes and may be able to destroy the activated T cells that induce CNS demyelination, thus producing stabilization or improvement in chronic MS,u3 In an IS-month clinical trial, MRI lesions that enhanced after gadolium administration were completely suppressed in the cladribine-treated patients by the sixth month of treatment. U4 At present, there is

CHAPTER. 62: MULTIPLE SCLEI~OSIS

no evidence to support the use of intravenous immunoglobulins in secondary or primary progressive MS.ll5 Sulfasalazine causes early improvement but no long-term benefit. 1I6 Linomide (quinoline 3-carboxamide) is a synthetic immunomodulator that can stimulate various lynlphocyte subpopulations 1I7 and increase the activity of natural killer cells. lIS Up-regulation of naive T cells and parallel down-regulation of memory T lymphocytes may represent one main mechanism by which Linomide inhibits MS activity. Clinical trials have revealed that Linomide not only significantly reduces clinical and MRI activity in secondary progressive 1I7 or relapsing/remitting 1I9 MS, but it also prevents the appearance of new active lesions on the MRI scan in secondary progressive MS.lls However, Linomide failed to induce remyelination in a viral model of MS.120 Recent studies have shown that INF-13-1 b 121 delays sustained neurologic deterioration in patients with secondary progressive MS, while INF-13-1a122 alters the course of relapsing/remitting MS. CopolYluer-l (glatiramer acetate) also reduces clinical disease activity in relapsing/ remitting MS.123 However, a 2-year longitudinal study showed that it had no effect on cognitive function in relapsing/remitting MS.124 It remains unclear whether the various therapeutic modalities used in the treatment of MS are effective against MS-associated uveitis. Clinical trials describing the natural course and treatment results specifically of uveitis associated with MS have not been reported to date. Currently, MS-associated inte:&mediate uveitis and its complications are treated in the same manner as idiopathic intermediate uveitis. I treat these cases with a stepladder approach, basing the decision to treat not only on the level of visual acuity but on the presence or absence of uveitis, even at low intensity. When visual acuity is less than 20/30 and there is active inflammation, I use transseptal injections of corticosteroids. If this fails or when aggressive inflammation is present, I administer methotrexate, azathioprine, cyc1osporine-A, or INF-l13, depending on the bias of the patient's neurologist.

MS is an immunologically mediated disorder in which inflammation of the CNS is the prominent feature, resulting in various neurologic signs and symptoms. MS mainly affects young females from the northern part of the globe. The most frequent ocular manifestations of the disease are optic neuritis, intermediate uveitis, and periphlebitis. Prognosis of the ocular disease is surprisingly good. Although there are new treatment modalities with promising results, their influence on the ocular disease is not yet known.

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62. Esparza ML, Sasaki S, Kesteloot H: Nutrition, latitude, and multiple sclerosis mortality: An ecologic study. Am J Epidemiol 1995;142:733-737. 63. Hutter CD, Laing P: Multiple sclerosis: Sunlight, diet, immunology and etiology. Med Hypotl1eses 1996;46:67-74. 64. Hogancamp WE, Rodriguez M, Weinshenker BG: The epidemiology of multiple sclerosis. Mayo Clin Proc 1997;72:871-878. 65. Sadovnick AD, Armstrong H, Rice GPA, et al: A population-based study of multiple sclerosis in twins: Update. Ann Neurol 1993;33:281-285. 66. Chataway J, Feakes R, Coraddu F, et al: The genetics of multiple sclerosis: Principles, background, and updated results of the United Kingdom systematic genome screen. Brain 1998;121:18691887. 67. Martin RJ: Genetics of multiple sclerosis-How could disease-associated HLA-types contribute to pathogenesis? Neural Transm SuppI1997;49:177-194. 68. Weinshenker BG, Santrach P, Bissonet AS, et al: Major histocompatibility complex class II alleles and tl1e course and outcome of MS: A population-based study. Neurology 1998;51:742-747. 69. Barcellos LF, Thomson G, Carrington M, et al: Chromosome 19 single-locus and multilocus haplotype association with multiple sclerosis. Evidence of a new susceptibility locus in Caucasian and Chinese patients. JAMA 1997;15:1256-1261. 70. Ferrante P, Fusi ML, Saresella M, et al: Cytokine production and surface marker expression in acute and stable multiple sclerosis: Altered IL-12 production and augmented signaling lyn1phocytic activation molecule (SLAM)-expressing lyn1phocytes in acute multiple sclerosis. J Immunol 1998;160:1514-1521. 71. Genc K, Reder AT: Increased B7-1 + B cells in active multiple sclerosis, and reversal by interferon beta-l b tl1erapy. J Clin Invest 1997;99:2664-2671. 72. Carrieri PB, Provitera V;' De Rosa T, et al: Profile of cerebrospinal fluid and serum cytokines in patients with relapsing-remitting multiple sclerosis: A correlation witl1 clinical activity. Immunopharmacol Immunotoxicol 1998;11 :293-298. 73. Calabresi PA, Tranquill LR, McFarland HF, Cowan EP: Cytokine gene expression in cells derived from CSF of multiple sclerosis patients. J Neuroimmunol 1998;89:198-205. 74. Monteyne P, Sindic CJ: Data on cytokine mRNA expression in CSF and peripheral blood mononuclear cells from MS patients as detected by PCR. Mult Scler 1998;4:143-146. 75. Rieckmann P, Albrecht M, Kitze B, et al: Cytokine mRNA levels in mononuclear blood cells from patients with multiple sclerosis. Neurology 1994;44:1523-1526. 76. Vandervyner C, Motmans K, Stinissen P, et al: Cytokine mRNA profile of myelin basic protein reactive T-cell clones in patients with multiple sclerosis. Autoimmunity 1998;28:77-89. 77. Libau RS, Fontaine B: Recent advances in immunology in multiple sclerosis. Curr Opin Neurol 1998;11:293-298. 78. Edelsten C, Stanford MR, Ormerod I, Welsh KI: Prevalence of HLA B7 in MS witl1 symptomatic uveitis. Lancet 1992;339:942. 79. Malinowski SM, Pulido JS, Goeken NE, et al: The association of HLA-B8, B51, DR2, and multiple sclerosis in pars planitis. Ophthalmology 1993;100:1199-1205. 80. Tang WM, Pulido JS, Eckels DD, et al: The association of HLADR15 and intermediate uveitis. AmJ Ophthalmol 1997;123:70-75. 81. Raja SC, Jabs DA, Dun JP, et al: Pars planitis. Clinical features and class II HLA associations. Ophthalmology 1999;106:594-599. .82. Bullington RJ, Waksman BH: Uveitis in rabbits with expelimental allergic encephalomyelitis. Arch Ophthalmol 1958;59:435-445. 83. Von Sallman L, Myers RE, Lerner EM II, Stone SH: Vasculoocclusive retinopathy in experimental allergic encephalomyelitis. Arch Ophthalmol 1967;78:112-120. 84. Ohguro H, Chiba S, Igarashi Y, et al: (3-Arrestin and arrestin are recognized by autoantibodies in sera Ji-om multiple sclerosis patients. Proc Natl Acad Sci USA 1993;90:3241-3245. 85. Lucchinetti CF, Bruck W, Rodriguez M, Lassmann H: Distinct patterns of multiple sclerosis pathology indicate heterogeneity in pathogenesis. Brain Pathol 1996;6:259-274. 86. Schumacher GA, Beebe G, Kilber RF, et al: Problems of experimental trials of tl1erapy in multiple sclerosis: Report by the panel on the evaluation of experimental uials of therapy in multiple sclerosis. Ann N Y Acad Sci 1965;122:552-568. 87. Poser CM, Paty DW, Scheinberg I, et al: New diagnostic criteria for

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Panagiota Stavrou and C. Stephen Foster

Sarcoidosis is a multisystem granulomatous disease that was first described by Jonathan Hutchinson in 1878. 1 In 1899, Cesar Boeck demonstrated that noncaseating granulomatous inflammation was the pathologic hallmark of sarcoidosis. 2 He found no microorganisms and postulate-a that the cause of the disease was defective blood formation or autointoxication. In 1909, Heerfordt reported an association between uveitis, enlargement of the lacrimal glands, and cranial nel've palsies. 9 Schumacher in 1909 and Bering in 1910 reported iritis in association with cutaneous lesions and Schaumann in 1914 recognized the multisystem nature of the disease. 4 ,5 In 1916; Boeck observed the lack of cutaneous reaction to tuberculin in patients with sarcoidosis and an absence of mycobacteria in guinea pigs inoculated with sarcoidal tissue. 6 The clinical manifestations of sarcoidosis are variable and its course can be unpredictable. The organs affected more often are the lungs, skin, and eyes. However, the severity of organ involvement varies between individuals and among ethnic groups with differei1tial expression of disease severity. It has been suggested that the clinical course may occasionally correlate with !he type and character of disease presentation. 7 An acute onset with erythema nodosum or asymptomatic bilateral hilar lymphadenopathy usually follows a self-limiting course, whereas an insidious onset, especially with multiple extrapulmonary lesions, is often followed by relentless, progressive fibrosis of the lungs and other organs. The spectrum of ocular manifestations is wide; almost every part of the eye and other orbital structures can be affected. Ocular involvement may coexist with asymptomatic systemic disease, or it may precede systemic involvement by several years. Definitive diagnosis is made by the demonstration of noncaseating granuloma by tissue biopsy. When a diagnosis of sarcoidosis is suspected but no affected tissue amenable to biopsy is identifiable, circumstantial evidence of the diagnosis may be obtained through noninvasive investigations, including measurement of serum angiotensin converting enzyme (ACE) and lysozyme, radiograph and computed tomography (CT) of the chest, gallium (Ga) scintillography, pulmonary function tests, bronchoalveolat lavage (BAL) , and measurement of serum and urinary calcium.

EPIDEMIOLOGY Sarcoidosis is characterized by a great diversity in its incidence in various parts of the world, racial predilection, and clinical course and prognosis. Differences in the global prevalence of sarcoidosis between the hemispheres, as. well as between the northern and southern regions of countries such as Italy and Japan, have also been reported. 7 It has been suggested that sarcoidosis is more common in certain geographic areas such as the

southeastern part of the United States, but when caseInatched controls have been used, these geographic differences are less striking. In the United States, the majority of patients are blacks, with a prevalence of 40 per 100,000, compared to 5 per 100,000 among whites. In Europe, the disease affects mostly whites, but there is great variation in prevalence among different countries: The prevalence per 100,000 is 64 in Sweden, 10 in France, 3 in Poland, and an extraordinary 200 for Irish women living in London. In contrast, the disease is rare in India, Southeast Asia, New Zealand, and mainland China. Diab and colleagues 8 reported on 20 Arab patients with sarcoidosis in Kuwait. All of them had thoracic lesions. When compared to westerners, these patients were older, and they more frequently demonstrated constitutional symptoms and presented with thoracic involvement with rare ocular and central nervous system manifestations. Pietinalho and colleagues9 reported that in 1984, the prevalence of sarcoidosis was 28.2 per 100,000 in Finland and 3.7 per 100,000 in Hokkaido, Japan. In Hok'kaido, the area with the. highest incidence in Japan, patients were significantly younger at diagnosis and eye symptoms were more frequent (45% vs 7%). However, respiratory and joint symptoms and erythelna nodosmn were more frequent in Finland. A change in the pattern of organ involvement has been reported in Japan, with an increase in the proportion of patients with ocular involvement (from 41.6% to 58.7% in women); an increase in the number of middle-aged and elderly patients is also noted. lO Gupta and Gupta ll reported on 125 cases of biopsy-proven sarcoidosis seen between 1972 and 1990 in Calcutta, India. The authors described that the presentation, clinical course, and radiologic features were considerably different from those seen in the West; elderly men over 40 years were more prevalent in this patient sample, and a previously unreported high susceptibility of medical personnel as well as doctors (8%) and their close relations (8.8%) was noted. Ocular symptoms (20%) included acute or chronic uveitis, corneal opacities, and lacrimal gland enlargelnent, but keratoconjunctivitis sicca secondary to lacrimal gland involvement was not as prevalent in this Indian study group as in prior reports of patient groups in western countries. There was no case of conjunctival involvement despite routine "blind" biopsy in a large number of patients. The sex ratios largely depend on the age at diagnosis, the mode of detection, and geography.7 When the data include large numbers of early, asymptomatic cases detected by mass x-ray screening efforts, male predominance is found. When the data deal with symptomatic cases, on the other hand, a slight female predominance is observed. Swedish and Japanese studies show that the incidence in both sexes is usually highest in the second and third decades, often forming a bimodal curve with the second peak in middle age, especially in women. 7 Although most patients present between the ages of 20

CHAPTER 63:

and 40 years, clinically evident disease onset can occur in children and in the elderly. Several cases of familial sarcoidosis (including in monozygotic twins) have been described, as well as husband-and-wife pairs. This, together with geographic ChlStel'S of sarcoidosis occurring among unrelated individuals living closely within a community, argues for environmental factors in the pathogenesis of the disease. 12 As the pathophysiology of sarcoidosis probably involves antigen recognition, processing, and presentation, there has been significant interest in finding possible associations with human leukocyte antigen (HLA)-related genes. Although no consistent association has been found, the HLA-B8 has been associated with patients who present acutely with erythema nodosum and who show early resolution of sarcoidosis.1 2-1 5 Epidemiologic studies attempting to link sarcoidosis to various environmental or occupational factors have been inconclusive. However, in 1992, tuberculosis mycobacter~al DNA was demonstrated by polymerase chain reaction in BAL samples in 50% of patients with sarcoidosis, and nontuberculosis mycobacterial DNA in a further 20% of the sarcoidosis patients. 16 Another study showed tuberculosis mycobacterial rRNA in sarcoid splenic tissues by liquid-phase DNA/RNA hybridization, suggesting that mycobacteria may playa part in the cause of sarcoidosisP Unlike many dise3cses -in which lungs are involved, sarcoidosis favors nonsmokers.

CLINICAL FEATURES

Systemic Manifestations The lung is the most frequently affected organ in patients with sarcoidosis. Histologically,' the lesions are distributed primarily along the lymphatics around bronchi and blood vessels, although alveolar lesions are also seen. The relative frequency of granulomas in the bronchial submucosa accounts for the high diagnostic yield of bronchoscopic biopsies. Lymph nodes are involved in almost all cases, especially the hilar and mediastinal nodes. The majority of patients are asymptomatic, although others may complain of cough or dyspnea. The spleen is clinically enlarged in only 18% of cases, although microscopic evidence of sarcoid granulomas in splenic tissue is present in three quarters of patients. Although the liver is affected less often than the spleen, elevated liver enzymes in a patient suspected of having sarcoidosis may prompt percutaneous liver biopsy in the search for histopathologic confirmation of the diagnosis. Renal insufficiency has been reported in patients with histologic involvement of the kidneys and has been attributed to hypercalcemia and interstitial granulomatous nephritis. Is Radiographic abnormalities of the bones can be identified in about one fifth of patients. The radiologically visible lesions are usually seen in the phalangeal bones of the hands and feet, .creating small, circumscribed areas of bone resorption within the marrow cavity (Fig. 63-1). Skin lesions are found in 9% to 37% of patients. They may be specific, showing histologically noncaseating granulomas, or nonspecific (e.g., erythema nodosum). The specific skin lesions include lupus pernio, infiltrated plaques, maculopapular eruptions, subcutaneous nod-

FIGURE 63-1. X-ray study of hands of a patient with sarcoidosis showing circumscribed areas of bone resorption within the marrow cavity.

ules, and infiltration of old scars (Figs. 63-2 and 63~3). Lupus pernio and plaques are associated with more severe systemic involvement and a more chronic course, whereas erythema nodosum is the halhnark of acute and benign disease. 19 Lesions may also appear on the mucous membranes of the oral cavity, larynx, and upper respiratory tract. Although direct cardiac involvement is seen in only 5% of patients, cor pulmonale is common in patients with severe pulmonary sarcoidosis. Cardiac complications include conduction abnormalities, myocardiopathy, pericarditis, and pericardial effusion. The clinical course of sarcoidosis maybe acute or chronic. Acute disease develops over a few weeks and is characterized by constitutional symptoms such as fever, erythema nodosum, arthralgias, and parotid enlargement or uveitis in 25% to 50% of patients. Acute disease may resolve with minimal residual sequelae or may progress

FIGURE 63-2. Umbilicated sarcoid skin lesion in a patient who presented with uveitis. (See color insert.)

63: SARCOIDOSIS

FIGURE 63-3. Sarcoid plaque-like skin lesion in a patient with sarcoidosis. (See color insert.)

to chronic sarcoidosis. In 40% to 70% of patients, sarcoidosis develops insidiously over several months. These patients usually present with respiratory symptoms and lack constitutional complaints. A summary of the extraocular organ involvement in patients with sarcoidosis is shown in Table 63-1.

Ocular Manifestations

Anterior Segment The frequency of ocular involvement ranges from 26% to 50%. This statistic is based on studies with varying population and geographic distributions and nonuniform criteria for diagnosis and follow-up, making comparisons between studies difficult and resulting in a wide range of reported ocular involvement. Anterior segment pathology is the most common ocular manifestation and is seen in 85% of patients with ocular sarcoidosis. Conjunctival involvement has been reported in 6.9% to 70% of patients with ocular sarcoidosis. 20- 25 Sarcoid granulomas have been described as solitary, yellow, "millet-seed" nodules (Fig. 63-4) .26 These may be difficult to differentiate clinically from lymphoid follicles; however, they are often larger, tend to be evenly distributed, and they show a characteristic disposition to confluence. 25 Although most patients are asymptomatic, diplopia from a large conjunc-

FIGURE 63-4. Conjunctival nodules in sarcoidosis. (See color insert.)

tival granuloma has been reported,22 and cicatrizing changes with symblepharon formation may occur. 21 Hunter and Foster24 reported a higher incidence of conjunctival involvement in patients younger than 35 years of age. Conjunctival chalky deposits were reported in 5 of 69 (7.2%) patients by Crick and colleagues. 25 Only one of these five patients had uveitis, prompting the authors to' suggest that the calcium deposits were secondary to hypercalcemia rather than to chronic inflammation; indeed, the deposits disappeared with a low calcium diet. Anterior uveitis has been reported in 22% to 70% of patients with ocular involvement, and it is usually granulomatous (Fig. 63-5) and chronic. 2o ,22-25 Karma and colleagues 21 classified the possible course of uveitis as being either monophasic, relapsing, or chronic. The visual prognosis was related to the course of uveitis, being better in patients exhibiting the monophasic type. Anterior uveitis is reported to be more common among black patients in the Netherlands. 22 Iris nodules (Figs. 63-6 and 63-7) have been reported in up to 12.5% of patients with sarcoidosis-associated

TABLE 63"':1. ORGAN INVOLVEMENT AT NECROPSY IN PATIENTS WITH SARCOIDOSIS ORGAN Lymph nodes Lung Liver Spleen Heart Skin Brain Kidney Eye

PERCENT OF PATIENTS

78 77 67 50

20 16 8

7 6

Adapted from Branson JH, Park]H: Sarcoidosis: Hepatic involvement. Ann Intern Med 1954;40:11.

FIGURE 63-5. Mutton fat keratic precipitates. (See color insert.)

CHAPTER 63: SARCOIDOSIS

FIGURE 63-6. Busacca iris nodules. (See color insert.)

uveitis. 20 , 21,23 Exacerbations of granulomatous uveitis are often associated with an appearance of fresh iris or fundus nodules. A large iris sarcoid nodule touching the corneal endothelium and extending to the pupil centrally, producing posterior synechiae and sector cortical cataract, was reported by Mader and colleagues,27 and secondary glaucoma due to occlusion of the angle by ap iris nodule was observed by Crickandcolleagues. 25 Posterior synechiae have been, reported in 20% to 26%,21,24 cataract in 4% to 35%,20-25,28,29 and glaucoma in 4% to 33%20-25,29,30 of patients with,,,sarcoidosis-associated uveitis. Corneal band keratopathy develops in 4.5 % to 11 % of patients,20,21,23,25, and it is associated with hypercalcemia in the majority of the cases. 20 , 21 Scleritis is a relatively rare manifestation. Scleral plaques have been reported in up to 2% of patients. 23 , 24

Posterior Segment Involvement of the posterior segment is seen in 25% of patients with ocular sarcoidosis, and it can be the sole manifestation of the disease in 5% of patients. The most common manifestations of sarcoidosis involving the posterior segment are vitritis (Fig. 63-8), occurring in 3%

FIGURE 63-7. True iris nodule in sarcoidosis. (See color insert.)

FIGURE 63-8. Vitritis, snow balls, and perivenular exudates in a patient with sarcoidosis. (See color insert.)

to 62%,20, 23, 24 intermediate uveItIs in 16% to 38%,24, 30 panuveitis in 9% to 30%,22,25,30 posterior uveitis in 12%,30 retinal vasculitis in 9% to 34%,20, 23, 24 and optic nerve involvement in 7.4% to 34%20,24 of patients. Periphlebitis is a hallmark, although not pathognomonic, of sarcoidosis and may be associated with yellow perivenous exudates ("taches de bougie" or candle wax drippings). Cellular infiltration of the vitreous may occur in clumps ("snowballs") in the inferior vitreous or in chains ("string of . pearls") . Other manifestations include choroidal nodules 20 ;' 23 and exudative retinal detachment,21, 23 which may result in phthisis. 21 Clinical and/or angiographic cystoid macular edema (CME) has been reported in 19% to 72% of patients 24 , 29, 30 and was noted to be more common in patients with posterior uveitis; it was correlated with the duration of active uveitis and delay in seeking treatment. 30 Rothova and colleagues 22 reported that sarcoidosisassociated posterior uveitis was usually chronic and was more common in white women with late onset of the disease. The same investigators noted that uveitis was an early feature of sarcoidosis, seen in 25 of 29 (86%) patients; moreover, in 9 of the 25 cases, ocular inflammation preceded any systemic signs of sarcoidosis by more than 1 year. Overall, patients with chronic posterior uveitis and panuveitis have significantly more complications than do patients with anterior uveitis. 21 , 22, 30 Vrabec and colleagues 31 reported "taches de bougie" in 22 patients with sarcoidosis. The authors described two clinical patterns, each with a dIfferent visual prognosis. The first and more frequent type, in the active phase, is associated with vitritis and segmental venous "sheathing" or perivenular exudates (Fig. 63-9). Small, discrete white spots occur in clusters around retinal venules, often limited to one or two retinal quadrants, frequently the inferior and nasal. This presentation may be indistinguishable from multifocal choroiditis and panuveitis. These lesions evolve into areas of cobblestone-like chorioretinal atrophy approximately one-third the disc area in size. Spots may develop several years after the initial presentation in some patients. The second type is characterized by yellow-orange lesions located at the level of the choroid, predominantly in the posterior and 11:asal fundus, simulating the

CHAPTER 63: SARCOIDOSIS

iridis. In all cases, there was concomitant peripheral retinal capillary nonperfusion. Although retinal neovascularization occurs in patients who show areas of nonperfusion by fluorescein angiography, it can also occur in response to inflammation alone. In these patients, anti-inflammatory treatment may induce involution of the neovascular tissue. Fluorescein angiography in patients with sarcoidosis may show retinal vascular staining, CME, and retinal or optic disc neovascularization. A recent study characterized the indocyanine green angiographic features in 19 patients with sarcoidosis-associated posterior uveitis into four patterns. 35 These are hypofluorescent choroidal lesions, focal hyperfluorescent pinpoints, fuzzy choroidal vessels with leakage, and diffuse late zonal choroidal hyperfluorescence. The authors reported that all 19 paFIGURE 63-9. Perivenular exudates in sarcoidosis. (See color insert.) tients were found to have choroidal involvement by indocyanine green angiography, yet eight patients had no evidence of retinal or choroidal involvement on clinical lesions of birdshot chorioretinopathy. These are discrete examination or fluorescein angiography. and depigmented but not atrophic. They have no surOther, less frequent complications of sarcoidosis-associrounding retinal pigment epithelial (RPE) clumping and ated uveitis include peripapillary36 and subfoveaP7 choroithey are not associated with retinal vasculitis or retinal dal neovascularization, posterior scleritis with annular vascular obstruction. Visual prognosis is thought to be ciliochoroidal detachment causing angle-closure glaubetter in patients with the latter type because of absence coma,38 branch vein occlusion,39 and solitary choroidal of retinal inflammation. . mass without inflammation. 40 In one report, central retiOther studies have also reporteci on the "punched- nal vein occlusion leading to a painful blind eye secondouf' multifocallesions (Fig. 63-10) seen in patients with ary to neovascular glaucoma was found on histopathouveitis secondary to sarcoidosis. 21 , 29, 32 These lesions may logic examination to be caused by a large noncaseating correspond to those described in a c1~n_icopathologic corgranuloma of the ciliary bodyY Other unusual presentarelation by Gass and 01son. 33 The authors reported intrations of sarcoidosis include serpiginous choroiditis 42 and retinal epithelioid cell nodules which, in some areas, birdshot-like chorio:retinopathy.43,44 extended from the retinal veins through the internal limiting membrane into the vitreous or beneath the RPE. Some retinal vessels appeared obliterated by the inflam- Neurosarcoidosis Posterior segment involvement may be accompanied by matory reaction. Severe retinal vasculitis and ischemic retinopathy with disease of the central nervous system in 25% to 30%.20,45 neovascularization, requiring scatter photocoagulation, Brinkman and Rothova'13 described six patients with neuhas been described in some patients. 22 ,30 Duker and col- rosarcoidosis and uveitis. All patients had posterior uveitis leagues 34 reported seven patients (11 eyes) with prolifera- or panuveitis consisting of multifocal chorioretinal letive sarcoid retinopathy. All of them displayed retinal sions, optic nerve granulomas (Fig. 63-11), periphleneovascularization. In addition, two eyes developed optic bitis, and papilledema. The neurologic features included disc neovascularization, and one developed rubeosis Babinski reflexes, spinal cord compression, myasthenia,

FIGURE 63-10. Viu"itis, -disc edema, disc neovascularization, nerve fiber layer hemorrhages, and multiple au"ophic chorioretinal lesions in sarcoidosis. (See color insert.)

FIGURE 63-1 I. Optic nerve granuloma in a patient with sarcoidosis. (See color insert.)

CHAPTER 63:

"schizophrenia," cranial nerve paresis (V, VII, XI, XII [VII being the most common]), hypothalamic-pituitary gland dysfunction, visual field loss, and normal pressure hydrocephalus. Optic atrophy with or without uveitis 20,46 and optic neuropathy 20, 47 have also been reported.

Orbit and Lids Although sarcoid granulomas have been described in several areas inside the orbit, the lacrimal gland appears to be the organ most commonly affected (Fig. 63-12). The frequency of lacrimal gland involvement varies from 7% to 69%.20-25 This range results from the diversity of criteria used in various studies, including palpable lacrimal gland enlargement, dry eye, and diagnosis by biopsy. Obenauf and colleagues20 and Rothova and colleagues 22 reported lacrimal gland involvement in 15.8% and 38%, respectively, of patients with ocular sarcoidosis and noted that it was more frequent among black patients. Dry eye can occur with or without palpable lacrimal gland enlargement,23 and histologic confirmation of the disease has been reported from a gland that was not palpable. 25 Obenauf and colleagues 20 reported bilateral acute dacryoadenitis in one patient, and nine patients who had bilateral lacrimal gland enlargement without any other ocular manifestations of sarcoidosis. The nasolacrimal drainage system (NLDS) may also become involved in patients with sarcoidosis. Dacryostenosis or total obstruction due to histologically proven sarcoidosis of the NLDS has been reported. 21 , 22, 48 The patients usually present with epipllora and nasal congestion that is due to coexistent paranasal and intranasal disease. 48 Extraocular muscle involvement can occur; it presents with diplopia or painful external ophthalmoplegia. 49 ,50 Evaluation of these patients by magnetic resonance imaging shows extraocular muscle enlargement; biopsy of the affected muscle is indicated to establish the diagnosis. Bilateral orbital, lid, and extraocular muscle involvement, together with thickening of the optic nerve sheath, has also been reported,51 Painless unilateral orbital swelling caused by sarcoid granulomas of the soft tissue around the eye outside the lacrimal gland was observed in two

TABLE 63-2. OCULAR MANIFESTATIONS IN .... A·..... E~I.-~ WITH SARCOIDOSIS MANifESTATION

PERCENT Of PATIENTS

Anterior segment Cor~junctival involvement Anterior uveitis Iris nodules Posterior synechiae Cataract Glaucoma Band keratopathy Posterior segment Vitritis Intermediate uveitis Panuveitis Posterior uveitis Retinal vasculitis Cystoid macular edema Optic nerve involvement Orbit Lacrimal gland involvement

85 6.9-70 22-70 11.4-12.5 20-26 4-35 4-33 4.5-11 25 3-62 16-38 9-30 12 9-34 19-72 7.4-34 26 7-69

REfERENCES

20-25 20, 22-25 20, 21, 23 21,24 20-25, 28, 29 20-25, 29, 30 20, 21, 23, 25 20,23, 24,30 22, 25, 30 20, 23, 24, 29, 20, 24

24 30 24 30

20-25

patients by Peterson and colleagues. 52 This regressed with oral prednisone therapy. Hunter and Foster24 described eyelid nodules in one of their 86 patients. A sUlnmary of the ocular manifestations in patients with sarcoidosis is shown in Table 63-2.

Sarcoidosis in Childhood Early onset or preschool sarcoidosis seen in children younger than 5 years of age is relatively rare. The classic triad of symptoms consists of skin, eye, andjoint lesions; pulmonary involvement is rare, at least initially. It can be easily misdiagnosed as juvenile rheumatoid arthritis (JRA), as the latter also presents with symptoms related to the joints and eyes. 53 ,54 However, children with JRAassociated uveitis usually suffer from pauciarticular arthritis, are antinuclear antibody (ANA) positive, and rarely develop skin lesions,55 whereas children with sarcoidosis usually develop polyarthritis, are ANA negative, have elevated serum ACE, and often exhibit skin lesions in the form of erythema nodosum. Sarcoidosis has been described in a 7-month-old child. 53 The ocular manifestations in children are similar to those seen in adults and include iridocyclitis, posterior uveitis, periphlebitis, macular edema, branch retinal vein occlusion, interstitial keratitis, and multiple corneal limbal nodules. 39, 56-59 Bilateral lower motor neuron facial palsy and bilateral hearing loss have also been reported. 60 Histologic diagnosis has been made by biopsy of parotid gland, lung, and cutaneous lesions. Ga scanning showed the typical "panda" appearance in a child of preschool age with posterior uveitis. 57 Oral steroids have been used with good response of the ocular inflammation and other symptoms.

Characteristic Presentations

fiGURE 63-12. Lacrimal gland enlargement in a patient with sarcoidosis. (See color insert.)

Heerfordt's syndrome (uveoparotid fever), described in 1909 by Heerfordt, consists of uveitis, parotitis, fever, and facial or other cranial nerve palsies. 3 It was not until 1936 that Bruins Slot linked the findings with sarcoidosis. 61 Lofgren's syndrome consists of erythema nodosum, fe-

CHAPTER. 63: SAR.COIDOSIS

brile arthropathy, and bilateral hilar lymphadenopathy. It was described by Lofgren in 1946 and is reported to be associated with a favorable prognosis. 52 The combination of salivary and lacrimal gland inflammatory enlargement with xerostomia is called Mikulicz's syndrmne. This term includes all forms of involvement of these glands including sarcoidosis, leukemia, and l)'luphoma.

probably representing large lysosomes contall1lng iron and protein material. They are not specific to sarcoidosis.

Kveim-Siltzbach Test

In 1941, Kveim reported the use of a suspension derived from the spleen of a patient with sarcoidosis that, when injected intracutaneously into patients with biopsy-proven sarcoidosis, yielded a cutaneous papule containing noncaseating epithelioid granulomas. 54 The test was later labeled the Kveim-Siltzbach (KS) test in recognition of HISTOLOGY Non-necrotizing (noncaseating) granulomas are the hall- Siltzbach's contributions. Four to 6 weeks after subcutanemark of sarcoidosis. Histiocytes, epithelioid cells, and ous injection of the KS reagent, the typical positive KS multinucleated giant cells make up the center of the lesion presents as a red or brownish raised papule ranggranuloma, surrounded by lymphocytes, plasma cells, and ing from a few millimeters to up to 1.5 em in diameter. fibroblasts in the periphery (Fig. 63-13). Gross necrosis Histopathologic analysis of the biopsied lesion reveals is not a feature of sarcoidosis, and suggests alternative a granuloma composed of epithelioid cells, occasional diagnoses (e.g., tuberculosis, fungal infection, vasculitis), Langhans' cells, and scattered lymphocytes at its center, but occasional granulomas may show central fibrinoid with a surrounding cuff of mononuclear cells, primarily necrosis. 53 The epithelioid cells are transformed bone lymphocytes. Pierard and colleagues 55 have suggested that marrow monocytes and are theiefore members of the the KS reaction parallels the evolution of pulmonary mononuclear phagocyte system. In contrast to luacro- sarcoidosis, with exuberant reaction during overt pulmophages, the epithelioid cells have marked secretory activ- nary granulomatous infiltration and a more bland reity that includes over 40 different cytokines and other sponse during chronic fibrotic disease. Positive KS tests mediators. Among the enz)'lues and other chemicals se- are reported in almost all patients with sarcoidosis who creted by granulomas are ACE, lysozyme, glucuronidase, present with erythema nodosum and hilar lyIuphadenop. athy with clear lung fields. collagenase, and calcitriol. The KS test has been reported to be positive in approxDeposits of immunoglobulins and various inclusion bodies, such as asteroid, Schaumann's bodies, or Wesen- imately 80% of patients with sarcoidosis, with less than berg-Hamazaki bodies, may be seen. They are found pre- 1% false-positive results when a properly prepared and dominantly within giant cells but niay be seen in the validated KS reagent is used. A negative result does not extracellular space. Asteroid bodies are seen in 2% to 9% exclude the diagnosis. Steroids suppress KS reactivity, and of cases, are formed from accumulations of cytoskeletal therefore the test should not be performed in patients filaments, and contain lipoprotein. Schaumann's bodies receiving systemic steroids or in those who will require are concentric, laminated, blue calcified structures. They treatment prior to the 4- to 6-week development period are seen in 48% to 88% of cases and indicate chronic of the KS lesion. In recent years, the KS test has fallen into disuse begranulomatous disease. Schaumann's bodies represent accumulations of oxidized lipid within lysosomes. Wesen- cause of the potential risks inherent in the use of human berg-Hamazaki bodies, observed in 11 % to 68% of lymph tissue (transmission of infectious agents such as hepatitis nodes with sarcoidosis, are giant lysosomes and are usu- B, human immunodeficiency virus, and the virus of the ally present extracellularly or within macrophages. They CreutzfeldtJakob syndrome), 55 the meticulous care reare yellow, ovoid, periodic acid-Schiff-positive inclusions, quired for the production and validation of the KS reagent, and the evolution of other diagnostic techniques to assess patients suspected of having sarcoidosis, such as BAL, Ga scanning, chest CT scanning, and measurement of serum ACE.

Cutaneous Anergy

FIGURE 63-13. Non-necrotizing granuloma in sarcoidosis. Histiocytes, epithelioid cells, and multinucleated giant cells are surrounded by lymphocytes, plasma cells, and fibroblasts. (See color insert.)

In 1916, Boeck first described cutaneous anergy to tuberculin in patients with sarcoidosis. 5 Later it was realized that this phenomenon was not limited to tuberculin alone, but that anergy to a variety of other skin test antigens such as Candida, mumps protein, streptococcal protein, and tetanus toxoid was also typical. In 1994, Kataria and Holter proposed a mechanism for the cutaneous anergy seen in sarcoidosis. 57 Compartmentalization of the immune response is well recognized in sarcoidosis. At sites of granulomatous inflammation, there is a predominance of T-helper l)'luphocytes, which proliferate and secrete large amounts of lymphokines, including interleukin (IL)-2, monocyte chemotactic factor (MCF) , and migration inhibition factor (MIF). These lymphokines induce and amplify the immune response by en-

CHAPTER 63: SARCOIDOSIS

hal1Cing T-Iymphocyte proliferation as well as by recruiting and retaining monocytes from the circulation. The concentration of lymphokines and monokines produced at sites of granulomatous inflammation is highest locally. Nevertheless, the protein molecules diffuse into blood, establishing a concentration gradient between the granulomatous inflammatory site and the remote site of the delayed-type hypersensitivity (DTH) skin test. As a result, the traffic of T-helper lymphocytes and monocytes is preferentially directed toward sites of granuloma formation. That leads to a preponderance of suppressor cells in the peripheral blood and competitively depletes the T-helper cells and monocytes available to sites of DTH. Although the initial cellular influx of DTH is similar to that of the early stages of granulomatous inflammation, the availability of the deposited antigen is only transient, and the DTH response must compete for the same cellular elements at multiple granulomatous sites in the body. The granulomatous sites have the advantage of steeper cytokine gradients to attracfT-helper cell and monocyte traffic. As a result, comparatively few cells migrate to the site of soluble recall antigens. Cutaneous anergy therefore is an epiphenomenon of active sarcoidosis, a nonspecific process that is seen in other granulomatous inflammations and that resolves when the underlying granulomatous disease activity wanes. Collagen alteration has been noted atKS antigen injection sites,68 but not in normal volunteers injected with KS antigen,69 suggesting that these collagen changes are limited to patients with sarcoidasis who harbor cognate lymphocytes. In patients with sarcoidosis, the antigen may bind to the altered collagen, immobilizing lymphocytes at the injection site for a focused immune response. Of particular interest is the initial mononuclear cell influx with T-helper lymphocytes and monocyte-macrophages, a process pathologically analogous to the mononuclear cell alveolitis that antedates granuloma formation in the lung.

ETIOLOGY

PATHOGENESIS

The processes involved in the pathogenesis of sarcoidosis in the lungs include accumulation of CD4 + lymphocytes at the affected site. The cytokines and factors secreted by these cells account for the influx of monocytes, alveolitis, and noncaseating granuloma formation in the lung, and for the resulting progressive fibrosis, all characteristic features of pulmonary sarcoidosis. Sarcoidosis is characterized by "compartmentalization" of the T cells, such that the relative proportion of CD4 + T cells in blood is reduced (e.g., CD4/CD8 = 0.8), while the reverse relation is observed in affected tissue (e.g., CD4/CD8 = 1.8 in lung). The CD4 + cells in the involved organs are "activated" and thus are releasing IL-2 and other mediators, while the CD4 + cells in other sites, such as blood, are quiescent. The result systemically (among other consequences) is a generalized immunologic dysregulation, as evidenced by hyperglobulinemia, autoantibody production, and impairment of T-cell-mediated DTH responses (anergy) . In 1992, Holter and colleagues 69 demonstrated a Kveim-like granulomagenic activity in nonviable autologous BAL cells (NABC) recovered soon after symptomatic onset or relapse of sarcoidosis, but not in patients with

chronic stable sarcoidosis. The authors suggested that macrophages bearing the putative granulomagenic factor become tightly interdigitated into the granuloma matrix as they differentiate into epithelioid cells, rendering theln unrecoverable by lavage. This is consistent with the "walling-off" function of granulomatous inflammation. The same· group of investigators demonstrated a Kveim-like granulomagenic activity of peripheral blood monocytes, the progenitors of the alveolar macrophage. 68 These findings suggest that the circulating monocyte is already primed with the granulomagenic factor before differentiation into alveolar macrophage. A monocyte source of the factor explains the multisystem distribution of granulomas in sarcoidosis. Consistent with these findings are recent reports of sarcoidosis recurring in recipients of allogeneic normal lung transplants 70 . and the development of sarcoidosis in the recipient of bone marrow harvested from a patient with sarcoidosis. 71 This evidence indicates that antigen processing and presentation triggers the T-lymphocyte activation and proliferation in the first place. Lymphocyte activation and proliferation antedate granuloma formation at the KS skin test sites and in the lung, and granulomagenic activity has been shown in autologous monocyte-macrophage preparations. These findings suggest that sarcoidosis represents a unique type of autoimmune disease, in which a monocyte-associated autoantigen is attacked by cellmediated immune mechanisms rather than by the traditional humoral ones. 68

Chest Radiology Sulavik and colleagues 72 suggested the following roentgen staging of sarcoidosis: 0 = normal chest radiograph; 1 = bilateral symmetric hilar lymphadenopathy (BSHL) only; 2 = BSHL with bilateral symmetric lung infiltration (Fig. 63-14); 3 = bilateral symmetric lung infiltration only; 4a = BSHL with bilateral symmetric lung infiltration indicative of pulmonary fibrosis (BSIF); and 4b = BSIF only (Table 63-3). Roentgen findings used to

FIGURE 63-14. Chest x-ray study in a patient presenting with uveitis showing bilateral symmetric hilar lymphadenopathy and bilateral lung infiltration.

63: SARCOIDOSIS TABLE 63-3. RADIOGRAPHIC STAGING Of PULMONARY SARCOIDOSIS STAGE

o 1 2 3 4a 4b

FINDINGS Normal chest radiograph Bilateral symmetric hilar lymphadenopathy (BSHL) only BSHL with bilateral symmetric lung infiltration Bilateral symmetric lung infiltration only BSHL with bilateral symmetric lung fibrosis Bilateral symmetric lung fibrosis only

Adapted from Sulavik SB, Spencer RP, Palestro q, et al: Specificity and sensitivity of distinctive chest radiographic and/or 67Ga images in the noninvasive diagnosis of sarcoidosis. Chest 1993;103:403.

indicate pulmonary fibrosis include (1) bilateral, usually mid- and upper lung fieldfibrobullous change; (2) bilateral retraction of fissures or hila upward, associated with significant volume loss; and (3) bilateral "honey-combing," defined as well-demarcated ringlets approxilnately 3 to 12 mm in diameter. The clinical use of stage 4 has been disputed by other authors, as identification of this stage may be inconsistent between observers. A worldwide survey reported in 1976 73 revealed the following frequencies of lung involvement in 3654 patients: stage 0 = 8%; stage 1 = 51 %; stage 2 = 29%; stage 3'= 12%. The lymphadenopathy in sarcoidosis is primarily hilar, with frequent involvement of the, right paratracheal chain. Involvement of the other mediastinal lymph nodes, and particularly the anterior medi~stinal ones, should lead to consideration of other diseases (e.g., lymphoma or metastatic malignancy).· A recent report has evaluated the use of CT and mediastinoscopy in the diagnosis of sarcoidosis. 74 CT is superior to plain roentgenograms as the mediastinum, as well as the lung parenchyma, can be better visualized.

Gallium Scan A gallium scan (67Ga) is performed 48 to 72 hours after intravenous injection of 5 to 8 mCi 67Ga citrate. Abnormal uptake is assessed in relation to liver activity. Although it has been suggested that activated lymphocytes and macrophages playa role in the localization of 67Ga, the exact mechanism of 67Ga uptake is not well known. A whole-body 67Ga scan is recommended in the evaluation of patients with suspected sarcoidosis, as there have been reports of extrapulmonary uptake. 75 It is also valuable in localizing sites for possible biopsy and may reduce the need for more invasive diagnostic procedures. Karma and colleagues21 reported that only 4 of 12 patients with chronic ophthalmic changes had increased 67Ga uptake over the orbits, and they thus concluded that (limited) 67Ga scanning was not valuable in the assessment of activity of chronic sarcoidosis. Sulavik and colleagues 76 have called the combined abnormal bilateral symmetric 67Ga uptake of the lacrimal and parotid glands (with or without submandibular gland 67Ga uptake) as·the "panda" image or pattern (Fig. 6315). The presence and pattern of 67Ga uptake in both (1) the .parahilar and infrahilar bronchopulmonary lymph nodes and (2) the right paratracheal (azygous) mediastinal lymph nodes is called the "lambda" image after its

resemblance to the Greek letter 'A.. The "lambda" pattern has been reported in 72% of patients with sarcoidosis but in none of 540 patients with other diseases. 76 Sulavik and colleagues 72 also reported that a "lambda" image (usually associated with a "panda" image) or a "panda" 67Ga uptake image together with BSHL or BSIF on chest radiography are highly specific in the noninvasive diagnosis of sarcoidosis. Pulmonary uptake of 67Ga is sensitive but not specific in the diagnosis of pulmonary sarcoidosis, as it can occur in a wide variety of other inflammatory and neoplastic diseases. Abnormal 67Ga uptake in salivary and lacrimal glands may also occur in Sjogren's syndrome and tuberculosis, and after radiation therapy. However, the combination of raised serum ACE and positive 67Ga uptake increases the specificity to 99%77, 7S and the sensitivity to 73%.7S Weinreb and colleagues 79 reported positive limited 67Ga uptake in patients with granulomatous uveitis with and without elevated serum ACE.

Angiotensin Converting Enzyme ACE cleaves the terminal dipeptide histine-Ieucine from the C-terminus of angiotensin I, converting it to angiotensin II. ACE is normally present in the vascular endothelium of many organs (lung, kidney, small intestine, uterus, prostate, thyroid, testes, adrenals) and in macrophages. It is the latter &ource that is thought to be responsible for elevated ACE levels in patients with sarcoidosis, reflecting granuloma "load." The induction of ACE synthesis in epithelioid cells and macrophages is caused by a soluble ACE-inducing factor (AlF). AlF activity has been detected in vivo in serum· and BAL fluid of patients with active sarcoidosis, and has been generated in vitro by co-culture of monocytes with autologous T lymphocytes, where the activity was present in the cell-free media. so In healthy controls, serum ACE is age dependent; individuals younger than 21 years of age have higher levels than those older than 21 years. S1 ACE is elevated in 60% to 90% of patients with active sarcoidosis. A normal serum ACE does not exclude the diagnosis, especially if the disease is in its early stages and localized to a small area (e.g., the eye), and therefore has a small epithelioid cell population. False low values are also measured in patients taking ACE inhibitors or in patients with endothelial abnormalities, such as deep vein

FIGURE 63-1 S. Panda sign in a patient with sarcoidosis. Bilateral symmetric 67Ga uptake of the lacrimal, parotid, and submandibular glands.

CHAPTER 63: SARCOIDOSIS

thrombosis, and in patients who have had chemotherapy or radiation. Treatment with systemic steroids or other immunosuppressive agents can also affect ACE levels, with values normalizing when there is adequate control of intraocular inflammation. Other disorders associated with elevated serum ACE include Gaucher's disease, leprosy, chronic pulmonary disease, rheumatoid arthritis, spondylitis, primary biliary cirrhosis, tuberculosis, histoplasmosis, histiocytic medullary fibrosis, hyperthyroidism, and diabetes mellitus (Table 63-4). However, most of these are not associated with uveitis, with the exception of tuberculosis, leprosy,and histoplasmosis. A careful history and ophthalmologic and systemic examination combined with other appropriate investigations should help to distinguish between these disorders. Serum ACE levels probably parallel the total body mass and activity of granulomas. Its levels may vary throughout the disease course in patients with chronic uveitis, from normal to elevated, reflecting underlying disease activity.32 ACE may not be elevated in patients with subclinical disease even in the presence of active uveitis. Karma and colleagues 21 reported that serum ACE was elevated in a significantly larger number of patients with ophthalmic sarcoidosis than with isolated pulmonary sarcoidosis or resolved disease. Power and colleagues 78 reported a sensitivity of an initially raised serum ACE in diagnosing sarcoidosis of 73% and a specificity of 83%. The sensitivity can increase to 84% and the specificity to ~5% when ACE levels of greater than 50 units/liter (i.e., the mean plus the standard deviation) are used. 81 Power and colleagues 78 found no association between ocular disease activity and initial serum ACE levels. They found elevated ACE in patients with uveitis caused by other diseases including Adamantiades-Beh<,;:et disease, HLA-B27-associated uveitis, syphilis, systemic lupus erythematosus, JRA, tuberculosis, sympathetic ophthalmia, acute retinal necrosis, intraocular lymphoma, birdshot chorioretinopathy, Lyme disease, Vogt-Koyanagi-Harada syndrome, and Wegener's granulomatosis.

TABLE 63-4. FREQUENCY OF INCREASED SERUM ANGIOTENSIN-CONVERTING ENZYME IN DISEASES OTHER THAN SARCOIDOSIS DISEASE Gaucher's disease Hyperthyroidism Berylliosis Silicosis Leprosy Primary biliary cirrhosis Cirrhosis Diabetes mellitus Histoplasmosis Asbestosis Allergic alveolitis Tuberculosis Coccidioidomycosis Pulmonary fibrosis Hodgkin's disease

PERCENT Of PATIENTS

90 70 44 42 34 24

23 22 16 15 9

7 6 5 5

ACE levels in tears have been reported to be elevated in patients with ocular sarcoidosis; however, the test is not specific for sarcoidosis. 82 Weinreb and colleagues83 reported on the value of measuring ACE levels in aqueous humor of patients with granulomatous uveitis and suspected sarcoidosis. The authors found high aqueous ACE levels in these patients, compared with controls; they also reported one patient in whom the serum ACE was normal but the aqueous humor ACE was elevated.

Pulmonary Function Tests Pulmonary function tests are useful in the initial diagnosis and follow-up of patients with sarcoidosis. Their sensitivity in disease with and without radiographic evidence of parenchymal involvement has been reported as 70% and 40%, respectively. The most common abnormalities seen early in the course of the disease are an increase after exercise in the alveolar-arterial oxygen gradient and diffusing capacity and a reduction in lung compliance. Moderate parenchymal involvement is associated with reduced inspiratory capacity, reduced total lung capacity, decreased diffusing capacity at rest, widened alveolararterial oxygen gradient, decreased partial pressure of oxygen in the blood, and increased respiratory rate. Late stages may be complicated by airways distortion, which may manifest as obstructive lung disease. Pulmonary hypertension is a late manifestation seen in a slnall proportion of patients.

Bronchoalveolar lavage The introduction of the fiberoptic bronchoscope in the early 1970s facilitated the study of the inflammatory process involved in sarcoidosis by the use of BAL. The earliest pathologic finding in patients with sarcoidosis is a mononuclear alveolitis composed of increased CD4 + lymphocytes (with an increased CD4/CD8 ratio), monocyte-macrophages, and rare B lymphocytes. Indirect evidence of heightened antigen-mediated activity is apparent from increased percentages of alveolar macrophages expressing DR antigens and increased density of human leukocyte antigen D surface antigens on sarcoid alveolar macrophages. In addition, lymphocytes rosetting about macrophages are seen in BAL speciInens and· in cells sloughed from in vitro-cultured intact sarcoid granulomas. Sarcoid alveolar macrophages express increased intercellular adhesion molecules (ICAM-l) and leukocyte function-associated antigen (LFA-l) to facilitate the process. Lung macrophages spontaneously release IL-I. BAL lung T cells and in vitro-cultured intact cutaneous sarcoid granulomas spontaneously release IL-2. These finding suggest that active antigen presentation is central in the pathogenesis of sarcoidosis. The consequence of antigen presentation to specific T lymphocytes is amplification of the irn,.mune response through proliferation of T lymphocytes and their production of cytokines. Monocytes are the predominant cellular resource required for granuloma architecture. Lung T lymphocytes produce about 25 times more MCF per cell than the autologous peripheral blood T lymphocytes. Another lymphokine, MIF, prevents the migration of monocyte-macrophages accumulated at the site of the granuloma formation. In

CHAPTER 63: SARCOIDOSIS

addition, the supernatants of sarcoid skin granulomas contain an inhibitor of monocyte leukotaxis with properties similar to the leukotactic inhibitor in the plasma of untreated sarcoid patients. Recruited monocytes become activated, and sequentially differentiate into macrophages, epithelioid cells, and Langhans' giant cells. Further development of granuloma structure appears to require the induction of interepithelioid adhesion molecules such as LFA-1 and ICAM1. Interferon (INF)-')' mediates the process and is known to be increased at sites of disease activity in sarcoidosis. Moller and colleagues84 found dominant T H 1 cytokine expression in BAL patients from patients with sarcoidosis. T H 1 cells is the subgroup of CD4+ T cells that mediate cellular immune responses, characteristically during infections caused by intracellular bacteria. They produce IL-2, INF-')', and tumor necrosis factor (TNF)-I3.

for calcitriol. Calcitriol promotes the differentiation of monocyte-macrophages, stimulates the proliferation of blood monocytes, and favors the formation of multinucleated giant cells. Calcitriol also enhances the cytotoxic function and mycobacterial killing of monocytes and their production of IL-1, TNF, and prostaglandin E 2 • Hypercalciuria is two to three times more common than hypercalcemia and is assessed by 24-hour urinary calcium determination. Hypercalcemia is always associated with hypercalciuria, while hyperca1ciuria may be present without hypercalcemia. 89 Persistent hypercalcemia is associated with risk of nephrocalcinosis 18 and is an indication for treatment. Systemic steroids are effective in normalizing serum calcium levels usually within 2 weeks, and they decrease serum ca1citriol levels even faster. 89 Patients with hypercalcemia should be advised to avoid a high calcium diet, vitamin D supplements, and exposure to sunlight.

Transbronchial lung Biopsy Tissue for biopsy from the bronchial mucosa or the adjacent lung is obtained through a fiberoptic bronchoscope. The procedure does not require general anesthesia, has a low complication rate, and is comfortable for the patient. The specimens obtained are slnall, but special fixation techniques permit accurate histologic diagnosis in most cases. 85 Gilman and Wang86 recommended that four. biopsies, obtained at each bronchoscopy, increased the diagnostic yield to 90%. Noncaseating granulomas have been reported in 54% to 88% of patients who underwent transbronchiallung biopsy (TBLB) .8~ 87. The rate of positive findings by TBLB is higher in patients with radiologic evidence of pulmonary infiltration, and it, is approximately 60% among patients with hilar lymphadenopathy whose chest radiographs show normal lung parenchyma. 85 Leonard and colleagues87 reported that simultaneous TBLB, transbronchial needle aspiration, and BAL gave a diagnostic sensitivity of 100% in the 13 patients examined. TBLB has been reported to show noncaseating granulomas in 37 of 60 patients (61.7%) with intraocular inflammation compatible with a diagnosis of sarcoidosis, who did not show bilateral hilar lymphadenopathy and had sparse contributory evidence for sarcoidosis. 88 The authors reported no complications apart from segmental pneumothorax in one patient.

Hypercalcemia Hypercalcemia has been reported in 10% to 15% of patients with sarcoidosis and is related to increased serum concentrations of 1,25-dihydroxy-vitamin D 3 (calcitriol). Hypercalcemia is not specific for sarcoidosis alld is seen in other granulomatous diseases such as tuberculosis, leprosy, coccidioidomycosis, histoplasmosis, and berylliosis. Calcitriol is produced at sites of active disease by alveolar macrophages and possibly T lymphocytes. 89 Elevated serum levels of calcitriol in hypercalcemic patients with sarcoidosis lead to increased absorption of calcium and phosphate from the gastrointestinal tract, which leads to hypercalcemia and hypercalciuria. Recent studies have shown a role of calcitriol in modulating the immune response. Activated lymphocytes and cells of monocyte-macrophage lineage express receptors

lysozyme Lysozyme is an enzyme normally secreted by monocytes and polymorphonuclear leukocytes. In healthy controls, serum lysozyme levels are age dependent, with an increase seen. in subjects over 60 years of age. 81 Several reports have shown that the levels of serum lysozyme are raised in patients with sarcoidosis and may be related to disease activity. Raised lysozyme levels have been reported in parallel to raised serum ACE levels. It is thought that the epithelioid cell of the sarcoid granuloma is the source for both lysozyme and ACE. In contrast to ACE, the lysozyme concentration is also high in patients with erythema nodosum. 89 The values of both biochemical markers return to normal levels with successful treatment of sarcoidosis. Abnormal values of serum lysozyme have been reported in tuberculosis, silicosis, asbestosis, and berylliosis. Baarsma and colleagues 81 reported that a lysozyme level of more than the mean plus two standard deviations has a sensitivity of 60%, a specificity of 76%, and a predictive value of only 12%. The predictive value of a positive test of 100% was reached at lysozyme levels seven standard deviations above the mean. The authors concluded that lysozyme levels have a limited value in the diagnosis of sarcoidosis. Other biochemical markers used in the investigation of patients suspected of having sarcoidosis include 132microglobulin, IL-2 receptors, hyaluronan, fibronectin, collagenase, histamine, and platelet-activating factor. These have not been studied in relation to eye disease.

Tissue Biopsy Conjunctival Biopsy Conjunctival biopsy is of particular importance in everyday clinical practice because the tissue is easily accessible, the procedure is simple, and there is a low complication rate. The lower fornix is the preferred site and topical anesthesia is sufficient. The technique usually consists of retraction of the lower lid and excision of a strip of stretched conjunctiva with Westcott scissors. Topical antibiotic is instilled and pressure is applied for 5 to 10 Inin to avoid hemorrhage and soft-tissue edema. The optimal

CHAPTER 63: SARCOIDOSIS

size of biopsy is approximately 1 cm long by 3 mm wide. No suturing is required. Although there have been no reports of infection or symblepharon, Karma and colleagues 21 noted minute scars at the site of the previous conjunctival biopsy in some patients. The efficacy of the technique in the diagnosis of sarcoidosis remains controversial. The positive yield of conjunctival biopsy ranges from 14% to 40.4% and is based on studies performing unilateral or bilateral biopsies in patients with histologically confirmed nonocular sarcoidosis, sarcoidosis suspects, patients with and without ocular involvement, and patients who had or had not been initiated on treatment for their disease. 21 , 26, 90-92 Spaide and Ward90 reported positive biopsies in 19 of 47 untreated patients (40.4%) and described higher yield in patients with follicles, those with ocular abnormality consistent with sarcoidosis, and those with pulmonary infiltrates. Crick and colleagues 25 also reported higher yield in patients with follicles and those with histologically confirmed nonocular sarcoidosis. Clinical interpretation of nodules may be difficult, as true sarcoid granulomas may be too small to be detected with slit-lamp examination, whereas more prominent nodules may turn out to be large follicles, an ectopic lacrimal gland, or foreign body fibrosis rather than noncaseating granulomas. These observations have led some investigators to perform blind (nondirected)hiopsy, which has been reported to be positive in 55% to 71.4% of patients with biopsy-proven extraocular sarcoidosis 92 ,26 and in 28.5% of patients with suspected sarcoidosis. 26 Repeat tiopsy may be useful in patients in whom the initial biopsy was negative, as it can be positive, revealing a previously false-negative result. 21 Furthermore, bilateral conjunctival biopsies with examination of multiple sections of each specimen are also recommended, as granulomas may be present in limited numbers, so they may be missed if the number of sections is not adequate. 92

Lacrimal Gland Biopsy Lacrimal gland biopsy is considered in patients with clinically enlarged lacrimal glands and in those with positive 67Ga uptake by the lacrimal glands. The biopsy can be performed either through a conjunctival or external (skin) approach. Transconjunctival biopsy of the palpebrallobe carries the risk of damage of the lacrimal gland ductules, which may lead to dry eye syn.drome.

Skin Biopsy As mentioned, skin lesions in sarcoidosis may be specific, showing histologically noncaseating granulomas such as lupus pernio, maculopapular eruptions, andsubcutaneous nodules, or nonspecific (e.g., erythema nodosum). Biopsy of coexisting skin lesions is indicated in patients with ocular findings suggestive of sarcoidosis so that a histologic diagnosis can be made.

DIAGNOSIS The definitive diagnosis of sarcoidosis requires histologic confirmation. Sometimes, sarcoidosis may manifest itself first in the eye, with uveitis, and clinically detectable extraocular manifestations may evolve slowly over several years. 22 Pursuit of such "sarcoid suspects," we believe,

should be vigorous and should be repeated annually, despite the bias of health maintenance organization "gate keepers" toward economy and parsimony, because the disease carries generally poor ocular prognosis, and one may well be faced with the decision about long-term immunomodulatory therapy. Clearly, a commitment to long-term therapy is best made in the context of a clear, definite diagnosis. The evaluation of patients with uveitis caused by suspected sarcoidosis can be staged from noninvasive laboratory and radiologic tests to invasive ones, depending on the ease or difficulty of diagnosis. Initial assessment consists of chest radiograph, serum ACE, lysozyme, serum and urine calcium, and liver enzymes. At this stage, biopsy of clinically suspicious, easily accessible tissue (conjunctiva, skin) is advised. If these initial studies are negative, chest CT, whole-body 67Ga scan, and pulmonary function tests should be performed. Chest CT and whole-body 67Ga scan are advised in the presence of elevated serum ACE, lysozyme, or serum and urine calcium. If the chest radiograph, chest CT, or 67Ga scan findings are characteristic of sarcoidosis, BAL and TBLB are advised. Open lung biopsy is reserved for patients with radiologic evidence of sarcoidosis in whom histologic proof is lacking despite systematic evaluation as previously outlined. An algorithm of the assessment of patients with suspected sarcoidosis is given in Figure 63-16.

DIAGNOSIS The differential diagnosis of ocular sarcoidosis depends on the primary anatomic site involved. Sarcoidosis may simulate anterior, intermediate, and posterior uveitis and those uveitides associated with vitritis and multiple chorioretinal lesions such as multifocal choroiditis, birdshot retinochoroidopathy, Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, tuberculosis, syphilis, toxoplasmosis, serpiginous chorioretinopathy, lymphoma, leukemia, and Whipple's disease (Table 63-5). A solitary choroidal mass appearing in an eye with sarcoidosis must be differentiated from metastatic tumor or a choroidal melanoma. Similarly, an optic nerve mass in a patient with sarcoidosis can be differentiated from a solitary granuloma due to tuberculosis or leprosy by a careful review of systems and skin testing with purified protein derivative. Central nervous system involvement secondary to sarcoidosis producing increased intracranial pressure and papilledema must be differentiated from other space-occupying lesions such as neoplasia or infections. Proliferative sarcoid retinopathy is distinguishable from other potential causes of retinal ischemia with neovascularization, such as Adamantiades-Beh<;;et disease, central retinal vein occlusion, diabetes mellitus, and sickle-cell retinopathy, based on careful clinical examination and ocular and systemic history. Periphlebitis appearing in sarcoidosis needs to be differentiated from that seen in multiple sclerosis, systemic lupus erythematosus, Eales' disease, and frosted branch angiitis. Finally, vitritis, together with focal or multifocal chorioretinal involvement, are features common to both sarcoidosis and many of the posterior uveitic entities listed in Table 63-5. For example, both sarcoidosis and birdshot retinochoroidopathy manifest vitritis and vasculitis, and the appearance of the choroidal

63: SARCOIDOSIS

Initial studies Chest X-Ray Angiotensin converting enzyme Lysozyme Serunl and urine calcium Intradermal skin tests Liver enzymes Biopsy of rash or conjunctival nodule

Positive studies

Negative studies

FIGURE 63-16. Algorithm for evaluation of patients with suspected sarcoidosis.

Chest spiral CT or 67 Ga scan

Chest spiral CT or 67 Ga scan Pulmonary function tests

Positive studies Bronchoalveolar lavage and Transbronchiallung biopsy or Open lung biopsy

granuloma seen in ocular sarcoid may be confused with typical birdshot lesions.

Ocular sarcoidosis is a potentially blinding disease that warrants aggressive treatment. 21 , 22,93 Mild anterior uveitis is treated by topical steroids and cycloplegics. Crick and colleagues 25 reported that prompt use of systemic steroids may save vision in patients with severe inflammation of the posterior segment. They noted that topical steroids were ineffective in posterior uveitis and reported one patient (who received only that treatment) who went totally blind within weeks of the onset of symptoms. Systemic steroids are indicated in anterior uveitis that does not respond to topical steroids, and in patients with posterior uveitis, neovascularization, or orbital disease with visual symptoms or optic nerve compromise. Peribulbar steroids may also be useful. Patients who are refractory to steroids may respond to the addition of oral nonsteroidal anti-inflammatory drugs. If inflammation persists, immunosuppressive chemotherapy may be required. Successful results have been reported with aza-

thioprine, cyclosporine, and cyclophosphamide. 21 • 28, 30 Dev and colleagues94 reported that low-dose methotrexate was effective in controlling previously uncontrolled inflammation in 20 eyes from 11 patients with sarcoidosisassociated panuveitis, allowed elimination of corticosteroids in certain patients, and permitted successful cata-

TABLE 63-5. DiffERENTIAL DIAGNOSIS Of SARCOIDOSIS Anterior uveitis Posterior uveitis HLA-B27-associated iridocyclitis Toxoplasmosis Fuchs' heterochromic cyclitis Toxocariasis Herpes simplex virus Histoplasmosis Tuberculosis Varicella zoster virus Syphilis Syphilis Tuberculosis Birdshot retinochoroidopathy Juvenile rheumatoid arthritis Serpiginous choroidopathy Idiopathic Vogt-Koyanagi-Harada syndrome Intermediate uveitis Intraocular lymphoma Pars planitis Sympathetic ophthalmia Adamantiades-Behyet disease Multiple sclerosis Whipple disease Lyme borreliosis

CHAPTER 63: SARCOIDOSIS

ract surgery in patients in whom it had previously been impossible. Guidelines on the preparation of patients with sarcoidosis for cataract surgery have been described by Akova and Foster. 28 The preoperative medications employed by these investigators included periocular steroids (71 %), systemic nonsteroidal anti-inflammatory drugs (71 %), oral prednisone (57%), azathioprine (7%), and cyclosporine (7%). Secondary glaucoma not responding to medical treatment has been treated by trabeculectomy and cryoablative therapy. 28, 30 Laser trabeculoplasty and conventional filtering procedures are usually not effective in these patients. Drainage devices or trabeculectomy enhanced by antimetabolites may be necessary. Retinal neovascularization with evidence of ischemia on angiography responds well to panretinal photocoagulation. 22 , 30, 34 Topical injection of steroids has been used successfully in the management of large sarcoid iris nodules. 27

COMPLICATIONS As mentioned, posterior segment involvement in sarcoidosis is associated with more severe visual loss than is anterior segment involvement. 21 ,22 The major cause of poor visual outcome in these patients is macular pathology (CME, epiretinal membrane, macular hole). Optic atrophy may occur either in association with uveitis Qr in patients with sarcoidosis of the central nervous system. Secondary glaucoma is another important cause of visual loss in patients with sarcoidosis and may be the result of "trabeculitis," angle closure irom peripheral anterior synechiae, or postelior syTlechiae and formation of iris bombe, or it may be steroid induced. 23 , 28 Vitreous hemorrhage secondary to retinal neovascularization can also cause visual morbidity. Cataract and vitreous opacities may be managed by cataract extraction and vitrectomy. Visually significant band keratopathy may require its removal with chelating agents.

PROGNOSIS In 1996, Rothova and colleagues93 reported that sarcoidosis was the leading systemic disease associated with unilateral blindness, seen in 8 of 56 patients (14%). Severe visual loss (20/200 or less) has been reported in 6% to 23.8% of patients with ocular sarcoidosis and is more common in patients with chronic posterior uveitis. 21 ,22 Glaucoma is another complication leading to significant visual loss in these patients. 23 , 28 Dana and colleagues 30 reported that visual acuity worse than 20/40 was related to black race, delay of more than 1 year between onset of symptoms and presentation to a uveitis subspecialist, development of glaucoma, and presence of posterior or intermediate uveitis. Akova and Foster 28 reported that visual acuity worse than 20/40 was seen in 39% of patients with ocular sarcoidosis following cataract extraction and lens implantation. The causes of reduced visual acuity were CME, epiretinal membrane, glaucomatous optic nerve damage, central retinal vein occlusion, and peripapillary neovascularization secondary to optic disc granuloma.

CONCLUSIONS Ocular involvement occurs in 26% to 50% of patients with confirmed diagnosis of sarcoidosis and, when· pres-

ent, is generally seen early in the course of disease. The ocular manifestations are variable, as any part of the eye and the other orbital structures can be affected. All patients who present with uveitis, lid lesions, proptosis, extraocular nerve palsies, or optic nerve disease should be assessed carefully with a complete review of systems and appropriate radiologic, serologic, and other ancillary tests as outlined in the Diagnosis section so that sarcoidosis is excluded. Histologic confirmation of sarcoidosis should be sought in patients with clinical or other evidence suggestive of the disease. Periodic reevaluation is advised in patients with chronic uveitis in whom the initial investigations are negative. Persistent ocular sarcoidosis is vision robbing and may lead to blindness. Aggressiveness of treatment should be adjusted according to the type and nature of the ocular manifestations and may range from short courses of topical corticosteroids to long-tenn immunomodulation.

References

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CHAPTER 63: SARCOIDOSIS 21. Karma A, Huhti E, Poukkula A: Course and outcome of ocular sarcoidosis. AmJ OphthalmolI988;106:467. 22. Rothova A, Alberts C, Glasius E, et al: Risk factors for ocular sarcoidosis. Doc Ophthalmol 1989;72:287. 23. Jabs DA, Johns CJ: Ocular involvement in chronic sarcoidosis. Am J Ophthalmol 1986;102:297. 24. Hunter DG, Foster CS: Ocular manifestations of sarcoidosis. In: Albert DM,Jakobiec FA, eds: Principles and Practice of Ophthalmology. Philadelphia, W.B. Saunders, 1994, pp 443-450. 25. Crick RP, Hoyle C, Smellie H: The eyes in sarcoidosis. Br J Ophthalmol 1961;45:461. 26. Karcioglu ZA, Brear R: Conjunctival biopsy in sarcoidosis. Am J OphthalmolI985;99:68. 27. Mader TH, Chismire KJ, Cornell FM: The treatment of an enlarged sarcoid iris nodule with injectable corticosteroids. AmJ Ophthalmol 1988;10.6:365. 28. Akova YA, Foster CS: Cataract surgery in patients with sarcoidosisassociated uveitis. Ophthalmology 1994;101:473. 29. Lardenoye CWTA, Van del' Lelij A, de Loos WS, et al: Peripheral multifocal chorioretinitis. A distinct clinical entity? Ophthalmology 1997;104:1820. 30. Dana M-R, Merayo-Lloves J, Schaumberg DA, et al: Prognosticators for visual outcome in sarcoid uveitis. Ophthalmology 1996;1 03: 1846. 31. Vrabec TR, Augsburger lJ, Fisher Dl-i, et al: Taches de bougie. Ophthalmology 1995;102:1712. 32. Stavrou P, Linton S, Young DW, et al: Clinical diagnosis of ocular sarcoidosis. Eye 1997;11:365. 33. Gass JDM, Olson CL: Sarcoidosis with optic nerve and retinal involvement. Arch Ophthalmol 1976;94:945. 34. Duker JS, Brown GC, McNamara JA: Proliferative sarcoid retinopathy. Ophthalmology 1988;95:1680. 35. Wolfensberger TJ, Herbort CP: Indocyanine green. angiographic features in ocular sarcoidosis. Ophthalmolo'gy 1999;106:285. 36. Gragoudas ES, Regan CDJ: Bilateral subretinal neovascularization in presumed sarcoidosis. Arch Ophthalmol 1981;99:1194. 37. Inagaki M, Harada T, Kiribuchi T, et al: Sub~veal choroidal neovascularization in uveitis. Ophthalmologica 1996;210:229. 38. Dodds EM, Lowder CY, Barnhorst DA, et al: Posterior scleritis with annular ciliochoroidal detachment. AmJ Ophthalmol1995;120:677. 39. Ohara K, Okubo A, Sasaki H, et al: Branch retinal vein occlusion in a child with ocular sarcoidosis. AmJ Ophthalmol1995;119:806. 40. Tingley DP, Gonder JR: Ocular sarcoidosis presenting as a solitary choroidal mass. CanJ OphthalmolI992;27:25. 41. DeRosa AJ, Margo CE, Orlick ME: Hemorrhagic retinopathy as the presenting manifestation of sarcoidosis. Retina 1995;15:422. 42. Edelsten C, Stanford MR, Graham EM: Serpiginous choroiditis: An unusual presentation of ocular sarcoidosis. Br J Ophthalmol 1994;78:70. 43. Brinkman ClJ, Rothova A: Fundus pathology in neurosarcoidosis. Int Ophthalmol 1993;17:23. 44. Priem HA, Oosterhuis JA: Birdshot chorioretinopathy: Clinical characteristics and evolution. Br J Ophthalmol 1988;72:646. 45. Gould H, Kaufman HE: Sarcoid of the fundus. Arch Ophthalmol 1961;65:453. 46. Wall M, Newman S, Slavin M, et al: Optic atrophy. Surv Ophthalmol 1991;36:51. 47. Galetta S, Schatz NJ, GlaserJS: Acute sarcoid optic neuropathy with spontaneous recovery. J Clin Neuroophthalmol 1989;9:27. 48. Wong RJ, Gliklich RE, Rubin PA, et al: Bilateral nasolacrimal duct obstruction managed with endoscopic techniques. Arch Otolaryngol Head Neck Surg 1998;124:703. 49. Simon EM, Zoarski GH, Rothman MI, et al: Systemic sarcoidosis with bilateral orbital involvement: MR findings. AJNR AmJ Neuroradio1 1998;19:336. 50. Cornblath WT, Elner V, Rolfe M: Extraocular muscle involvement in sarcoidosis. Ophthalmology 1993;100:501. 51. hnes RK, Reifschneider JS, O'Connor LE: Systemic sarcoidosis presenting initially with bilateral orbital and upper lid masses. Ann OphthalmolI998;20:466. 52. Peterson EA, Hymas DC, Pratt DV, et al: Sarcoidosis with orbital tumor outside the lacrimal gland: Initial manifestation in 2 elderly white women. Arch Ophthalmol 1998;116:804. 53. Cancrini C, Angelini F, Colavita M, et al: Erythema nodosum: A presenting sign of early onset sarcoidosis. Clin Exp Rheumatol 1998;16:337.

54. Sahn EE, Hampton MT, Garen PD, et al: Preschool sarcoidosis masquerading as juvenile rheumatoid arthritis: Two case reports and a review of the literature. Pediatr Dermatol 1990;7:208. 55. O'Brien JM, Albert DM, Foster CS: Juvenile rheumatoid arthritis. In: Albert DM,Jakobiec FA, eds: Principles and Practice of Ophthalmology: Clinical Practice. Philadelphia, W.B. Saunders, 1993, p 2873. 56. Hegab SM, al-Mutawa SA, Sheriff SM: Sarcoidosis presenting as multifocallimbal corneal nodules. J Pediatr Ophthalmol Strabismus 1998;35:323. 57. Lennarson P, Barney NP: Interstitial keratitis as presenting ophthalmic sign of sarcoidosis in a child. J Pediatr Ophthalmol Strabismus 1995;32:194. 58. Sakurai Y, Nakajima M, Kamisue S, et al: Preschool sarcoidosis mimicking juvenile rheumatoid arthritis: The significance of gallimn scintigraphy and skin biopsy in the differential diagnosis. Acta Paediatr Jpn 1997;39:74. 59. Ukae S, Tsutsumi H, Adachi N, et al: Preschool sarcoidosis manifesting as juvenile rheumatoid arthritis: A case report and a review of the literature ofJapanese cases. Acta Paediatr Jpn 1994;36:515. 60. Vaphiades MS, Eggenberger E: Childhood sarcoidosis. J Neuroophthalmol 1998;18:99. 61. Bruins Slot ~: Ziekte van Besnier-Boeck en febris uveoparotidea (Heerfordt). Ned Tijdschr Geneeskd 1936;80:2859. 62. Lofgren S: Erythema nodosum: Studies on etiology and pathogenesis in 185 adult cases. Acta Med Scand 1946;124(suppl):I. 63. Kobzik L, Schoen FJ: The lung. In: Cotran RS, Kumar V, Robbins SL, eds: Robbins Pathologic Basis of Disease, 5th ed. Philadelphia, W.B. Saunders, 1994, pp 673-734. 64. Kveim A: En ny og spesifikk kutan-reaksjon ved Boeck's sarcoid. Nord Med 1941;9:169. • 65. Pierard GE, Damseaux M, Franchimont C, et al: The histological structure of Kveim tests parallels the evolution of pulmonary sarcoidosis. AmJ Dermatopathol 1982;4:17. 66. Wigley RD: Moratorium on Kveim tests. Lancet 1993;341:1284. 67. Kataria YP, Holter JF: Cutaneous anergy in sarcoidosis. In: James DG, ed: Sarcoidosis and Other Granulomatous Disorders (vol 73, Lung Biology in Health and Disease). New York, Marcel Dekker, 1994, p 18I. 68. Kataria YP, Holter JF: Immunology of sarcoidosis. Clin Chest Med 1997;18:719. 69. Holter JF, Park HK, Sjoerdsma KW, et al: Nonviable autologous bronchoalveolar lavage cell preparations induce intradermal epithelioid cell granulomas in sarcoidosis patients. Am Rev Respir Dis 1992;145:864. 70. Martinez FJ, Orens JB, Deeb M, et al: Recurrence of sarcoidosis following bilateral allogeneic lung transplantation. Chest 1994;106:1597. 71. Heyll A, Meckenstock G, Aul C, et al: Possible transmission of sarcoidosis via allogeneic bone marrow transplantation. Bone Marrow Transplant 1994;14:161. 72. Sulavik SB, Spencer RP, Palestro Cj, et al: Specificity and sensitivity of distinctive chest radiographic and/ or 67Ga images in the noninvasive diagnosis of sarcoidosis. Chest 1993;103:403. 73. James DJ,. Neville E, Siltzbach LE, et al: A worldwide review of sarcoidosis. Proceedings of the Seventh International Conference on Sarcoidosis and Other Granulomatous Disorders. Ann N Y Acad Sci 1976;278:32I. 74. Kosmorsky GS, Meisler DM, Rice TW, et al: Chest computed tomography and mediastinoscopy in the diagnosis of sarcoidosis-associated uveitis. AmJ Ophthalmol 1998;126:132. 75. Sulavik SB, Palestro Cj, Spencer RP, et al: Extrapulmonary sites of radio gallium accumulation in sarcoidosis. Clin Nucl Med 1990;15:876. 76. Sulavik SB, Spencer RP, Weed DA, et al: Recognition of distinctive patterns of gallium-67 distribution in sarcoidosis. J Nucl Med 1990;31:1909. 77. Nosal A, Schleissner LA, Mishkin FS, et al: AIl.giotensin-l-converting enzyme and gallium scan in noninvasive evaluation of sarcoidosis. Ann Intern Med 1979;90:328. 78. Power ~' Neves RA, Rodriguez A, et al: The value of combined serum angiotensin-converting enzyme and gallium scan in diagnosing ocular sarcoidosis. Ophthalmology 1995;102:2007. 79. Weinreb RN, Barth R, Kimura SJ: Limited gallium scans and angiotensin converting enzyme in granulomatous uveitis. Ophthalmology 1980;87:202.

CHAPTER 63: SARCOIDOSIS 80. Conrad AK, Rohrbach MS: An in vivo model for the induction of angiotensin-converting enzyme in sarcoidosis. Am Rev Respir Dis 1987;135:396. 81. Baarsma GS, La Hey E, Glasius E, et al: The predictive value of serum angiotensin converting enzyme and lysozyme levels in the diagnosis of ocular sarcoidosis. AmJ Ophthalmol 1987;104:211. 82. Immonen I, Friberg K, Sorsila R, et al: Concentration of angiotensin-converting enzyme in tears of patients with sarcoidosis. Acta Ophthalmol 1987;65:27. 83. Weinreb RN, Sandman R, Ryder MI, et al: Angiotensin-converting enzyme activity in human aqueous humor. Arch Ophthalmol 1985;103:34. 84. Moller DR, Forman JD, Lin MC, et al: Enhanced expression of IL-12 associated with Th1 cytokine profiles in active pulmonary sarcoidosis. J Immunol 1996;156:4952. 85. Mitchell DM, Mitchell DN, Collins]V, et al: Transbronchial lung biopsy through fibre optic bronchoscope in diagnosis of sarcoidosis. Br MedJ 1980;280:679. 86. Gilman MJ, Wang KP: Transbronchial lung biopsy in sarcoidosis. An approach to determine the optimal number of biopsies. Am Rev Respir Dis 1980;122:721.

87. Leonard C, Tormey "1, Okeane C, et al: Bronchoscopic diagnosis of sarcoidosis. Em Respir J 1997;10:2722. 88. Ohara K, Okubo A, Kamata K, et al: Transbronchiallung biopsy in the diagnosis of suspected ocular sarcoidosis. Arch Ophthalmol 1993;111:642. 89. Costabel U, Teschler H: Biochemical changes in sarcoidosis. Clin Chest Med 1997;18:827. 90. Spaide FR, Ward DL: Conjunctival biopsy in the diagnosis of sarcoidosis. Br J Ophthalmol 1990;74:469. 91. Hershey JM, Pulido JS, Folberg R, et al: Non-caseating cOl~unctival granulomas in patients with multifocal choroiditis and panuveitis. Ophthalmology 1994;101 :596. 92. Nicholls CW, Eagle RC,. Yanoff M, et al: Conjunctival biopsy as an aid in the evaluation of the patients with suspected sarcoidosis. Ophthalmology 1980;87:287. 93. Rothova A, Suttorp-van Schulten MSA, Treffers WF, et al: Causes and frequency of blindness in patients with intraocular inflammatory disease. Br J Ophthalmol 1996;80:332. 94. Dev S, McCallum RM, Jaffe GJ: Methotrexate treatment for sarcoidassociated panuveitis. Ophthalmology 1999;106:111.

I Vakur Pinar, Nicolette Gion, and C. Stephen Foster

DEFINITION Acute tubulointerstitial nephritis (ATIN) is an ilnportant cause of renal failures. It may be idiopathic or associated with drug hypersensitivity, infections, and immunologic diseases. 1 Idiopathic acute tubulointerstitial nephritis and uveitis (TINU) is an uncommon syn.drome involving the kidney and the eye. It occurs mainly in children and young adults, and females are affected more often than males. 2-4 Patients usually present with systemic symptoms including fatigue, malaise, anorexi.a, abdominal pain, fever, and anemia. The nephritis usually precedes the uveitis, although simultaneous onset in both organs has been described. 2, 5, 6 The nephropathy typically resolves spontaneously or responds favorably to systemic steroid therapy,2, 6-10 but the uveitis often becomes chronic and is treatment resistant. 2, 9-19

HISTORY The association of idiopathic ATIN and uveitis was first described by Dobrin and associates in 1975. 2 They reported two adolescent girls (ages 14ai\d 17) with severe eosinophilic interstitial nephritis and renal failure. Both patients had bilateral anterior uveitis, and bone marrow granulomas were found on bone marrow biopsy, with one patient also having lymph node granulomas. The authors proposed that these cases represented a "new syndrome" because extensive investigation for an etiologic agent was unrevealing and neither patient's condition could be classified as a known disease entity. In most of the cases reported since then, the infiltration of eosinophils in the renal interstitium was not as marked, and bone marrow or lymph node granulomas were reported only in two subsequent cases. 20, 21 Thus, the term renal-ocular syndrome, or more recently, TINU syndrome seems to be more suitable for the clinicopathologic entity. In 1988, Rosenbaum's article on five patients with bilateral uveitis associated with interstitial nephritis drew attention to this syndrome in the ophthalmic literature. 6

EPIDEMIOLOGY TINU syndrome is a rare and relatively new syndrome, but it may have been underrecognized. Since the initial description in 1975, about 60 cases have been reported in the ophthalmologic and nephrologic literature. In Rosenbaum's study, 5 of 244 patients with uveitis were found to suffer from TINU, which ranked as the sixth most common systemic illness associated with uveitis in his clinic. 6 BenEzra, in a letter to the editor of the American Journal of Ophthalmology, argued with this prevalence of 2% and estimated the prevalence to be 0.5% in most uveitis clinics. s The diagnosis, and hence prevalence studies, may be difficult because (1) definite diagnosis requires kidney biopsy, (2) nephropathy can resolve sponta-

neously, and (3) systemic complaints are nonspecific. TINU syndrome is an illness of childhood and adolescence but can appear at any age. 2-4, 17, 19-22 There is a marked female predominance; most of the reported young patients and all, except one,17 of the adult patients (aged 23-74) have been females. 2-4, 19

CLINICAL FEATURES TINU is a systemic disease. Most patients have systemic complaints that include fatigue, malaise, anorexia, weight loss, abdominal pain, and· fever and there is usually a typical time sequence for the appearance of these clinical features in TINU syndrome. 5 These first nonspecific signs and symptoms usually precede the nephropathy by up to 1 month. Nausea, vomiting, headache, and myalgia can also form a part of the initial group of symptoms. Mter a .few weeks, the disease is fully developed, with a triad consisting of an inflammatory syndrome, nephropathy, and somewhat later, usually uveitis. The inflammatory syndrome is always present and consists of a markedly increased sedimentation rate, high plasma proteins (mainly hypergammaglobulinemia), and anemia. The nephropathy generally appears a few weeks later. Proteinuria is a constant feature. Laboratory findings of tubulointerstitial damage include normoglycemic (renal) glycosuria, leucocyturia, aminoaciduria, microhematuria, and increased urinary excretion of 132-microglobulin. Most urine casts, when seen, are granular, hyaline, or leukocyte casts. Diuresis is maintained, and polyuria may even be prominent, sometimes causing nocturia. There is also a low glomerular filtration rate (GFR) with elevated blood urea nitrogen (BUN) and creatinine levels. Hypertension is typically absent. The nephritis usually resolves or responds to steroid or immunosuppressive therapy, but nephrotic syndrome may develop, and chronic renal failure may occur. A few patients eventually require dialysis. Uveitis, the third component of the triad, usually occurs a few weeks to several months after the onset of the renal disease, not infrequently when renal function is recovering and initial symptoms are waning. Uveitis may precede or occur simultaneously with nephropathy. It is typically bilateral, anterior, acute, and nongranulomatous (Table 64-1). Pain, photophobia, ciliary ir~jection, a mild to severe degree of anterior chamber cells, and flare are usually present, and posterior synechiae can occur. Hausmann and colleagues reported a 53-year-old woman with TINU syndrome who presented with bilateral granulomatous anterior uveitis,15 and we also saw a 13-year-old girl with TINU syndrOlne who presented with granulomatous anterior uveitis to the Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary. A 14year-old boy with bilateral nongranulomatous panuveitis

CHAPTER 64: TUBULOINTERSTITIAL TABLE 64-1. CHARACTERISTICS OF UVEITIS IN TINU SYNDROME Bilateral anterior uveitis Acute onset in one or both eyes Usually nongranulomatous Recurrences are COllllllon Usually responds to topical corticosteroid therapy

was also examined on our service. Panuveitis, pars planitis, and posterior uveitis in the relapsing disease have been described in some patients with TINU syndrome. 2,6-29 A I5-year-old boy who developed unilateral posterior uveitis with papillitis, optic disc hemorrhage, and macular plicae 1 month after bilateral anterior uveitis has been described. 30 Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) has been reported in association with acute nephritis in one patient, but renal biopsy was not done owing to spontaneous recovery of the nephropathy.18 As a summary of clinical features, a typical patient profile is an adolescent girl or adult woman with bilateral, recurrent anterior uveitis who has had systemic complaints and laboratory findings or a history of ATIN. PATHOlOG~ IMMUNOlOG~AND

PATHOGENESIS The histologic picture of renal biopsy specimens in ATIN is characterized by cellular infiltffition and edema of the interstitiumY-33 The majority of the inflammatory cells are T lymphocytes. The remaining cells (forming up to half of the cellular infiltrate) are monocytes and macrophages, with very few cells expressing B lymphocyte markers. Plasma cells. granulocytes, neutrophils, and eosinophils may be seen. The eosinophilic component, emphasized originally by Dobrin,2 is variable and may be minimal or absent. The tubules show some edema with patchy epithelial degeneration, focal necrosis, and dilation or atrophy. Fibrosis is occasionally seen, but there are no glomerular or vascular changes present. Occasionally granulomas are found. 5,13 Immunofluorescence microscopic studies are negative for fibrinogen, immunoglobulins, and complement components. Circulating immune complexes have been detected in only a minority of cases, and in the patients studied, immune complexes were detected in the aqueous and the serum. 6, 7, 13, 16,34 There are several reports of elevated immunoglobulin G (IgG) levels in the serum of TINU patients. l l , 13, 21, 35 Immunohistopathologic studies reveal that the majority of the infiltrating cells were CD4 + (helper or inducer) T lymphocytes, suggesting the involvement of T-cell-mediated delayed type hypersensitivity33,35-37 in the pathogenesis of TINU. Dominant infiltration of CDS + (suppressor/cytotoxic) T cells in the renal interstitium was found in some studies. 21 ,22 There is no clear explanation for this discrepancy at present. Chan and coworkers reported that CD4 + T-cell subtype is predominant in ocular infiltrates during the early stages of experimental autoimmune uveitis (EAU)-and sympathetic ophthalmia-whereas CDS + T cells predominate in the later stages. 25 , 26 This subset change was explained

NIFPII-lIIIU-nlb;;

AND UVEITIS SYNDROME

as a reflection of the kinetics and regulation of the inflammatory response in autoimmune diseases, but the actual cause of this phenomenon is still controversial. Yoshioka and coworkers demonstrated the expression of the interleukin-2 (IL-2) receptor on infiltrating mononuclear cells, which is expressed mainly and transiently on recently activated T cells. 36 Three of the four patients with TINU syndrome, seen on the Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary,28 showed elevated soluble IL-2 receptor (sIL-2R) levels. Rodriguez-Perez and colleagues found a clear predominance of activated memory T lymphocytes (CD45RO + ) in the interstitial infiltration. 29 Increased immunologic reactivity in the renal tissue was also demonstrated, together with a suppressed peripheral T-cell function both in vivo (anergy to skin test) and in vitro (decreased lymphokine secretion) .29 It is noteworthy that four patients reported in that study were studied during remission of the disease. In contrast, a temporary depression of the cellular immunity was observed in the acute phase, as opposed to the strongly positive tuberculin reaction before illness and during remission in Van Acker and coworkers' study.4 Birnbacher and associates found cytotoxic T-cell, macrophage, and granulocyte activation in blood immunologic analysis and serum analysis of a I4-year-old boy with TINU syndrome. 24 They interpreted these findings as either a significant role in its pathogenesis or as part of a microbe-triggered immune response. Antineutrophil cytoplasmic antibodies (ANCAs), both with a cytoplasmic and a perinuclear pattern, were detected in three patients, suggesting autoimmunity.30-32 However, ANCAs were not regularly examined in previous studies, and they were not detected in 13 cases (not yet published) .30-34 The presence of ANCAs has been reported in some patients with uveitis of various etiologies, albeit with a low prevalence and questionable pathogenic significance. 33 ,34 Various human leukocyte antigen (HLA) associations have been described. Tissue typing for HLA-A, -B, -C, and -DR antigens in the study conducted by Iitsuka and coworkers revealed identical HLA-CW3 in three patients and identical HLA-A24 in all four cases, whereas Gafter and colleagues found a high frequency of HLA-DR6 in three patients. 30, 37 Interestingly, BenEzra noted that three of his four patients with interstitial nephritis and bilateral anterior uveitis were HLA-B27 positive, but this might be a random association because there are no other reports of HLA-B27 positivity in TINU patients described in the literature. 8 The etiology and pathogenesis of TINU syndrome is still unknown. Search for an infectious agent has been negative, despite extensive culture and serologic testing. Abnormalities of both humoral and cellular immunity have been reported emphasizing an immunologic disorder, accompanying or causing this syndrome. An immunologic disorder, probably T-cell-mediated, is most likely because (1) the interstitial infiltrate consists luainly of T lymphocytes; (2) granulomas are seen occasionally; (3) imluunofluorescence studies are mostly negative for tubulointerstitial deposits; (4) hypergammaglobulinemia, circulating immune complexes, and ANCAs were detected in some patients; and (5) there is a favorable response to

CHAPTER 64: TUBULOINTERSTITIAL NEPHRITIS AND UVEITIS SYNDROME

steroid treatment in most cases. A possible role of chlamydia infection has been suggested based on the course of the antichlamydial antibody titers in a 38-year-old woman with TINU.38 In our series of six TINU patients, abnormal findings included Epstein-Barr virus IgG, highly elevated anticardiolipin-IgM and increased complement 4 (C4) in one patient, antinuclear antibody (ANA) positivity and decreased total complement levels in another patient, and elevated sIL-2R levels in three patients. 28 HLA-typing in one case showed HLA-A9, -A33, -B65, and -Cw8.

DIAGNOSIS DIAGNOSIS

DiffERENTIAL

The first step in the diagnosis of TINU syndrome is perhaps an awareness of the entity itself and a high index of suspicion. Anterior uveitis is the most common form of intraocular inflammation, and it is frequently associated with systemic diseases such as HLA-B27-associated seronegative spondyloarthropathies, juvenile rheumatoid arthritis, sarcoidosis, and diabetes mellitus. TINU syndrome takes its place on this list, albeit as a rare cause. All patients with bilateral anterior acute uveitis in association with systemic s)'luptoms such as fatigue, fever, headache, anorexia, weight loss, and abdominal or flank pain should undergo careful evaluation of renal function. The interval between systemic signs andterlal and ocular sYJ-TIptoms may range between 0 and 14 months 28 ; hence, the importance of careful history taking. Laboratory findings of high sedimentation rate, nofmochromic normocytic anemia, elevated serum creatinine and BUN levels, abnormal urinalysis· findings (renal glycosuria, proteinuria, aminoaciduria,microhematuria) support the diagnosis, and nephrology consultation should be requested. TINU syndrome is a clinicopathologic entity, and definitive diagnosis is established by kidney biopsy. Because nephropathy can recover spontaneously in some cases and kidney biopsy is not a routine procedure, the definitive diagnosis of TINU syndrome may be unfortunately missed in some cases. The differential diagnosis (Table 64-2) must include diseases associated with uveitis and interstitial nephritis, which may be either isolated or accompanied by glomerulonephritis. The concurrence of uveitis and ATIN is uncomluon. Potential causes illclude sarcoidosis, Sjogren's s)'l1drome, Adamantiades-Beh~et disease, IgA nephropathy (Berger's disease), Kawasaki's disease, systemic lupus erythematosus, tuberculosis, syphilis, toxoplasmosis, brucellosis, and leptospirosis. Drug hypersensitivity (e.g., nonsteroidal anti-inflammatory drugs, antibiotics, diuret-

TABLE 64-2. DIFFERENTIAL DIAGNOSIS OF TINU SYNDROME Sarcoidosis Sjogren's syndrome Post streptococcal uveitis Juvenile rheumatoid arthritis ORA) IgA nephropathy (Berger's disease) Vasculitides (e.g., systemic lupus erythematosus, Wegener's granulomatosis)

Adamantiades-Beh~et disease

Syphilis Tuberculosis Brucellosis Leptospirosis

ics) is the most common cause of ATIN in adults and can be rarely associated with anterior uveitis. 39 The possibility of drug-induced ATIN, with the incidental (or druginduced) findings of anterior uveitis, should be considered in the presence of maculopapular rash, arthralgia, eosinophilia, and eosinophiluria. Bilateral, recurrent anterior uveitis of sudden onset, similar to that seen in TINU s)'l1drome, has been described in association with past streptococcal infection, which is also a common cause of ATIN in children. 40-42 Most of these differential diagnoses can be excluded by a detailed history, physical examination, and serologic tests. The TINU syndrome can be regarded as distinct from these and other oculorenal syndromes on the basis of clinical features, pathology, and natural history.

AND PROGNOSIS In most cases, topical steroids have been adequate in controlling the uveitis, whereas some patients require systemic steroid treatment. 5 ,23 In steroid-resistant patients and in those who exhibit recurrent attacks of uveitis after discontinuation of steroids, immunomodulatory agents can achieve control of the inflammation and prevent relapses. In general, the outcome of TINU syndrome is favorable. The interstitial nephritis usually resolves completely, either spontaneously or after systeluic corticosteroid treatment. I, 5, 13, 43 The aim of steroid therapy is to alter the course of the acute renal failure by achieving a rapid improvement of renal function and to minimize any residual damage. Full recovery occurs in children, and relapse of nephritis is not seen. The course of ATIN may be less predictable and more guarded in adults. Cases of nephrotic syndrome, relapsing nephritis, and development of chronic renal failure, despite the use of systemic steroids and other immunosuppressants (chlorambucil and cyclophosphamide), have been reported. 1, 11, 12 In a review of the literature, Cacoub and coworkers described one adult patient who developed terminal renal failure and two patients with deterioration of renal function who were not treated with corticosteroids; interstitial fibrosis and tubular atrophy were correlated with poor renal function prognosis. Io Rodriguez-Perez and colleagues reported on five patients with a I-year follow-up, whose renal function and uveitis responded dramatically to steroid treatment maintained for a period of 6 to 9 months. 29 Gafter and associates reported on four patients with TINU s)'l1drome (one adolescent and three adult females) who were treated with systemic prednisone. I3 There was a favorable response of the renal disease in all cases, as indicated by the decrease of serum creatinine and disappearance of proteinuria. Treatment lasted from 5 to 12 months because a rapid taper in the prednisone dosage was associated with a rise in serum creatinine. Mter cessation of treatment, there was no exacerbation of nephritis during a follow-up period of 2.5 to 9.5 years. In contrast, the anterior uveitis relapsed many times in all patients. Its response to systemic steroid treatment was regarded as inconsistent, with several exacerbations occurring during steroid treatment. No controlled studies to date confirm whether use of systemic corticosteroids is truly beneficial in the treatment of ATIN in TINU syn-

CHAPTER 64: TUBULOINTERSTITIAl NEPHRITIS AND UVEITIS SYNDROME

drome. Clearly, all patients with TINU syndrome should be managed in collaboration with a nephrologist, partiClllarly if ATIN occurs simultaneously with uveitis or follows it. Bilateral anterior uveitis usually responds well to topical corticosteroid treatment. It should be treated aggressivelyinitially (e.g., one drop every hour while awake), with slow tapering. In case of failure, the compliance of the patient and dosing schedule should be checked before advancing to a more aggressive treatment (e.g., periocular injection; per oral route). Cycloplegic and mydriatic agents should be used to prevent posterior synechiae and to relieve pain. Cyclopentolate is better avoided, because it has been shown to be a chemoattractant for leukocytes in one study.44 Should there be an ocular hypertensive response to local steroids, another preparation (e.g., fluorometholone, rimexolone) or topical antiglaucomatous agents (beta blockers, carbonic anhydrase inhibitors) can be used. CC?mplications such as posterior synechiae, cystoid macular edema, and progression of intraocular inflammation to the posterior segment (optic disc edema, pars planitis, and panuveitis) have been reported. 28 If uveitis persists in both eyes despite topical steroid therapy or posterior segment complications develop, systemic corticosteroid treatment should be consicl.ered. Serious side effects of long-term steroid treatment, partiClllarly in children, are well-known, and monitoring of these side effects as well as the clinical response to the therapy should be done regularly. S(~roid-sparing strategies should be considered in steroid-dependent cases. This is usually achieved by use of other immunosuppressive agents such as methotrexate (7.5 mg to 20 mg/week), cyclosporine A (3 mg to 5 mg/kg/ day), or azathioprine (1 mg to 2.5 mg/kg/day), either alone or in combination, in order to increase efficiency and decrease toxicity. To our knowledge, the report by Sanchez Roman and coworkers is the first to describe the use of steroid-sparing agents in a patient with posterior uveitis in the TINU syndrome. 45 The authors described several relapses of uveitis despite the use of oral steroids, which persisted after addition of azathioprine. Their patient responded favorably to cyclosporine A as monotherapy. At the Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary, we examined six patients who were referred to us because of recurrences of uveitis despite treatment with topical, regional, and systemic steroids, and in one patient, methotrexate. Introduction or addition of immunosuppressants such as methotrexate, azathioprine, or cyclosporine A in five of six patients achieved control of the ocular inflammation and prevented relapses over a mean follow-up period of 19.66 months. 28 Methotrexate alone (in three patients) or in combination with cyclosporine A (in one patient) was successful in controlling the uveitis. One patient did not respond to the combination of methotrexate and systemic steroids, and developed steroid-induced side effects. He responded well to a combination of cyclosporine A and azathioprine. All patients tolerated the chemotherapy well, apart from one patient who complained of nausea and abdominal pain after taking methotrexate. These symptoms resolved after dividing the dose of methotrexate on two successive days.

Our case series confirms and extends the observation of Sanchez Roman and associates that the introduction of immunosuppressive agents can achieve control of the intraocular inflammation and prevent relapses in TINU patients. 45 Because no "best drug" is known for TINU syndrome, the selection of the most effective immunosuppressant must follow a "sequential stepladder approach," with low-dose once-weekly methotrexate generally being the first step, followed by cyclosporine A or azathioprine. As always, the use of such immunomodulatory therapy should be under the management of an individual (ophthalmologist, nephrologist, oncologist) who is, by virtue of training and experience, expert in such Inanagement.

CONCLUSION TINU syndrome is a distinct clinicopathologic entity characterized by acute tubulointerstitial nephritis with nonoliguric acute renal failure accompanied or followed by bilateral anterior acute nongranulomatous uveitis, which tends to be relapsing and treatment resistant. TINU is most frequently seen in children and adult women, but it can occur at any age. The differential diagnosis includes systemic diseases and oculorenal syndromes associated with anterior uveitis. TINU syndrome is probably an immunologic disorder involving the kidney and eye, but its etiology and pathogenesis are still unknown. In general, the outcome of TINU syndrome is favorable. Nephropathy resolves either spontaneously or after systemic corticosteroid treatment and does not relapse. The uveitis usually responds to topical steroid therapy, but some patients require systemic steroid treatment or the introduction of immunosuppressive agents, or both, to achieve control of the ocular inflammation and to prevent relapses.

References 1. Smoyer WE, Kelly Cj, Kaplan BS: Tubulointerstitial nephritis. In: Holliday MA, Barrat TM, Avner ED, eds: Pediatric Nephrology, 3rd ed. Baltimore, Williams & Wilkins, 1994, p 890. 2. Dobrin RS, Vernier RL, Fish AJ: Acute eosinophilic interstitial nephritis and renal failure with bone marrow-lymph node granulomas. A new syndrome. Am] Med 1975;59:325. 3. Steinman TI, Silva P: Acute interstitial nephritis and iritis. Renalocular syndrome. Am] Med 1984;77:189. 4. Van Acker Iq, Buyssens N, Neetens A, et al: Acute tubulointerstitial nephritis with uveitis. Acta Paediatr Belg 1980;33:171. 5. Vanhaesebrouck P, Carton D, De Bel C, etal: Acute tubulointerstitial nephritis and uveitis syndrome (TINU syndrome). Nephron 1985;40:418. 6. Rosenbaum ]T: Bilateral anterior uveitis and interstitial nephritis. Am] Ophthalmol 1988;105:534. 7. Rosenbaum ]T: Uveitis. An internist's view. Arch Intern Med 1989;149:1173. 8. BenEzra D: Bilateral anterior uveitis and interstitial nephritis. Am] Ophthalmol 1988;106:766. 9. Burnier M,]aeger P, Campiche M, et al: Idiopathic acute interstitial nephritis and uveitis in the adult. Am] Nephrol 1986;6:312. 10. Cacoub P, Deray G, Le Hoang P, et al: Idiopathic acute interstitial nephritis associated with anterior uveitis in adults. Clin Nephrol 1989;31:307. 11. Riminton S, O'Donnel J: Tubulo-interstitial nephritis and uveitis (TINU) syndrome in an adult. Aust NZ] Med 1993;23:57. 12. Salu P, Stempels N, Vanden Houte K, et al: Acute tubulointerstitial nephritis and uveitis syndrome in the elderly. Br ] Ophthalmol 1990;74:53. 13. Gafter U, Ben-Basat M, Zevin D, et al: Anterior uveitis, a presenting symptom in acute interstitial nephritis. Nephron 1986;42:249. 14. Itami N, Akutsu Y, Yasoshima K, et al: Acute tubulointerstitial nephritis with uveitis. Arch Intern Med 1990;150:688.

64: TUBULOINTER.STITIAL NEPHRITIS AND UVEITIS SYNDR.OME 15. Hausmann N, Neyer U, Hammerle W: Akut rezidivierende Uveitis und idiopathische interstitielle Nephritis-eine nosologische Einheit (TINU-Syndrom). Klin Monatsbl Augenheilk 1988;193:35. 16. Burghard R, Brandis M, HoyerPF, et al: Acute interstitial nephritis in childhood. Eur J Paediatr 1984;142:103. 17. Waeben M, Boven K, D'Heer B, et al: Tubulo-interstitial nephritisuveitis (TINU) syndrome with posterior uveitis. Bull Soc BeIge Ophtalniol 1996;261:73. 18. Laatikainen LT, Immonen IJR: Acute posterior multifocal placoid pigment epitheliopathy in connection with acute nephritis. Retina 1988;8:122. 19. Savir H: Uveitis and interstitial nephritis. In: Regenbogen LS, Eliahou HE, eds: Diseases Affecting the Eye and the Kidney. Basel, S Karger AG, 1993, P 381. 20. Iida H, Terada Y, Nishino A, et al: Acute interstitial nephritis with bone marrow granulomas and uveitis. Nephron 1985;40:108. 21. Kobayashi Y, Honda M, Yoshikawa N, et al: Immunohistological study in sixteen children with acute tubulointerstitial nephritis. Clin NephroI1998;50:14. 22. Pamukcu R, Moorthy AV, Singer JR, et al: Idiopathic acute interstitial nephritis: Characterization of the infiltrating cells in the renal interstitium as T helper lymphocytes. Am J Kidney Dis 1984;4:24. 23. Hirano K, Tomino Y, Mikami H, et al: A (:ase of acute tubulointerstitial nephritis and uveitis syndrome with a dramatic response to corticosteroid therapy. Am J Nephrol 1989;9:499. 24. Birnbacher R, BaIzaI' E, Aufricht C, et al: Tubulointerstitial nephritis and uveitis: An immunological disorder? Pediatr Nephrol 1995;9:193. 25. Chan CC, Mochizuki M, Palestine AG, et al: Kinetics of T-Iymphoeyte subsets in the eyes of Lewis rats with experimental autoimmune uveitis. Cell Immunol 1985;96:430. 26. Chan CC, BenEzra D, Rodligues MM, et al: .ImmunohistochemistYy and electron microscopy of choroidal infiltrates and Dalen-Fuchs nodules in sympathetic ophthalmia. Ophthalmology 1985;92:580. 27. Derzko-Dzulyhsky L, Rabinovitch T: Tubulointerstitial nephritis and uveitis with bilateral multifocal choroiditiis. Am J Ophthalmol 2000;129:807-809. 28. Gion N, Stavron P, Foster CS: Immunomodulatory therapy for chronic tubulointerstitial nephritis-associated uveitis. Am J Ophthalmol 2000;107:764. 29. Rodriguez-Perez JC, Cruz-Alamo M, Perez-Aciego P, et al: Clinical and immune aspects of idiopathic acute tubulointerstitial nephritis and uveitis syndrome. AmJ Nephro11995;15:386.

30. Gafter U, Kalechman Y, Zevin D, et al: Tubulointerstitial nephritis and uveitis: Association with suppressed cellillar immunity. Nephrol Dial Transplant 1993;8:821. 31. Simon AH, Alves-Filho G, Ribeiro-Alves MA: Acute tubulointerstitial nephritis and uveitis with antineutrophil cytoplasmic antibody. Am J Kidney Dis 1996;28:124. 32. Chen HC, Sheu MM, TsaiJH: Acute tubulo-interstitial nephritis and uveitis with anti-neutrophil cytoplasmic antibodies in an adult: An immune disorder? Nephron 1998;78:372. 33. Okada K, Okamato Y, Kagami S: Acute interstitial nephritis and uveitis with bone marrow granulomas and anti-neutrophil cytoplasmic antibodies. AmJ Nephrol 1995;15:337. 34. Hagen EC, van de Vijyer-Reenalda H, de Keizeer RJ, et al: Uveitis and anti-neutrophil cytoplasmic antibodies. Clin Exp Immunol 1994;95:56. 35. Young DW: The antineutrophil antibody in uveitis. BrJ Ophthalmol 1991;75:208. 36. Yoshioka K, Takamova T, Kanasaki M, et al: Acute interstitial nephritis and uveitis syndrome: Activated immune cell infiltration in the kidney. Pediatr Nephrol 1991;5:232. 37. Iitsuka T, Yamaguchi N, Kobayashi M, et al: HLA tissue types in patients with acute tubulointerstitial nephritis accompanying uveitis. Nippon Jinzo Gakkai Shi 1993;35:723. 38. Stupp R, Mihatsch MJ, Matter L, et al: Acute tubulo-interstitial nephritis with uveitis (TINU syndrome) in a patient with serologic evidence for chlamydia infection. Klin Wochenschr 1990;68:971. 39. Tilden ME, Rosenbaum JT, Fraunfelder FT: Systemic sulfonamides as a cause of bilateral anterior uveitis. Arch Ophthalmol 1991;109:67. 40. Cokingtin CD, Han DP: Bilateral nongranulomatous uveitis and a poststreptococcal syndrome. AmJ Ophthalmol 1991;112:595. 41. Leiba H, Barasch J, Pollack A: Poststreptococcal uveitis. Am J Ophthalmol 1998;126:317. 42. Holland GN: Recurrent anterior uveitis associated with streptococcal pharyngitis in a patient with a history of poststreptococcal syndrome. AmJ Ophthalmol 1999;127:346. 43. Bunchman TE, BloomJN: A syndrome of acute interstitial nephritis and anterior uveitis. Pediatr Nephrol 1993;7:520. 44. Tsai E, Till GO, Marak GEJr: Effects of mydriatic agents on neutrophil migration. Ophthalmic Res 1988;20:14. 45. Sanchez Roman J, Gonzalez Reina I, Castillo Palma MH, Rocha Castilla JL: Posterior uveitis associated with acute tubulointerstitial nephritis with favorable response to cydosporin. Pathogenic implications. Med Clin (Barc) 1995;104:118.

I Albert

Vitale

Birdshot retinochoroidopathy (BSRC) is a clinically distinct, uncommon form of chronic intraocular inflammation characterized by vitritis and multiple, bilateral, hypopigmented, postequatorial fundus inflammatory lesions. Although its etiology remains unknown, a putative autoimmune mechanism is likely to play an important pathogenic role given the demonstration of retinal autoantigen reactivity and the very strong association with the human leukocyte antigen (HLA)-A29 phenotype unique to this disease.

HISTORY The term birdshot retinochoroidopathy was coined in 1980 by Ryan and Maumenee 1 in their initial description of a group of 13 patients who shared certain similarities with the pars planitis syndrome. These patients were remarkable for the notable absence of a pars plana exudate and the unique presence of multiple, hypopigmented lesions at the level of the retinal pigment epithe.lium (RPE) reminiscent of the scatter pattern seen With birdshot fired from a shotgun onto.a paper target. Undoubtedly, the striking clinical appearance of these spots must have inspired Gass 2 in 1981 to d~scribe this same entity as vitiliginous choroiditis, given the similarity of the fundus lesions to cutaneous vitiligo. Indeed, two patients were thought to have developed vitiligo after the onset of visual symptoms in his series. 2 In the absence of a specific etiology, other descriptive names have been used to describe this entity. Priem and Oosterhuis3 note that the earliest report of this disease was probably by Franceschetti and Babe14 in 1949 who named it chorioretinopathie en taches de bougies to describe the fundus of a 63-year-old woman with characteristic features of birdshot retinochoroidopathy but with systemic features of sarcoidosis. Likewise, Aaberg5 dubbed this condition salmon patch choroidopathy, and AInalric and Cuq6 preferred chorioretinopathie en grans de riz, seeing in it a rice grain pattern. Although the term birdshot retinochoroidopathy is graphically descriptive and is currently the most widely accepted nomenclature, Opremcak 7 suggests that the term birdshot retinochoroiditis be advanced to more specifically reflect the essential inflaInmatory nature of this condition.

EPIDEMIOLOGY BSRC is an uncommon disease. The largest series reported in the literature to date consists of 102 patients (203 eyes) collected from 14 European ophthalmology clinics between 1980 and 1986. 3 In the United States, Henderly and coworkers8 reported only seven cases of BSRC among a population of 600 patients referred to a specialized uveitis clinic. The emergence of BSRC as a "new" uveitic entity is reflected by our experience in caring for 19 such individuals, representing 7.9% of 240

patients with posterior uveitis referred to the Immunology Service of the Massachusetts Eye and Ear Infirmary from 1982 to 1992. 9 In contrast to most other uveitic entities in which the onset of disease is in younger age groups, BSRC typically occurs during middle age, presenting at an average age of 50, with a range of between 35 and 70 years of age. 1-3, 9-11 The reason for this age shift is unclear. BSRC is found almost exclusively among whites, with a higher incidence in those of Northern European descent. I - 3, 11, 12 Finally, an apparent gender preference is observed in some series, with women representing up to 70% of reported cases,l, 2, 12 whereas no significant predilection for sex is found in others. 3 , 9, 13, 1'1

CLINICAL FEATURES Patients with BSRC present most commonly with varying degrees of gradual, painless visual loss, frequently··. complaining of floaters. The onset of visual symptoms may initially involve only one eye, but over time the fellow eye is almost always affected, albeit asymmetrically. Photophobia, some degree of nyctalopia, and disturbances in color vision are frequently reported. 2, 11 Visual complaints are not infrequently dramatically out of proportion to the measured visual acuity, with some patients complaining of debilitating visual loss in the face of 20/20 Snellen acuity. 7, 12 Such sytnptoms are indicative of diffuse retinal dysfunction underlying this disease, documented by electroretinography (see later). In general, BSRC occurs in otherwise healthy patients. However, careful medical history, examination, and review of symptoms may reveal associated systemic pathology. Priem and Oosterhuis3 noted an unusually high prevalence of vascular disease in their series of 102 patients with BSRC; 16 had systemic hypertension, 5 had coronary artery disease, 2 had suffered a cerebrovascular accident, and 3 had evidence of central retinal vein occlusion. Likewise, my group noted systemic hypertension in 3 of our 19 patients with BSRC.15 Although Gass initially forged the association of BSRC with vitiligo, the hypopigmented spots observed on the arms and legs of his patients with vitiliginous choroiditis appear to be more closely related to idiopathic guttate hypomelanosis than to vitiligo. 16 Only one patient in both the series of my group15 and that of Priem and Oosterhuis 3 had evidence of cutaneous depigmentation.Moreover, evidence of BSRC was found in only one of 223 patients with vitiligo examined by Wagoner and associates. 17 Other systemic associations include case reports of patients with autoimmune sensorineural hearing 10ss,18 myelodysplasia syndrome,19 and psoriasis 20 together with funduscopic lesions typical of BSRC. Although these may be coincidental findings, it is interesting to note that both the ocular and cutaneous problems of the patient with psoriasis resolved following treatment with aromatic retinoids. 20

65: BIRDSHOT RETINOCHOROIDOPATHY

In their original description of BSRC, Ryan and Mau- pole and midperiphery, but they are often more easily menee 1 cited the following diagnostic criteria: (1) a quiet visualized in the inferonasal quadrant. 22 BSRC lesions may (i.e., externally uninflamed), nonpainful eye, (2) mini- be diffuse or asymmetric, they may be macular sparing or mal to no anterior uveitis, (3) vitritis 'without pars plana macular involving, and they frequently assume a radial exudate (in contradistinction to pars planitis), (4) retinal orientation peripherally, being distributed along the large vascular leakage, particularly involving the perifoveal cap- choroidal vessels. 3, 10 The lesions are not associated with illaries leading to cystoid macular edema (CME) and significant hyperpigmentation within or at their maroccasionally to disc edema, (5) distinctive, discrete, gins. 16 cream-colored or depigmented spots scattered throughBiomicroscopic examination discloses that these leout the posterior fundus. sions are at the level of the outer retina, RPE, and inner Examination of the anterior segment reveals a quiet choroid. The overlying retina appears normal during the eye without conjunctival injection or circumlimbal flush. early stages of depigmentation, with large choroidal vesWhile a mild nongranulomatous iritis with fine keratic sels frequently visible within the lesion. Absence of visible precipitates on the corneal endothelium may be present choroidal vessels within the BSRC spots, either during in approximately 25% of cases/ iridocapsular syl1.echiae, episodes of severe vitritis or early in the evolution of posterior subcapsular cataract, and ocular hypotony sec- depigmentation, may give the appearance of an elevated ondary to ciliary body hyposecretion are unusual. In my choroidal inflammatory infiltrate. 16 Such lesions have experience, intraocular pressures are typically normal. been described as having "substance" and interpreted as However, Priem and Oosterhuis noted a 19% incidence evidence of inflammatory activity.12 As will be discussed of open angle glaucoma unassociated with pigment dis- later, these early lesions frequently show no angiographic persion or elevated episcleral venous pressure. 3 No other abnormality. Later in their evolution, BSRC spots may be study has reported such an association. associated with atrophy of both the overlying retina and Biomicroscopic examination consistently reveals the the RPE as demonstrated biomicroscopically and angiopresence of diffuse inflammatory cells in both the ante- graphically. Hyperpigmentation may rarely be observed rior and posterior vitreous body. The severity and location in some lesions in the later stages of the disease. 7 , 16 of the vitreous cellular infiltration varies, being more. Other clinical features indicative of chronic intraocular pronounced during earlier stages of the disease,21 some- inflammation in BSRC include vasculitis, involving pretimes forming "mutton fat" precipitates on the posterior dominantly the retinal venules, manifested by sheathing vitreous face during periods of disease activity.2 Alterna- and associated vascular leakage on fluorescein angiogrative diagnoses should be considered inr the absence of vi- phy (FA).1O Vascular incompetence as a result of retinal tritis. 7 vasculitis and posterior segment inflammation is a consisFunduscopic examination highlights the multiple, bi- tent feature of this disease and may produce marked lateral, cream-colored birdshot lesions scattered through- thickening of the retina on biomicroscopic examination. out the postequatorial retina, characteristic of this entity. Cystoid macular edema, either diffuse or focal, and optic These spots tend to be round to ovoid, varying in size nerve head swelling are commonly observed. Progressive from 50 to 1500 /-Lm 7 ,16 (Fig. 65-1). Occasionally, they papillitis may develop into optic atrophy. Attenuation of may become confluent, producing large areas of geo- retinal arterioles and vascular tortuosity,l, 21, 22 nerve fiber graphic depigmentation and even a blond appearance to layer hemorrhages,21,22 retinal and subretinal neovascuthe fundus. 1, 16 BSRC lesions are often best appreciated larization,3, 23, 24 and epiretinal membranes 3, 15 have also with indirect ophthalmoscopy, as their borders are indis- been reported. tinct and not sharply demarcated. The distribution pattern of these spots is variable throughout the posterior The most common complication of BSRC is chronic cystoid macuIar edema, occurring in upward of 50% of cases, and this is the most frequent cause of reduced central visual acuity. 3, 1.5 Its presence is important in establishing the diagnosis 12 and is itself an indication for therapeutic intervention so that permanent structural damage to the macula (cystic macula) is averted and good visual function is preserved. 15 Epiretinal membrane formation occurs in up to 10% of cases 3 and may be responsible for significant visual compromise. 15 Macular pucker has been observed to progress as part of a cicatricial phenomenon during resolution of intraocular inflammation. 13 , 22 Any pathologic process (including intraocular inflammation) that disrupts the integrity of the choriocapillaries-RPE-Bruch's membrane complex, creates an environment that permits the development of choroidal neovascularization (CNV). Priem and Oosterhuis reFIGURE 65~ I. Typical appearance of birdshot lesions in the posterior ported both macular and peripapillary subretinal neovaspole consisting of scattered cream-colored spots varying in size from 50 cularization iIi 6% of their 102 cases of BSRC.3 Likewise, to 1500 f..Lm. (See color insert.)

CHAPTER 65: BIRDSHOT RETINOCHOROIDOPATHY

serous neurosensory elevation associated with juxtapapillary subretinal new vessels has been described in BSRC patients by Soubrane and colleagues. 25 Choroidal neovascular membranes involving the macula may arise adjacent to classic depigmented lesions between 6 months and 5 years after the onset of disease. 24 No specific study has been performed to evaluate the efficacy of laser photocoagulation in the treatment of CNV in eyes affected by BSRC. However, based on the experience with other macular diseases complicated by CNV for which abundant data exist, laser therapy, performed under fluorescein and/or indocyanine green (ICG) guidance, is recommended to prevent loss of central vision. 3, 22, 24, 25 . Of the 203 eyes studied by Priem and Oosterhuis, retinal neovascularization located on the optic disc and in the retinal periphery occurred in 2 and 13 eyes, respectively, apparently in the absence of retinal capillary nonperfusion. 3 Retinal neovascularization has been reported in uveitic eyes without eviq.ence of capillary nonperfusion,26, 27 presumably caused by the release of vasogenic substances by inflammatory mediators. In contrast, peripheral retinal neovascularization associated with capillary closure and localized vitreous hemorrhage in a patient with BSRC was described by Barondesand associates. 23 Other late complications include optic atrophy, either as a sequela to chronic inflammation' or secondary to acute ischemic anterior neuropathy,28 cataract, rubeosis iridis, glaucoma, or rhegmatogenous retinal detachment.lO, 15 '~

ETIOLOGY The etiology of BSRC remains elusive. Although the disease has been reported to occur in monozygotic twins,29 there is no strong familial association or established mode of inheritance. BSRC is unique in having the strongest association between an HLA and a disease that has ever been described. Specifically, the HLA-A29 phenotype is present in 80% to 98% of white patients with BSRC, compared to 7% of controls. 14, 30-33 The relative risk of developing BSRC in a patient bearing the HLA-A29 phenotype is between 50 and 224 times greater than that with other phenotypes. 32 ,33 The sensitivity (96%) and specificity (93%) of HLA type in BSRC patients can be useful in confirming the diagnosis. 34 Feltkamp has calculated that the probability of a diagnosis of BSRC rises from 70% to 97% in HLA-A29-positive patients and drops from 70% to 8.5% in HLA-A29-negative individuals. 35 The strength of this HLA association with BSRC points to an underlying genetic predisposition for the development of the disease. The HLA-A29 antigen can be divided into u,yo subtypes, A29.1 and A29.2, as described by Yang. 36 The distribution of these subtypes varies with· ethnicity: The A29.1 subtype is found more commonly among populations from Southeast Asia (where BSRC has not been reported) ,22,37 whereas the A29.2 subtype is observed in approximately 90% of healthy whites of Northern European extraction. 38 In their analysis of a subgroup of 33 patients with BSRC, Le Hoang and colleagues found the A29.2 subtype in all subjects (100%).14 The significant absence of the A29.1 subtype in this population of pa-

tients has been interpreted as representing a "resistance motif" associated with this molecule by Tabary and coworkers. 39 They found that whereas the sequence of HLA-A29.2 was identical both in BSRC patients and in healthy control subjects, a single substitution in the extracellular domain differentiated the two HLA-A29 subtypes. As the mutation observed in HLA-A29.1 is unique to that molecule, these authors suggest that the ancestral type is HLA-A29.2, vvith resistance to BSRC being conferred by the more recently mutated HLA-A29.1 subtype. They further postulate that the nature of the HLA-A29.1 mutation might influence the binding of the CD8 T-cell glycoprotein, or another accessory molecule, impeding its interaction with the T-cell receptor, and so impairing T-cell activation. 12 , 22, 39 De Waal and coworkers, on the other hand, found that the distribution of HLA-A29 subtypes in their group of 20 Northern European patients with birdshot chorioretinopathy did not differ from that found among healthy controls. 38 Whereas both sUbtypes were found among BSRC patients, HLA-29.2 was more frequently identified because of its overwhelming prevalence (90%) in this particular study population. These authors suggest that disease susceptibility is conferred by a common determinant expressed on both variants of HLA-A29, but the possibility exists that a gene in tight linkage disequilibrium with both subtypes may be involved in the pathogenesis of the disease. 38

PATHOGENESIS It is well established that the class I major histocompatibility (MHC) molecules play an important regulatory role in the immune response, controlling the selection, degradation, and presentation of antigens within antigen presenting cells and their recognition by effector T cells. 40 Retinal autoimmunity may play an important pathogenetic role in the development and perpetuation of intraocular inflammation for HLA-A29-positive individuals, as a result of a genetic error of immune regulation. Evil. del1Ce in support of this notion is found in the strong in vitro. cell-mediated responses to a variety of retinal autoantigens, including S-antigen (S-Ag) and interphotoreceptor retinoid binding protein (IRBP) observed in 92% of patients with BSRC. 32,41 Opremcak and Cowans reported a frequency of between 4 and 7 S-Ag-specific T cells/106 peripheral blood lymphocytes in patients with BSRC.'12 Furthermore, these autoreactive T cells were found to produce interleukin 2 (IL-2) in response to autoantigens, and such cells were not detectable during disease quiescence or during therapy with cyclosporine. Animals immunized with S-Ag develop severe intraocular inflammation termed experimental autoimmune uveitis (EAU) , a disease not dissimilar to that seen in the human patient with BSRC, replete with specific humoral and cellular immune responses to autoantigen. 43 Finally, lymphocytes specifically primed to these autoantigens will produce EAU when adoptively transferred into naive recipients. 44 The histopathologic findings of a single, phthisical eye enucleated from a patient with BSRC, who also exhibited a positive in vitro lymphocyte proliferative response to retinal S-Ag, has been reported. 32 Examination of the iris

CHAPTER 65: BIRDSHOT RETINOCHOROIDOPATHY

and ciliary body revealed a mild lymphocytic infiltration, pigmentation. 55 Opremcak postulates that intercurrent whereas the retina was involved with a diffuse, chronic inflammation of the pineal gland in patients with BSRC granulomatous inflammation with giant cells, epithelioid may playa role in the development of vitiliginous BSRC cells, lymphocytes, and plasma cells in the outer retinal lesions and in the disturbances in the sleep cycles and layers. The inflammatory response in the choroid was mood often observed in these patients. 7 Indeed, patients likewise granulomatous, but it was milder and thought to with chronic posterior uveitis, including those with BSRC, be a secondary response. Similar histopathologic findings show a decrease in the nocturnal peak plasma melatonin are observed in S-Ag-induced EAU in primates. 45 These levels by approximately 45%.56 histopathologic similarities, as well as those seen clinically between S-Ag-induced EAU and that of BSRC, strongly DIAGNOSIS implicate a role for S-Ag and autoimmunity in the patho- The diagnosis of BSRC is essentially a clinical one, based genesis of this disease. 32 on a thorough ophthalmic and medical history, review of The precise mechanisms or inciting events that might systems, and ocular examination revealing the characterlead to the development of retinal autoimmunity or to istic funduscopic picture (Table 65-1). The absence of the abnormal expression of an immune determinant dur- significant anterior inflammatory sequelae (syrlechiae), ing the course of the inflammatory reaction are un- and the presence of vitritis and/or CME without pars known. Whereas autoimmunity may represent an epiphe- plana exudation, all serve to solidify the diagnosis. Except nomenon that develops after an unrelated insult to the for atypical cases, laboratory and ancillary testing are retina, the work of Nussenblatt32 , 4~ and others 46 strongly usually not necessary to establish the diagnosis of BSRC, suggests its bona fide role in the pathogenesis of this but they are most useful in confirming the initial clinical disease. Alternatively, autoimmune phenomena may act impression and in excluding other differential diagnostic to perpetuate the inflammatory disease process rather considerations. than initiate it. 22 Several theories have been proposed to explain the laboratory Investigations genesis of autoimmunity in a genetically predisposed indi- A directed laboratory work-up to rule out likely infectious vidual. 12, 40, 47, 48 One such theory invokes a receptor mech- . (syphilis, tuberculosis) and noninfectious (sarcoidosis, anism in which the MHC antigens provide a specific cell masquerade syndromes) causes of uveitis is essential at surface marker for the binding of an inciting infectious presentation, prior to the commencement of any systemic agent. HLA-A29 patients would develop disease by provid- therapy. It includes the following: complete blood count ing the necessary receptor to a putativ~ "birdshot patho- with differential, fluorescent treponemal antibody absorpgen." Alternatively, an "altered self" model proposes that tion and rapid plasma reagin tests, skin testing for anergy the host's immune system recognizes the HLA-A29 MHC- and with purified protein derivative, tests for angiotensinantigen complex as foreign, having been distorted as a converting enzyme and serum lysozyme, and a chest raresult of binding with an exogenous pathogen (i.e., a diograph. virus, antigen, or hapten). Extended laboratory investigations, unless clinically inThe potential role of such HLA disease mechanisms dicated, are rarely fruitful. Despite the putative autoimin the pathogenesis of BSRC is intriguing, especially in mune etiology, autoantibody studies have not provided the light of recent reports of patients with BSRC and further insights into BSRC pathogenesis and are not useserologic evidence of concomitant infection with a variety ful diagnostically. For example, while anticardiolipin antiofmicroorganisms. 49 ,50 Suttorp-Schulten and associates 50 found antibodies to Borrelia burgdorferi in 3 of 11 patients with BSRC, all of whom carried the HLA-A29 antigen. TABLE 65-1. BIRDSHOT RETINOCHOROIDOPATHY: Further investigation will be necessary to determine DIAGNOSTIC FEATURES whether these results represent false-positive reactions or if, .in fact, B. burgdorferi plays a causative role in the Patient characteristics Whites pathogenesis of BSRC. Likewise, Kuhne and colleagues49 Average age, 50 years speculate on the pathogenetic role of Coxiella burnetii Ocular examination in their two patients with retinal vasculitis and Q fever. Anterior segment Although one of these patients was HLA-A29 positive, a Mild nongranulomatous iridocyclitis Iridocapsular synechiae rare causative role for this organism in BSRC could not be Posterior segment demonstrated. Vitritis Finally, the role of the pineal gland in the pathogenesis Pars plana snowbank absent of BSRC .has been questioned, based on direct evidence Multiple, postequatorial, ovoid, deep, cream-colored ofits involvement in EAU and on indirect evidence sur(depigmented) lesions 50 to 1500 fLm Retinal vascular leakage, cystoid macular edema roundirig the function of this organ.. The retina and the Subretinal, retinal neovascularization pineal gland share a common embryologic origin and, Ancillary tests not surprisingly, common antigens, namelyS-Ag and HLA-A29 positive IRBP.51,52 Moreover, animals immunized with S-Ag and Retinal autoantigen reactivity 53 IRBP develop not only EAU, but also pinealitis. , 54 In Abnormal electroretinogram, electro-oculogram, dark adaptation thresholds healthy individuals, the pineal gland is responsible for Enhanced visualization of choroidal lesions on indocyanine green the secretion of melatonin in a diurnal fashion, a horangiography mone that is thought to control the level of dermal

CHAPTER 65:BIRDSHOT RETINOCHOROIDOPATHY

fiGURE 65-2. Late-phase fluorescein angiogram depicting diffuse leakage and cystoid macular edema.

bodies have been associated with thrombosis and retinal vasculitis, only 3 of 24 patients with retinal vasculitis and none of 10 patients with BSRC were positive for this antibody in a study by Klok and associates. 57 These authors discourage the routine use of this test for diagnostic purposes.

fluorescein AngiographyFA is most helpful in delineating the extent of retinal vascular leakage and in following the clinical course. Indeed, the most prominent findings on angiography include hyperfluorescence of the optic disc, and dye leakage from the retinal venules and capillaries late in the study, resulting in cystoid macular and retinal edelna (Fig. 65-2) .1, 3, 11, 32 Apparent large-vessel perfusion abnormalities are manifested by a delay in the retinal artery filling time, by prolongation of the arteriovenous transit time, and by varying degrees of subnormal fluorescence of the retinal vessels during the course of the study. 2, 16 Interestingly, although the arteriovenous circulation time was observed to be delayed in four patients with BSRC studied by FA, it was found to be nearly normal when viewed with ICG angiography in a reportby Guex-Crosier and Herbort. 58 The authors conclude that the apparent increased retinal circulation time seen on FA is caused by gradual tissue permeation and delayed venous reabsorption of small molecules such as fluorescein (in contradistinction to larger, highly protein-bound ICG molecules) as a result of a deranged blood-retinal barrier rather than as a true reflection of the intravascular hemodynamics. In contrast to their striking appearance when viewed by indirect ophthalmoscopy, the birdshot lesions are far less conspicuous, fewer in number, and manifest inconsistent findings on FA. The angiographic heterogeneity of these lesions seems to depend on their age and associated degree of activity, as well as on the presence of many lesions at different stages of evolution within the same eye. 22 Not infrequently, the early, cream-colored lesions may show no angiographic abnormality, remaining silent throughout all stages of the angiogram. 16, 59 On the other hand, these early lesions, particularly those interpreted as being active, may mask fluorescence in the early phase

of the angiogram and stain in the late phase. 2 , 3, 15 In the former situation, angiographic silence would be predicted by a deep location of the lesions or by those very early in their evolution, such that the overlying RPE and choriocapillaries remain unaffected. 22 An inflammatory infiltrate at the level of the outer choroid associated with large choroidal vessels might, in the latter scenario, disrupt the choriocapillaries' perfusion and cause a secondary alteration in the RPE, producing early hypofluo'rescence with subsequent late-phasehyperfluorescence. 3 , 22, 59 Later in their evolution, the typical focally depigmented or atrophic-appearing BSRC lesions demonstrate uniform hypofluorescence in the early phase of the angiogram, with visualization of the large choroidal vessels through an attenuated RPE and nonperfused choriocapillaries. Diffuse hyperfluorescence and staining of these lesions are seen in the late phases. 2 , 16, 22

Indocyanine Green Angiography Whereas retinal vascular abnormalities are better studied with FA, ICG angiography provides the additional dimension of choroidal analysis in BSRC. ICG reveals welldelineated hypofluorescent choroidal spots in the midphase of the study, which not only correspond to the location of the birdshot lesions but also are far more numerous than those seen either on FA or clinically (Fig. 65-3) .59,60 This again underscores the diffuse nature of the disease process. A one-to-one correspondence in terms of the size of the hypofluorescent dark spots seen

fiGURE 65-3. Indocyanine green (ICG) angiogram disclosing welldelineated hypofluorescent choroidal spots, which not only correspond to the location of the birdshot lesions but also are far mOjre numerous than those seen either on fluorescein angiography or clinically.

CHAPTER 65: BIRDSHOT RETINOCHOROIDOPATHY

on ICG and the size of the lesions seen clinically or on the red-free photographs is not observed. 61 These hypofluorescent choroidal lesions aSSlllne a vasotropic orientation, being bordered by large to medium-sized choroidal vessels, a configuration that appears to be specific to BSRC.60, 62, 63 The choroidal vessels themselves are nonhal, without evidence of large-vessel choroidal inflammatory involvement. 61 The hypofluorescent nature of these lesions may represent hypoperfusion of the choriocapillaris. 22 , 59 Alternatively, they may represent nonvascularized inflammatory foci, as evidenced by the observation that (occasionally) hypofluorescent areas on ICG, especially those corresponding to early lesions, may mask fluorescence from underlying choroidal vessels.59 In other cases, hyperfluorescent spots in the late phases of the ICG study have been demonstrated in patients with active inflammation. 62

Electrophysiology Although the electroretinogram (ERG) is a mass response to light stimuli, the pattern of that response is distinct in BSRC, pointing to topographic retina pathologyY' 64, 65 The a-wave of the ERG is well preserved, whereas the bwave exhibits a reduction in amplitude and an increased latency time. 64 , 65 This negative b-wave configuration is indicative of pathology affecting the inner neural retinal layer with little or no involvement of the photoreceptors, a pattern also seen in central retinal artery occlusion, congenital retinoschisis, and congeni~fll stationary night blindness. 64 These findings are co:hsistent with the marked retinal vasculopathy seen clinically and on FA in patients with BSRC. Depending on the severity and stage of the disease, abnormalities may range from the mere absence of oscillatory potentials to a nonrecordable ERG.3, 6'1, 65 Similarly, abnormal ratios of slow oscillations (light rise versus dark trough [LID < 1.85J) have been reported in the vast majority of patients with BSRC.2,3, 11,64,65 Although' both the slow (LID) and fast (D/L) oscillations are thought to reflect changes in the degree of polarization of the RPE, the slow oscillation appears to be affected by vasculopathy affecting the inner retina, whereas the fast oscillation is not. 65, 66 Other commonly observed electrophysiologic abnormalities include elevation of the dark adaptation thresh0Ids,3, 11, 64, 65 and reduced amplitudes and delayed responses in the pattern-evoked cortical potentials. 65

Other Ancillary Tests Laser flare-cell photometry of four patients with BSRC demonstrated maintenance of the integrity of the blood aqueous barrier (5.7 ± 1.1 photonslmsec versus 4.7 ± 0.16 photons/msec for controls) .67 This finding is consistent with the absence of flare seen clinically and the paucity of anterior segment findings seen in patients with BSRC. Finally, visual field testing has revealed a variety of defects, including constriction of the peripheral visual field, central and paracentral scotomata, and enlargement of the blind spot.2,3, 10,65 Acquired dyschromatopsias, mainly of the blue-yellow type,65 have been reported, while some patients Inay exhibit both blue-yellow and red-green defects. 3

The diagnosis of BSRC is relatively straightforward in patients manifesting vitritis and the classic funduscopic appearance. In these individuals, the differential diagnosis includes the so-called white dot syndromes as well as systemic infectious and noninfectious diseases that produce panuveitis and light-colored fundus lesions at some stage in their clinical course (Table 65-2). As in any case of posterior uveitis, exclusion of potentially treatable infectious causes of intraocular inflammation is imperative. Both syphilis and tuberculosis can produce vitritis and choroiditis with light-colored fundus lesions. 68 , 69 However, these lesions tend not to be ovoid, and they develop varying degrees of RPE hyperplasia. Moreover, signs and symptoms of underlying systemic disease are usually present. These findings, together with positive serology for syphilis, positive intradermal skin testing, and abnormal chest radiographic findings of tuberculosis, serve to distinguish these entities from BSRC. Other presumably infectious entities producing white dots to be considered in the differential diagnosis include diffuse unilateral subacute neuroretinitis (DUSN) and the ocular histoplasmosis syndrome (OHS). While DUSN may present with scattered, deep, gray-white fundus lesions and a moderate vitritis, as the name implies, the . pathology is unilateral.70 In addition, the disease is caused by a nematode, which may leave subretinal tracks, massive RPE disruption, and optic atrophy in its wake. 71 Histoplasma capsulatum is the presumed etiologic agent in OHS, which is characterized by the following cardinal clinical features: peripheral histo spots, peripapillary pigmentary changes, maculopathy, and a quiet vitreous. 72 In contradistinction to the classic BSRC lesions, histo spots are punched out, well delineated, relatively small (200 /-Lm), and may be associated with pigment clumping centrally.73 Furthermore, the absence of vitritis clearly separates OHS from BSRC. Sarcoidosis must be excluded in the work-up of patients suspected of having BSRC. This is particularly important in the absence of anterior segment stigmata of granulomatous inflammation (mutton-fat keratic precipi-

TABLE 65-2. BIRDSHOT RETINOCHOROIDOPATHY: DiffERENTIAL DIAGNOSIS White dots present Infectious Tuberculosis Syphilis Ocular histoplasmosis syndrome Diffuse unilateral subacute neuroretinitis Noninfectious Sarcoidosis Vogt-Koyanagi-Harada syndrome Sympathetic ophthalmia Multifocal choroiditis and panuveitis Punctate inner choroidopathy Multiple evanescent white dot syndrome Acute posterior multifocal placoid pigment epitheliopathy White dots absent Retinal vasculitis Pars planitis Idiopathic (senile) vitritis Intraocular lymphoma

CHAPTER 65: BIRDSHOT RETINOCHOROIDOPATHY

tates and Koeppe or Busacca iris nodules), as both entities manifest vitritis and vasculitis, and the appearance of the choroidal granulomata seen in ocular sarcoid may be confused with typical birdshot lesions. In 22 patients with sarcoidosis, Vrabec and colleagues observed two patterns of "taches de bougie" (candle wax spots), one of which (the . large, posterior, pale yellow-orange streak) developed in six patients and was indistinguishable frOlu the lesions of BSRC.74 Priem and Oosterhuis examined 38 patients in their series of 102 patients with BSRC for evidence of sarcoidosis and identified one individual with biopsy-proven sarcoid. 3 Brinkman and Rothova 75 described six patients with neurosarcoidosis, all of whom had vitritis, disc edema, periphlebitis, and multifocal chorioretinal lesions similar to those seen in BSRC. Likewise, Brod 76 and Kuboshiro and Yoshioka77 each reported patients exhibiting characteristic ocular signs of BSRC who, in fact, had systemic, biopsy-confirmed sarcoidosis. Patients with Vogt-Koyanagi-Harada (VKH) disease may have choroidal lesions in the active phase and present with bilateral intraocular inflammation similar to BSRC. 78 Exudative retinal detachment is an essential feature of VKH, as is the predominance of choroidal versus retinal vascular inflammation appreciated clinically and angiographically. Furthermore, VKH is a systemic disease with characteristic extraocular differentiating features, including poliosis, vitiligo, hearing loss, and meningeal symptoms. Sympathetic ophthalmia, like VKH, is another form of chronic uveitis in which multiple '?cream-colored choroidal inflammatory foci (Dalen-Fuchs nodules) are observed. 79 Although these lesions tend to be more discrete, it is the context of their appearance in the fellow eye after trauma or surgery and inflammation in the inciting eye that distinguishes them from those of BSRC. Multifocal choroiditis and panuveitis syndrome (MCP) , punctate inner choroidopathy (PIC), multiple evanescent white dot syndrome (MEWDS), and acute posterior multifocal placoid pigment epitheliopathy (APMPPE) are other white dot syndromes to be distinguished from BSRC. MCP, as its name implies, is characterized by multiple bilateral, postequatorial lesions of 50 to 200 IJvm in diameter at the level of the RPE or inner choroid, together with vitritis, and frequently anterior segment inflammation. 8o Except for the presence· of inflammation, the funduscopic appearance of MCP and OHS share many similarities that clearly differentiate them from BSRC-namely, the presence of hyperpigmented scars surrounding the peripapillary region, and the smaller, discrete, punched-out peripheral lesions. Likewise, PIC, which shares the ocular characteristics of MCP except for the presence of inflammation, can be distinguished from BSRC.81 MEWDS typically presents in young women as a sudden unilateral loss of vision and is characterized by multiple small (100 to 200 IJvm) white dots at the level of the outer retina or RPE, particularly in the perifoveal and peripheral macula. 82 Not only are the size, color, location, and ephemeral nature of these white dots distinct from those seen in BSRC, but vitritis is minimal and visual recovery is usually observed after 7 weeks in patients with MEWDS. APMPPE, like MEWDS, presents in otherwise healthy adults as acute transient visual loss with minimal

vitritis. But the process is bilateral, albeit asymmetric, in APMPPE.83 In contrast to those seen in BSRC, the creamcolored lesions of APMPPE have a plaque-like morphology and are located predominantly in the posterior pole. Moreover, the FA features of these plaques (i.e., early blockage and late staining) are characteristic and distinct from those of BSRC. Finally, resolution of the acute lesions in APMPPE is usually accompanied by hyperpigmentation and visual recovery. Difficulties in the diagnosis of BSRC may arise in the absence of classic clinical features early in the disease course, in mildly affected eyes, or before the evolution of typical hypopigmented fundus lesions. Priem and Oosterhuis noted that in 5 of their 102 patients, clear-cut evidence of BSRC spots did not develop until several years after their initial presentation with varying degrees of vitritis, papillitis, and retinal vasculitis. 3 This peculiar pattern of late-developing hypopigmented spots, as long as 8 years after the onset of vitritis, papillitis, and retinal vasculitis in patients with BSRC, was subsequently reported. 84, 85 Soubrane and colleagues85 suggest HLA-A29 antigen assessment in cases of longstanding uveitis and vasculitis in an effort to avoid misdiagnosis of idiopathic retinal vasculitis in BSRC patients with late-evolving lesions. Further insight into the evolution of BSRC lesions and the prognostic significance of the HLA-A29 phenotype in patients with retinal vasculitis is provided by Bloch-Michel and Frau86 in their study of 20 patients with BSRC (95% of whom were HLA-A29 positive) and 36 patients with retinal vasculitis (62% HLA-A29 positive). Aluong the 22 patients with retinal vasculitis followed for an average of 8 years who carried the HLA-A29 phenotype, only one developed fundus lesions consistent with BSRC. Patients with BSRC were found to have a more severe disease course than those with idiopathic retinal vasculitis. However, among patients with idiopathic retinal vasculitis, those with the HLA-A29 phenotype tended to have bilateral disease, more posterior involvement, and a poorer visual prognosis than those without the HLA-A29 phenotype, who had more peripheral vascular involvement. Whether BSRC and HLA-A29-positive retinal vasculitis represent different stages of the same disease or two separate entities is not currently known. Bergink and colleagues87 suggest classifying patients with the HLAA29 phenotype and retinal vasculitis who have not yet developed depigmented fundus lesions typical of BSRC as having HLA-A29-positive idiopathic vasculitis. Patients with the pars planitis variant of intermediate uveitis and idiopathic senile vitritis may present with bilateral vitreal inflammation. Unlike patients with BSRC, those with pars planitis are younger and present with inflammatory cells located predominantly in the anterior vitreous with characteristic changes in the peripheral retina and vitreous base known as snowballs or snowbanks. 88 Idiopathic senile vitritis occurs in older individuals, and, as is the case with pars planitis, it is not characterized by fundus lesions, further distinguishing these entities from BSRC.89 Finally, masquerade syndromes, particularly intraocular large-cell lymphoma, may present with bilateral luultipIe, yellow subretinal/sub-RPE infiltrates and a vitritis

CHAPTER 65: BIRDSHOT

RE'Ti~~O~CHO~lOIDC~PA~HIY

that is typically only partially responsive to systemic steroids. 90 Usually, the clinical context, together with the smaller size, larger number, and subretinal location of the lesions· distinguishes this entity from BSRC. While Inany patients with intraocular lymphoma may present with central nervous system disease, a high index of suspicion is necessary to make the diagnosis, beginning with a thorough history and neurologic exam. A systelnic workup, including hematology testing, lumbar puncture, and magnetic resonance imaging, should be performed. Diagnostic vitrectomy is often essential in making the definitive diagnosis.

TREATMENT A definitive therapeutic strategy for the care of patients with BSRC has yet to be formulated, given its uncertain natural history, and the relatively small number of individuals with this disease. The mainstay of treatment has been the use of periocular and systemic steroids, but their efficacy is inconsistent, with an unclear effect on the longterm visual prognosis. 1-3,10,32 Although some patients may experience a dramatic initial improvement in visual acuity in response to relatively high doses of systemic prednisone (1.0 mg/kg daily) or periocular triamcinolone (40 mg/ml), others may not. The benefits of periocular steroid therapy are transient, providing short-term reduc:-: tion in vitreal inflammation and hastening the resolution of CME. Hence, the use of regional corticosteroids is mainly adjunctive, employed in the treatment of inflammatory exacerbations for patients on syg.temic therapy or in cases of asymmetlic disease. Of those patients treated with systemic steroids, less than 15% achieve an adequate clinical response and are able to be maintained on low to moderate doses of prednisone. 7 This, together with steroid intolerance and concerns regarding the highly undesirable side effects associated with prolonged administration, limit the utility of systemic steroids in the treatment of BSRC. Similarly, nonsteroidal anti-inflammatory drugs 91 and various cytotoxic agents have been employed without substantiated efficacy. 1, 2, 11 Cyclosporine A (CSA) , a fungal metabolite that prevents the production of IL-2, and thus helper T-cell function, has been of value in treating retinal S-Ag-induced experimental autoimmune uveitis,92 and posterior uveitis in humans. 93 Because retinal autoimmunity is thought to play an important role in the pathogenesis of BSRC, one might expect CSA to be efficacious in its treatment. Nussenblatt and colleagues 93 , 94 reasoned in this manner and treated a small group of patients with BSRC with CSA, reporting good results. These findings were corroborated by Le Hoang and associates,13 who treated 21 patients (42 eyes) suffering from BSRC with CSA. A marked reduction of vitritis was reported in all eyes, improved visual acuity in 23 (54.8%) eyes, and stabilization of vision in 11 (26.2%) eyes. These reports, other uncontrolled studies,95-97 two nonrandomized98 ,99 and one randomized clinical trial,lOo each reporting the efficacy of CSA in the treatment of various forms of noninfectious uveitis, all employed doses of 10 mg/kg daily, a dose that is now known to be associated with a very high incidence of untoward nephrotoxic and hypertensive effects. In an effort to curtail these and other secondary com-

plications of CSA therapy, low-dose regilnens (2.0 to 5.0 mg/kg daily), with vigilant monitoring for toxicity, have been advocatedYll Studies employing low-dose CSA alone,102, 103 in combination with low-dose prednisone,104-107 or with other immunosuppressive agents 15 , 94, 108-110 have demonstrated anti-inflammatory efficacy while reducing, but not eliminating, CSA-associated toxicity. Indeed, with careful monitoring, renal side effects were well tolerated and vision improved or stabilized in 76% of 22 uveitis patients treated with long-term (mean, 7 years), low-dose (0.75 to 2.0 mg/kg daily) CSA.lll However, systemic hypertension occurred in 81 % of 16 previously normotensive patients with idiopathic autoimmune uveitis treated with low-dose CSA (5.0 mg/kg daily) for at least 2 years. Blood pressure was controlled with a single medication in all but two patients. 112 In our study of 19 patients with BSRC, a favorable visual outcome, inflammatory control, and a lack of demonstrable CSA-associated nephrotoxicity with few secondary side effects were achieved employing very low initial doses of CSA (2.5 mg/kg daily), alone or in combination with azathioprine as a steroid-sparing agent. 15 Vitreous inflammation was controlled in 23 eyes (88.5%) treated according to this strategy. Visual acuity improved or stabilized in 20 eyes (83.3%) receiving CSA alone or in combination with azathioprine, whereas 6 of 11 eyes (54%) receiving only periocular steroids experienced a significant deterioration in visual acuity. Serum creatinine levels were virtually unchanged from baseline during the follow-up period (median, 36 months) and it was necessary to discontinue CSA because of hypertension in only one patient. The paucity of hypertensive side effects and renal toxicity, as reflected by the change in the serum creatinine from baseline, may have been the result of the very low initial dose of CSA (2.5 mg/kg daily) employed and subsequent escalation to the target range of 3.0 to 5.0 mg/kg daily, and to vigilant monitoring of these parameters. Finally, a philosophy of zero tolerance for even lowgrade inflammation and a limited tolerance for steroid use in patients for whom alternative anti-inflammatory medication is a reasonable option, to limit permanent ocular structural damage, underlies our approach to uveitis patients in general and those with BSRC in particular. Given the uncertain natural history and visual prognosis, the presence of intraocular inflammation rather than an arbitrary visual acuity level was the primary indication for the initiation of low-dose CSA. This parameter also determined the threshold for subsequent dosage adjustInents and for the addition of azathioprine as a steroidsparing agent. In this way, perhaps patients with BSRC may achieve long-term benefits from low-dose CSA therapy early in the course of their disease, even when the visual acuity is better than 20/40 prior to the onset of visually limiting sequelae.

NATURAL HISTORY AND PROGNOSIS The natural history of BSRC is unknown. The disease is chronic, marked by multiple exacerbations and remissions that may extend over a period of decades. Although some investigators believe that BSRC has a tendency to stabilize over a 3- to 4-year period and go into remission,l,o

CHAPTER 65: BIRDSHOT

others are more pessimIstIC about the long-term visual prognosis. I - 3, 15,32 Some patients may have relatively good visual acuity on presentation, but as many as 20% may experience a reduction in visual acuity of three Snellen lines or more, with greater than one third of such eyes reaching a level of 20/200 or worse in at least one eye. I - 3, 10,11, 32 Visual loss is most commonly the result of CME and optic atrophy.21 The long-term outcome of treatment with various low-dose CSA regimens for BSRC is unknown. Given the rationale for the use of CSA in this disease entity, it is hoped that permanent ocular structural damage can be limited by its use in achieving complete control of intraocular inflammation and thus an improved visual outcome in patients suffering from BSRC.

CONCLUSIONS BSRC is a recently recognized, distinct, uveitic entity characterized by the presence of vitritis, retinal vascular incompetence, and a striking funduscopic picture of multiple hypopigmented lesions. ICG angiography reveals many more of these lesions than are appreciated on either FA or on clinical exam, reflecting the diffuse nature of the disease process. Although its etiology is unknown, autoimmune mechanisms are likely to play an important role, given the demonstration of retinaJ autoantigen reactivity and the strong association with HLAA29. Untreated, the natural history for useful vision in at least one eye appears to be poor, and therapy with corticosteroids is of inconsistent.~fficacyand is associated with an uncertain visual prognosis. Given the putative autoimmune pathogenesis, a rationale exists for the use of CSA in the treatment of BSRC. Clinical experience suggests that low-dose regimens of CSA, used alone or in combination with other immunosuppressive agents, are both safe and effective, and offer a useful steroid-sparing strategy in the management of BSRC, provided vigilant monitoring for potential druginduced toxicities is exercised.

References 1. Ryan S], Maumenee AE: Birdshot retinochoroidopathy. Am] Ophthalmol 1980;89:31. 2. Gass ]DM: Vitiliginous chorioretinitis. Arch Ophthalmol 1981; 99:1978. 3. Priem HA, Oosterhuis]A: Birdshot chorioretinopathy: Clinical characteristics and evolution. Br] Ophthalmol 1988;72:646. 4. Franceschetti A, Babel]: La chorio-retinite en "taches de bougie" manifestation de la maladie de Besnier-Boek. Ophthalmologica 1949;118:701. 5. Aaberg TM: Diffuse inflammatory salmon patch choroidopathy syndrome. International Fluorescein Macula Symposium. Carmel, CA,1979. 6. Amalric P, Cuq G: Une forme tres particuliere de chorioretinopathie en grans de riz. Bull Soc Ophtalmol Fr 1981;81:131. 7. Opremcak EM: Birdshot retinochoroiditis. In: Albert DM,]akobiec FA, eds: Principles and Practice of Ophthalmology, vol 1. Philadelphia, W.E. Saunders, 1994, p 475.. 8. Henderly DE, Genstler A], Smith RE, et al: Changing patterns of uveitis. Am] Ophthalmol 1987;103:131. 9. Rodriguez A, Calonge M, Pedroza-Seres M, et al: Referral patterns of uveitis in a tertiary eye care center. Arch Ophthalmol 1996;114:593. 10. Fuerst D], Tessler HH, Fishman GA, et al: Birdshot retinochoroidopathy. Arch Ophthalmol 1984;102:214. 11. Kaplan H], Aaberg TM: Birdshot retinochoroidopatl1Y. Am] Ophthalmol 1980;90:773.

RE·Tli'~O'CHORlOIDC.PAJ"HIY

12. Nussenblatt RB, Whitcup SM, Palestine AG: Birdshot retinochoroidopathy. In: Nussenblatt RB, Whitcup SM, Palestine AG, eds: Uveitis: Fundamentals and Clinical Practice, 2nd ed. St Louis, Mosby-Year Book, 1996, p 325. 13. Le Hoang P, Girard B, Keray G, et al: Cyclosporine in the treatment of birdshot retinochoroidopathy. Transplant Proc 1988;20(suppl 4):128. 14. Le Hoang P, Ozdemir N, Benhamou A, et al: HLA-A29.2 subtype associated with birdshot retinochoroidopathy. Am ] Ophthalmol 1992;113:33. 15. Vitale AT, Rodriguez A, Foster CS: Low-dose cyclosporine therapy in the treatment of birdshot retinochoroidopatl1Y. Ophthalmology 1994;101:822. 16. Gass ]DM: Inflammatory diseases of the retina and choroid. In: Stereoscopic Atlas of Macular Diseases, Diagnosis and Treatment, 4th ed, vol II. St Louis, Mosby-Year Book, 1997, p 710. 17. Wagoner MD, Albert DM, Lerner AB, et al: New observations on vitiligo and ocular disease. Am] Ophthalmol 1983;96:16. 18. Heaton ]M, Mills RP: Sensorineural hearing loss associated with birdshot retinochoroidopathy. Arch Otolaryngol Head Neck Surg 1993;119:680. 19. Noble KG, Greenberg]: Appearance of birdshot retinochoroidopathy in a patient with myelodysplasia. Am ] Ophthalmol 1998;125:108. 20. Hesse S, Berhis P, Chemila ]F, et al: Psoriasis and birdshot chorioretinopathy: A response to aromatic retinoids. Dermatology 1923;187:137. 21. Ryan S], Dugel PU, Stout T]: Birdshot retinochoroidopathy. In: Ryan S], ed: Retina, 2nd ed, vol 2, Medical Retina. St. Louis, Mosby-Year Book, 1994, p 1677. 22. Le Hoang P, Ryan S]: Birdshot retinochoroidopatl1y. In: Pepose ]S, Holland GN, Wilhelmus KR, eds: Ocular Infection and Immunity. St Louis, Mosby-Year Book, 1996, p 570. 23. Barondes M], Fastenberg DM, Schwartz PL, et al: Peripheral retinal neovascularization in birdshot retinochoroidopathy. Ann Ophthalmol 1989;21:306. 24. Brucker A], Deglin EA, Bene C, et al: Subretinal choroidal neovascularization in birdshot retinochoroidopathy. Am ] Ophthalmol 1985;99:40. 25. Soubrane G, Coscas G, Binaghi M, et al: Birdshot retinochoroi~ dopathy and subretinal new vessels. Br] Ophthalmol 1983;67:461. 26. Felder KS, Brockhurst R]: Neovascular fundus abnormalities in peripheral uveitis. Arch Ophthalmol 1982;100:750. 27. Shorb SB, Irvine AR, Kimura SL, et al: Optic disk neovascularization associated with chronic uveitis. Am] Ophthalmol1967;82:175. 28. Caballero-Presencia A, Diaz-Guia E, Lopez-Lopez ]M: Acute anterior ischemic optic neuropathy in birdshot retinochoroidopathy. Ophtl1almologica 1988;196:87. 29. Fich M, Rosenberg T: Birdshot retinochoroidopathy in monozygotic twins. Acta Ophthalmol 1992;70:693. 30. Baarsma GS, Kijlstra A, Oosterhuis ]A, et al: Association of birdshot retinochoroidopathy and HLA-A29 antigen. Doc Ophthalmol 1986;61 :267. 31. Baarsma GS, Priem HA, Kijlstra A: Association of birdshot retinochoroidopathy and HLA-A29 antigen. Curr Eye Res 1990;9:63. 32. Nussenblatt RB, Mittal KK, Ryan S, et al: Birdshot retinochoroidopatl1Y associated with HLA-A29 antigen and immune responsiveness to retinal S-antigen. Am] Ophtl1almol1982;94:147. 33. Priem HA, Kijlstra A, Noens L, et al: HLA typing in birdshot chorioretinopathy. Am] Ophthalmol 1988;105:182. 34. Feltkamp TEW: Ophtl1almological significance of HLA associated uveitis. Eye 1990;4:839. 35. Feltkamp TEW: HLA and uveitis. Int Ophthalmol 1990;14:327. 36. Yang SY: Population analysis of class I HLA antigens by onedimensional isoelectric focusing gel electrophoresis: Workshop summary report. In: Dupont B, ed: Immunobiology of HLA. New York, Springer-Verlag, 1989, p 309. 37. Tabary T, Le HoangP, Betuel H, et al: Susceptibility to birdshot choroidopatl1Y is restricted to the HLA-A29.2 subtype. Tissue Antigens 1990;36:177. 38. de Waal LP, Lardy NM, van der Horst AR, et al: HLA-A29 subtypes and birdshot retinochoroidopathy. Immunogenetics 1992;35:51. 39. Tabary T, Prochnicka-Chalufour A, Cornillet P, et al: HLA subtypes and "birdshot" choroido-retinopathy susceptibility: A possible "resistance motif" in the HLA-A29.1 molecule. C R Acad Sci III 1991;313:599.

CHAPTER 65: BIRDSHOT RETINOCHOROIDOPATHY 40. Svejgaard A: HLA and disease. In: Rose NR, Friedman H, eds: Manual of Clinical Immunology, 2nd ed. Washington, DC, Alnerican Society of Microbiology, 1980, p 1049. 41. de Smet MD, Yamamoto JH, Mochizuki M, et al: Cellular immune responses of patients with uveitis to retinal antigens and their fragments. A1nJ Ophthalmol 1990;110:135. 42. Opremcak EM, Cowans AB: Limiting dilution analysis of S-antigen specific IL-2 secreting autoimmune T-lymphocytes inpatients with uveitis. Invest Ophthalmol Vis Sci 1990;32(suppl):66. 43. Wacker VVB, Donoso LA, Kalsow CM, et al: Experimental allergic uveitis. Isolation, characterization, and localization of a soluble uveitopathogenic antigen from bovine retina. J Immunol 1977;119:1949. 44. Mochizuki M, Kuwabara T, McAllister C, et al: Adoptive transfer of experimental autoimmune uveoretinitis in rats: Immunopathogenic mechanisms and histologic features. Invest Ophthalmol Vis Sci 1985;26:1. 45. Nussenblatt RB, Kuwabara T, de Montasterio F, et al: S-antigen uveitis in primates: A new model for human disease. Al'ch Ophthalmol 1981;99:1090. 46. Jobin D, Thillaye B, de Kozak Y, et al: Severe retinochoroidopathy: Variations of humoral and cellular immunity to S-antigen in a longitudinal study. Curr Eye Res 1990;9(suppl):91. 47. Bejamin R, Parham P: HLA-B27 and ankylosing spondylitis. Immunol Today 1990;11:132. 48. Tiwari JC, Terasaki PI: Guilt by Association. HLA and Disease Association. New York, Springer-Verlag, 1989, pp 25 and 264. 49. Kuhne F, Morlat P, Riss I, et al: Is A29, B12 vasculitis caused by the Qfever agent (Coxiella burnetii)? J Fr Ophthalmol1992;15:315. 50. Suttorp-Schulten MS, Luyendijk L, van Dam AP, et al: Birdshot chorioretinopathy and Lyme borreliosis. Am J Ophthalmol 1993;115:149. 51. Kalsow CM, Wacker VVB: Pineal gland invDlvement in retina-induced experimental allergic uveitis. Invest Ophthalmol Vis Sci 1978;17:774. 52. Rodrigues MM, Hackett J, Gaskins R, et al: Interphotoreceptor retinoid-binding protein in retinal rod ce'fls and pineal gland. Invest Ophthalmol Vis Sci 1986;27:844. 53. Gery I, Wiggert B, Redmond TM, et al: Uveoretinitis and pinealitis induced by immunization with IRBP. Invest Ophthalmol Vis Sci 1986;27:1296. 54. Mochizuki M, Charley J, Kuwabara T, et al: Involvement of the pineal gland in rats with experimental autoimmune uveitis. Invest Ophthalmol Vis Sci 1983;24:1333. 55. Lewy AJ: The pineal gland. In: Wyngaarden JB, Smith LH, Bennett JC, eds: Cecil Textbook of Medicine, 19th ed, vol II. Philadelphia, W.B. Saunders, 1992, p 1246. 56. Touitou Y, Le Hoang P, Claustrat B, et al: Decreased nocturnal plasma melatonin peak in patients with a functional alteration of the retina in relation with uveitis. Neurosci Lett 1986;70:170. 57. Klok AM, Geertzen R, Rothova A, et al: Anticardiolipin antibodies in uveitis. Curl' Eye Res 1992;11 (suppl) :709. 58. Guex-Crosier Y, Herbort CP: Prolonged retinal arterio-venous circulation time by fluorescein but not by indocyanine green angiography in birdshot retinochoroidopathy. Ocul Immunol Inflamm 1997;5:203. 59. Howe LJ, Stanford MR, Graham EM, et al: Choroidal abnormalities in birdshot retinochoroidopathy: All indocyanine green angiography study. Eye 1997;11:554. 60. Chang B, Goldstein DA, Rabb MF, et al: Indocyanine green angiographic features in birdshot retinochoroidopathy. Invest Ophthalmol Vis Sci 1995;36:S782. 61. Coscas G: Personal communication, Paris, 1999. 62. Herbort CP, Borruat F, de Couten C, et al: Allgiographie au vert d'indocyanine dans les uveites posterieures. Klin Monatsbl Augenheilkd 1996;208:321. 63. Yannuzi LA, Sorenson JA, Guyer DR, et. al: Indocyanine green angiography: Current status. Eur J Ophthalmol 1994;4:69. 64. Hirose T, Katsumi 0, Pruett RC, et al: Retinal function in birdshot retinochoroidopathy. Acta Ophthalmol 1991;69:327. 65. Priem HA, De Ruuck A, De Laey jJ, et al: Electrophysiological studies in birdshot chorioretinopathy. Am J Ophthalmol 1998;106:430. 66. De Rouck. A, Kayembe D: A clinical procedure for the simultaneous recording of fast and slow EOG oscillations. Int Ophthalmol 1981;3:179.

67. Guex-Crosier Y, Pittet N, Herbort CP: Evaluation of laser flarecell photometry in the appraisal and management of intraocular inflammation in uveitis. Ophthalmology 1994;101:728. 68. Helm CJ, Holland GN: Ocular tuberculosis. Surv Ophthalmol 1993;38:229. 69. Tamesis RR, Foster CS: Ocular syphilis. Ophthalmology 1990;97:1281. 70. Gass JDM, Scelfo R: Diffuse unilateral subacute neuroretinitis. J R Soc Med 1978;71:95. 71. Kazacos KR, Vestre WA, I(azacos EA, et al: Diffuse unilateral subacute neuroretinitis syndrome: A probable cause. Arch Ophthalmol 1984;102:967. 72. Woods AC, Whalen HE: The probable role of benign histoplasmosis in the etiology of granulomatous uveitis. Aln J Ophthalmol 1960;49:205. 73. Smith RE, Ganley JP, Knox DL: Presumed ocular histoplasmosis. II. Patterns of peripheral and peripapillary scarring in persons with nonmacular disease. Arch Ophthalmol 1972;85:251. 74. Vrabec TR, Augsburger jJ, Fischer DH, et al: Taches de bougie. Ophthalmology 1995;102:1712. 75. Brinkman CJ, Rothova A: Fundus pathology in neurosarcoidosis. Int Ophthalmol 1993;17:23. 76. Brod RD: Presumed sarcoid choroidopathy mimicking birdshot retinochoroidopathy. A1n J Ophthalmol 1990;109:357. 77. Kuboshiro T, Yoshioka H: Birdshot retinochoroidopathy: A possible relationship to ocular sarcoidosis. Krume Med J 1998;35: 193. 78. Moorthy RS, Inomata H, Rao NA: Vogt-Koyanagi-Harada syndrome. Surv Ophthalmol 1995;39:265. 79. Marak GE: Recent advances in sympathetic ophthalmia. Surv Ophthalmol 1979;24: 141. 80. Nozik RA, Dorsch W: A new chorioretinopathy associated with anterior uveitis. A1n J Ophthalmol 1973;76:758. 81. Watzke RC, Packer AJ, Folk JC, et al: Punctate inner choroidopathy. Aln J Ophthalmol 1984;98:572. 82. Jampol LM, Sieving PA, Pugh D, et al: Multiple evanescent white dot syndrome. 1. Clinical findings. AlTh Ophthalmol1984;102:671. 83. Gass JDM: Acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol 1968;80:177. 84. Godel V, Baruch E, Lazar M: Late development of chorioretinal lesions in birdshot retinochoroidopathy. Ann Ophthalmol 1989;21:49. 85. Soubrane G, Bokobza R, Coscas G: Late developing lesions in birdshot retinochoroidopathy. Anl J Ophthalmol 1970;109:204. 86. Bloch-Michel E, Frau E: Birdshot retinochoroidopathy and HLAA29 + and HLA-A29-idiopathic retinal vasculitis: Comparative study of 56 cases. CanJ Ophthalmol1991;26:361. 87. Bergink GJ, Ooyman FM, Maas S, et al: Three HLA-A29 positive patients with uveitis. Acta Ophthalmol Scand 1996;74:81. 88. Brockhurst RJ, Schepens CL, Okamura ID: Uveitis. II. Peripheral uveitis. Clinical description, complications, and differential diagnosis. AlnJ Ophthalmol 1960;49:1257. 89. Brinton GS, Osher RH, Gass JD: Idiopathic vitritis. Retina 1983; 3:95. 90. Whitcup SM, de Smet MD, Rubin BI, et al: Intraocular lymphoma: Clinical and histopathologic diagnosis. Ophthalmology 1993; 100:1399. 91. Hofman HM, Feicht B: Birdshot chorioretinopathy: Systemic therapy with corticosteroids and nonsteroidal anti-inflammatory drugs. Klin Monatsbl Augenheilkd 1990;197:159. 92. Nussenblatt RA, Rodrigues MM, Wacker VVB, et al: Cyclosporine A. Inhibition of experimental autoimmune uveitis in Lewis rats. J Clin Invest 1981;67:1228. 93. Nussenblatt RB, Palestine AG, Chan CC: Cyclosporine therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents. A1n J Ophthalmol 1983;96:275. 94. Nussenblatt RB, Palestine AG, Chan CC: Cyclosporine therapy for uveitis: Long-term followup. J Ocul Pharmacol 1985;1:369. 95. Binder AI, Graham EM, Sanders MD, et al: Cyclosporine A in the treatment of severe Beh<;:et's uveitis. Br J Rheumatol 1987;26:285. 96. Graham EM, Sanders MD, James DG, et al: Cyclosporine A in the treatment of posterior uveitis. Trans Ophthalmol Soc U K 1985;104:146. 97. Wakefield D, McCluskey P: Cyclosporine: A therapy in inflammatory eye disease. J Ocul Pharmacol 1991;7:221.

CHAPTER 65: BIRDSHOT RETINOCHOROIDOPATHY 98. de Vries ], Baarsma GS, Zaal M]W, et al: Cyclosporine in the treatment of severe chronic idiopathic uveitis. Br ] Ophthalmol 1990;74:344. 99. Masuda K, Nakajima A, Urayama A, et al: Double-masked trial of cyclosporine versus colchicine and long-term open study of cyclosporine in Beh~et's disease. Lancet 1989;1:1093. 100. Nussenblatt RB, Palestine AG, Chan CC, et al: Randomized, double-masked study of cyclosporine compared to prednisolone in the treatment of endogenous uveitis. Am] OphthalmoI1991;112:138. 101. Benezra D, Nussenblatt RB, Timonen P: Optimal use of Sandimmune in endogenous uveitis. Berlin, Springer-Verlag, 1988. 102. Cohen E, Raz], Maftzir G, et al: Low-dose cyclosporine A in uveitis: A long term follow-up. Ocul Immunol Inflamm 1993;1:195. 103. Towler HM, Cliffe AM, Whiting PH, et al: Low dose cyclosporine A therapy in chronic posterior uveitis. Eye 1989;3:282. 104. Bielory L, Holland C, Gaslon P, et al: Uveitis, cutaneous and neurosarcoid: Treatment with low-dose cyclosporine A. Transplant Proc 1998;20(suppl 4):144. 105. Diaz-Llopis M, Cervera M, Menezo]L: Cyclosporine A treatment of Bell~et's disease: A long-term study. Curl' Eye Res 1990;9(Suppl):17.

106. Towler HM, Lightman SL, Forrester ]V: Low-dose cyclosporine therapy of ocular inflammation: Preliminary report of a long-term follow-up study.] Autoimmun 1992;5 (suppl A) :259. 107. Towler HM, Whiting PH, Forrester ]V: Combination low dose cyclosporine A and steroid therapy in chronic intraocular inflammation. Eye 1990;4:514. 108. Hooper PL, Kaplan H]: Triple agent immunosuppression in serpiginous choroiditis. Ophthalmology 1991;98:944. 109. Nussenblatt RB, Palestine AG, Chan CC, et al: Improvement of uveitis and optic nerve disease by cyclosporine in a patient with multiple sclerosis. Am] Ophthalmol 1984;97:790. 110. Vitale AT, Rodriguez A, Foster CS: Low-dose cyclosporine A therapy in treating chronic, noninfectious uveitis. Ophthalmology 1996;103:365. 111. Callanan DG, Cheung MK, Martin DF, et al: Outcome of uveitis patients treated with long term cyclosporine. Invest Ophthalmol Vis Sci 1994;35:2094. 112. Deray G, Benhmida M, Le Hoang P, et al: Renal function and blood pressure in patients receiving long-term, low-dose cyclosporine therapy for idiopathic autoimmune uveitis. Ann Intern Med 1992;117:578.

I

I

William J. Power

Sympathetic ophthalmia is probably the best-known intraocular inflammatory condition to practitioners outside of ophthalmology. It is a bilateral granulomatous. uveitis that occurs after either surgery or penetrating trauma to one· eye. The traumatized eye is called the exciting eye and the noninjured eye is called the sympathizing eye. Although not a common disease, it remains one of the most feared complications in ophthalmology today because of its potentially blinding effects in both eyes. Newer observations have helped put this disorder into perspective.

HISTORY Sympathetic ophthalmia has stimulated enormous interest since its clinical description by William MacKenzie in the middle of the 19th century.l In his series of six patients, all of whom followed penetrating trauma, he found that the recurrent attacks of inflammation led to eventual blindness and that no treatment was effective for the condition. MacKenzie postulated that the in:.: flammatory process spread from the exciting to the sympathizing eye via the optic nerve and optic chiasm. Ernest Fuchs has been credited with .,.the first detailed histopathologic description of the disease and established it as a separate disease entity, distinct from other ocular inflammatory disorders. 2 He described a mixed-cell inflammatory infiltration of the uveal tract particularly affecting the choroid. He and Dalen independently described the inflammatory nodular aggregates (DalenFuchs nodules) that now bear their names. 3

INCIDENCE AND EPIDEMIOLOGY There' are numerous reports in the literature regarding the incidence of sympathetic ophthalmia, but in many purported cases pathologic proof of the diagnosis is lacking. In the older literature in particular, sympathetic ophthalmia was probably often confused with other forms of uveitis. Sympathetic ophthalmia occurs more often after nonsurgical trauma. Liddy and Stuart reported the disorder as occurring in 0.2% of nonsurgical wounds,4 and Holland found it in 0.5% of eyes with trauma. 5 Marak has estimated the incidence of this disease to be less than 10 cases per 100,000 surgical penetrating wounds. 6 SYlnpathetic ophthalmia has occurred after intraocular procedures such as paracentesis, iridectomy, iris inclusions, cyclodialysis, transscleral neodYlnium:YAG (yttrium alulninum garnet) cyclodestruction, cataract extraction, evisceration, retinal detachment repair, and pars plana vitrectomy.7-12 Gass 12 reports that the prevalence of sympathetic ophthalmia is 0.01 % following routine pars plana vitrectomy but 0.06% when pars plana vitrectomy is performed in the context of other penetrating wounds, suggesting that the clinical impression of an increased prevalence of sympathetic ophthalmia following multiple surgical pro-

cedures 13 may in fact be accurate. It has also been reported to have occurred following proton beam irradiation, and after helium ion therapy for choroidal melanOlna.14, 15 No cases of sympathetic ophthalmia were seen as a result of trauma suffered during the Vietnam War, the Korean Conflict, or the Six Days' War. 13 This is in contrast to the older literature suggesting an incidence of about 2%. Duke-Elder and Perkins claimed an unreferenced incidence of over 16% occurring during the American Civil War. 16 It must be borne in mind that there were no specialized ophthalmologists among the physicians in the Civil War, and so this figure is almost certainly an overestimate of the true incidence. Indeed, during the last century, and in particular over the last 30 years, there has been a dramatic decrease in the incidence of sympathetic ophthalmia, resulting in large part from the advent of corticosteroids and antibiotics, together with improved surgical management of traumatic ocular injuries. 4, 17, 18 It is thought to be more common in men, almost certainly because of their higher incidence of ocular trauma. It is also thought'to be more common in lighterskinned races, but this may be because of better reporting and recognition of the disease.

CLINICAL Sympathetic ophthalmia is a bilateral panuveitis. The onset of inflammation in the sympathizing eye is quite often insidious. The latent period is usually between 2 weeks and 3 months, but cases have been reported as early as 5 days and as late as 66 years after the initial incident. 19 , 20 Ninety percent of cases become manifest in the first year after the injury. The inflammatory response seen in the anterior chamber is granulomatous in the classic case, with muttonfat keratic precipitates on the corneal endothelium and findings of an acute anterior uveitis (Fig. 66-1). There is generally a moderate to severe vitritis accompanied by posterior segment abnormalities. Of particular note are multiple white-yellow lesions seen in the periphery of the choroid, sometimes becoming confluent (Fig. 66-2). These represent the clinical appearance of the DalenFuchs nodule. Papillitis can be most prominent and circumpapillary 'choroidal lesions may be seen as well. It should be remembered that the clinical appearance of sYlnpathetic ophthalmia represents a spectrum, which can range from very mild to severe. Alopecia, poliosis, vitiligo, dysacousia, and cells in the cerebrospinal fluid, typically found in Vogt-Koyanagi-Harada sYl1drome (VKH), may rarely be associated with sympathetic ophthalmia. The sequelae of the inflammation noted in sympathetic ophthalmia are quite variable, depending on the severity of the ocular inflammation and whether therapy has been instituted. Secondary glaucoma as well as cataract can be seen. In addition, retinal and optic atrophy may occur, which may be seen in association with retinal detachment or subretinal fibrosis and underlying choroidal atrophy.

CHAPTER 66: SYMPATHETIC

FIGURE 66-1. Granulomatous anterior uveitis in a patient with acute sympathetic ophthalmia.

In the acute phase of· sympathetic ophthalmia, the fluorescein angiogram typically demonstrates multiple hyperfluorescent sites of leakage at the level of the retinal pigment epithelium during the venous phase, and, like those seen in VIlli, they persist. In severe cases, these foci may coalesce, with pooling of dye beneath areas of exudative neurosensory detachment. Less commonly, the angiogram demonstrates multiple hypofluorescent areas followed by late staining, as seen in acute posterior multifocal placoid pigment epitheliopathy. The sites of early blocked fluorescence gener<;!lly correspond to the clinically observed Dalen-Fuchs nctdules (Fig. 66-3). It is probably the status of the pigment epithelium overlying the Dalen-Fuchs nodules or the integrity of the choriocapillaris that determines the hyperfluorescent or hypofluorescent nature of these lesions on angiography. The optic nerve head may demonstrate leakage in the later stages of the angiogram. B-scan ultrasonography can be used to demonstrate the marked choroidal thickening seen in cases of sYlupathetic ophthalmia (Fig. 66-4).

FIGURE 66-3. Multiple areas of hyperfluorescence on fluorescein angiography. The smaller areas of hyperfluorescence corresponded to the clinically observed Dalen-Fuchs nodules.

The histopathology of the inflammatory changes in sympathetic ophthalmia are identical in the exciting and

sympathizing eyes. 21 A diffuse granulomatous infiltration is seen throughout the uveal tract, with marked thickening in the posterior choroid (Fig. 66-5). Classically, the choriocapillaris is spared and there is a relative lack of retinal involvement. However, atypical histopathologic features in the history of sYlupathetic ophthalmia have been reported. Specifically, variable degrees of retinal involvement, including perivasculitis, retinitis, detachment, and gliosis, have been described. s The other characteristic histopathologic finding in sympathetic ophthalmia is that of Dalen-Fuchs nodules, which are present in about one third of eyes. 22 These nodules represent collections of lymphocytes, histiocytes, and altered pigment epithelial cells that lie just internal to Bruch's membrane. Jakobiec and coworkers 22 and Chan and colleagues 23 have used monoclonal antibodies to demonstrate that Dalen-Fuchs nodules are composed of a mixture of Ia + cells, OKMI cells (presumably histiocytes), and depigmented retinal pigment epithelial cells that are Ia - and OKMI -. The subsets of infiltrating lymphocytes in the choroid have also been identified

FIGURE 66-2. Multiple cream-colored lesions scattered throughout the midequatorial region of the fundus in a patient with sympathetic ophthalmia. (See color insert.)

FIGURE 66-4. B-scan ultrasonography demonstrating marked choroidal thickening.

PATHOLOGY AND PATHOGENESIS

66: SYMPATHETIC OPHTHALMIA

FIGURE 66-5. Histopathologic examination of an eye with sympathetic ophthalmia show~ an intense mononuclear cell infiltrate in the choroid with relative sparing of the choriocapillaris. (H&E original magnification X 80.) (See color insert.)

using immunohistochemical techniques. While ]akobiec and colleagues22 noted a predominance of CDS cells in the choroid of patients in eyes rem.oved well after the initial surgical trauma, Chan and coll~agues23 have noted there is a predominance of CD4 T cells in an. eye enucleated only several months after initial npnsurgical trauma. They later found that the sympathizing eye of the same patient, which ultimately came to be studied, had a predominance of CDS cells. These changes in T-cell subsets over time may reflect a dynamic situation in which there is an attempt to down-regulate the immune response with the influx of suppressor T cells. Another highly characteristic histopathologic feature of sympathetic ophthalmia is pigment phagocytosis by the epithelioid cells in the absence of uveal necrosis. The frequency of phacoantigenic uveitis (PAD) associated with sympathetic ophthalmia has been well documented. 25 In a review of 105 cases by Lubin and coworkers,21 46% demonstrated histopathologic evidence of PAlJ. All the eyes with PAD had sustained a break in the lens capsLJ.le. It is interesting to note that in their series of cases, spanning the years 1913 to 1975, only one case of PAD associated with sympathetic ophthalmia was detected after 1949. The authors attribute this to the introduction of corticosteroid therapy and the more complete treatment that lens injuries currently receive. It has been suggested that the strong association between the two conditions may indicate a predisposition to autoimmune disease in certain patients, or that there are some common antigens shared between the lens and uveal tissue. 26

The concept that an autoimmune inflammatory response is the basis of this disorder is not a new one, having been proposed by Elschnig in 1910 with uveal pigment being thought of as the putative antigenic stimulus. 26 In vitro cell culturing techniques have been used to evaluate responses of lymphocytes from patients with sympathetic

ophthalmia. The patients have demonstrated a positive proliferative response to uveal or uveoretinal preparations, underscoring the predominance of T-cell responses in this disorder. 28 In contrast, humoral immune mechanisms are not thought to be pathogenetic,· as demonstrated by Chan and colleagues who found no circulating antiretinal S-antigen antibodies in a group of patients with sympathetic ophthalmia using the enzyme-linked immunosorbent assay technique. 29 Although no exact experimental model for sympathetic ophthalmia yet exists, the induction of uveitis with the ocular antigens interphotoreceptor retinoid binding protein and S-antigen produces a disease in monkeys that has many of the characteristics of sympathetic ophthalmia, including the development of Dalen-Fuchs nodules. An important factor in the development of sympathetic ophthalmia may be that penetrating trauma permits access to lymphatics and the presentation of ocular antigens to the systemic immune system in a different way from the usual, setting the stage for autoimmune inflammatory sequelae.

The Role of the Penetrating Wound Any theory on the pathogenesis of sympathetic ophthalmia must take into account the fact that sympathetic ophthalmia develops almost exclusively after a penetrat; ing wound. To study this more closely, Rao and colleagues used the retinal S-antigen uveitis model to compare intraocular antigen presentation with extraocular antigen presentation. 29 Intraocular antigen presentation represents a situation comparable to nonpenetrating trauma, and extraocular antigen presentation a situation comparable to a penetrating wound with uveal prolapse, None of the animals injected intraocularly developed contralateral inflammation, whereas 4 of 10 injected subconjunctivally developed chorioretinal lesions in both, eyes 14 to 16 days after sensitization. Animals receiving subconjunctival injections of antigen had evidence of cell-mediated hypersensitivity as well as precipitating antibodies to retinal S-antigen, whereas the animals receiving intraocular inoculations had no immune responses to retinal S-antigen detected by the screening tests employed. Rao and coworkers suggested that the penetrating wound participated in the development of sympathetic ophthalmia by exposing uveoretinal antigens to the conjunctival lymphatics and thereby inducing a subsequent immunopathologic response. 29 It has long been postulated that an infectious agent may be required concurrently with the antigen to initiate an immune response resulting in sympathetic ophthalIuia. 31 Active proliferation of the organism may in fact not be necessary. Products such as bacterial cell wall, which may be present in the wound, could act as immunostimulators and thereby up-regulate a local immune response. The possible adjuvant role of an infectious agent correlates well with the strong association between sympathetic ophthalmia and perforating wounds with uveal prolapse and its lack of association with nonperforating injuries.

Immune Privilege

the Eye

The immune privilege of the eye has been recognized for over a century: Early investigators discovered that tumor

CHAPTER 66: SYMPATHETIC

tis.sue injected into the anterior chamber of the eye survived for an unusually long time, whereas tumor tissue taken from one animal and grafted subcutaneously into another was quickly destroyed. The lack of a recognizable lymphatic drainage pathway was identified as a common anatomic feature of the anterior chamber of the eye, brain,ovary, and testis. It was concluded that antigenic material was sequestered in these immunologically privileged sites and was probably ignored by the immune system. But we now know that immune privilege in the anterior chamber of the eye is not the result of immunologic ignorance of the antigen but of an active regulation of immunity that suppresses cell-mediated immunity while promoting humoral immunity.32 This anterior chamber-associated immune deviation (ACAID) depends on unique features of both the spleen and the eye for its initiation. 33 In particular, cells from the iris and ciliary body are able to down-regulate the earliest events of antigen presentation and lymphocyte activation, thereby initiating a selective impairment of delayed hypersensitivity. Mizuno and coworkers have demonstrated that mice and rats develop ACAID when S-antigen is injected uniocularly.33 In an effort to determine whether the induction of ACAID could prevent experimental autoimmune uveitis, susceptible animals were pretreated with a Ulliooular injection of retinal S-antigen. When these rats were subsequently injected subcutaneously with S-antigen, minimal uveitis was noted. Thus, an experimentally induced suppression of S-antigen-specific del'hyed hypersensitivity was able to prevent the subsequent development of S-antigen-specific retinitis. One might wonder whether there might be, in certain genetically susceptible individuals, and under certain immunologically stimulating conditions with bacterial adjuvant stimulation, loss of immune tolerance and induction of autoimmune uveitis called sympathetic ophthalmia.

Genetic Predisposition to Sympathetic Ophthalmia Many studies have shown associations between specific histocompatibility antigenic determinants in a variety of ocular diseases. Typically, there is a statistically significant increase in the incidence of one particular histocompatibility antigen in the patient population with a specific disease, compared with a matched control population. Reynard and colleagues have demonstrated an increased

OP'Hl"-Ht~U~I1IA

frequency of the human leukocyte antigen 1 in a group of 20 patients with histopathologically proven sympathetic ophthalmia. 34 The relative risk in the disease group compared to the control group was 11. This association suggests that a genetic factor may play an important role in the pathogenesis of s)'lnpathetic ophthalmia. HLA-DR4 (and the closely linked HLA-DQw3 in Americans and HLA-DRw53 in Japanese) is over-represented in populations of patients with sympathetic ophthalmia. 36 These same alleles are overrepresented in Japanese and American patients with VKH, and in patients with a variety of nonocular autoimmune diseases, lending support to the idea that a genetic susceptibility factor is operative, at least in some patients with sympathetic ophthalmia. It is possible to hypothesize that the perforating injury permits several events to take place. The first is that drainage of antigen from the eye can occur through the lymphatics, an event that does not occur under normal conditions. The second is that small amounts of adjuvant, such as bacterial cell wall or other immunostimulators, might now enter the eye. These products may then profoundly upgrade the local immune response, causing it to bypass certain inherent suppressor mechanisms in genetically prone individuals. This leads then to the inflammatory response that ultimately leads to the clinical entity that is recognized as sympathetic ophthalmia.

DIFFERENTIAL DIAGNOSIS The diagnosis of sympathetic ophthalmia is a clinical one depending essentially on the history of ocular injury by surgery or trauma followed by bilateral granulomatous uveitis. The pathologic diagnosis is defined by characteristic features, as mentioned previously, including a predominant T-cell inflammatory infiltrate in the uvea, the early phagocytosis of pigment granules, and the presence of Dalen-Fuchs nodules. Occasionally, it may be difficult to distinguish s)'lnpathetic ophthalmia from VKH (Table 66-1). But patients with VKH have no history of tramna. Typically, they have bilateral localized serous detachments of the retina, which are not seen in sympathetic ophthalmia. VKH is also more prevalent in certain racial and ethnic groups. It has been estimated to constitute approximately 8%· of all cases of endogenous uveitis in Japan. 37 It appears to be extremely rare in patients of northern European extraction.. In the typical case of s)'lnpathetic ophthalmia,

TABLE 66-1. COMPARISON OF SYMPATHETIC OPHTHALMIA AND VOG"f-KOYANAGI-HARADA SYNDROME

Age Racial predisposition Penetrating trauma Skin changes CNS findings Hearing dysfunction Retinal serous detachment Choriocapillaris involvement CSF findings CNS, central nervous system; CSF, cerebrospinal fluid.

SYMPATHETIC OPHTHALMIA

VOG"f-KOYANAGI-HARADA SYNDROME

All ages None Always'present UncoIIuuon Uncommon Uncommon Rare Usually absent Usually normal

20-50 years Asian and black Absent Common (60% to 90%) Common (85 %) Common (75%) Frequently seen Frequently seen Pleocytosis (84%)

CHAPTER 66: SYMPATHETIC OPHTHALMIA

no laboratory studies are necessary for diagnosis. If it is necessary to differentiate the syndrome from Villi, a lumbar puncture should be performed early in the course of·the disease. This reveals a pleocytosis in 84% of cases of VKH, with mostly lymphocytes and monocytes present.3S Sarcoidosis, when it produces multiple small foci of choroiditis, may also (rarely) be confused with postoperative sympathetic ophthalmia.

PREVENTION AND MANAGEMENT

Surgical Treatment The only known prevention for sympathetic ophthalmia is enucleation, and this must be performed prior to the development of the autoimmune response if it is to be effective. The classic teaching has been that enucleation within 14 days after ocular injury protects the second eye from the development of sympathetic ophthalmia. Exceptions to this rule do occur but are rare. 39 Controversy still exists regarding the advisability of enucleating the exciting eye once sympathetic ophthalmia has commenced. The review by Lubin and coworkers would suggest that enucleation within 2 weeks of the initiation of the inflammatory response may beneficially affect the visual outcome of the remaining eye. 21 Reynard and associates, in their retrospective clinicopathologic. study, also noted that enucleation within 2 weeks of the beginning of symptoms resulted in a fairly benign course-:-specifically, less frequent and milder relapses and a good visual outcome (visual ac~ity better than 20/ 50).39 In contrast, another review indicates no benefit to the sympathizing eye from enucleation of the exciting eye, whether performed immediately before, concomitant with, or subsequent to the development of sympathetic ophthalmia at various elapsed intervals following injury.s It must be stressed that enucleation should be considered only when the visual prognosis is nil for the eye being considered for enucleation, because not uncommonly the exciting eye may ultimately be the· one with better vision. Sympathetic ophthalmia may occur after evisceration probably as a result of remaining uveal tissue in the scleral emissary channels. 9 It would seem prudent not to perform eviscerations except perhaps in cases of endophthalmitis or in patients whose general condition is very poor.

Medical Treatment Corticosteroids If the decision has been made to intervene with antiinflammatory therapy, the initial approach, in most cases, should be with corticosteroids. They may be given topically, by sub-Tenon or transseptal injection, and systemically. Systemic steroids are recommended on a daily basis, beginning with a high dose of a short-acting agent (e.g., 1.0 to 1.5 mg/kg/day prednisone). Three months is a sensible time frame in which to evaluate whether the therapeutic approach has worked, the clinical criteria for improvement depending largely on the seriousness of the inflammatory response. If steroid therapy is effective, then a slow taper should be initiated. However, in some

patients, the disease may not be controlled with this approach, because of either persistent disease activity or the necessity f01:. long-term maintenance with systemic steroids with attendant intolerable side effects. In a longterm follow-up of sympathetic ophthalmia patients treated with steroids, Makley and Azar found that 65% of eyes had a stable visual acuity of 20/60 or better. 4o Others have reported similar' success rates. 22 , 40

Cyclosporine Other forms of immunosuppressive therapy have been tried with success in steroid-resistant cases of sympathetic ophthalmia. In a group of five patients, Nussenblatt and Palestine 41 used systemic cydosporine and noted that the inflammatory response appeared to respond well to this agent. Thirty-two patients with sympathetic ophthahnia were followed at the National Eye Institute (Bethesda, MD) over a 10-year period. 43 Seven required a combination of cyclosporine and oral prednisone to control their disease. Towler and colleagues also reported good results with cydosporine and corticosteroid combination therapy in patients with sympathetic ophthalmia. 43

Cytotoxic Agents Jennings and Tessler found chlorambucil to be particularly effective in those patients with severe disease in a series of 20 patients with sympathetic ophthalmia. 44 They noted that the subsidence of inflammation coincided with a decrease in white blood cell count. Despite previous reports of major complications with chlorambucil, they had no complications with this form of treatment, although evaluations of fertility were not conducted. Azathioprine, at a dose of 50 mg three times a day, has also been used effectively in combination with low-dose corticosteroids. 45 Use of these agents must be performed by individuals who by virtue of their training and experience are truly expert in the indications for and side effects of treatment with such medications. To this end, collaborative management with an internist, rheumatologist, or hematologist is advisable.

PROGNOSIS The relapsing nature of sympathetic ophthalmia and the potential toxicity of treatment modalities warrant a carefullong-term follow-up of patients with this disease. Spontaneous improvement is rare. The use of corticosteroid and other immunosuppressive agents, together with stateof-the-art microsurgical techniques for wound repair, have improved the prognosis of sympathetic ophthalmia such that good vision can be expected in the sympathiZing eye. Cataract, secondary glaucoma, and chronic maculopathy are the major causes of visual loss. Fortunately, s)Tlnpathetic ophthalmia is a relatively rare condition; but it remains an enigmatic disease with the potential for bilateral blindness.

References 1. MacKenzie W: A practical treatise on diseases of the eye, 3rd ed. London, Longmans, 1840, pp 523-534. 2. Fuchs E: Uber sympathisierende Entzundung (Zuerst Bermerkunen uber serose traumatische Iritis). Graefes Arch Clin Exp Ophthalmol 1905;61:365-456. 3. Dalen A: Zur Kenntnis der sogenannten Choroiditis sympathetica. Mitt Augenklin Carolin Med-Chirurg Inst Stockholm 1904;6:1.

CHAPTER 66: SYMPATHETIC OPHTHALMIA 4. Liddy N, Stuart J: Sympathetic ophthalmia in Canada. Can J Ophthalmol 1972;7:157-159. 5. Holland G: About the indications and time for surgical removal of an i1uured eye. KEn Monatsbl Augenheilkd 1964;145:732-740. 6. Marak GE: Recent advances in sympathetic ophthalmia. Surv Ophthalmol 1979;24:141-156. 7. Rao NA: Sympathetic ophthalmia. In: Ryan SJ, ed: Retina, vol. 2: Medical Retina. St Louis, CV Mosby, 1989, pp 715-721. 8. Winter FC: Sympathetic uveitis: A clinical and pathologic study of the visual result. AmJ Ophthalmol 1955;39:340-347. 9. Green WR, Maumenee AE, Sanders TE, Smith ME: Sympathetic uveitis following evisceration. Trans Am Acad Ophthalmol Otolaryngol 1972;76:625-644. 10. Lam S, Tessler HH, Lam BL, Wilensky JT: High incidence of sympathetic ophthalmia after contact 'and noncontact neodymium: YAG cyclotherapy. Ophthalmology 1992;12:1818-1822. 11. Wang V\~: Clinical and histopathological report of sympathetic ophthalmia after retinal detachment surgery. Br J Ophthalmol 1983;67:150-152. 12. GassJDM: Sympathetic ophthalmia following vitrectomy. AmJ Ophthalmol 1982;93:552-558. 13. Albert DM, Diaz-Rohena R: A historical review of sympathetic ophthalmia and its epidemiology. Sury Ophthalmol 1989;34:1-14. 14. Margo CE, Pautler SE: Granulomatous uveitis after treatment of a choroidal melanoma with proton-beam irradiation. Retina 1990;10: 140-143. 15. Fries PD, Char DH, Crawford JB, Waterhouse W: Sympathetic ophthalmia complicating helium ion irradiation of a choroidal melanoma. Arch Ophthalmol 1987;105:1561-1564. 16. Duke-Elder ES, Perkins EA: Diseases of the uveal tract. In: DukeElder WS, ed: System of Ophtlnlmology, vol 9. St. Louis, CV Mosby, 1966, pp 558-593. 17. Wykes WN: A ten-year survey of pen~trating eye injury in Gwent, 1979-1985. BrJ OphthalmoI1988;72:607-611. 18. Green WR: The uveal tract. In: Spencer WH, ed: Ophthalmic Pathology: An Atlas and Textbook, 3rd ~d, vol 3. Philadelphia, W.B. Saunders, 1986, pp 1915-1956. 19. Verhoeff F: An effective treatment for sympathetic uveitis. Arch OphthalmoI1927;56:28. 20. Easom HA, Zimmerman LE: Sympatlletic ophtllalmia and bilateral phacoanaphylaxis: A clinicopatllological correlation of the sympathogenic and sympathizing eyes. Arch Ophthalmol 1964;72:9-15. 21. Lubin JR, Albert DM, Weinstein M: Sixty-five years of sympathetic ophthalmia: A clinicopatll010gical review of 105 cases (1913-1978). Ophthalmology 1980;87:109-121. 22. Jakobiec FA, Marboe CC, Knowles DM II, et al: Human sympathetic ophthalmia. An analysis of tlle inflammatory infiltrate by hybridoma monoclonal antibodies, immunohistochemistry, and correlative electron microscopy. Ophthalmology 1983;90:76-95. 23. Chan CC, Ben Ezra D, Rodrigues MM, et al: Immunohistochemistry and electron microscopy of choroidal infiltrates and Dalen-Fuchs nodules in sympathetic ophthalmia. Ophthalmology 1985;92:690695. 24. de Veer JA: Bilateral endophthalmitis phacoanaphylactica. Arch Ophthalmol 1953;49:607-632.

25. Blodi Fq: Sympathetic uveitis as an allergic phenomenon. Trans Am Acad Ophtllalmol Otolaryngol 1959;63:642-649. 26. Elschnig A: Studien zur sympathischen ophthalmie. Die antigene Wirkung des Augenpigmentes. Arch Ophthalmol 1910;76:509. 27. Wong VG, Anderson R, O'Brien PJ: Sympathetic ophthalmia and lymphocyte transformation. AmJ Ophthalmol 1971;72:960-965. 28. Chan CC, Palestine AG, Nussenblatt RB, et al: Antiretinal autoantibodies in Vogt-Koyanagi-Harada syndrome, Beh<;:et's disease, and sympathetic ophthalmia. Ophtllalmology 1985;92:1025-1 028. 29. Rao NA, Robin J, Hartmann D, et al: The role of the penetrating wound in the development of sympathetic ophthalmia. Experimental observations. Arch Ophtlnlmol 1983;101:102-104. 30. Joy HH: Sympatlletic ophtllalmia: The history of its patllogenic studies. AmJ OphthalmoI1953;36:1100-1120. 31. Streilein]W, Niederkorn JY, Shadduck JA: Systemic immune unresponsiveness induced in adult mice by anterior chamber presentation of minor histocompatibility antigens.J Exp Med 1980;152:112125. 32. Williamson JSP, Bradley D, Streilein]W: Immunoregulatory properties of bone marrow derived cells in the ids and ciliary body. Immunology 1989;67:96-102. 33. Mizuno K, Clark AF, Streilein ]W: Ocular injection of retinal S antigen: Suppression of autoimmune uveitis. Invest Ophthalmol Vis Sci 1989;30:182-184. 34. Reynard M, Schulman IA, Azen SP, Minckler D: Histocompatibility antigens in sympathetic ophthalmia. Am J Ophthalmol 1983;95:216-221. 35 .. Sugiura S: Vogt-Koyanagi-Harada disease. Jpn J Ophthalmol 1978;22:9-35. 36. Davis JL, Mittal KK, Freidlin V, et al: HLA association and ancestry in VIlli and sympathetic ophthalmia. Ophthalmology 1990;97:1137-1142. 37. Ohno S, Minakawa R,.Matsuda H:Clinical studies on Vogt-KoyanagiHarada's disease. Jpn J Ophthalmol 1988;32:334-343. 38. Gion N, Stavrou P, Foster CS: Immunomodulatory therapy for chronic tubulointerstitial nephritis associated uveitis (TINU). Am J OphtllalmoI2000;129:764-768. 39. Reynard M, Riffenburgh RS, Maes EF: Effect of corticosteroid treatment and enucleation on the visual prognosis of sympathetic ophthalmia. Am J Ophtllalmol 1983;96:290-294. 40. Makley TA, Azar A: Sympathetic ophtllalmia: A long term follow up. Arch Ophthalmol 1978;96:257-262. 41. Nussenblatt RB, Palestine AG: Sympathetic ophthalmia. In: Uveitis Fundamentals and Clinical Practice. Chicago, Year Book, 1989, pp 257-271. 42. Chan CC, Roberge FG, Whitecup SM, et al: Thirty-n\To cases of sympathetic ophthalmia: A retrospective study at the National Eye Institute, USA from 1982-1992. Arch Ophtllalmol 1995;113:597600. 43. Towler HMA, Whiting PH, Forrester ]V: Combination low-dose cyclosporin A and steroid therapy in chronic intraocularinflammation. Eye 1990;4:514-520. 44. Jennings T, Tessler H: Twenty cases of sympathetic ophthalmia. Br J Ophthalmol 1989;73:140-145. 45. Hakin KN, Pearson RV, Lightman SL: Sympathetic ophthalmia: Visual results with modern immunosuppressive therapy. Eye 1992;6:453-455.

Nattaporn Tesavibul

cent ofVKIj patients present to ophthalmologic attention Vogt-Koyanagi-Harada syn.drome (VKH), formerly known durinK this phase with bilateral uveitis. 10 In 30%, there as uveomeningitic syndrome, is a systemic disorder involv- may be a delay of 1 to 3 days before the second eye ing multiple organ systems, including the ocular, audi- becomes involved. Thickening of the posterior choroid, tory, nervous, and integumentary systems. Severe bilateral manifested as an elevation of the peripapillary retinopanuveitis .associated with exudative retinal detachment choroidal layer, and disc hyperemia are early findings. IS is the hallmark of ocular disease. It was first described by Subsequent retinal pigment epithelium (RPE) barrier a' Persian physician, Ali-ibn-Isa (940 to 1010 AD),1 who breakdown causes subretinal fluid accumulation and mulreported whitening of the eyelashes, eyebrows, and hair tiple serous retinal detachments (Fig. 67-1). As the disorder evolves, optic nerve head swelling is (poliosis) associated with inflammation of the eyes. In 1873, this association was reported again by Schenkl,2 noted in 87% of the cases,19 usually accompanying severe followed by Hutchinson 3 in 1892 and Vogt in 1906. 4 In inflammation. The findings associated with posterior uve1926, Einosuke Harada described a posterior uveitis asso- itis, serous retinal detachment, and CSF pleocytosis in the ciated with exudative retinal detachment and cerebrospi- absence of extraocular manifestations are often termed nal fluid (CSF) pleocytosis. 5 Koyanagi in 1929 described Harada's form of this syn.drome. Early in the course of patients with bilateral iridocyclitis associated with vitiligo, the disease, exudative retinal detachment may appear as alopecia, and poliosis accompanied by tinnitus and deaf- retinal striae secondary to choroidal folds. In addition, ness. 6 In 1932, Babel,7 and later in 1949 Bruno and Mc- exudative maculopathy may vary from loculated to Pherson,s consolidated the descriptions of Vogt, Koya- multifocal to frank bullous exudative retinal detachment, nagi, and Harada and suggested that these signs and the pathophysiology being choroidal inflammation leadsymptoms are manifestations in a spectrum of the same . ing to RPE derangement and subsequent exudative retiunderlying disease process, and that" only the intensity nal detach'ment. and distribution varies from patient to patient. Since Eventually the inflammation, which is usually granulothen, the term uveomeningo-encepha,$itic syndrome has matous, extends to the anterior segment, causing muttonbeen commonly replaced by VKH. . fat keratic precipitates and iris nodules (Fig. 67-2). Early on, the anterior chamber may be shallow20 because of ciliary edema,21,22 serous detachment of the ciliary EPIDEMIOLOGY The disease has a worldwide distribution but has a predi- body,23-25 and forward displacement of the lens-iris dialection for darkly pigmented races such as Asians, Hispan- phragm, which resolves after the inflammation subsides. 20 ics, and Native Americans. In the United States, Nussen- This may cause a moderate rise in intraocular pressure 22 blatt and coworkers reported that 44% of the patients in and acute angle-closure glaucoma. , 26 Corneal anesthetheir series were blacks. 9 VIlli is uncommon in whites. lO sia, tonic pupils, and accommodative impairment have 27 It is a common cause of endogenous uveitis in Japan, been reported in one case. Bilateral iridocyclitis associconstituting at least 8% of cases. lO This is also true for ated with vitiligo, poliosis, and auditory problems are certain parts of Latin America, particularly Brazil. In the widely known as the Vogt-Koyanagi form of this disease. The convalescent phase follows gradually, with skin and United States, it accounts for 1% to 4% of all uveitis uveal depigmentation. Sugiura's sign or perilimbal vitiligo referrals.ll, 12 There appears to be some global variation in gender is the earliest depigmentation to occur, often within 1 predilection of these patients, but most studies suggest that women are affected somewhat more frequently than men}I-16 Most patients are in the second to fifth decades of life at the onset of the disease,lo':"13,16 although Cunningham and colleagues reported a4-year-old boy with;> the disease. 17

CLINICAL MANIFESTATIONS The clinical course has been divided into four distinct phases. 1o The prodromal phase mimics a systemic viral infection. Symptoms include fever, headache, nausea, vertigo, orbital pain, and neurologic involvement such as meningismus. Tinnitus is a characteristicdinical symptom. Additionally, less common neurologic symptoms include ataxia, confusion, and focal neurologic signs. Symptoms usually last for a few days and are followed by an acute uveitic phase that may last for several weeks. Seventy per-

FIGURE 61-1. Optic disc edema and exudative retinal detachment in early VIm syndrome. (See color insert.)

67:

FIGURE 67-2. Multiple iris Koeppe nodules in a patient with VIlli syndrome. (Courtesy C. S. Foster, M.D.)

FIGURE 67-4. "Blond" appearance of fundus in Asian patient after the active inflammatory stage of VIlli syndrome. (See color insert.)

tomosis,30 and subretinal neovascular membrane (SRNVM) formation usually develop during this stage.

month of disease onset. 28 This form of depigmentation is reported to occur in 85% of Japanese patients and is virtually unheard of in white patients (Fig. 67-3).19 Depigmentation of the choroid causing sunset-glow appearance of the fundus occurs 2 or 3 months after the uveitic phase and is more common in Asian patients (Fig. 67-4).18 Hoci of hyperpigmentation from RPE alterations can be found, especially in Hispanic patients. 29 Yellow-white, wellcircumscribed lesions similar to Dalen-Fuchs nodules in sympathetic ophthalmia are comthon, usually in the mid periphery (Fig. 67-5). The convalescent phase may last for several months. This stage may be interrupted by the chronic recurrent phase, which manifests as a recurrent, mainly anterior uveitis. Recurrent posterior uveitis is uncommon. These episodes of granulomatous uveitis are often resistant to steroid therapy. Another characteristic finding in recurrent disease is the development of iris nodules. Focal pigment atrophy of the iris may also occur. Complications of chronic inflammation such as glaucoma, cataract, neovascularization of the retina and disc, arteriovenous anas-

Integumentarysystem involvement is seen at various stages of the disease. Seventy-two percent of patients report sensitivity to touch of the hair and skin in the prodromal stage. lO , 19 Alopecia has been reported in 73% of VKH patients in one study31 but in only 13% of patients reported by Beniz and coworkers. 13 Poliosis and vitiligo usually occur during the convalescent stage. The occurrence of vitiligo varies from 10% to 63% between races

FIGURE 67-3. Periocular vitiligo in an Asian patient with VIlli syndrome. Note also the poliosis of cilia nasally, upper lid. (See color insert.)

FIGURE 67-5. Fundus photo from the same patient demonstrating advanced glaucomatous optic disc cupping, severe chorioretinal scar with severe RPE alteration, and old Dalen-Fuchs nodules. (See color insert.)

Because VKH is a systemic disease with no confinnatory laboratory tests, the presence of extraocular manifestations is very important in securing the diagnosis. Some authors assert that even with ocular findings typical of this disease, VKH canriot be definitively diagnosed without concurrent extraocular findings. 9 However, the incidence of extraocular manifestations varies markedly in different reported series, which may reflect racial differences in the expression of these findings.

Integumentary System

CHAPTER 67: VOG1=-KOYANAGI-HARADA SYNDROME

(see Fig. 67-3 and Fig. 67-6) .13, 31 Hispanic people have a lower incidence of dermatologic involvement,13 whereas Asians are more commonly affected. Axillary involvement of vitiligo is frequently overlooked by patients and physicians alike (see Fig. 67-4).

Neurologic Manifestations Headache, confusion, orbital pain, and stiff neck are common in the prodromal stage. Headache was by far the most common neurologic complaint in a study reported by Beniz and coworkers. 13 CSF pleocytosis with a predominance of lymphocytes and monocytes and normal glucose have been found in more than 80% of patients widl VKH and may persist for up to 8 weeks. 1o , 11 Focal neurologic signs such as cranial neuropathies, hemiparesis, aphasia, transverse myelitis, and ganglionitis, although rare, have been reported. 32 . 33

Auditory Manifestations Auditory problems occur in 75% 'of the patients, often concomitant with active ocular disease. 31 , 34 Hearing loss usually involves the high frequencies but may affect all frequencies in the early stage. 35 Improvement is often noted in 2 to 3 months, although persistent alterations may occur. 10 Vestibular dysfunction is uncommon. 18

ETIOLOGY AND PATHOGENESIS Although the exact etiology of VKH is unknown, the disease is thought to be a primarily inflammatory condition directed against melanin-containi~g cells or a common antigen expressed therein and shared by the skin, eye, meninges, and ear. Alternatively, some investigators have invoked a primary infectious etiology, and others postulate a microbe as initiating or triggering the autoimmune process. Several studies have suggested that the inflammation in VKH may represent a cellular immune process directed against melanocytes. 10 ,36-39 Close contact between lymphocytes and uveal melanocytes as seen on electron microscopy with locally associated choroidal basement membrane destruction has been demonstrated. 36 Lymphocytes from peripheral blood and CSF of patients with the disease have been shown to be cytotoxic to the B-36 mela-

noma cell line. 37,40 McClellan and coworkers also found interleukin (IL)-2-dependent T tells with specificity toward normal melanocytes, as well as melanoma cellsY These studies suggest that autoimmunity to melanocytes in the uveal tract and integumentary system may be pathogenetic in the development of inflammation in the eyes, other parts of the nervous system, and skin in VKH patients. Attempts to identify antigens causing ocular inflammation inVKH have yielded contradictory results. DeSmet and colleagues42 found no lymphocyte proliferatiof? in the presence of retinal antigens in patients with chronic VKH,. whereas a study by Naidu and colleagues showed a positive response to retinal S-antigen and interphotoreceptor retinoid binding protein in untreated patients with active disease. 43 Autoantibodies against photoreceptor outer segments and Muller cells have been detected in the sera of VKH patients. 44 However, these antibodies could be a secondary response that follows retinal damage in patients with this disease.

HISTOPATHOLOGY The major histopathologic feature of VKH is a diffuse granulomatous inflammation of the uveal tract with a preponderance of lymphocytes and epithelioid cells. ,Some investigators reported a nongranulomatous inflammation.38, 45-48 Dalen-Fuchs nodules, consisting of epithelioid cells, macrophages, lymphocytes, and altered RPE cells, are often present in the chronic stage. 47 In longstanding cases, the retina may be gliotic, with areas of RPE alteration. The choriocapillaris is usually but not always involved, followed by the disappearance of choroidal melanocytes, chorioretinal scarring,47, 49, 50 and, occasionally, choroidal neovascularization. 51 Although much has been said about the differences histologically between VKH and sympathetic ophthalmia, with choriocapillaris sparing in the former, it is clear that standard histologic study cannot definitively differentiate one from the other. Recent studies of sympathetic ophthalmia and VKH suggest that anti-inflammatory products secreted by the RPE, including transforming growth factor-beta (TGF-f3) and RPE protective protein, may allow preservation of the retina and choriocapillaris by the suppression of oxidant release in the inflamed choroid. This may save the uvea from necrotic damage and extensive inflammatory cell infiltration.52

Immunocytology

FIGURE 67-6. Vitiligo of hair (white forelock) in a patient with VIm. (Courtesy C. S. Foster, M.D.) (See color insert.)

Immunohistochemical studies in active VKH revealed an increased ratio of T-helper to T-suppressor cells, and activated T lymphocytes with CD25 and CD26 markers within choroidal inflammatory foci. 38, 45, 53 The same results were also reported on skin biopsy specimens from vitiligo patches of these patients.54 In contrast, patients in the convalescent stage of VKH, evaluated by Inomata and Sakamot0 46 and Sakamoto and coworkers,55 demonstrated a ratio of 2:3 for CD4 + cells to CD8 + cells. This has also been demonstrated in studies by Ariga and coworkers 56 and Nonaka and coworkers. 57 The disappearance of choroidal melanocytes has also been reported. 46 ,55 Choroidal melanocytes do not normally express more than minimal amounts of class II major histocompatibility

CHAPTER 61: VOG"T-KOYANAGI-HARADA SYNDROME

(MHC) proteins. However, these proteins have been found in large quantity in the choroidal melanocytes and the endothelium of the choriocapillaris ofVKH patients. 38 This suggests that T-cell-mediated delayed-type hypersensitivity against choroidal melanocytes that aberrantly express class II MHC antigens may contribute to the autoimmune inflammatory process. CD4 + cells are reported to be more numerous than CD8 + cells in the aqueous humor of patients with acute disease. This proportion is reversed in convalescent disease. 58 The majority of CD4+ IYJ-TIphocytes in aqueous humor and CSF from patients with active VKH disease expressed memory marker and Fas antigen. 59 ,50 Okubo and coworkers reported a decrease in the total number of T cells (OKT3+), helper T cells (OKT4+), and suppressor T cells (OKT11 +) in the peripheral blood of patients with active disease. 51 Liu and Sun noted that the CD4jCD8 ratio was increased in patients with active recurrent disease. 52 Okubo and coworkers also reported an increased number of cells with DR expression~in patients whose disease recurred. 51 High levels of IL-2 and interferon-gamma (IFN-)') in patients' serum,53 and increased levels of IL-6 in aqueous humOl,58 during active disease have also been reported. T-cell clones from aqueous humor of VKH patients were found to produce significantly larger amounts of ILT8, IL6, and IFN-)' than T-cell clones from healthy donors. These results suggest that cytokines produced by T cells infiltrating in the eye may playa role in the pathogenesis ofVKH.54 'lJ'

GENETIC FACTORS Among Chinese, Japanese, and Hispanic persons, there is a strong association between HLA-DR4 and -Dw53 with VKH.55-59 HLA-DR4 has also been reported to be related to VKH disease in Italian and Brazilian patients. 7o ,71 Martinez and colleagues reported HLA-DRw52 in VKH patients of Cherokee ancestry.72 The role of genetics in VIlli is strengthened by reports of familial cases (siblings and monozygotic twins). 73-75

DIAGNOSIS

Although the diagnosis of VIlli is made by clinical examination, laboratory tests may be useful for supporting the diagnosis and assisting managelTIent.

Fluorescein Angiography Fluorescein angiography (FA) in the acute stage of VKH is characteristic and typically demonstrates lTIultiple punctate hyperfluorescent dots at the level of the RPE. These hyperfluorescent dots gradually enlarge and pool in the subretinal fluid underlying areas of exudative retinal detachment. 75-78 Seventy percent of the patients have disc leakage in the acute phase (Fig. 67-7) .75 In the chronic stage, the angiogram shows multiple hyperfluorescent RPE window defects or areas of blocked fluorescence corresponding to RPE atrophy or hyperpigmentation. Alternating hyper- and hypofluorescence from RPE alteration lTIay give a moth-eaten appearance. 29 SRNVM, retinochoroidal anastomoses, and neovascularization of the disc were also documented. 75 Vascular leakage, sheathing, and staining are rare. 12 , 18, 75, 79

Indocyanine Green Angiography Indocyanine green angiography shows a dark background in the early phase. 8o This finding may be detected as early as the prodromal stage of the disease.81 During the niidphase of the angiogram, multiple patchy hypofluorescent lesions in the posterior fundus, which may represent areas of choroidal inflammation and circulatory· disturbance, have been described. These lesions are more numerous than areas either of serous retinal detachment or of punctate hyperfluorescence seen on FA. In severe cases, hyperfluorescent spots are also visible throughout the entire fundus. In the recovery stage of the disease, the dark background resolves and the patchy hypofluorescent lesions slowly disappear after the disease activity has subsided in most cases. 80

Ultrasonography and Ultrasound Biomicroscopy Ultrasonography is often helpful in malting a diagnosis and planning management when the fundus view is ob-

Patients with VIlli who manifest all the ocular and extraocular manifestations pose little diagnostic uncertainty, but unfortunately they are rare. Given the wide variation in clinical presentation, the American Uveitis Society adopted the following criteria in 1978 for the diagnosis ofVKHl2:

1. No history of ocular trauma or surgery 2. At least three of four of the following signs: a. Bilateral chronic iridocyclitis b. Posterior uveitis, including exudative retinal detachment, disc hyperemia or edema, and sunset glow fundus c. Neurologic signs of tiIlllitus, neck stiffness, headache, cranial nerve or central nervous system problems or CSF pleocytosis d. Dermatologic manifestations of alopecia, poliosis, or vitiligo These criteria were offered as general guidelines for the diagnosis of VKH.

FIGURE 67-7. Fluorescein angiogram of a patient with VIlli. Note the characteristic starry night appearance produced by the multitude of hot spots of active choroiditis.

CHAPTER

VOGl:KOYANAGI-HARADA SYNDROME

scure, when presentation is atypical, or if extraocular signs are absent. Echographic manifestations of VKH were described by Forster and colleagues as follows 82 : 1. Diffuse thickening of the posterior choroid with low to medium reflectivity 2. Serous retinal detachment around posterior pole or inferiorly 3. Vitreous opacities without posterior vitreous detachment 4. Posterior thickening of the sclera or episclera Scleritis, tuberculosis, sarcoidosis, leukemia, and lymphoma are other diseases with similar ultrasonographic findings. Ultrasound biomicroscopy of the anterior chamber by several investigators has demonstrated ciliochoroidal detachment, which directly explains the shallow anterior chamber encountered in the early stage ofVKH.22-25

Lumbar Puncture Lumbar puncture has not been used routinely as a diagnostic procedure in most recent studies. In a report by Ohno and coworkers,ll more than 80% of patients had CSF· pleocytosis composed mainly of lymphocytes. CSF pleocytosis has been shown to occur within 1 week and to resolve within 8 weeks. Eighty-five percent of the lyrrt~ phocytes in the CSF were OKTll +., and 65 % were OKT4+ .83 Melanin-laden macrophages have been found in the CSF of patients with this disease. 84

ELECTROENCEPHALOGRAPHY, ELECTRORETINOGRAPH~

ELECTROOCULOGRAPHY Electrophysiologic tests are nondiagnostic in the setting of VKH. Abnormalities vary greatly, although worsening generally accompanies disease recurrence. 85

Magnetic Resonance Imaging Magnetic resonance imaging discriminates sclera from choroid and permits the differentiation of VKH from primary scleral disease. It also allows the detection of subclinical ocular and central nervous system (CNS) disease. Choroidal thickening can be demonstrated even when the fundus and FA appear normaI.S6 Nonspecific punctate areas of high signal in the periventricular white matter and brain parenchyma have been reported. 86 ,87

Serologic Tests No serologic tests have been proved useful ingVKH.

Multiple evanescent white dot syndrome Bilateral diffuse melanocytic hyperplasia Lupus choroidopathy Uveal effusion syndrome Posterior scleritis Other systemic disorders causing exudative retinal detachment, such as toxemia of pregnancy and renal disease

TREATMENT Corticosteroids The treatment of VKH usually begins with early and aggressive use of systemic steroids, to which this disease is quite responsive, particularly in the early stages. These may be tapered slowly, usually over 3 to 6 months. In severe cases, some investigators have employed high-dose pulsed steroid therapy intravenously (l g of methylprednisolone) followed by oral prednisone 1 mg/kg/day is recommended. 88 The oral dosage may be as high as 2 mg/kg/day. 9 Hayasaka and colleagues89 suggested that lower-dose steroids may be needed for the Harada form of the disease compared with the Vogt-Koyanagi type. Early and aggressive treatment appears to be associated with a shorter duration and less progression of the disease. A recent studyby Sakaguchi and coworkers reported that hydrocortisone significantly suppressed the production of IL-6, IL-8, and granulocyte-macrophage colonystimulating factor by T-cell clones from aqueous humor of VIlli patients. 64 Duration of treatment and rate of drug tapering is case specific depending on the clinical response. Rubsamen and Gass treated their patients with steroids for 6 months on average. 16 The average initial dosage was 80 to 100 mg/day. They found that recurrences occurred in 43% and 52% of their patients in the first 3 to 6 months, respectively, and these were associated with rapid tapering of the steroids. In the same study, 66% of their patients had a visual acuity of 20/30 or better at an average followup of 53 months. Nussenblatt and colleagues suggested that steroid treatment may continue for a year in some severe cases, with a slow and gradual taper. 9 Associated anterior segment inflammation should also be treated with topical prednisolone 1% and cycloplegic drugs to lessen the inflammation and to reduce pain and synechiae. Topical steroids should be tapered according to the response.

Cytotoxic and Immunosuppressive Agents 111

diagnos-

DIFfERENTIAL DIAGNOSIS The differential diagnosis.of VIlli includes conditions that involve granulomatous inflammation, exudative retinal detachment, and white dot syndromes: .. .. .. .. ..

.. .. .. .. .. "

Sympathetic ophthalmia Primary intraocular B-celllymphoma Ocular Lyme disease Sarcoidosis Acute posterior multifocal placoid pigment epitheliopathy

Cytotoxic and immunosuppressive agents are reserved for patients who are refractory to corticosteroid therapy or for those who have developed unacceptable side effects thereof. Their use may also provide steroid-sparing effect, whereby the dose of steroid necessary to achieve quiescence is dramatically reduced or discontinued altogether. 90 Immunosuppressive or cytotoxic agents used in the management of VKH have been recommended by Moorthy and colleagues as follows 91 : .. Cyclophosphamide 1 to 2 mg/kg/day .. Chlorambucil 0.1 to 0.2 mg/kg/day; adjust every 3 weeks to maximum of 18 mg/day .. Azathioprine 1 to 2.5 mg/kg/day

CHAPTER 67:

.. Cyclosporine 5 mg/kg/day, trough 0.1 to 0.4 f.Lg/ml .. Tacrolimus (FRS06) 0.1 to 0.15 mg/kg/day, trough <20 ng/ml As previously discussed, the T-cell-mediated damage to melanocytes might be an immunopathologic basis of this' disease. It is therefore appropriate to consider cyclosporine, which inhibits T-cell response and thus cell-mediated immunity, in treating VKH disease. Several studies support the use of cyclosporine in refractory cases, either alone or with low-dose steroids. 16, 90-95 Nussenblatt and colleagues reported such a steroid-sparing effect after using cyclosporine A.90, 92 Similar results were described by Wakatsuki and coworkers93 and Moorthy and coworkers. 91 Cytotoxic agents have been used in the treatment of VKH and sympathetic ophthalmia with a positive therapeutic response, but the number of patients treated is small. 91 ,96 Concerns regarding their myelosuppressive and toxic side effects may have limited their use. A case report by Helveston and Gilmore described the use of azathioprine and intravenous immunoglobulin therapy with encouraging results. 97

VOG"f..KOYANAGI~HARADA

SYNDROME

Glaucoma is a common complication of VIlli. Acute angle-closure glaucoma has been reported, presulnably as a result of ciliary body edema with anterior displacement of the lens-iris diaphragm in the acute stage of the disease. 2o , 21, 26 In chronic cases, glaucoma secondary to chronic angle closure from extensive peripheral anterior synechiae and posterior synechiae has been reported in 6% to 45% of patients (see Fig. 67-5),n, 16, 34, 103 Openangle glaucoma secondary to corticosteroid use can occur during the treatment. In a study by Forster and colleagues,103 evidence of glaucoma was noted in 16 (38 %) of 42 patients. Eleven patients (69%) required surgical intervention. In patients with angle closure secondary to pupillary block, laser iridotomy appears to have a lower success rate than surgical iridectomy. Adjunctive 5-fluorouracil or mitomycin C may increase the success rate of trabeculectomy when filtering surgery was required. 12 , 26 Implantation of aqueous drainage devices may be prefelTed in patients with persistent inflammation. 103

Subretinal Neovascularization Nonmedical Treatment In patients whose detachment did not resolve after adequate medical treatment, drainage of the nonrhegmatogenous detachment might prove beneficial. Rhegmatogenous retinal detachment can also occur and should be treated properly as quickly as th~~condition permits.

COMPLICATIONS Three major complications of VKH for which therapy or surgical intervention may be required include cataracts, glaucoma, and SRNVM. Optic atrophy and pigmentary changes are also cominon.

Cataracts Cataracts are reported to occur in 11 % to 38%· of the eyes involved as the result of both longstanding inflammation and steroid therapy. 11, 12, 16, 64, 98 Moorthyand coworkers found that cataracts developed in 26 of their 65 patients over the course of therapy.98 In their study, steroid therapy for longer than 6 months and chronic recurrent anterior segment inflammation appeared to be significant determinants of cataract development. Cataract extraction can be performed safely and. can result in significant visual ilnprovement in these patients, provided that pre- and postoperative management are judicious. Inflammation should be controlled for at least 3 months prior to surgery. In the same study by Moorthy and colleagues,98 19 eyes underwent cataract surgery after 3 months of minimal or no inflammation. These patients were also treated with pre- and postoperative steroids. Mter surgery, median visual acuity improved significantly from 20/400 to 20/40 after a median follow-up time of 13 months. Some investigators have suggested that intraocular lens placement can be performed safely in selected cases without exacerbation of the disease.98-102 However, it should be kept in mind that extensive synechiae and lens capture by iris, as well as precipitates on the surface of the lens may develop after the surgery.

Along with cataracts and glaucOlna, SRNVM formation is an important cause of late visual loss in patients with VKH. Snyder and Tessler 12 reported an incidence of 5% in their patients, and Ober and coworkers found 36% in their series. In a recent study by Moorthy and colleagues,104 SRNVM developed in 10 (9%) of 116 eyes with VKH disease, which was consistent with an earlier report by Rubsamen and Gass. 16 The presence of extensive fundus pigmentary derangement or chronically recurrent inflammation, and recurrence of predominantly anterior segment inflammation appear to be risk factors for the d,evelopment of SRNVM in VKH. 10 4 There is a propensity for the SRNVM to develop in the peripapillary, subfoveal, and extrafoveal macular regions, where inflalnmatory foci appear to be concentrated in these areas. 51 , 104 The visual Ollt~ome of eyes with SRNVMs is generally poor. The use of indocyanine green angiography may be a useful adjunct in the laser treatment of these patients. With early reco~nition and appropriate intervention, visual acuity may be preserved in some cases.

PROGNOSIS The use of corticosteroids and immunosuppressive agents has greatly improved the visual outcome in VIlli patients. Overall prognosis of VKH is fair, with 48% to 93% of patients retaining visual acuity of 20/40 or better. Moorthy and colleagues showed that 53% of 130 eyes studied had final visual acuity of 20/30 or better after treatment for a mean of 5.6 months. 91 Rubsamen and Gass reported that 66% of the patients had a final visual acuity of 20/30 or better with corticosteroids and/or immunosuppressive treatment with a mean follow-up time of 53 months. 16 Seven percent of the eyes followed had a visual acuity of less than 20/400. These investigators cited three factors to be predictive of poor visual outcOlne: (1) increased age at the onset of the disease, (2) chronic inflammation requiring prolonged treatment with corticosteroids, and (3) SRNVM.16

61: VOG"f-KOYANAGI·HARADA SYNDROME

VIm is a systemic disorder involving multiple organ systems, including the ocular, auditory, nervous, and integumentary systems. The etiology is unknown. Autoimmunity to melanocytes in the uveal tract and integumentary system is believed to be the pathogenesis. In the early stage of the disease, patients usually present with bilateral panuveitis, exudative retinal detachment, and optic disc hyperemia. Neurologic involvement such as headache, meningismus, and CSF pleocytosis is common. Fundus and skin depigmentation occurs months after the initial onset of the disease. The diagnosis of VKH is a clinical one, with FA, B-scan ultrasonography, and lumbar puncture being useful adjuvants diagnostically and in following the course of the disease. Systemic corticosteroids are the mainstay of treatment, with immunosuppressive agents being useful in refractory cases or as steroid-sparing agents in patients who have become intolerant of steroids or who have developed unacceptab~e steroid-induced side effects. The overall prognosis is fair, with a substantial number of patients achieving visual acuity of 20/50 or better with early and aggressive treatment. Ultimate visual potential may be limited by the development of cataract, glaucoma, and choroidal neovascular membrane.

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s

CHAPTER 61: VOG'T--KOYANAGI·HARADA SYNDROME

44.

45.

"46.

47.

48.

49.

50. 51.

52. 53.

54.

55.

56.

57. 58.

59.

60.

61.

62.

63.

64.

65. 66.

67.

68.

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69. Zhao M, Jiang Y, Abrahams IW: Association of HLA antigens with Vogt-Koyanagi-Harada syndrome in a Han Chinese population. Arch Ophthalmol 1991;109:368-370. 70. Goldberg AC, Yamamoto JH, Chiarella JM, et al: HLA-DRB1 *0405 is the predominant allele in Brazilian patients with Vogt-KoyanagiHarada disease. Hum Immunol 1998;59:183-188. 71. Pivetti-Pezzi P, Accorinti M, Colabelli-Gisoldi RA, et al: Vogt-Koyanagi-Harada disease and HLA type in Italians. Am J Ophthalmol 1996;122:889-891. 72. Martinez JA, Lopez PF, Sternberg P, et al: Vogt-Koyanagi-Harada syndrome in patients with Cherokee Indian ancestry. Am J Ophtllalmol 1992;114:615. 73. Ishikawa A, Shino T, Uchida S: Vogt-Koyanagi-Harada disease in identical twins. Retina 1994;14:435-437. 74. Itho S, Kurimato S, Kouno T: Vogt-Koyanagi-Harada disease in monozygotic twins. Int Ophthalmol 1992;16:49-54. 75. Rutzen AR, Ortega-Larrocea G, Schwab IR, et al: Simultaneous onset of Vogt-Koyanagi-Harada syndrome in monozygotic twins. AmJ OphthalmoI1995;119:239-240. '16. Brinkley JR, Dugel PU, Rao NA: Fluorescein angiographic findings in Vogt-Koyanagi-Harada syndrome (abstract). Ophthalmology 1992;99 (suppl) :151. 77. Gass JDM: Harada's disease. In: Gass JDM, ed: Stereoscopic Atlas of Macular Disease. Diagnosis and Treatment. St. Louis, Mosby, 1987, pp 150-153. 78. Yoshioka H: Early fundus changes in Harada's syndrome. Jpn J Clin Ophthalmol 1967;21:135-141. 79. Okamura S: Harada's disease. Acta Soc Ophthalmol Jpn 1938;42:196. 80. Oshima Y, Harino S, Hara Y, et al: Indocyanine green angiographic findings in Vogt-Koyanagi-Harada disease. Am J Ophthalm&l,,1996;122:58-66. " 81. Yuzawa M, Kawamura A, Matsui M: Indocyanine green video-angiographic findings in Harada's disease. Jpn J Ophthalmol 1993; 37:456-466. 82. Forster DJ, Cano MR, Green RL, et al: Echographic features of the Vogt-Koyanagi-Harada syndrome. Arch Ophthalmol 1990;108:1421-1426. 83. Okubo K, Kurimoto S, Okubo K, et al: Surface marker studies of cerebrospinal fluid lymphocytes in Vogt-Koyanagi-Harada disease. Nippon Ganka Gakkai Zasshi 1985;89:726-732. 84. Nakamura S, Nakazawa M, Yoshioka M, et al: Melanin-laden macrophages in cerebrospinal fluid inVogt-Koyanagi-Harada syndrome. Arch Ophthalmol 1996;114:1184-1188. 85. Nagaya T: Use of tlle electro-oculogram for diagnosing and following the development of Harada's disease. Am J Ophthalmol 1972;74:99-109. 86. Ibanez HE, Grand MG, Meredith TA, et al: Magnetic resonance imaging findings in Vogt-Koyanagi-Harada syndrome. Retina 1994;14:164-168. 87. Ikeda M, Tsukagoshi H: Vogt-Koyanagi-Harada disease presenting meningoencephalitis. Report of a case with magnetic resonance imaging. Eur Neurol 1992;32:83-85. 88. Sasamoto Y, Ohno S, Matsuda H: Studies on corticosteroid therapy in Vogt-Koyanagi-Harada disease. Ophthalmologica 1990;201:162167. " 89. Hayasaka S, Okabe H, Takahashi J: Systemic corticosteroid treatment in Vogt-Koyanagi-Harada disease. Graefes Arch Clin Exp" Ophthalmol 1982;218:9-13. 90. Nussenblatt RB, Palestine AG, Chan CC: Cyclosporin A therapy in tlle treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents. Am J Ophthalmol 1983;96:275-282. 91. Moorthy RS, Inomata H, Rao N: Vogt-Koyanagi-Harada syndrome. Surv Ophthalmol 1995;39:269-292. 92. Nussenblatt RB, Palestine AG, Rook AH, et al: Treatment of intraocular inflammatory disease with cyclosporin A. Lancet 1983; 2:235-238. 93. Wakatsuki Y, Kogure M, Takahashi Y, et al: Combination tllerapy witll cyclosporin A and steroid in severe case of Vogt-KoyanagiHarada disease. Jpn J Ophtllalmol 1988;32:358-360. 94. Wakefield D, McCluskey P: Cyclosporine: A tllerapy in inflammatory eye disease. J Oenl Pharmacol 1991;7:221-226. 95. Walton RC, Nussenblatt RB, Whitcup S: Cyclosporine therapy for severe sight-threatening uveitis in children and adolescents. Ophthalmology 1998;105:2028-2034.

VOG1=-KOYANAGI-HARADA SYNDROME 96. Limon S, Girard P, Bloch-Michel E, et al: Les aspects actuels du syndrome du Vogt Koyanagi Harada. Apropos de 9 cas. J Fr Ophtah mol 1985;8:29-35. 97. Helveston WR, Gilmore R: Treatment of Vogt-Koyanagi-Harada syndrome with intravenous immunoglobulin. Neurology 1996; 46:584-585. 98. Moorthy R, Rajeev B, Smith RE, et al: Incidence and management of cataracts in Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 1994;1 i8:197-204. 99. Chung YM, Yeh TS: Intraocular lens implantation following extracapsular cataract extraction in uveitis. Ophthalmic Surg 1990;21 :272-276. 100. Foster CS, Fong LP, Singh G: Cataract surgery and intraocular

101.

102. 103.

104.

lens implantation in patients with uveitis. Ophthalmology 1989;96:281-288. Foster RE, Lowder CY, Meisler DM, et al: Extracapsular cataract extraction and posterior chamber intraocular lens implantation in uveitis patients. Ophthalmology 1992;99:1234-1241. Harada T, Takeuchi T, Kuno H, et al: Results of cataract surgery in patients with uveitis. J Fr Ophtalmol 1996;19:170-174. Forster DJ, Rao NA, Hill RA, et al: Incidence and management of glaucoma in Vogt-Koyanagi-Harada syndrome. Ophthalmology 1993;100:613-618. Moorthy RS, Chong LP, Smith RE, et al: Subretinal. neovascular membranes in Vogt-Koyanagi-Harada syndrome. AmJ Ophthalmo1 1993;116:164-170.

I I I Albert T. Vitale andJames G. Kalpaxis

DEfiNITION Multifocal choroiditis and panuveitis (MCP) is a posterior chorioretinal inflammatory disease of unknoWn etiology with prominent elements of vitritis and anterior segment uveitis. The acute chorioretinal lesions subsequently scar with proliferation of retinal pigment epithelium (RPE) and fibrosis, which may, in turn, lead to the frequent occurrence of choroidal neovascular membranes (CNVMs) and irreversible visual loss. Enlargement of the blind spot occurs frequently with MCP. This, together with multifocal chorioretinal pathology, with or without scarring, are features shared by a group of possibly related inflammatory syndromes of unknown etiology, namely, multiple evanescent white dot syndrome (MEWDS) , punctate inner choroidopathy (PIC), and subretinal fibrosis and uveitis syndrome (SFU). Whether these syndromes represent distinct clinical entities or are a spectrum of a single disease remains controversia~.

HISTORY

N ozik and Dorsch 1 first reported two distinctive cases of bilateral chorioretinopathy wit:b anterior uveitis in late 1973, which resembled the presumed ocular histoplasmosis syndrome (POHS). By 1984, 28 additional patients with anterior uveitis, vitritis and multiple lesions at the level of the RPE were described by Dreyer and Gass, 2 who coined the descriptive term multifocal choroiditis and panuveitis, in contradistinction to POHS. Subsequently, Deutsch and Tessler 3 described 28 patients with inflammatory pseudohistoplasmosis, a condition that featured vitritis; however, systemically, the majority of these cases were presumed to have sarcoidosis, syphilis, or tuberculosis. Coincidentally, in 1984, Jampol and colleagues 4 used the term multiple evanescent white dot syndrome to describe a series of 11 young, predominantly female patients with acute, transient, monocular visual loss accompanied by numerous white dots in the fundus. In the same year, Watzke and colleagues5 described punctate inner choroidopathy occurring in 10 healthy, young, myopic women who presented with visual symptoms in the absence of vitreous or anterior chamber inflammation, inner chorioretinal lesions that subsequently evolved into pigmented scars, and the frequent development of CNVMs. Subsequently, Morgan and Schatz 6 described a series of 11 patients with features of both MCP and PIC, which they termed recurrent multifocal choroiditis. The syndrome of diffuse subretinal fibrosis was initially described in 1982 by Doran and Hamilton 7 in four patients with antecedent CNVMs. Palestine and associates 8 and later Cantrill and Folk9 described two series of patients with progressive chorioretinal fibrosis, which appeared to be the terminal manifestation of a multifocal choroiditis of unknown etiology in young, healthy women, which could not be attributed to pre-existing

CNVMs alone. We prefer the term subretinal fibrosis and uveitis for this entity, to underscore its inflammatory nature. Recently, Reddy and colleagues lO described the association of enlargement of the blind spot, together with other clinical, angiographic and electroretinographic features, in a group of 79 patients comprised of 41 with MCP, 16 with PIC, 6 with SFU, and 16 with MEWDS. Finally, the visual prognosis, incidence, treatment and natural history of CNVMs, and the medical management of this same group of patients were reviewed by Brown and colleagues. I1

EPIDEMIOLOGY MCP affects predominantly young, otherwise healthy adults in their mid-30s, with a range of 9 to 69 years. 2, 6,10 In several series, patients were either exclusively women,6 or women outnumbered men by more than 3:1. 2,10 Moderate myopia was. present in 10 of 11 women examined by Morgan and Schatz, 6 whereas a range of refractive errors from -9.00 to + 2.50 diopters was reported by Reddy and colleagues. 10 There is no apparent racial or familial predilection. The geographic distribution and epidemiologic background of patients with MCP are distinctly different from those with POHS,2 which is endelnic to North Alnerican river valleys and other areas with a historically high prevalence of histoplasmin skin test positivity. 12

The majority of patients have bilateral disease, albeit asymmetric, with the involved fellow eye at times being totally quiescent and asymptomatic. Bilaterality ranged from 66% to 79% as reported by Reddy and coworkers 10 and Dreyer and Gass 2 respectively, whereas, this figure was only 45% in the series of Morgan and Schatz. 6 Patients commonly present with blurred or decreased central vision and scotomata. Photopsias and floaters are less common complaints. Although the mean initial visual . acuity in the 68 eyes of 41 patients with MCP reported by Brown and colleagues l l was 20/50, the range Inay be considerable, varying from 20/20 to light perception. Signs of mild to moderate anterior uveitis, including nongranulomatous keratic precipitates, posterior synechiae, and cells and flare, were observed in 52% of patients studied by Dreyer and Gass,2 whereas 32% of those reported by Reddy and associates io exhibited anterior chamber cells. Similarly, mild to Inoderate vitreous cellular activity was more commonly observed in both series, and was present in 76%10 and 100%2 of patients, respectively. Biomicroscopic examination during the acute phase of MCP reveals multiple round to oval, yellow-gray lesions at the level of the RPE, ranging in size from 50 to 350 "",m, and in number from several to more than 100, scattered

MUlTIFOCAl CHOROIDITIS AND PAN UVEITIS

FIGURE 68-1. A, Typical picture of an eye affected by MCP, with vitreous cells (note the obscuration of a view of the retina) and multifocal lesions of inflammation in the choroid. B, Same eye as in lA after successful control of the inflammation. Note the clearing of the vitreous, disclosing the multiple foci of prior inflammation in the choroid.

Acute symptomatic enlargement of the blind spot in the absence of disc edema was initially described in three

patients with MCP by Korram and coworkers,17 who attributed the defect to peripapillary retinal dysfunction. Callanan and Gass 18 subsequently reported acute enlargement of the blind spot in seven patients who later developed findings consistent with MCP, four of whom had transient white dots typically seen in MEWDS, and .suggested a common link in their etiology. Indeed, enlargement of the blind spot not solely attributable to disc swelling or peripapillary scarring was the most common visual field defect observed by Reddy and colleagues,10 occurring in 47% of 51 eyes examined. In the same study, 22 eyes (43%) were found to have full visual fields, whereas 13 (25%), 4 (8%) and 2 (4%) eyes had central or paracentral, peripheral, and cecocentral field abnormalities, respectively, with a distinct predilection for involvement of the nasal retinal quadrant (Fig. 68-4). Although the etiology of the blind spot enlargement in MCP is unknown, Brown and Folk have offered two possible explanations-the first involving the vascular arborization to the nasal retina, and the second relating to regional variation in the distribution of photoreceptors. In the first scenario, should MCP arise from hematogenous dissemination of an etiologic pathogen, the nasal retina may be more likely to be involved by preferential shedding of this agent to the medial posterior ciliary

FIGURE 68-2. A photograph of a patient with MCP showing a linear peripheral arrangement of the spots of now inactive choroiditis.

FIGURE 68-3. Extensive peripapillary atrophy in a patient with MCP.

throughout the posterior pole and midperiphery (Fig. 68-1) .13 They may occur singly, in clusters, or in' streak configuration, parallel to the ora serrata retinae as seen in POHS (Fig. 68-2) .14 A distinct propensity for a peripapillary and nasal midperipheral and peripheral distribution of these lesions has been observed. 10 The active lesions evolve into round, atrophic chorioretinal scars with a punched-out appearance and varying degrees of hyperpigmentation. Optic disc swelling and hyperemia are not uncommon, occurring in 34% of 68 eyes examinf?d by Reddy and associates. lO Peripapillary atrophy, similar to that seen in POHS, is frequently seen on follow-up examination (Fig. 68-3). The development of cystoid macular edema (CME) is variable, occurring in 14% of eyes reported by Dreyer and Gass,2 as opposed to 41 % of patients with MCP studied at the National Eye Institute. 15 CNVMs, in either a macular or peripapillary location, have been observed in 32% to 46% of patients with MCP.2. 6, 11 Less commonly observed findings include retinal vasculitis 16 and retinal and optic disc neovascularization. 2

Perimetry

CHAPTER 68: MUlTIFOCAl CHOROIDITIS AND PANUVEITIS

HAAG

mm

Nomen:

~

_ _~ ~ .

~~

Sarvicalne. 135

Mason. OK 45040

Detum:

Diameter pupillae

Prinled In USA 940·2414

I

I

FIGURE 68-4. Goldmann field showing the cecocentral scotomata in a patient with Mep.

artery, which supplies the pt?ripapillary choroid extending nasally to the equator. 19 More immediate access to this vessel could be achieved by virtue of its earlier and more acute bifurcation from the ophthalmic artery, as compared to the lateral posterior ciliary artery, which nourishes the temporal retina. 2o ,21 The second explanation for enlargement of the blind spot posits preferential involvement of rod photoreceptors in MCP, owing to their topographic distribution in the retina. Cuccio and colleagues 22 have found that the highest relative density of the rods to cones in the retina is in a peripapillary distribution extending nasally. Hence, if rods are more severely affected than cones in MCP, as electroretinography (ERG) suggests,10 enlargement of the blind spot may be explained.

Electroretinography ERG suggests that MCP is a diffuse disease process, with the degree of dysfunction relating to the severity and the extent of chorioretinal involvement. Nonnal to borderline ERGs were seen in 16 eyes (41 %) of 16 patients (29 eyes) studied by Dreyer and Gass, 2 whereas moderately reduced and severely depressed ERG amplitudes were found in five and six eyes, respectively. Similarly, Reddy and coworkers 10 reported ERG data on 10 patients in relation to the number of choi'ioretinallesions observed. Two patients with mild disease (20 or fewer lesions per eye) had essentially normal ERGs. Five patients with moderate disease (21 to 50 lesions per eye) exhibited abnormal ERG responses characterized by rod dysfunction, prolonged cone B-wave implicit times, and poor oscillatory potentials. Three patients with more than 50 lesions per eye were judged to have severe chorioretinal involve-

ment and were found to have 'markedly depressed rod and cone function with poor oscillatory potentials.

COURSE MCP is a chronic disease that may persist for many years, with the vast majority of patients experiencing multiple inflammatory recurrences in one or both eyes. Indeed, of 21 patients with MCP followed for 1 year or more, 18 (86%) demonstrated symptomatic, recurrent inflammation. 10 Inflammatory reactivation may manifest as vitreous or anterior chamber cellular infiltration and swelling of the choroidal scars with surrounding subretinal fluid, with the rare appearance of distinctly new lesions. Although recurrent lesions become larger and more pigmented with time, no new chorioretinal lesions were noted by Folk and Reddy,IO who were able to trace these recurrent foci to previous lesions seen on color photographs or fluorescein angiograms. As previously noted, although CME may complicate the course of MCP in a variable though significant number of patients, the most serious threat to central vision is the development of CNVMs, which are found in 32% to 46% of patients at some point in time during the· course. 2, 6,11 Typically, CNVMs arise either from atrophic scars or from yellow, nodular subretinal lesions, frequently in association with active inflammation. They may occur in a subfoveal, juxtafoveal, extrafoveal, or peripapillary location, ranging in number from one to as many as eight foci in a single eye, and varying in size from less than 100 /-Lm in diameter to large lesions exceeding 200 /-Lm.l1 In some of these eyes, the CNVMs appear to be anterior to the RPE. In others, Brown and colleagues ll have noted that areas of neovascularization may be sur-

CHAPTER68: MULTIFOCAL CHOROIDITIS AND PANUVEITIS

FIGURE 68-5. A, Fluorescein angiogram in a patient with MCP, early (arterial) phase. Note in particular the areas of choroidal fluorescence "blocking" temporal to the macula. B, Fluorescein angiogram in a patient with MCP, late phase. Note, in addition to the macular edema, the extensive areas of staining in the areas previously "blocking" the choroidal fluorescence pattern.

rounded by thick, hypofluorescent rings as seen on fundus fluorescein angiography and probably correlate to hyperplasia of the RPE. This pattern of proliferating RPE cells and small size (~100 /-Lm) of CNVMs was associated with spontaneous involution of the neovascular complexy,19

DIAGNOSIS The diagnosis of MCP is in essence clinical, based on a thorough ophthalmic and medical history, review of systems, and ocular examination revealing the characteristic funduscopic findings in the presence ofvitritis or anterior segment inflammation. As previously noted, choroidal neovascularization is common,may be apparent at presentation, or may evolve at any time during the disease course. There are no typical systemic disease associations, and features characterizing other ocular disorders (e.g., HLA-A29 suggestive of birdshot retinochoroidopathy) are absent. In fact, there are no specific laboratory or ancillary tests that establish the diagnosis of MCP; rather, they are most useful in excluding other differential diagnostic entities.

Fluorescein Angiography The active yellow-gray lesions that are characteristic of the acute phase of MCP may be nonfluorescent in the early phase of the fluorescein angiogram (FA), with gradual staining and late leakage (Fig. 68-5). Atrophic, punched-out scars behave as window defects with early

hyperfluorescence that fades in the late phase of the study. Disc swelling and hyperemia, together with CME, manifest angiographically by late dye leakage from retinal and optic disc capillaries. Characteristic angiographic features of choroidal neovascularization include early hyperfluorescence with late leakage (Fig. 68-6). In addition, as previously noted, . Brown and associates ll , 19 have observed that some of these foci may be surroi.lnded by thick hypofluorescent rings corresponding to hyperplastic RPE, a pattern that may be indicative of spontaneous involution of the neovascular complex. 23 ,24

Indocyanine Green Angiography Indocyanine green (ICG) angiography may provide additional information that is not detectable by clinical examination or FA. This feature may be useful not only in the differentiation of MCP from other inflammatory multifocal chorioretinal entities but may also serve to improve our understanding of the underlying nature of the disease, its progression, and its response to therapeutic intervention. In a study of 28 eyes with active inflammation associated with MCP, Slakter and colleagues25 observed that 14 (50%) had large (200 to 500 /-Lm) and 17 (61 %) had small (50/-Lm) hyperfluorescent lesions in the posterior pole on ICG angiography, which were more numerous and involved a more extensive area than those appreciated on FA or clinical examination (Fig. 68-7). These hyperfluorescent spots were thought to be indica-

FIGURE 68-6. A, Fluorescein angiogram in a person with a choroidal neovascular membrane in the macula, exhibiting early fluorescence. B, Fluorescein angiogram in a person with a choroidal neovascular membrane in the macula, exhibiting late staining.

68: MUlTlfOCAl CHOROIDITIS AND

FIGURE 68-7. Indocyanine green angiogram, showing the areas of hypofluorescence in the choroid, indi,cative of foci of active inflammation in the choroid in a patient with MCP.

tive of acute or subacute disease, with an increase in their density and number ,corresponding to periods of increased vitritis and visual field loss. Conversely, hypofluorescent lesions were seen to resolve, either spontaneously as the acute disease process waned, or in response to systemic therapy with oral prednisone. In five eyes, a dense confluence of hypofluorescent spots surrounding the optic nerve was associated with enlargement of the blind spot on visual field .exainination. Interestingly, in four of' these cases, resolution of the hypofluorescence was associated with resolution of the visual field defect, representing for the first time a direct relationship between enla'tgement of the blind spot and a structural or functional defect in the peripapillary choroidal anatomy. 25 Although the nature of these hypofluorescent spots could conceivably be attributed to underlying perfusion abnormalities of the choroid or choriocapillaris, no such defects were noted in areas of acute disease during the early phase of the ICG study in any of the eyes studied. 25 Rather, the authors implicate focal collections of inflammatory cells or postinflammatory debris, either at the level of the choriocapillaris as blocking fluorescence, or in the middle layers of the choroid producing a spaceoccupying effect, and so, preventing the egress of dye and diluting its concentration in the inflamed areas. The latter effect would produce an area of relative. hypofluorescence in the mid- and late phase of the ICG study. 25 Finally, Slakter and coworkers 25 have identified ce:t~in patterns on ICG angiography that may serve to dIstInguish MCP from POHS and may provide insi?~t into fundamental differences between these two entItles. Although hypofluorescent spots are a characteristic feature of active disease in eyes with MCP, patients with POHS fail to manifest this finding, despite repeated examinations at various intervals during the course of their disease. In fact, some patients with POHS demonstrated focal areas of hyperfluorescence in the posterior pole during the midphase of the ICG study, presumably representing. subclinical inflammatory activity. No hypofluorescent leSIOns, characteristic of MCP, were noted in eyes with POHS. The differential diagnosis of MPC includes those infectious and noninfectious causes of white dot syndromes

(Table 68-1). Although it shares many similar logic features with POHS, Mep was originally in contradistinction to this entity, as exhibiting anterior chamber and vitreous cells, a female predilection, subnormal ERGs, and recurrent inflammatory disease. POHS has a significant association with HLA-DR2 (76%), whereas this genetic background is apparently absent in patients with MCP.26 Furthermore, as previously mentioned, there are certain patterns on ICG angiography that may be useful in distinguishing these two diseases. 25 MEWDS, like MCP, may present in young WOlnen with acute blind spot enlargement and vitreous inflammation. However, although important exceptions exist, MEWDS is predominantly a unilateral disease. As its name implies, it rarely produces permanent funduscopic pigmentary changes and resolves in most cases with resolution of the visual field abnormality and a favorable visual outcome. IS, 27 In MCP, resolution of the blind spot and peripapillary dysfunction are less certainY Although it has been suggested that SFU represents a terminal stage of MCP, because both share multifocality early in the disease course and recurrent inflammat~ry episodes, the pathology in SFU is limited to the postenor pole and eventuates in severe subretinal scarring not seen in MCP or PIC. Despite these changes, full-field ERGs were normal in the two patients with SFU studied by Reddy and colleagues. lo This is in contrast to the markedly abnormal ERGs in patients with more advanced MCP, which are indicative of a more diffuse disease process. Perhaps PIC is most closely related to MCP, with the frequent development of CNVMs and with its tendency toward bilaterality.5,11 Although by definition PIC has no vitreous or anterior cellular inflammation, it differs from MCP in that the chorioretinal lesions tend to be smaller than those seen in MCP, enlargement and recurrent inflammation around the choridretinal scars are not observed, and electrophysiology is normal. Other noninfectious entities to be considered in the

TABLE 68-1. MULTI fOCAL CHOROIDITIS AND PANUVEITIS: DiffERENTIAL DIAGNOSIS Of WHITE DOT SYNDROMES INFECTIOUS: Tuberculosis Syphilis Presumed ocular histoplasmosis syndrome (POHS) Diffuse unilateral subacute neuroretinitis (DUSN) Lyme disease Outer retinal toxoplasmosis Viral retinitis (cytomegalovirus, herpes simplex, herpes zoster) Septic choroiditis NONINFECTIOUS: Multiple evanescent white dot syndrome (MEWDS) Punctate inner choroidopathy (PIC) Subretinal fibrosis and uveitis (SFU) Sarcoidosis Birdshot retinochoroidopathy Sympathetic ophthalmia Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) Vogt-Koyanagi-Harada syndrome (VIlli) Masquerade syndrome (CNS/intraocular large celllymphorna)

CHAPTER 68:

.'-"-"'L.~lW"_

CHOROIDITIS AND PAN UVEITIS

differential diagnosis of MCP include sarcoidosis, birdshot retinochoroidopathy, APMPPE, and intraocular large-cell lymphoma. Although the diagnosis of sarcoidosis is suggested by elevation of the angiotensin-converting enzyme (ACE) .level, together with characteristic findings on chest x-ray study and gallium scanning, these studies may be negative, with the definitive diagnosis depending on the demonstration of noncaseating granulomata on tissue biopsy. Birdshot retinochoroidopathy tends to occur in older patients, with characteristic hypopigmented fundus lesions, the frequent occurrence of optic neuropathy, CME, HLA-A29 positivity, and the rare development )f CNVMs. APMPPE is a self-limited chorioretinal inFlammation presenting in young adults, usually with a liral prodrome. In contrast to MCP, there is less vitreous lnd no anterior segment inflammation, the lesions of '\PMPPE tend to be larger, and the disease resolves within ~ to 3 months without recurrences and with a good visual yutcome in most patients. 28 Furthermore, the visual field iefects in APMPPE vary, and there is a higher prevalence )f HLA-B27 and HLA-DR2. 28 Finally, the diagnosis of ntraocular large cell lymphoma should be entertained, ~specially in elderly patients presenting with vitritis and nultifocal choroidal infiltrates. Patients presenting with an MCP-like picture and a apidly progressive clinical course may, in fact, have an ll1derlying infectious disease. Entities to qe considered re listed in Table 68-1 and include, but ar:e not limited 0, diffuse unilateral subacute neuroretinitis (DUSN), eptic choroiditis, and viral retinitis due to ~ytomegalovi­ us, herpes simplex, or herpes zoster. Timely diagnosis nd institution of specific antimicrobial therapy are essenal in these cases, which otherwise carry a very poor rognosis.

:TIOPATHOGENESIS 'he etiology of MCP is unknown. Patients with MCP have o systemic disease associations, a negative history for ving in areas where histoplasmosis is endemic, and in ~neral, negative histoplasmin skin tests. In one study, though HLA-DR2 was found in 76% of patients with OHS26 and may represent a risk factor for the developlent of this disease, particularly in association with cho>idal neovascularization,26, 29 no patients with MCP were lund to express this antigen. A viral etiology has been suggested by some investiga'rs. Grutzmacher and colleagues cultured herpes simex type I from separate chorioretinal and vitreous sames in a 20-year-old previously healthy patient, with nduscopic findings consistent with MCP.3o Likewise, nong seven patients with MCP, Frau and associates demlstrated the intraocular synthesis of specific antibodies 'ainst varicella zoster in two cases and against herpes nplex virus in one case. 31 Tiedeman 32 described 10 patients with. MCP, all of 10m had serologic evidence suggestive of chronic or Tsistent Epstein-Barr virus (EBV) infection. All were nerally healthy individuals, with no evidence of systemic lease consistent with infectious mononucleosis. In this Ldy, patients with MCP, but none of the eight controls, d positive viral capsid antigen IgM or the Epstein-Barr rly antigen antibody titers. All patients with MCP, and

most of the controls, had viral capsid antigen IgG and Epstein-Barr nuclear antigen antibodies indicative of previous exposure to the virus. This serologic pattern is in contradistinction to that produced by infectious m.ononucleosis, in which the viral capsid antigen IgM followed by the viral capsid antigen IgG titers rise in a parallel fashion during viral in<;ubation, 4 to 5 weeks following exposure to the virus. The early antigen rises with the onset of clinical disease, usually within 5 to 10 weeks of exposure, rises to a maximum, and then falls to undetectable levels 6 to 12 months after resolution of the infection. The Epstein-Barr nuclear antigen antibody appears slowly, within 2 months, and persists for life, whereas the viral capsid antigen IgM titer falls to undetectable levels after resolution of infection. Because the diagnosis of chronic EBV infection is best supported by abnormally elevated antiviral capsid antigen IgM and anti-early antigen antibody levels,33, 34 Tiedeman suggested that individuals with MCP might be immunologically unable to resolve the infection and may represent a subgroup of patients with chronic Epstein-Barr syndrome with manifestations limited to the eye. A reappraisal of the association between chronic EBV infection and MCP by Spaide and colleagues 35 failed to support this hypothesis. They found that neither the antiviral capsid antigen IgG nor the antinuclear antigen titers of 11 patients with MCP were significantly different from those of 11 sex- and age-matched controls. Furthermore, one would expect that a state of chronic EBV infection would eventually produce systemic signs and symptoms. This has not been the case in patients with MCP. Finally, the intraocular inflammatory manifestations of chronic EBV, as described by Wong and colleagues,36 are distinct from those of MCP. Pathologic examination of MCP lesions has revealed inflamed choroidal vessels in association with early neovascular membrane formation, retinal pigment epithelial hyperplasia, and immunocytochemical evidence of a mixed population of lymphocytes. 37- 4o One study demonstrated a large number ofB cells in the choroid,39 whereas another pointed to a T-cell predominance in the choroid 37 and vitreous. 4o Ultrastructural studies and in situ hybridization failed to disclose herpes virus or other microbes. Although a causal link between an external infectious pathogen has not been conclusively demonstrated, we believe, as do others,15 that MCP probably develops in the genetically susceptible individual after contact with an inciting microbe, viral or otherwise, with the subsequent development of autoimmune choroiditis that is only amenable to anti-inflammatory and immunosuppressive chemotherapy. It is quite possible that MCP may have more than one cause producing a pattern morphologically indistinguishable on clinical examination. Whether MCP, PIC, SFU, and MEWDS represent distinct clinical entities, or various manifestations of a single disease, remains controversial. Although MCP and PIC are ipso facto distinct by definition, the presence or absence of anterior chamber or vitreous cells in these two particular entities may indeed reflect essential differences in their nature, as the visual prognosis and response to treatment seem to indicate. Likewise, MEWDS and SFU

68: MUlTIFOCAl CHOROIDITIS

are distinguishable on clinical grounds; they carry prognoses sufficiently distinct from each other, and from MCP and PIC, that it is sensible, from a clinical point of view, to treat these diseases as separate entities. From an etiopathogenetic viewpoint, these distinctions may prove to be artificial. The retina and choroid have a sufficiently varied but definitively limited repertoire of morphologic responses to inflammatory disease, irrespective of primary etiology. Underlying host immunologic and genetic factors are likely to be equally important in determining the eye's response to a particular inciting pathogen, the clinical course of disease, and the morphologic manifestations thereof. For example, as previously noted, individuals who express HLA-DR2 antigen may be at greater risk for developing POHS and CNVMS.26,29 In a nonhuman primate model of histoplasmic choroiditis, Smith and colleagues 41 -'13 demonstrated that lymphocytic infiltrates may persist around choroidal lesions for as long as 10 years following the initial infection, and that these lesions may be reactivated with antigenic challenge. Similarly, the lesions of MCP, PIC, and SFU may evolve from a primary exposure to a single antigen or group of closely related antigens, with future reactivations depending on the host's underlying immunologic response to a particular antigen, the induction of autoilllmunity, or subsequent exposure to other cross-reacting inflamrrptory stimuli.

Steroids and Immunomodulatory Therapy Systemic and periocular administration of corticosteroids may be of value, at least in the short term, in controlling intraocular inflammation and that associated with CNVMs and in preventing visual loss in some patients with MCP. However, our experience and that published in the literature suggest that MCP is more often resistant to protracted effective treatment with systemic and regional steroids. Dreyer and Gass 2 treated 18 of 28 patients with either systemic or periocular steroids, noting an improvement in vision in six, no change in nine, and the prevention of rapid visual deterioration in two. Morgan and Schatz6 reported visual improvement in all nine of their patients treated with steroids. In contrast, Cantrill and Folk9 noted that in their series of patients with multifocal choroiditis associated with progressive subretinal fibrosis, the acute lesions responded to systemic steroids initially in approximately 40% of cases, whereas some progressed to the fibrotic stage despite treatment. Brown and colleagues 11 treated 17 patients (28 eyes) with oral or subtenon corticosteroids, with 12 patients (16 eyes) showing definite improvement in visual acuity or decreased vitritis. Of the 16 eyes that showed visual improvement, four had CM£. Nevertheless, on extended follow-up, 11 of 28 eyes had a final visual acuity of 20/200 or worse, with the majority of these eyes (8 of 11) having developed CNVMs. Nolle and colleagues44 noted that the benefit of corticosteroids in their group of 20 patients with MCPwas temporary and limited, with most patients eventually becoming refractory to treatment, with deterioration in visual acuity during cortico-

steroid therapy in the vast majority of patients. Finally, Nussenblatt and colleagues 15 described a moderately good initial response to steroid therapy in their patients with MCP, particularly those with CME, but advocated the addition of other immunosuppressive agents, because this disease is frequently recalcitrant to therapy. its Given the chronic and recurrent nature of refractory response to long-term tolerable steroid treatment, and the well-known undesirable side effects of such therapy, we offer our patients the option of long-term immunomodulatory therapy as an alternative therapeutic approach. Our criteria for the selection of patients for immunomodulatory therapy and the guidelines for collaboration for proper monitoring are described in Chapter 12. The immunomodulatory agents that we have employed in the care of our patients with MCP have included methotrexate, azathioprine, cyclosporine, cyclophosphamide, chlorambucil, tacrolimus, leflunomide, mycophenolate lllofetil, and etanercept. The dosage ranges, routes of administration, and major potential side effects of these agents are presented in Chapter 12. Of the 19 patients with MCP followed on the Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary for a mean of 72.7 months (range 5 to 278 months), 15 patients (30 eyes) were treated with immunomodulatory therapy.45 This regimen was not associated with any significant medication-related cOlllplications and was effective in controlling inflammation and preserving good vision in patients with this potentially blinding disease. Ten of these 15 patients had previously been treated with systemic steroids. Four patients were treated with systemic nonsteroidal anti-inflammatory drugs (NSAIDs) or systemic steroids alone, and topical and regional steroids were used as adjunctive treatment. Systemic complications related to steroid treatment included duodenal perforation in one patient and cushingoid changes in three patients, whereas 12 patients developed cataract or glaucoma related to topical, regional, or systemic use of this drug. In contrast, an immunomodulatory-related complication was seen in only one patient, who experienced transient and reversible elevation of liver enzymes in association with methotrexate therapy. Of the 15 patients (30 eyes) who received immunomodulatory therapy at some point during their disease course, seven patients (seven eyes) lost considerable vision in one eye while on steroid therapy alone. However, good vision in the fellow eye was preserved when immunomodulatory therapy was commenced. There was no visual loss among any of the eyes treated with imlllunomodulatory agents. Of the 30 eyes in this group, 20 have maintained a visual acuity of 20/80 or better, with one eye at 20/80, another at 20/60, and 18 eyes at 20/40 or better.

laser Photocoagulation No study has been performed that specifically addresses the safety and efficacy of laser photocoagulation for the treatment of CNVMs complicating MCP. Nevertheless, based on the experience with other macular diseases complicated by CNVMs for which abundant data exist, laser photocoagulation under fluorescein or ICG guidance is recommended for extrafovealandjuxtafoveal but

CHAPTER 68:

•.-.....,..........,"-- CHC)R()I[JIITIIS AND PANUVEITIS

not for subfoveal membranes, to prevent loss of central vision. Although thenatural history of choroidal neovascularization in MCP is unknown, regression of CNVMs has occurred, either in association with corticosteroid therapy or spontaneously.5, 11, 19 Brown and colleagues 11 observed that regression was more likely to occur with small « 1OO/-Lm in diameter) as opposed to large (> 200 /-Lm in diameter) areas of neovascularization, and that those which did regress were not infrequently associated with a hypofluorescent rim surrounding the CNVM, due to hyperplastic RPE, on fluorescein angiography. Accordingly, these investigators recommend laser photocoagulation for areas of neovascularization greater than 200 /-Lm in diameter in an extrafoveal or juxtafoveal location, whereas lesions less than 100 /-Lm in diameter may either be observed closely for signs of regression or treated with laser. 19 Subfoveal lesions should be observed and not treated. Extrafoveal and juxtafoveal CNVMs arising in four eyes of four patients with MCP treated with laser photocoagulation regressed nicely, with preservation of central vision in three and visual loss in one due to late expansions of scarY' 19

of these being subfoveal. Although. these initial results are encouraging, they are neither randomized nor controlled, and more extended follow-up is necessary to assess the impact of recurrent neovascularization on the ultimate visual prognosis. Therefore, at the present time, submacular surgery for subfoveal choroidal neovascularization in general, and that complicating MCP, is best performed in the context of a multicentered, randomized, prospective clinical trial, as is ongoing in the Submacular Surgery Trial (SST).

PROGNOSIS

Pars Plana Vitrectomy and Subfoveal Surgery The efficacy of pars plana vitrectomy (PPV) , with or without lensectomy, in the treatment of uveitis in general and specifically with respect to MCP, remains an open question, especially in light of the fact that, to date, no controlled randomized data in a homogenous population of uveitics are available to begin to answer this question. With this in mind, Nolle and Eckardt40 found no impressive or sustained therapeutic benefit from PPV in nine patients (10 eyes) with MCP who were refractory to medical therapy. Although a modest visual improvement was achieved immediately postoperatively. in most cases, the visual acuity decreased to preoperative values or less within 6 months. Neither the intensity nor the frequency of inflammatory relapses was altered by vitrectomy. CNVMs associated with MCP, like those of PORS, are thought to arise from acquired damage to the choriocapillaris-Bruch's membrane-RPE complex due to focal choroiditis, with the growth of new blood vessels through these defects in Bruch's membrane extending laterally in the subretinal space, anterior to the RPE. Gass was the first to differentiate this path of advancing neovascularization (type II subretinal choroidal neovascularization) from that directed beneath the RPE as seen in age-related macular degeneration (type I sub-RPE neovascularization) and suggested that type II subretinal choroidal neovascularization may be amenable to surgical excision. 45 In the Rosenthal Lecture to the Macula Society in 1995, Thomas47 presented his experience with subretinal surgery for the management of subfoveal CNVMs in 247 consecutive cases of eyes with various underlying disease entities, including 17 with MCP. With a median follow-up of 8 months (range: 2 to 31 months), 59% of eyes were 20/40 or better postoperatively, compared with none preoperatively. Sixty-five percent of eyes had an improvement of three or more Snellen lines postoperatively. Recurrent neovascularization occurred within 3 months in 18% of eyes during the follow-up period, 67%

j

Given the chronic, bilateral and recurrent nature of MCP, its visual prognosis is clearly guarded despite steroid treatment, with progression to permanent visual loss in 60% to 75% of reported cases. 2 , 8, 9, 11, 44 Indeed, although Brown and colleagues11 have reported an average final visual acuity of 20/54 in their 25 patients (47 eyes) with MCP followed for 6 months or more, with 26 eyes (60%) having 20/40 visual acuity or better, overall, 14 eyes (32%) had a final visual acuity of 20/200 or worse. Visual loss from CME, epiretinal membrane formation, RPE atrophy and macular scarring, optic neuropathy, neovascular glaucoma, subretinal fibrosis, and choroidal neovascularization occur as a consequence of chronic and recurrent inflammation or from complications of steroid use (secondary glaucoma and cataract). Our experience suggests that the early introduction of immunomodulatory therapy in MCP poses less risk for medication-related morbidity compared with the use of systemic steroids, and is effective in controlling inflammation, and so, preserving those ocular structures that are vital for good visual function. Laser photocoagulation appears to be an effective treatment modality for larger juxtafoveal and extrafoveal CNVMs, with preservation of good visual function. The natural history of smaller foci of choroidal neovascularization is not known; however, as previously discussed, some have a tendency to regress spontaneously or with antiinflammatory treatment. Vigilant monitoring of such lesions may be the prudent choice in an effort to obviate the inherent risks and putative proinflammatory stimulus of laser photocoagulation, particularly when these lesions are multiple, are not a direct threat to central.vision, or are associated with inflammation. The ultimate role of submacular surgery with respect to the visual prognosis in MCP awaits further evaluation in the context of the SST.

CONCLUSIONS MCP is a relatively newly recognized, chronic, recurrent, bilateral, potentially blinding uveitic syndrome of unknown etiology. The clinical features, visual prognosis, and response to treatment suggest that it is a distinct clinical entity, developing perhaps in genetically susceptible individuals following exposure to an inciting microbe, viral or otherwise, with subsequent development of an autoimmune choroiditis. The visual prognosis is guarded, with visual loss as a direct consequence of the sequelae of chronic and recurrent inflammation. Steroid therapy for MCP is only transiently effective, with most patients becoming refractory to conventional treatment or suffering intolerable side effects thereof. Our experience sug-

CHAPTER 68: MUlTlfOCAL CHOROIDITIS AND PANUVEITIS

gests that the early introduction of immunomodulatory therapy is a safe and effective alternative· to the use of steroids that impacts positively on the ultimate visual prognosis in eyes with Mep.

25.

26.

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cells release inhibitors of neovascularization. Ophthalmology 1987;94:780. Slakter JS, Giovannini A, Yannuzzi LA, et al: Indocyanine green angiography of multifocal choroiditis. Ophthalmology 1997; 104:1813. Spaide RF, Skerry JE, Yannuzzi LA, et al: Lack of the HLA-DR2 specificity in multifocal choroiditis and panuveitis. Br J Ophthalmol 1990;74:536. Daniele S, Daniele C, Ferri CA: Association of peripapillary scars with lesions characteristic of multiple evanescent white-dot syndrome. Ophthalmologica 1995;209:217. Wolf MD, FolkJC, Nelson JA, Peeples ME: Acute posterior multifocal placoid pigment epitheliopathy and Lyme disease [letter]. Arch OphthalmoI1992;110:750. Meredith TA, Smith RE, Duquesnoy RJ: Association of HLA-DRw2 antigen with presumed ocular histoplasmosis. Am J Ophthalmol 1980;89:70. Grutzmacher RD, Henderson D, McDonald PJ, et al: Herpes simplex chorioretinitis in a healthy adult. Am J Ophthalmol 1983;96:788. Frau E, Dussaix E, Offret H, et al: The possible role of herpes viruses in multifocal choroiditis and panuveitis. Int Ophthalmol 1990;14:365. TiedemanJS: Epstein-Barr virus antibodies in multifocal choroiditis and panuveitis. AmJ Ophthalmol 1987;103:659. Tosato G: The Epstein-Barr virus and the immune system. Adv Cancer Res 1987;49:75. Thorley-Lawson DA: Immunological responses to Epstein-Barr virus infection and the pathogenesis of EBV-induced diseases. Biochem Biophys Acta 1988;948:263. Spaide RF, Suqin S, Yannuzzi LA: Epstein-Barr virus antibodies in multifocal choroiditis and panuveitis. Am J Ophthalmol 1991; 112:410. Wong KW, D'Amico DJ, Hedges TR, et al: Ocular involvement associated with chronic Epstein-Barr virus disease. Arch Ophthalmol 1987;105:788. Charteris DG, Lee WR: Multifocal posterior uveitis: Clinical and pathological findings. Br J Ophthalmol 1990;74:688. Dunlop AA, Cree IA, Hague S, et al: Multifocal choroiditis: Clinicopathologic correlation. Arch Ophthalmol 1998;116:801. Martin DF, Chan CC, deSmet MD, et al: The role of chorioretinal biopsy in the management of posterior uveitis. Ophthalmology 1993;100:705. Nolle B, Eckardt C: Vitrectomy in multifocal choroiditis. Gel' J Ophthalmol 1993;2:14. Al1.derson A, Clifford W, Palvolgy I, et al: Immunopathology of chronic experimental histoplasmic choroiditis in the primate. Invest Ophthalmol Vis Sci 1992;33:1637. Smith RE, Dunn S, Jester ]V: Natural history of experimental histoplasmic choroiditis in the primate. II. Histopathologic feat{lres. Invest Ophthalmol Vis Sci 1984;25:810. . Palvolgy I, Anderson A, Rife L, et al: Immunopathology of reactIvation of experimental ocular histoplasmosis. Exp Eye Res 1993; 57:169. Nolle B, Faul S,Jenisch S, et al: Peripheral multifocal chorioretinitis with panuveitis: Clinical and immunogenetic characterization in older patients. Graefes Arch Clin Exp Ophthalmol 1998;236:451. Michel SS, Ekong A, Baltatzis S, et al: Multifocal choroiditis and panuveitis (MCP): Immunomodulatory therapy. Ophthalmology, in press. Gass JDM: Biomicroscopic and histopathologic considerations regarding the feasibility of surgical excision of subfoveal neovascular membranes. Ann OphthalmoI1994;118:285. Thomas MA. Updated results in subfoveal surgery. Rosenthal Lecture. Macula Society, Palm Beach, Florida, 1995. Macula Society, Tucson, Arizona, 1996.

\NII-II

Harvey Siy Uy and Pik Sha Chan

ITION Multiple evanescent white dot syndrome (MEWDS) is a rare disorder of unknown etiology characterized by the presence of white lesions deep in the outer retina or at the level of the retinal pigment epithelium (RPE). Other RPE inflammatory disorders, such as acute posterior multifocal placoid pigment epitheliopathy (APMPPE), birdshot retinochoroidopathy (BSRC), multifocal choroiditis and panuveitis, punctate inner choroidopathy (PIC), and presumed ocular histoplasmosis syndrome (POHS), may present with white dots in the fundus. However, the lesions of MEWDS are distinguished by their distinct morphology, associated macular granularity, transient nature, characteristic angiographic appearance, unilaterality, self-limiting course, lack of significant sequelae, absence of associated systemic involvement, rapid recovery, and excellent visual outcome.

HISTORY AND EPIDEMIOLOGY The term multiple evanescent white dot syndrome was first used by J ampol and coworkers in 19841 to describe a series of 11 young adults wi1J1 transient loss of vision accompanied by white dots in the fundus. MEWDS is an uncommon ocular disease. Over the following decade, 69 additional cases were reported worldwide, with the largest series published to date consisting of 11 patients. Just as with most of the other white dot syndrome entities, the majority of patients with MEWDS are within the younger age groups. The average age at presentation is 28, with a range of 17 to 47 years. A definite female predominance is observed (male to female ratio of approximately 1:3). The significance of this age and sex distribution is unknown. White, black, Hispanic, Chinese, and Japanese l - 3 patients have been reported, and it is likely that other races are susceptible to this condition as well.

The lesions of MEWDS appear as multiple small (100 to 200 /-1m), round, slightly indistinct, white to yellow-white spots distributed over the posterior fundus, especially at the perifoveal and peripapillary regions (Fig. 69-1). Each "dot" is composed of aggregates of many smaller dots found deep in the retina or at the level of the RPE. These lesions are best appreciated by slit-lamp biomicroscopy using a contact or noncontact lens. Typically, these lesions tend to concentrate around the vascular arcades or the optic nerve head and extend to the midperiphery. Foveal involvement by these white dots is relatively rare; however, the fovea may exhibit fine mottling or hyperpigmentation. Macular granularity is a uniform and distinguishing feature of MEWDS and appears as multiple, minute, white or light orange specks (see Fig. 69-1). Other common clinical features include visual acuity reduction, anterior chamber cells, vitreous cells, an afferent pupillary defect,

irregularity of the internal limiting-membrane reflex, and mild optic disc swelling. Anterior chamber inflammation is occasionally observed and is Inild; vitritis is also usually mild and may be present in about half of all affected eyes. Associated retinal findings are infrequent and may include retinal splinter hemorrhages and mild venous sheathing. 1, 4-10 Although the majority of cases are unilateral and nonrecurrent, there have been at least 10 reported cases of bilateral involvement ll - 12 and at least five cases of chronic recurrence. 4,13 In bilateral involvement, the findings are usually asymmetric. Patients may describe blurred or dim vision or the presence of floaters during an episode of MEWDS. The visual acuity may acutely deteriorate, even to 20/200. There is rapid recovery of visual function to normal or near normal levels, with some patients improving within 1 to 2 weeks of disease onset. The majority of patients achieve visual acuities of 20/30 to 20/20 within 4 to 8 weeks after onset of the disease.1, 7 Regression of retinal lesions is coincident with visual recovery. The white dots and granularity of the macula tend to fade, leaving subtle RPE pigment alterations seen as window defects. 1 Several authors have reported an association of MEWDS with the acute idiopathic blind-spot enlargement syndrome (AIBES) .5, 14, 15 This subset of patients may additionally manifest disc edema, afferent pupillary defect, loss of central vision, blind-spot enlargement, other visual field defects, color vision disturbance, and optic disc hyperfluorescence on fluorescein angiography. The optic nerve disturbances may be more prominent than the chorioretinalmanifestations; however, in these instances, the diagnosis of MEWDS can be established by fluOl'escein angiography. AIBES can occur in patients with multifocal chorioretinitis and panuveitis and punctate inner choroidopathy (PIC) and may represent a common ocular response to chorioretinal inflammation. 16 Late sequelae of MEWDS are rare and include subfoveal neovascular membrane formation, which may develop weeks or months after initial symptoms and may spontaneously resolve.l7' 18 Two cases of acute macular neuroretinopathy in association with MEWDS in the same eye have also been reported, suggesting common pathogenic mechanisms. 19

PATHOGENESIS The pathogenesis of MEWDS is currently unknown. An infectious etiology is suggested by the prodromal flulike symptoms experienced by some patients and by findings of elevated total serum IgM and IgG in at least one patient. 2 No specific etiologic agent has yet been identified despite extensive laboratory_ testing by different authors. An autoimmune or immunologic mechanism is suspected and is supported by reports of MEWDS developing after hepatitis B vaccination 20 and by detection

69: MULTIPLE EVANESCENT WHITE DOT SYNDROME TABLE 69-1. DIAGNOSTIC FEATURES OF MULTIPLE EVANESCENT WHITE DOT SYNDROME

FIGURE 69-1. Fundus photograph of a patient with MEWDS. Note the deep, slightly indistinct, yellow-white lesions in the posterior pole. (See color insert.)

of HLA-B51 haplotype in 4 of 9 (44.4%) patients with MEWDS.21 It is well known that autoimmune diseases can be incited by normal immune responses to foreign antigens such as microbial agents. Infectious prodromes often precede the onset of autoimmune disease. Infectious agents can cause dysregulation of the immune. system by several mechanisms. Inflammation caused by an infectious agent can lead to local tissue injury with resulting alteration of self-antigens to create cross-reactive neWt antigens. Tissue injury can also lead to exposure of self antigens that were previously concealed from the immune system. An infectious process can also heighten immune responses by means of polyclonal lymphocyte activation and proliferation and by release of inflammatory costimulators. Last, normal antibodies or T cells directed against the initiating viral or bacterial antigen can cross react with self proteins, resulting in autoimmune disease. These processes may be at work in the pathogenesis of MEWDS and other white dot syndromes, such as acute posterior multifocal placoid pigment epitheliopathy, in which viral prodromes have been reported. Molecular mimicry, wherein short homologous sequences exist between microbial antigens and self-major histocompatibility antigens, is another theoretical mechanism by which an infectious agent can cause autoimmunity. The' subset of patients with relapsing MEWDS is reminiscent of the 'recurrences experienced by patients with autoimmune uveitis or with herpetic disease and further strengthens the case for an autoimmune or infectious pathogenic mechanism. Likewise, the frequent presence of optic nerve involvement in patients with MEWDS occurs in other autoimmune or infectious uveitis entities, with posterior segment findings associated with optic nerve dysfunction, such as sarcoidosis,- multiple sclerosis, syphilis, Lyme disease, cat scratch disease, toxoplasmosis, and herpetic eye disease. Further studies are needed to elucidate the pathogenesis of MEWDS.

DIAGNOSIS The diagnosis of MEWDS is primarily based on its characteristic clinical findings, transient course, and excellent visual outcome (Table 69-1). As part of the uveitis evalua-

Patient characteristics Young Female predominance Unilateral involvement usually Viral prodrome possible Ocular characteristics Anterior segment Mild anterior chamber inflammation Posterior segment Acute onset Visual dysfunction variable: 6/6 to 6/60 Rapid recovery with return of good visual function Mild vitritis in 50% Multiple grainy white dots, mostly in posterior pole with foveal sparing Macular granularity Optic disc edema or hyperemia Ancillary testing Fluorescein angiography: early hyperfluorescence witll late staining; optic disc hyperfluorescence Indocyanine green angiography: hypofluorescent spots all over the fundus Perimetry: blind-spot enlargement and central, cecocentral, and arcuate scotomas Electrophysiology: abnormal ERG, ERP, and EOG Test results return to normal with visual recovery ERG, electroretinogram; ERP, early receptor potential; EGG, electro-oculogram.

tion, a thorough review of systems should be conducted. A targeted medical work-up is advisable to rule out potentially treatable infectious or inflammatory disease such as syphilis, sarcoidosis, and toxoplasmosis. The most useful diagnostic examinations are fluorescein angiography and indocyanine green (leG) angiography. These imaging studies are particularly useful when the clinical findings are equivocal, when the disease is relapsing or recurrent, and when atypical features are encountered such as optic nerve involvement or subretinal neovascularization. During the acute phase of MEWDS, fluorescein angiography shows patchy or punctate, early hyperfluorescence of the white dots (Fig. 69-2) with late deep staining

FIGURE 69-2. Fluorescein angiogram, midphase, of a patient witl1. MEWDS. Note tlle extensive grouped granular lesions which, although they blocked choroidal fluorescence in the early phases of the transit, are beginning to stain at this midpoint of the transit.

CHAPTER

of the RPE and peripapillary area (Fig. 69-3). These lesions are mostly located in the posterior pole. Occasional leakage from the optic disc and retinal capillaries may be observed. RPE window defects may also be noted in severe cases. The choroidal background fluorescence between lesions is usually normal. As the fundus returns to 'normal, the angiographic changes becOIue less !1.oticeable and the angiogram may return to normal. 1, 4-1 ICG angiography has several advantages over flum-escein angiography in visualizing the choroidal ci~culation. Because ICG dye is a larger molecule than sodIum fluorescein and binds more tightly to serum albumin, ICG does not significantly leak from the choriocapillaris ~nd thus is able to provide improved images of the chorOIdal vasculature. In addition, ICG absorbs and emits infrared light with resulting improved light transmission throu&,h melanin, xanthophyll, blood, and infiltrates present ~n the layers of the retina. ICG angiography of MEWDS In the acute phase is characteristic and has not only been used to provide additional' supportive evidence for the diagnosis of MEWDS but has also provided insight as to the pathophysiology of this disease. . The arteriovenous phase of the ICG study typIcally does not reveal any distinct abnormal findings (Fig. 69-4), with the first lesions appearing at the lO-minute phase of the angiogram and persisting to the lat~ phases. A pattern of multiple deep, small, round, hypofluor~scent spots are appreciated in the posteri?r pole extendIng to the periphery (Fig. 69-5). The leSIOns are denser and may be confluent in the posteriJ)~ pole and ?eco~e less concentrated as they radiate out Into the mIdpenphery. Upon resolution of the disease, the hypofluorescent spots become smaller and eventually disappear. 22 , 23 The nature and location of these spots are suggestive of deep choroidallesions. Some of these spots may correspond to lesions seen on ophthalmoscopy or fluorescein angiography. Typically, many more spots are visible on ICG angIOgraphy than on fluorescein angiography.22-24 The pattern of hypofluorescent spots in MEWDS suggests th~t th~r: is choriocapillaris or choroidal precapillary artenole Injury in addition to RPE and photoreceptor involvement. The absence of early-phase lesions indicates that the larger

fiGURE 69-3. Fluorescein angiogram, late phase, of a patient with MEWDS. Note the staining pattern, with ring, wreath, and halo hyperfluorescence around the macula, and staining of the disc.

MULTIPLE

ES4CEiNT

WHITE DOT SYNDROME

fiGURE 69-4. Indocyanine green angiogram, early phase, of a patient with MEWDS. Note the subtle block-early spots, which become much more apparent in the later transit. (Courtesy of John 1. Loewenstein, M.D.)

choroidal vessels are spared. Several theories have been proposed by Obana and colleagues 23 to explain t~: apparent discrepancy between hyperfluorescence vIsIble. on fluorescein angiography and hypofluorescence dunng ICG angiography. A retinal lesion is unli~ely to selectiv:ly. block ICG transmission without blockIng fluoresceIn transmission. A filling defect of the choriocapillaris would result in simultaneous fluorescein and ICG hypofluorescence. Inflammatory thickening of the choriocapillaris vessel walls with narrowing of the precapillary arterioles may result in decreased blood circulation with decreased entry or retention of the larger ICG m~l~c.ule. yet all?w fluorescein transmission. A further possIbIlIty IS that Increased numbers of inflammatory cells in the choroidal interstitial tissue may result in tissue changes that may prevent entry or retention of the ICG I~~lecule but ~1.ot the smaller fluorescein molecule. A definItIve explanatIOn of this phenomenon awaits further studies. Visual field testing will frequently reveal enlargement of the blind spot. Visual field defects associated with

fiGURE 69-5. Indocyanine green angiogram, late phase, same case as seen in Figure 69-4. Note the mUltiple prominent foci of choroidal nonperfusion. (Courtesy ofJohn 1. Loewenstein, M.D.)

CHAPTER

MULTIPLE EVANESCENT WHITE DOT SYNDROME

MEWDS include blind-spot enlargement, and central, cecocentral, and arcuate scotomas. These scotomas may be the presenting complaint. Many of these patients manifest mild disc swelling, vascular congestion, and optic disc hyperfluorescence on fluorescein angiography. The size of the visual field defect may be disproportionately large or may not be commensurate with ophthalmoscopic findings. The enlarged blind spot may persist longer than the other symptoms, but the size of the blind spot almost always returns to normaL Blind-spot enlargement is not unique to MEWDS but is found in other posterior seglllent inflammatory disorders, such as multifocal choroiditis and panuveitis, pseudo-presumed ocular histoplaslllosis, acute macular retinopathy, and the acute idiopathic blind spot syndrome. This has prompted some authors to speculate on whether these conditions comprise a spectrum of disease or share a common pathogenesis. 5, 14, 15,25 Electrophysiologic abnormalities are observed in patients with acute MEWDS. Electroretinogram (ERG) and early receptor potential (ERP) amplitudes are often profoundly decreased, and ERP regeneration times are prolonged. These changes indicate pathology at the photoreceptor-RPE-Bru:ch membrane complex. 1 Foveal densitometry and color-matching testing during the active stage of MEWDS demonstrate gross abnormalities at the level of the cone photoreceptor outer segments. 26 Scal~:­ ning laser densitometry studies reveal reduction of visual pigments during active MEWDS.27 These two studies support the theory that there are metabolic disturbances at the level of the pigment epithelium-plYvtoreceptor complex in patients with active MEWDS. Prolonged latency and decreased amplitude of P100 complexes on electro-oculography, when optic disc swelling is present, indicate concomitant optic nerve dysfunction. 28 Focal electroretinography, however, reveals that macular ERG amplitude reduction is associated with central scotoma formation and that peripapillary ERG reduction is related to blind-spot enlargement. 29 This finding suggests that visual field disturbances in MEWDS primarily result from retinal rather than optic nerve dysfunction. Collectively, the results of these laboratory investigations indicate that the pathophysiologic mechanisms of MEWDS are complex and have yet to be fully elucidated. c

DIAGNOSIS The differential diagnosis of MEWDS includes acute posterior multifocal placoid pigment epitheliopathy (APMPPE), multifocal choroiditis and panuveitis (MCP) , BSRC, acute retinal pigment epitheliitis (ARPE) , PIC, sarcoidosis, and diffuse unilateral subacute neuroretinitis. A targeted medical work-up is advisable to rule out treatable infectious or inflammatory diseases such as syphilis, toxoplasmosis, tuberculosis, and sarcoidosis. APMPPE is characterized by transient visual loss in young patients, rapid and full visual recovery, and resolution of the RPE placoid lesions. APMPPE may also be associated with viral prodromes, papillitis, and mild anterior chamber and vitreous inflammation. However, APMPPE is usually bilateraL APMPPE lesions are larger and exhibit blocked fluorescence early in the angiogram, as opposed to early hyperfluorescence in MEWDS. RPE

pigmentary changes are more prominent in APMPPE than in MEWDS. Multifocal choroiditis and uveitis is a disease of young, healthy, myopic women that may cause acute loss of vision. MCP is an RPE-choroidal inflammatory disorder characterized by multiple relapses and prominent vitreous cavity and anterior chamber inflammation. The lesions of MCP are usually more concentrated in the periphery and resolve, leaving atrophic punched-out scars with hyperpigmented borders. Treatment of MCP may require corticosteroid or immunosuppressive agents. Visual prognosis is guarded, with visual function frequently cOlllpromised by cystoid macular edema and choroidal neovascular membrane formation. BSRC manifests as multiple cream-colored lesions at the level of RPE or deeper. BSRC is accompanied by prominent anterior chamber inflammation and vitritis. BSRC occurs mainly in older patients, and it is usually bilateraL The HLA A29 phenotype is highly (90%) associated with BSRC. Acute BSRC lesions may be angiographically silent, whereas older lesions may demonstrate early blocked fluorescence and late hyperfluorescence. ARPE is similar to MEWDS in that it affects relatively young patients and causes acute visual loss followed by almost total recovery in 7 to 10 weeks. However, the :macular lesions of ARPE are dark spots surrounded by a halo of depigmentation at the level of the RPE. The lesions, as seen on angiography, are hypofluorescent areas surrounded by hyperfluorescence. The ERG and cortical evoked responses are normaL PIC predominantly affects young women and is usually bilateraL Small yellow-white lesions (100 to 300 /-Lm) of the inner choroid and RPE are visible and may later form pigmented, atrophic, cylindrical lesions from which choroidal neovascular membranes often arise. Inflammation is characteristically absent in PIC. Recurrences are common but vision is not usually affected unless the fovea is directly involved. Sarcoidosis may present with deep, small, white lesions of the retina, but it is easily distinguishable from MEWDS by the presence of Dalen-Fuchs nodules, choroidal granulomas, retinal vasculitis, pars planitis, and vitreous snowballs. Diffuse unilateral subacute neuroretinitis is caused by an intraocular nematode and occurs in young adults presenting with loss of vision and, occasionally, white dots in the retina.· The clinical course is marked by progressive loss of vision, optic atrophy, retinal vessel narrowing~ and diffuse and focal RPE degeneration.

TREATMENT The lesions of MEWDS spontaneously resolve without treatment. Patients should be reassured of the self-limiting course of this disease and of the good visual prognosis.

SUMMARY MEWDS is an uncommon disorder of the RPE and choroid. It should be considered in the differential diagnosis of young, healthy patients who present with unilateral or bilateral acute visual loss or optic neuritis. A correct diagnosis of MEWDS can be made after careful history taking and biomicroscopic examination of the fundus.

CHAPTER 69: MULTIPLE EVANESCENT WHITE

The presence of characteristic fundus findings and the transient clinical course are usually sufficient to establish the diagnosis. Fluorescein and ICG angiography, perimetry, and electrophysiologic studies may help distinguish MEWDS from other disease entities that present with white dots. This disorder is characterized by spontaneous, rapid, and full recovery of visual function; however, careful follow-up of these patients is necessary for detection of potential, albeit rare, complications. The pathogenesis of this disease. is not well understood and awaits further investigation.

References 1. Jampol LM, Sieving PA, Pugh D, et al: Multiple evanescent white dot syndrome. 1. Clinical findings. Arch Ophthalmol 1984;102:671. 2. Chung YM, Yeh TS, Liu JH: Increased serum IgM and IgG in the multiple evanescent white-dot syndrome. Am J Ophthalmol 1987;104:187. 3. Nakao K, Isashiki M: Multiple evanescent white dot syndrome. Jpn J Ophthalmol 1986;30:376. 4. Aaberg TM, Campo RV, Joffe L: Recurrences and bilaterality in the multiple evanescent white dot syn.drome. Am J Ophthalmol 1986;101:489. 5. Dodwell DD, Jampol LM, Rosenberg M, et al: Optic nerve involvement associated with multiple evanescent white dot syndrome. Ophthalmology 1990;97:862. 6. Laatikainen L, Immonen I: Multiple evanescent white dot syndrome. Graefe's Arch Clin Exp Ophthalmol 1988;226:37. 7. Mamalis N, Daily Nij: Multiple evanescent white dot syndrome. A report of eight cases. Ophthalmology 1987;94:1209. 8. Palacios PT, Hurtado EP, Ramos MJM: Multiple evanescent white dot syndrome. Ann Ophthalmol 1993;25:216. 9. Slusher MM, Weaver RG: Multiple evanescent white dot syndrome. Retina 1988;8:132. 10. Jost BF, Olk RJ, McGaughy A: Bilateral symptomatic multiple evanescent white-dot syndrome. AmJ Ophthalmol 1986;101:489-490. 11. Lefrancois A, Hamard H, Corbe C, et al: A case of MEWDS, the multiple evanescent white-dot syndrome. J Fr Ophthalmol 1989;12:103. 12. Meyer RJ, Jampol LM: Recurrences and bilaterality in the multiple evanescent white dot syndrome. AmJ Ophthalmol 1985;100:29. 13. Tsai L, Jampol LM, Pollock SC, Olk J: Chronic recurrent multiple evanescent white dot syndrome. Retina 1994;14:160.

14. Kimmel AS, Folk JC, Thompson HS, Strand LS: The multiple evanescent white-dot syndrome with acute blind spot enlargement. Am. J Ophthalmol 1989;107:425. 15. Singh K, de Frank MP, Shults WT, Watzke RC: Acute idiopathic blind spot enlargement. A spectrum of disease. Ophthalmology 1991;98:497. . 16. Reddy CV, Brown J JI~ Folk JC, et al: Enlarged blind spots in chorioretinal inflammatory disorders. Ophthalmology 1996; 103:606. 17. Barile GB, Reppucci VS, Schiff WM, Wong DT: Circumpapillary chorioretinopathy in multiple evanescent white-dot syndrome. Retina 1997;17:75. 18. Wyhinny GJ, JacksonJL, Jampol LM, Caro NC: Subretinal neovascularization following multiple evanescent white-dot syndrome [letter]. Arch Ophthalmol 1990;108:1384. 19. GassJDM, Hamed LM: Acute macular neuroretinopathy and multiple evanescent white dot syn.drome occurring in the same patients. Arch Ophthalmo1 1989;107:189. 20. Baglivo E, Safran AB, Borruat FX: Multiple evanescent white dot syndrome after hepatitis B vaccine. AmJ Ophthalmol 1996;122:431. 21. Desarnaulds AB, Borruat FX, Herbort CP, Spertini F: Le multiple evanescent white dot symdrome: Dne predisposition genetique? Klin Monatsbl Augenheilkd 1996;208:301. 22. Ie D, Glaser BM, Murphy RP, et al: Indocyanine green angiography in multiple evanescent white-dot syndrome. Am J Ophthalmol 1994;117:7. 23. Obana A, Kusumi M, Tokuhiko M: Indocyanine green angiographic aspects of multiple evanescent white dot syndrome. Retina 1996;16:97. 24. Borruat FX, Auer C, Piguet B: Choroidopathy in multiple evanescent white dot syndrome. Arch Ophthalmol 1995;113:1569. 25. Callanan D, Gass JDM: Multifocal choroiditis and choroidal neovascularization assoc.iated with the multiple evanescent white dot and acute idiopathic blind spot enlargement syndrome. Ophthalmology 1992;99:1678. 26. Keunen JEE, van NorrenD: Foveal densitometry in the multiple evanescent white-dot syndrome. AmJ Ophthalmol 1988;105:561. 27. Van Meel GJ, KeunenJEE, van Norren D, van de KraatsJ: Scanning laser densitometry in multiple evanescent white dot syndrome. Retina 1993;13:29. 28. Takeda N, Numata K, Yamamoto S: Electrophysiologic findings in optic nerve dysfunction associated with multiple evanescent whitedot syndrome. Doc Ophthalmol 1992;79:295. 29. Horigchi M, Miyake Y, Nakamura M, Fl~ii Y: Focale1ectroretinogram and visual field defect in multiple evanescent white dot Sy11drome. Br J Ophthalmol 1993;77:452.

Miguel Pedroza-Seres

DEFINITION Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an inflammatory retinal! choroidal disease characterized by sudden loss of vision caused by the sudden appearance of multiple yellow-white, flat inflammatory lesions lying deep within the sensory retina, most notably at the level of the retinal pigment epithelium (RPE) and choriocapillaris. Characteristically, patients with APMPPE experience a rapid recovery in vision, with resolution of the acute lesions, leaving a permanently altered RPE. APMPPE affects otherwise healthy, young individuals. In addition, the etiology is unknown, and there is considerable controversy about the pathogenesis.

discussing patients with ocular findings consistent with APMPPE.In addition, numerous case reports have appeared reporting various ocular and systemic associations with this disease.

EPIDEMIOLOGY

APMPPE has been recognized as a distinct entity only for the past 30 years, and it represents an infrequent diagnosis in uveitis clinics. It was diagnosed in only five patients, representing 2% of the 240 with posterior uveitis, seen at the Immunology Service of the Massachusetts Eye and Ear Infirmary over one 10-year period. 6 This is an underrepresentation of cases, however, since at least as many cases of APMPPE were also treated by the Retina Service of the same hospital without referral to the Immunology HISTORY APMPPE was originally described by Gass in 1968. 1 He Service. APMPPE has a predilection for young adults, with peak reported the clinical and angiographic findings in three occurrence between the ages of 20 and 30 years (mean young women who presented with loss of central vision, age at onset, 26.5 years) and a range of 8 to 66 years. 7 associated with multiple round and confluent yellowwhite placoid lesions at the level of the RPE and choroid. Both sexes are equally affected. It has been observed These lesions resolved spontaneously over a few weeks, primarily in whites, although dark-piglnented racial 8 11 leaving scarring of the RPE with s"Lfustantial return of groups develop this disease as well. - Some authors be12 visual acuity and continued improvement over several lieve that APMPPE cases appear to occur in clusters. months. 1 Two of the patients reported by Gass showed a The true incidence and prevalence are unknown. positive skin test for tuberculin, and one had a family history of pulmonary tuberculosis. All were taking some CLINICAL CHARACTERISTICS kind of medical drug before the onset of their eye symp- APMPPE patients suddenly develop painless loss of vision in one or both eyes without external evidence of ocular toms. Gass 1 named this disease pigment epitheliopathy be- inflammation. Retinal fundus examination discloses mulcause. the pigment epithelium appears to be the tissue tiple round, circumscribed, flat, yellow-white, subretinal most significantly affected. He postulated that the clinical lesions involving the RPE. Depending on the localization course· of APMPPE suggests the presence of an acute of the lesions, patients may develop central or paracentral pigment epithelial cellular response to some local injuri- loss of vision. The overlying retina usually appears norous agent, rather than to transient pathology of choroidal mal. The lesions are usually well circumscribed and disvascular insufficiency or to a primary degeneration of the crete; they may be multiple and confluent, forming large patches (Fig. 70-1). Mter several days to weeks, the lepigment epithelium. Maumenee 2 reported in 1970 that he had six patients sions begin to disappear, and these areas are replaced by with lesions similar to those described by Gass, and he scattered areas of depigmentation and fine to coarse classified APMPPE as a distinct clinical uveitis entity. clumping of the pigment epithelium (Fig. 70-2). Mt~r Van Buskirk and colleagues, 3 in 1971, reported on a several weeks, some patients develop new lesions; these 15-year-old girl who developed blurred vision in both new lesions may appear in the peripheral fundus, tending eyes, 1 day after she was diagnosed with pretibial ery- to be round or linearly oriented radially (Fig. 70-3). thema nodosum. on both legs. They suggested, for the Indeed, new lesions may develop in areas of unaffected first time, that the delay infilling seen at the choriocapil- retina, but they also may appear adjacent to healing laris represented a focal choroidal vasculopathy rather lesions. These new lesions adjacent to healing lesions than a primary pigment epitheliopathy. have a characteristic fluorescein angiographic appearDeutman and coworkers4 suggested, based on their ance, the early phase of the angiogram showing a ring own and previous reports, that APMPPE may be caused of choroidal hypofluorescence representing the acute by a general hypersensitivity vasculitis. Retinal vasculitis APMPPE lesion and surrounding an area of choroidal associated with APMPPE in two patients reported by Kirk- hyperfluorescence representing the healed APMPPE leham and colleaguesS in 1972 additionally support the sion. Ocular findings in patients with APMPPE include anteidea that this disease is probably caused by a choroidal rior or postelior chamber cells,13, 14 keratic precipitates,13, IS vasculitis. Since then, more than 250 articles have appeared episcleritis,8, 14, 16 corneal melting,17 retinal vasculitis,S pap-

CHAPTER 70: ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT

FIGURE 70-1. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE). A and B, Fundus photograph of APMPPE. A 25-year-old Hispanic man presented to our clinic after 10 days of blurred vision in both eyes. Headache was the only symptom that preceded his eye disease. His visual acuity in the right eye was counting fingers (CF) to 12 ft and in the left eye was 20/30. Note the multiple round lesions. The right eye was the more affected (A)· compared with the left eye (B). Note the well-circumscribed multifocal placoid lesion in the left eye (B).

FIGURE 70-2. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE). A to D, Fundus photograph of APMPPE. This 22-year-old Hispanic man presented with sudden loss of vision in his right eye (A) 2 weeks before his first visit to our clinic. The left eye (B) was affected one week after his right eye started with symptoms. Three weeks before his eye symptoms, he had severe headache accompanied by loss of appetite and nausea. He lost 11 pounds in that period. His initial visual acuity in the right eye (A) was CF 1 ft and his visual acuity in his left eye (B) was CF 3 ft. Nine months later, his visual acuity was 20/20 in both eyes (C and D). Note that the acute creamy lesions seen in the acute stage of the disease (A and B) were replaced by areas of depigmented RPE, and irregular clumping of pigment occurs (dark areas in C and D).

CHAPTER 70: ACUTE POSTERIOR

....Lj'\L-...... PILAC::OID PIGMENT EPITHELIOPATHY

FIGURE 70-3. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Fundus photograph. Some round irregular lesions are oriented radially following the direction of l~etinal vessels.

illitis,5, 14 serious retinal detachment,14, 15, 18 subretinal helnorrhages, 15 optic neuritis,12 and vein occlusion. 19 Most of the patients with APMPPE have a history of a flulike syndrome before the onset of ocular symptoms. Fever, malaise, and headache may precede the ocular symptoms, suggesting a viral disease. APMPPE has been reported in patients with adenovirus .type 5. 9 Systemic associations include cerebral vasculitis,15, 20, 21 erythema nodosum,3, 4 thyroiditis,17 sarcoidosis,22 ;vp.icrovascular nephropathy;23 Lyme disease,24 and elevated protein and pleocytosis in spinal fluid. 15, 21, 25 APMPPE is most commonly bilateral, although unilateral cases have been described. 8, 7, 14 Patients complain of visual symptoms in one eye or both eyes simultaneously, although sometimes the fellow eye is involved within days or weeks after the first eye is affected. The loss of vision is sudden, and patients recover their vision after several weeks of the onset of visual loss, usually to 20/30 or even better (20/20}. Recurrences are rare. 26 , 27 FhlOrescein angiography in patients with APMPPE during the acute, active stage shows hypofluorescence during the early transit phase of the dye through the choroidal vasculature because the lesions block fluorescence resulting from RPE swelling, the presence of inflammatory cells, and tissue or choriocapillaris nonperfusion. In the late venous phase, they become hyperfluorescent, with fluorescence persisting up to 30 minutes (Fig. 70-4). This late hyperfluorescence is thought to represent diffusion of the fluorescein from the choroid into or between damaged pigment epithelial cells. The finding of leakage of dye from the periphery to the center of the lesions had been thought to support the theory that blockage is caused by inflammatory cells and inflamed tissue. In the inactive stage of APMPPE, the. fluorescein angiogram shows fluorescence in the background of areas of RPE atrophy and depigmentation. The late phases of the angiogram are remarkable for the lack of persistent fluorescence (Fig. 70-5). In those patients in whom acute lesions begin to resolve, the transition from the active to the inactive lesion can be useful in determining the presence and amount of residual activity.

Indocyanine green angiography (ICG) in APMPPE patients with acute lesions shows marked choroidal hypofluorescence in both the early and the late phases of the angiogram. In the early phases, large choroidal vessels can be seen in the hypofluorescent areas. Iil the late phases, the hypofluorescent lesions become well demarcated and irregularly shaped. Healed APMPPE lesions on ICG demonstrate choroidal hypofluorescence in the early and late phases. These lesions are smaller and less pronounced than the acute lesions of APMPPE,28, 29 Patients with APMPPE may have different responses in electrophysiologic studies. Although some patients have a normal electroretinogram (ERG) and electro-oculogram (EOG) ,30 others have abnormal responses. Smith and colleagues 31 reported one patient with APMPPE who had abnormalities in color vision testing, subnormal EOG and subnormal l3-wave in ERG, abnormally dark adaptation, and disorientation of the photoreceptors as demonstrated by an abnormal Stiles Crawford effect in the acute stage of APMPPE. Three weeks after the acute episode, they found normal visual acuity and normal EOG.One year later, the visual field, color testing, the Stiles Crawford effect, and dark adaptation were almost normal. Additional studies demonstrated abnormal densitometric results in parafoveal fixating APMPPE patients. 32 These :findings, together with variation in the visual field abnormalities seen in patients 'Yith APMPPE, suggest that there may be a widespread, albeit transient, disruption to the RPE-photoreceptor complex in this disease. In general, the visual prognosis in patients with APMPPE is good. Patients may experience a sudden drop in their vision ranging from a distorted 20/20 to counting fingers 1,8, 23 at the onset of the disease, with recovery even to 20/20; the time between the onset of visual loss to improvement may take as long as 6 months.

PATHOPHYSIOLOGY/IMMUNOLOGY/ PATHOLOGY The etiology of APMPPE is unknown. An infectious. etiology is suspected by the frequent occurrence of an antecedent viral illness. Some patients have developed APMPPE after swine flu vaccination,33 hepatitis B vaccination,34 mumps,35 or bacterial infection. 36 ,37 An increased incidence of a positive tuberculin skin test has also been reported in patients with APMPPE.l, 5, 9 It is conceivable that a hypersensitivity reaction to antigens from different pathogens or antimicrobial agents 15 participates in the pathophysiology, leading to choroidal vasculitis and changes in the RPE. The anatomic site of primary involvement in APMPPE is controversial. Some authors have favored the RPE. Gass 38 suggests that the primary area of pathology is in the RPE and perhaps retinal and receptor cells, but others have documented abnormal choroidal perfusion, indicating the choroid as the primary site of involvement. Deutman and Lion 28 propose that an acute inflammation resulting from a hypersensitivity reaction leads to occlusion of the precapillary choroidal arterioles feeding the lobules of the choriocapillaris, with subsequent secondary RPE changes. ICG angiography studies in patients with active and healed APMPPE support the hypothesis that the main cause of the placoid lesions is a partial choroidal

CHAPTER 70: ACUTE POSTERIOR MUlTIFOCAl PlACOID PICiMENT EPITHEUOPATHY

FIGURE 70-4. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE). A to F, Fluorescein angiography in the acute stage of APMPPE.Same patient as in Figure 70-1. Red free photographs show clearly the multifocal placoid lesions in the right (A) and the left (B) eyes. Early transit of fluorescein revealed blockage of fluorescence in the region of the acute placoid lesions in the right (C) and the left (D) eyes. Mter several minutes of the injection of fluorescein, late staining of the acute lesions is evident in both eyes (E and F).

vascular occlusion, explaining the persistent pattern of choroidal hypofluorescence in the active or healed stages of APMPPE. 29, 39 Wolf and coworkers40 studied both human leukocyte antigen (HLA) classes I and II antigens in a series of 30 patients with APMPPE. They found HLA-B7 in 40% of

patients cOlupared with 16.6% of controls and HLA-DR2 in 56.7% of patients compared with 28.2% of controls. The immune system responds to a peptidic fragment of a foreign protein, which binds to specific major histocompatibility complex (MHC) molecules. Genes of MHC molecules are highly polymorphic: Diverse alleles exist within

·CHAPTER 10: ACUTE POSTERIOR MULTlfOCAL PLACOID PIGMENT EPITHELIOPATHY

FIGURE 70-5. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE). A to C, Fluorescein angiogram in the inactive stage of APMPPE. Same patient as in Figure 70-2. The red free photographs (A) show clearly the inactive stage of APMPPE. Comparing the early (E) and late (C) phases of the a~giogram's lack of persistent fluorescence is evident. This angiogram-was obtained nine months after the acute stage of APMPPE.

the population, and they are different in their ability to bind and present different antigenic determinants of proteins. If a peptidic determinant (e.g.; one derived from an infectious agent) does not bind to any allelic MHC molecules expressed by an individual, that person's T cells cannot respond to that antigen. It is probable that certain HLAs predispose to develop certain diseases. HLA-B7 and HLA-DR2 were previously reported in high frequency in presumed ocular histoplasmosis 41 and HLAB7 in serpiginous choroiditis. 42 It is possible that HLADR2 and HLA-B7 bind certain peptides from an infectious protein (viral or bacterial) predisposing to a specific pathophysiology event in APMPPE: choroidal nonperfusion secondary to vasculitis with subsequent RPE changes.

PATHOGENESIS Delayed-type hypersensitivity (DTH) or type IV hypersensitivity has been implicated in the pathogenesis of APMPPE.43 In a DTH response, antigen-specific CD4 + T H I cells secrete cytokines that recruit and activate effector cells such as macrophages and natural killer cells. One of the most important effector cytokines produced by T H I cells is interferon-')', which stimulates microbicidal activities of phagocytes, promoting the intracellular de5truction of phagocytosed microbes. T HI cells also secrete lnterleukin-2, which functions as an autocrine growth factor and stimulates the proliferation and differentiation

of CD8 + T cells. Additionally, T H I cells secrete lymphotoxin, which promotes the recruitment and activation of neutrophils. Cytokines function to (1) activate venular endothelial cells to recruit monocytes and other leukocytes at the level of the antigen challenge and (2) activate macrophages, enhancing their killing functions directed against intracellular microbes or viruses. Cytokines produced by CD8 + T cells can initiate the same reaction. In response to viral infections mediated by cytolytic T lymphocytes (CTLs), CD8 + T cells differentiate into functional CTLs. This process of differentiation requires cytokines secreted by antigen-active T cells. The function of CTLs is to destroy cells, other than macrophages, with intracellular viruses. 44 Park and colleagues43 cite several lines of indirect evidence, including the histopathology of some associated diseases seen in patients with APMPPE, that suggest that the pathogenesis was mediated by a DTH response:

1. The histopathologic findings in a patient with cerebral vasculitis showed cerebral arterial walls infiltrated with cells composed of monocytes, lymphocytes, histiocytes, epithelioid cells, and multinucleated giant cells. 2. Renal biopsy in a patient with sarcoidosis and APMPPE disclosed granulomatous cellular infiltration. 3. Tuberculin skin tests were positive in some patients with APMPPE.

CHAPTER 10: ACUTE POSTERIOR MUlTIFOCAl PlACOID PIGMENT EPITHELIOPATHY

4. Histopathologic results were positive in a patient with an ischemic infarct in the pons 6 months after he had APMPPE.

serpiginous choroiditis and APMPPE. Visual recovery is poorer and recurrences are more frequent in serpiginous choroiditis. Patients with Harada's disease develop an initial acute Additionally, fluorescein and ICG angiographic findillgs bilateral visual loss caused by serous retinal detachment, showing choroidal hypofluorescence could be explained, which may be preceded by headache, malaise, vOlniting, because a DTH response with infiltrating T cells on the and occasionally neurologic signs and symptoms. Comchoroidal vessels leads to a partially obstructive vasculitis. monly, patients have vitreous cells, iridocyclitis, and a This partial choroidal vascular occlusion explains the ICG hyperemic optic nerve. Some patients with Harada's dischoroidal hypofluorescence of acute and healed APMPPE ease eventually develop severe anterior uveitis, alopecia, lesions.29, 39 poliosis, cutaneous and perilimbal vitiligo, and dysacousis Other systemic vasculitic disorders reported in associa- (Vogt-Koyanagi-Harada syndrome). Smne patients . With tion with APMPPE can be on the basis of cell-mediated Harada's disease may have multifocal, gray-white patches immunity. These include thyroiditi~,n erythema nodo- at the level .of the RPE similar to, although less well sum,3,4 and microvascular nephropathy,23 retinal· vasculi- defined than, those seen in patients With APMPPE. Fluotis,5 papillitis,5, 14 and choroidal periphlebitis. Additionally, rescein angiography findings in patients with Harada's the frequent prodromal flulike syndrome suffered by disease can be identical to those in patients with most patients suggests a viral disease. It is well known APMPPE, but patients with Harada's disease show an that cell-mediated immunity is most important against accumulation of the. fluorescein dye in the subretinal microbes and viruses that live intracellularly.44 space in the late phases of the angiogram. Harada's Clisease and 'APMPPE are different mainly in the course of DIAGNOSIS the di.sease. Although in a few patients with Harada's The diagnosis of APMPPE is clinical. A thorough diagnos- disease the retinal detachment may resolve spontaneously tic evaluation must include medical history, review of within several weeks, usually the course is prolonged.and systems, and ocular examination. Careful questioning for patients need systemic corticosteroid therapy to shorten a prodromal viral disease is important. Patients may cQm- the duration of the retinal detachment and to improve plain that they have had headache, fever, malaise, myal- the visual prognosis. Additionally, other immunosuppresT gia, or upper respiratory symptoms weeks before the sive drugs may be required. Recurrences are common in onset of eye symptoms. Approximately one third of pa- patients with Harada's disease and uncommon in patients tients with APMPPE have a hisrory of recent viral ill- with APMPPE. ness. I5 ,36 Because some patients may have neurologic symptoms, admission to the hospital may be necessary. Usually pa- ASSOCIATED DISEASES tients with neurologic mal1.ifestations of the disease need APMPPE has been associated with systemic viral illness, rapid medical treatment and studies, including magnetic different transient cerebral disturbances, cerebral vasculiresonance imaging of the brain, computed tomography, tis, eythema nodosum, subclinical nephropathy, thyroiditis, sarcoidosis, juvenile rheumatoid arthritis, tuberculosis, and cerebrospinal fluid studies. and streptococcal infection.

DIFfERENTIAL DIAGNOSIS Many entities must be considered in the differential diagnosis of APMPPE. The presenting features of the disease will determine the focus of the differential diagnosis. The following diseases must frequently be excluded in diagnosing APMPPE: serpiginous choroidopathy, diffuse unilateral subacute neuroretinitis, multiple evanescent white dot syndrome, multifocal choroiditis with panuveitis, vitiliginous choroiditis, acute retinal pigment epitheliopathy (ARPE) , punctate inner choroidopathy, sarcoidosis, syphilis, Harada's disease, sympathetic uveitis, primary or metastasic neoplastic infiltrates of the choroid or sub-RPE space, and choriocapillaris infarcts secondary to systemic hypertension (e.g., toxemia of pregnancy). Because of clinical similarities at presentation, it is important to differentiate APMPPE from serpiginous choroiditis and Harada's disease. Serpiginous choroiditis usually begins in the third decade of life, it resolves slowly compared with APMPPE, and it produces profound choroid atrophy. Lesions in serpiginous choroiditis are localized around the optic nerve involving the macular area. In APMPPE, lesions are localized mainly at the postequatorial area. These lesions are isolated and multifocal, and fluorescein angiography shows similar patterns in both

TREATMENT APMPPE has a self-limiting clinical course. Prednisolone has been used effectively by many authors, but patients who did not receive steroids also showed improvement in their final visual acuity.46 Therefore, it is often argued that APMPPE needs no treatment: it resolves without treatment, with 80% of patients enjoying 20/40 or better vision. However, 20% are left with impaired vision, and 20/40 is not good enough. Patients with APMPPE and neurologic disease (e.g., cerebral vasculitis) improve with steroid therapy and cytotoxic drug therapy.21 Bridges and colleagues47 reported on a 16-year-old girl who had juvenile rheumatoid arthritis and developed APMPPE. She was treated initially with steroids but did not improve. Cyclosporin A therapy produced improvement in visual acuity within 14 days. I suggest that systemic steroid therapy be considered in APMPPE patients with macular involvement because it is an inflammatory problem, 20% of eyes affected by APMPPE never recover vision above 20/40, even many patients with a final acuity of better than 20/40 are affected by the imperfect recovery of vision, and uncontrolled experience suggests that prompt systemic steroid

70: ACUTE POSTERIOR MUlTIFOCAl PlACOID PIGMENT EPITHEUOPATHY

therapy is effective flammation.

Hl

rapidly resolving the retinal in17.

CONCLUSIONS APMPPE is a recently recognized posterior uveItIs presenting mainly in young patients. Characteristically, patients with APMPPE experience a rapid loss of vision in one eye or both eyes simultaneously, and funduscopic examination shows multiple round, creamy subretinal lesions. Mter several days or weeks, these lesions disappear and are replaced by areas of pigment epithelium. The fluorescein angiographic and ICG findings are characteristic of this disorder and are frequently helpful in differentiating it from other entities. Although the pathogenesis and etiology are indeed unknown, recent ICG findings and systemic associations suggest that a hypersensitivitymediated obstructive vasculitis resulting in partial choroidal vascular occlusion may be responsible for the lesions seen in APMPPE. The visual prognosis is generally good without treatment, but it may well be that early and aggressive treatment may result in altering the natural history of the disease and improvement of visual outcome. Future histopathologic and immunopathologic study may prove valuable in understanding the pathogenesis and in developing treatment strategies for patients with this disease.

References 1. Gass JDM: Acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol 1968;80:177-185. '1/ 2. Maumenee AE: Clinical entities in "uveitis": An approach to the study of intraocular inflammation. Am J Ophthalmol 1970;69: 1-27. 3. Van Buskirk EM, Lessell S, Friedman E: Pigmentary epitheliopathy and erythema nodosum. Arch Ophthalmol 1971;85:369-372. 4. Deutman AF, OosterhuisJA, Boen-Tan TN, Aan De Kerk AL: Acute posterior multifocal placoid pigment epitheliopathy. Br J Ophthalmol 1972;56:863-874. 5. Kirkham TH, Ffytche TJ, Sanders MD: Placoid pigment epitheliopathy with retinal vasculitis and papillitis. Br J Ophthalmol 1972;56:875-880. 6. Rodriguez A, Calonge M, Pedroza-Seres M, et al: Referral patterns of uveitis in a tertiary eye care center. Arch Ophthalmol 1996;114:593-599. 7. Ryan SJ, Maumenee AE: Acute posterior multifocal placoid pigment epitheliopathy. Am J Ophthalmol 1972;74:1066-1074. 8. Annesley WH, Tomer TL, Shields JA: Multifocal placoid pigment epitheliopathy. AmJ Ophthalmol 1973;76:511-518. 9. Azar P, Gohd RS, Waltman D, Gitter KA: Acute posterior multifocal placoid pigment epitheliopathy associated with an adenovirus type 5 infection. AmJ Ophthalmol 1975;80:1003-1005. 10. Isashiki M, Koide H, Yamashita T, et al: Acute posterior multifocal placoid pigment epitheliopathy associated with diffuse retinal vasculitis and late haemorrhagic macular detachment. Br J Ophthalmol 1986;70:255-259. 11. Kim RY, Holz FG, Gregor Z, et al: Recurrent acute multifocal placoid pigment epitheliopathy in two cousins. Am J Ophthalmol 1995;119:660-662. 12. Wolf MD, Folk JC, Goeken EN: Acute placoid multifocal epitheliopathy and optic neuritis in a family. Am J Ophthalmol 1990;110:89-90. 13. Fitzpatrick PJ, Robertson DM: Acute placoid multifocal pigment epitheliopathy. Arch Ophthalmol 1973;89:373-376. 14. Savino PJ, Weinberg RJ, YassinJG, Pilkerton AR: Diverse manifestations of acute posterior multifocal placoid pigment epitheliopathy. Am J Ophthalmol 1974;77:659-662. 15. Holt WS, Regan CDJ, Trempe C: Acute placoid multifocal pigment epitheliopathy. AmJ Ophthalmol 1976;81:403-412. 16. Gass JDM: Acute posterior multifocal pigment epitheliopathy: A

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long term follow-up study. In: Fine SL, Owens SL, eds: Management of Retinal Vascular and Macular Disorders. Baltimore, Williams & Wilkins, 1983, p 176. Jacklin HN: Acute posterior multifocal placoid pigment epitheliopathy and thyroiditis. Arch Ophthalmol 1977;95:189-194. Bird AC, Hamilton AM: Placoid pigment epitheliopathy presenting with bilateral serous retinal detachment. Br J Ophthalmol 1972;56:881-886. AIle SD, Marks SJ: Acute posterior multifocal placoid pigment epitheliopathy with bilateral central retinal vein occlusion. Am J Ophthalmol 1998;126:309-312. Sigelman J, Behrens M, Hilal S: Acute posterior multifocal placoid pigment epitheliopathy associated with cerebral vasculitis and homonymous hemianopsia. Am] Ophthalmol 1979;88:919-924. Sinan C, Thierry V, Jeffrey SR, Neil AB: Neurological manifestations of acute posterior multifocal placoid pigment epitheliopathy. Stroke 1996;27:996-1001. Dick DJ, Newman PK, RichardsonJ, et al: Acute posterior multifocal placoid pigment epitheliopathy and sarcoidosis. Br J Ophthalmol 1988;72:74-77. Laatikainen LT, Immonen IJR: Acute posterior multifocal placoid pigment epitheliopathy in connection with acute nephritis. Retina 1988;8:122-124. Bodine SR, Marino J, Camisa TJ, Salvate AJ: Multifocal choroiditis with evidence of Lyme disease. Ann Ophthalmol 1992;24: 169-173. BullockJD, Fletcher RL: Cerebrospinal fluid abnormalities in acute posterior multifocal placoid pigment epitheliopathy. Am J Ophthalmol 1977;84:45-49. Lewis R, Martonyi CL: Acute posterior multifocal placoid pigment epitheliopathy: A recurrence. Arch Ophthalmol 1975;93:235-238. Lyness AL, Bird AC: Recurrences of acute posterior multifocal placoid pigment epithf;liopathy. Am J Ophthalmol 1984;98: 203-207. Deutman AF, Lion F: Choriocapillaris nonperfusion in acute posterior multifocal placoid pigment epitheliopathy. Am J Ophthalmol 1977;84:652-658. Howe LJ, Woon H, Graham EM, et al: Choroidal hypoperfusion in acute placoid multifocal pigment epitheliopathy: An indocyanine green angiography study. Ophthalmology 1995;102:790-798. Fishman GA, Rabb MF, KaplanJ: Acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol 1974;92:173. Smith VC, Dokorny J, Ernest JT, et al: Visual function in acute placoid multifocal pigment epitheliopathy. Am J Ophthalmol 1978;85:192. KeunenJEE, van Meel GJ, van Norren D, et al: Retinal densitometry in acute posterior multifocal placoid pigment epitheliopathy. Invest Ophthalmol Vis Sci 1989;30:1515-1521. Hector RE: Acute posterior multifocal placoid pigment epitheliopathy. Am J Ophthalmol 1978;86:424-425. Brezin AP, Massin-Korobelnik P, Boudin M, et al: Acute posterior multifocal placoid pigment epitheliopathy after hepatitis B vaccine. Arch Ophthalmol 1995;113:297-300. Borruat FX, Piguet B, Herbort CP: Acute posterior multifocal placoid pigment epitheliopathy following mumps. Ocul Immunol Inflamm 1998;6:189-193. Brown M, Eberdt A, Lodos G: Pigment epitheliopathy in a patient v\lith mycobacterial infection. J Pediatr Ophthalmol 1973;10:278. Lowder CY, Foster RE, Gordon SM, et al: Acute posterior multifocal placoid pigment epitheliopathy after acute group A streptococcal infection. AmJ OphthalmoI1996;122:115-117. Gass JDM: Inflammatory diseases of the retina and choroid. In: Stereoscopic Atlas of Macular Diseases. Diagnosis and Treatment, 4tl1 ed. St. Louis, c.v. Mosby, 1997, pp 668-675. Park D, Schatz H, McDunald R, Johnson RN: Indocyanine green angiography of acute placoid multifocal pigment epitheliopathy. Ophthalmology 1995;102:1877-1883. Wolf MD, Folk JC, Panknene CA, Goeken EN: HLA-B7 and HLADR2 antigens and acute placoid multifocal pigment epitheliopathy. Arch Ophtl1almol 1990;108:698-700. Meredith TA, Smith RE, Duquesnoy RJ: Association of HLA-DRw2 antigen with presumed ocular histoplasmosis. Am J Ophthalmol 1980;89:70-76. Chan CC, Hooks jJ, Nussenblatt RB, et al: Expression of Ia antigen

CHAPTER 70: ACUTE POSTERIOR MUlTIFOCAl on retinal pigment epithelium in experimental autoimmune uveitis. Cun Eye Res 1988;5:325-330. 43. Park D, Schatz H, McDonald HR, et al: Acute multifocal posterior placoid pigment epitheliopathy: A theory of pathogenesis. Retina 1995;15:351-352. 44. Abbas AK, Lichtman AH, Pober JS: Cytokines. In: Abbas AK, Lichtman AH, Pober JS, eds: Cellular and Molecular Immunology. Philadelphia, W.B. Saunders, 1997, p 249. 45. Anderson K, Patel KR, Webb L, et al: Acute placoid multifocal

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pigment epitheliopathy associated with pulmonary tuberculosis. Br J Ophthalmol 1996;80:186. . 46. Williams DF, Mieler WF: Long-term follow-up of acute ljlacoid multifocal pigment epitheliopathy. Br J Ophthalmol 1989;73:985990. 47. Bridges~, Saadeh C, Gerald R: Acute placoid multifocal pigment epitheliopathy in a patient with systemic-onset juvenile rheumatoid arthritis: Treatment with cyclosporin A and prednisone. Arthritis Rheum 1995;38:446-447.

I

I

Benalexander A.Pedro

flulike symptoms in the otherwise healthy patient. The systems review is generally unremarkable. On clinical examination, the visual acuities of patients with ARPE are typically 20/20 to 20/100 at the time of presentation; visual acuity is 20/30 or better in about three fourths of patients. Bilateral ocular involvement is seen in about 40% of cases. 1, 2, 4, 5, 8, 13 The anterior segment examination is usually normal, without stigmata of acute inflammation. On the Amsler grid, patients may show a central scotoma or metamorphopsia. These findings may also be reflected in visual field examinations. Color vision abnormalities have been detected. 1, 2 Funduscopy early in the disease shows the typical round macular lesions that are the hallmark of the disease. These are discrete clusters of small, hyperpigmented, dark-gray spots at the level of the retinal pigment epithelium surrounded by a yellowish white "halo" or HISTORY Acute retinal pigment epitheliitis (ARPE) , or Krill's dis- area of depigmentation 1 , 2 (Fig. 71-1). Each cluster typiease, is a rare, yet relatively new, clinical entity, first de- cally contains one to four spots. As the condition resolves, scribed by Krill and Deutman 1 in six patients less than, the dark, grayish spots may further darken, displaying a three decades ago (1972). Deutman 2,described two addi- pattern of pigment migration, or they may fade and tional patients 2 years later in 1974. Since the publication become difficult to detect clinically. The halo noted of these two reports, other cases with similar clinical around these spots also becomes less distinct as the disfindings and courses have been descri.t>ed in the ophthal- ease resolves. I - 3 , 5,7 The lesions are generally confined to mic literature. 3- 9 Some atypical cases believed to be ARPE the macular region. However, extramacular lesions may also be observed, albeit rarely. 1 Other structures such as were also reported. 5 ,10-12 the optic nerve, retina, and retinal vasculature are normal, with absence of subretinal fluid, retinal edema, or Patients with ARPE are typically young, healthy adults in perivasculitis. Infrequently, in some cases, a mild vitritis 4 the second to fourth decade of life. This condition has may be seen. , 7, 9 A case of a 36-year-old male is shown in Figure 71-1. been reported to affect individuals from 16 to 75 years of He initially complained of acute-onset blurring of vision age. The median age of onset is about 45 years. There appears to be neither a racial nor a genetic predilection. in both eyes, which he described as a "haze." There was Of the more than 70 well-documented cases of ARPE, it no history of illness or flulike symptoms. Review of sysappears that more than two thirds occur in male pa- tems was unremarkable except for a history of thyroiditis. tients. 1 , 2, 4, 5, 8, 13 The perturbation of the RPE in these patients may be bilateral or unilateral. Acute retinal pigment epitheliitis (ARPE) is not a common disease. It is likely that this condition is underreported, given the transient nature of the disease and the often Inild and negligible symptoms noted by patients, who may not seek ophthalmologic consultation. Furthermore, the inexperienced examiner may easily miss the subtle clinical findings in the macula and posterior pole. These factors increase the likelihood that the acute phase of the disorder will be missed. It is likely that, because of these factors, ARPE went unrecognized before Krill first described the condition in 1972.

Acut~

retinal pigment epitheliitis (ARPE) is a distinct clinical entity characterized by acute inflammation of the retinal pigment epithelium (RPE) and manifested by transient and relatively subtle alterations at the level of the RPE. These are seen ophthalmoscopically as discrete clusters of small, dark-gray spots at the macular area, which clinically cause blurring of vision. Each of these spots appears to be surrounded by a yellow, halo-like zone. These lesions spontaneously resolve within weeks to months, accOlnpanied by recovery of vision. Although there are many theories as to the nature of this transient RPE inflammation, its etiology currently remains unknown. A viral etiology seems plausible in light of the acute yet transient clinical course of this disorder.

CLINICAL FEATURES Typically, ARPE is characterized by a patient history of acute visual disturbance characterized by unilateral blurred vision or metamorphopsia. A small proportion of patients end up complaining of a central scotoma. 1, 2 In one study, 15% of affected individuals were asymptomatic. 4 There is usually no preceding history of illness or

FIGURE 71-1. This photograph shows the left fundus of a 36-year-old male who complained of acute onset blurring of vision in both eyes. There are discrete clusters of small, hyperpigmented gray spots with a yellowish white halo at the level of the RPE at the macular area.

CHAPTER 71: ACUTE RETINAL PIGMENT

The patient's visual acuity was 20/20 in both eyes. A "doughnut"-shaped scotoma was elicited on Amsler grid. The anterior segment was quiet.

COMPLICATIONS No significant ocular complications have been described in association with ARPE; the typical course of the disease is one of complete resolution of the symptoms. This natural history is so characteristic that an alternative diagnosis should be considered, should there be significant ocular complications or sequelae in a suspected case of ARPE.

ETIOLOGY, PATHOGENESIS, AND PATHOLOGY The precise etiology and pathogenesis of ARPE are still unknown. It has been thought that this disorder represents an inflammatory condition at the level of the retinal pigment epithelium. Owing to the similarity of the retinal lesions of ARPE to those of rubella retinopathy, some have postulated a viral etiology. This notion is supported by cases of ARPE that were discovered to have an association with hepatitis C,14, 15 and by the case of a woman with bilateral ARPE who had concurrent fever, chills, and myalgia of unknown etiology.12

The EAPU Animal Model Experimental autoimmune pigment epithelial membrane protein-induced uveitis (EAPU) has been induced in Lewis rats by immunization with RPE membrane protein. 16 EAPU is mainly characterized by retinal pigment epithelial inflammation; this animal model provides new insight into the pathology of pigment epitheliitis. Clinical signs of EAPU begin to manifest at days 7 and 9 after immunization and peak by days 12 and 14. Histologic studies show typical plaque-shaped cell accumulations containing macrophages along the RPE. Broekhuyse and colleagues studied the effect of macrophage depletion on EAPU.16 They found that systemic treatment with a macrophage-depleting substance, C12MDP-containing liposomes (dichlorOluethylene diphosphate), immediately before the expected onset of the clinical signs of EAPU (days 7 and 9 after immunization) considerably delayed the inflammatory process. However, 2 weeks after treatment, a rebound EAPU was noted. Systemic treatment at the peak stage of EAPU (days 12 and 14 after immunization) resulted in rapid disappearance of the clinical signs of uveitis. Previously deposited cellular accumulations along the RPE neither regressed nor demonstrated further progression. Broekhuyse and· associates concluded that hematogenous macrophages appear to playa crucial role in the development of EAPU, but that the effect of early macrophage depletion on EAPU appears temporary owing to blood repopulation of this cell line. As further studies on animal models of pigment epitheliitis continue to be performed, new insights into the pathophysiology of this condition are sure to evolve,16,17

DIAGNOSIS The diagnosis of ARPE is clinical and is based on a history of acute. visual decline or metamorphopsia in an

1C1DI.'"lrL-'IC.

otherwise healthy adult in the second or third decade of life, coupled with the characteristic retinal findings described previously. The review of systems typically is noncontributory. Aside from the changes noted in 'Amsler grid and visual field examinations, other ancillary procedures such as fluorescein angiography (FA) and electrophysiologic studies aid in the diagnosis of this condition. In the early phases of the fluorescein angiogram, multiple, small hyperfluorescent spots at the level of the RPE in the posterior pole and luanda are noted. This hyperfluorescence corresponds to the depigluented halo around the hypofluorescent central dark spot. The dark spot central to the halo shows hypofluorescence, consistent with dye blockage from hyperpigluentation (Fig. 712). The hyperfluorescence increases mildly in mid-transit, consistent with window defect transmission, without late leakage or staining.1-4, 5 Rarely, the FA fails to highlight this macular lesion. 2 At times, the peripapillary area may be involved; rarely, in the late frames, the hyperfluorescent dots may appear to have slightly fuzzy margins, which may be indicative of mild leakage. Electro-oculography (EOG) performed in patients with ARPE is abnormal in the acute stages.1, 2With clinical resolution of the disease, the EOG reverts to normal. 1, 2, 5 This abnormality.in the acute stages appears to imply a more widespread dysfunction at the level of the RPE despite the paucity of findings on ophthalmoscopy or angiography. Electroretinography (ERG) and visual evoked response (VER) are· normal. 1, 2, 5 Figure 71-2 shows the FA of the patient in the previous figure (Fig. 71-1), Hyperfluorescence at the luacular area and posterior pole mildly increases at the mid-phase of the angiogram and fades slightly in late frames with no late leakage or staining. EOG performed on this patient was abnormal, showing a low Arden's ratio. ERG was normal. A summary of the diagnostic features of ARPE is shown in Table 71-1.

The differential diagnoses of ARPE appear in Table 71..;;.2. These include acute macular neuroretinopathy (AMN) , acute posterior multifocal placoid pigment epitheliopathy (APMPPE), central serous chorioretinopathy (CSCR), and viral retinitides (particularly rubella retinitis).

Acute Macular Neuroretinopathy Bos and Deutman first described acute macular neuroretinopathy in 1975. 1s This is another rare condition that typically afflicts young adults, with acute onset of decreased central or paracentral vision and a history of a flulike prodrome. In AMN, there are subtle findings of superficial, dark, reddish-brown, petalloid or wedgeshaped retinal lesions in the macular area that resolve over several weeks to months. Acute macular neuroretinopathy is bilateral. Vision generally improves to baseline acuity over time, although paracentral scotomata may persist. On fluorescein angiography, the clinician may detect no abnormalities. IS More commonly, however, nonleaking

CHAPTER 11: ACUTE RETINAL PIGMENT EPITHEUITIS

j

dilated perifoveal capillaries 18 may be noted or early hyperfluorescence, followed by late staining of the macular lesions. 19-21

Acute Posterior Multifocal Placoid Pigment Epitheliopathy APMPPE is another condition typically included in the differential diagnosis of ARPE. Gass first described APMPPE in 1968. 22 This syndrome has been well characterized clinically by an acute decrease in central visual acuity in association with yellow-white placoid lesions at the level of the RPE and scattered throughout the posterior pole. As in ARPE, this is followed by spontaneous recovery. APMPPE usually presents in the third decade of life, but has been reported in patients from 8 to 57 years of age. 23-26 It has neither racial nor sexual predilection. It is most commonly bilateral but may be unilateral at initial presentation. Vision may range from 20/20 to count fingers at the acute stage. Unlike in ARPE, the anterior segment of patients with APMPPE may show episcleritis,24, 25, 27,28 marginal corneal thinning,29 and iritis. 23 - 28 , 30-33 Fundic findings are distinctly different from those of ARPE. Multiple, flat, cream-colored patches at the level of the pigment epithelium and choriocapillaris are the ophthalmoscopic hallmarks of APMPPE. 22, 23 The lesions are round and ovoid, with indistinct borders, and they are larger than ARPE

FIGURE 71-2. Fluorescein angiography of the patient seen in Figure 71-1 shows (AJ the early phase of the angiogram in which hyperfluorescence that corresponds to the yellowish halo and hypofluorescence of the central dark spot is seen at the macular area in clusters. B, In mid-films, there is little change in the characteristics seen in the early films. C, Late films show no leakage from the pigment epithelial defects, which slightly fade.

lesions. They vary in size from 1/8- to 1/4-disc diameters. 34 The lesions may become confluent and plaquelike. Initial lesions usually involve the posterior pole. As the disease evolves, fresh patches tend to arise in the periphery. Typically, there is a mild vitritis. 26-28, 30, 35 Less common fundic findings include retinal edema or hemorrhage,24, 25, 36 retinal vasculitis,25, 28, 36, 37 papillitis,27, 29, 36, 38, 39 and serous retinal detachment. 25-27 ,40-42 Resolution of these subretinal lesions takes around 2 to 5 weeks. Pigment clumping and depigmentation occur with resolution. Recurrences are not common but have been noted. 4o ,43-45 APMPPE may occur as a solitary entity or, unlike ARPE, it may be associated with other systemic inflammatory disorders. 26 , 46-52 Like ARPE, although an infectious etiology is postulated, no specific agents have been isolated. APMPPE Inay represent a nonspecific ocular manifestation of a systemic inflammatory disease, possibly affecting the central nervous system. 27 , 46, 47 Fluorescein angiography of the placoid lesions of APMPPE is distinctive and cannot be confused with ARPE. Hypofluorescence is observed early, followed by hyperfluorescence in the late venous phase. Each individual placoid lesion seen clinically may represent an area of focal swelling of the pigment epithelium overlying a nonperfused lobule of choriocapillaris. No treatments specific for APMPPE have been discov-

CHAPTER 71: ACUTE RETINAL PIGMENT EPITHEUITIS TABLE 71-1. ACUTE RETINAL PIGMENT EPITHEUITIS: DIAGNOSTIC FEATURES PATIENT CHARACTERISTICS @ @ @

Average age 45 years Sex incidence shows slight male-to-female preponderance No race or genetic predilection

OCULAR EXAMINATION

Anterior segment @ Typically quiet Posterior segment @ Only fundus lesions noted @ Mild vitritis seen rarely @ Fundus lesions with round gray-black spots surrounded by yellow-white halo ANCILLARY TESTS @

@ @ @

@

Amsler grid may show central metamorphopsia or central scotoma Visual field examinations may show a central scotoma Color vision abnormalities have been detected Angiographic findings show hypofluorescence of gray-black spots with surrounding early hyperfluorescent halo that fades later Electrophysiologic tests may show an abnormal electrooculogram (EOG) with typically normal electroretinogram (ERG) and visual evoked response (VER)

DISEASE CHARACTERISTICS @ @ @ @ @

@ @

Visual acuity may range from 20/20 to 20/100 on presentation Occasionally bilateral Visual resolution noted within 6 to 12 weeks Recurrence has been noted but is atypical No systemic disease involvement Etiology is unknown, presumed viral Currently needs no therapy

ered, but high-dose systemic prednisone Inay hasten resolution of the problem. Overall, the visual prognosis of APMPPE is favorable, with about 80% of affected eyes having a final visual acuity of 20/40 or better. 53 However, persistent paracentral scotomata have been observed23 ,32, 36, 43, 44, 49, 54 and, unlike ARPE, cases with foveal involvement or recurrent inflammation tend to have poorer final visual acuities. 23 , 24, 28, 45 The overall favorable natural history of APMPPE may breed complacency among ophthalmologists, who may treat this entity less aggressively than ARPE. Although the decision to treat with systemic steroids may be straightforward in patients presenting with severe or recurrent disease, it may well be that early and aggressive systemic treatment in patients with less severe disease may hasten visual recovery and improve overall visual outcome. Such is not the case with ARPE, in which adverse sequelae of inflammation are not described and excellent visual recovery is the rule.

Central Serous Chorioretinopathy Among the differential diagnoses of ARPE, CSCR is probably the most difficult and important to exclude in the latter stages of disease. TABLE 71-2. ACUTE RETINAL PIGMENT EPITHEUITIS: DIFFERENTIAL DIAGNOSES Acute macular neurbretinopatl1Y Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) Central serous chorioretinopathy (CSCR) Rubella retinitis (and other viral retinitides)

Von Graefe first described CSCR in 1866. 55 It is typically seen in young adults to middle-aged individuals, with ages ranging from 20 to 45 years. 55- 66 There is a greater male-to-female preponderance of 8 to 10:1. 56 ,66, 67-70 Patients with CSCR may occasionally complain of migraine-like headaches. 57 Additionally, they typically have type A personality traits. 71 Unilateral or bilateral involvement may be seen clinically. Like with ARPE, patients may complain of decreased or blurred vision, metamorphopsia, paracentral scotomata, and chromatopsias. Vision in the acute stage of this disorder may range from 20/20 to 20/200. 66 The ophthalmoscopic hallmark of CSCR is a neurosensory retinal detachment. In addition, serous RPE detachment, subretinal precipitates, extramacular RPE atrophic tracts, multiple bullous serous retinal and RPE detachments, and RPE atrophic changes have been described. 57, 58, 66 Fluorescein angiography in the acute stage typically shows a hyperfluorescent focal RPE defect that leaks dye. The dye· accumulates beneath a neurosensory retinal detachment, which manifests as dye pooling in the late phases of the angiogram. This finding is the most important differentiating point between ARPE and CSCR in the acute stages. Unlike nonleaking focal RPE defects seen in ARPE, angiography in CSCR shows leakage of dye in the early stages, with pooling of dye within the serous detachment in the late frames. In the resolution phase of both diseases, it is difficult to differentiate CSCR from ARPE. Like ARPE, CSCR may, upon its resolution, leave pigmentary changes in the macula. Krill and Deutman postulated that the RPE disturbance may lead to serous fluid leakage due to the breakdown of the pigment epithelial blood-ocular barrier. 1 Earlier studies have also shown a link between ARPE and CSCR in nine patients. 4 Piermarocchi and coworkers documented a case of ARPE that developed into CSCR with focal leakage in areas where ARPE lesions were initially noted. 13 It remains a possibility that in the pathogenesis of CSCR, retinal pigment epitheliitis Inay playa significant role. Other authors, however, prefer that CSCRrelated ARPE be considered as a "secondary" form of CSCR, distinct from the idiopathic form of CSCR.72

Viral retinitides, particularly rubella retlIlltls, show remarkably similar pigmentary changes in the retina compared with those of ARPE. 73 The most common ocular finding in ocular rubella syndrome is retinopathy, which occurs in 25% to 50% of eyes. 74 It is most commonly seen in children and may be unilateral or bilateral. 75 When there is no significant coexisting pathologic condition, visual acuity may range from 20/20 to 20/60, with a median range of 20/25. 76 The pigmentary changes appear as fine, granular, sYlnmetric mottling of the pigment epithelium, with a "saltand-pepper" fundus appearance. However, one may differentiate rubella retinopathy from ARPE by the coarser pigmentation, the more widespread involvement of the retina, and the associated systemic findings associated with the former sYl1.drome. Occasionally, pigment spicules and choroidal vascular changes are seen in rubella reti-

CHAPTER 71: ACUTE RETINAL PIGMENT EPITHELIITIS TABLE 71-3. DiffERENTIATING fEATURES AMONG ARPE, AMN, APMPPE, AND CSCR ACUTE POSTERIOR MULTI FOCAL PLACOID PIGMENT EPITHELIOPATHY (APMPPE)

ACUTE RETINAL PIGMENT EPITHELIITIS (ARPE)

ACUTE MACULAR NEURORETINOPATHY (AMN)

Age Sex Systemic Association

16-75 years (median, 45) M>F None

Young adults F>M Flulike (viral) prodrome

8-57 years (3rd decade) M=F May have associated cerebral vasculitis, CSF pleocytosis, tinnitus, sarcoidosis, etc.

Laterality

Unilateral/bilateral

Usually bilateral

An.terior Segment Findings Funduscopic Findings

None

None

Discrete clusters of small, dark-gray spots in the RPE surrounded by a yellmvish halo

Superficial dark, reddishbrown, petalloid or wedge-shaped lesions

Usually bilateral but may initially be unilateral Occasionally, episcleritis, marginal corneal thinning, and iridocyclitis may be seen Multiple yellowish-white placoid lesions at the level of pigment epithelium or choriocapillaris

Associated Posterior Segment Findings Fluorescein Angiogram Findings

None. Vitritis has been reported

None

Resolution

6-12 weeks

Visual Recovery

Good

Central hypofluorescence with a surrounding hyperfluorescence, corresponding to the central gray spot and surrounding yellowish halo, respectively

May present as: 1. Normal angiogram 2. Nonleaking dilated perifoveal capillaries ~ 3. Hyperfluorescence followed by late staining of the macular lesions Weeks to months Minimal

Mild vitritis, occasional retinal hemorrhage, retinal edema, vasculitis, serous RD, and papillitis may be seen Hypofluorescence of th~ placoid lesions seen early, followed by hyperfluorescence in the late venous phase

2-5 weeks; recurrence noted Good, if fovea not involved

CENTRAL SEROUS CHORIORETINOPATHY (CSCR)

20-45 years M>F Migraine-type headaches, type A personality, hysteria, and hypochondriasis Unilateral/bilateral None

Serous retinal detachment, serous RPE detachment, subretinal precipitates, extramacular RE atrophic tracts, multiple bullous serous retinal and RPE detachment, and RPE atrophic changes None

Hyperfluorescent focal RPE defect that leaks, with pooling and accumulation of dye within a serous detachment in late films

3-12 months; recurrence noted Fair (25% with VA <20/ 200)

RD, retinal detachment; RPE, retinal pigment epithelium; VA, visual acuity.

nopathy. Patients usually have a normal electroretinogram and electro-oculogram. 77 Other viral retinitides include those caused by herpes simplex, measles, and cytomegalovirus. Reports also ilnplicate hepatitis C in cases of ARPE.14, 15 However, despite a strong suspicion of a viral etiology, systemic evaluations have failed to reveal conclusive evidence pointing to a viral etiology in ARPE. The differentiating characteristics among ARPE, acute Inacular neuroretinopathy, APMPPE, and CSCR appear in Table 71-3.

Owing to the spontaneous resolution of the disease, its self-limited course, and associated favorable outcomes, no therapy is advocated. Furthermore, the brief clinical course of ARPE makes the assessment and evaluation of any therapeutic intervention very difficult to study scientifically. Steroid treatment has been used in some cases, but the efficacy of steroid therapy is difficult to differentiate from the natural history of the disease. 1, 12, 13 Whether

steroid therapy has a salutary effect on the vitritis seen in some cases of ARPE is unknown; however, the risks of such an approach seem to be outweighed by any poten-' tial benefit. Studies performed on Lewis rats with induced retinal pigment epitheliitis showed that systemic treatment with a macrophage-depleting agent at the peak stage of experimental pigment epitheliitis resulted in the rapid disappearance of the clinical signs of uveitis. 16 Such an approach may prove useful in the future for the prevention and treatment of other inflammatory conditions affecting the RPE that potentially have a greater number of destructive ocular sequelae, such as APMPPE.

NATURAL

ISTORY

PROGNOSIS

ARPE is typically benign. Its natural course demonstrates a total or near-total resolution of the symptoms, particularly with respect to vision. Return to baseline visual acuity and normalization of visual field defects are usually observed within 6 to 12 weeks without treatment. In a study of eight patients with ARPE, who were followed by Chittum and Kalina3 for an average of 4.2

CHAPTER 71: ACUTE RETINAL PIGMENT ...........-., .... ,

years, all recovered 20/20 VISIOn. In another study by Prost/ five patients were followed for 6 years and likewise showed complete recovery of previous visual acuity. There have been a few reports of recurrent,5 as well as bilateral cases, but these cases are very atypical. 1, 5, 7

CONCLUSIONS Acute retinal pigment epitheliitis is a rare, yet relatively new clinical entity, which was first described less than three decades ago. It is characterized clinically by an acute disturbance in central vision, metamorphopsia, or scotomata. There appears to be no underlying systemic involvement, and the patient's review of systems and medical history are typically noncontributory. The anterior segment examination is quiet. The funduscopic findings reveal the hallmark of this disease-discrete clusters of small, dark-gray spots at the level of the retinal pigment epithelium, surrounded by a round, yellowish halo in the central macula. Fluorescein angiography shows a central hypofluorescence with a sllrrounding hyperfluorescence, corresponding to the central gray spot and surrounding yellowish halo, respectively. Although its etiology is unknown, a viral etiology is highly suspected. The disease is typically benign with total or near-total resolution of the sYInptoms and complete visual recovery within 12 weeks, even without treatment. Studies of animal models with pigment epitheliitis are ongoing; and· it is h-~ped that they will provide new insight into the pathogenesis of this disease entity and other related inflammatory conditions.

References 1. Krill AE, Deutman AF: Acute retinal pigment epitheliitis. Am J Ophthalmol 1972;74:193-205. 2. Deutman AF: Acute retinal pigment epitheliitis. Am J Ophthalmol 1974;78:571-578. 3. Chittum ME, Kalina RE: Acute retinal pigment epitheliitis. Ophthalmology 1987;94:1114-1119. 4. Eifrig DE, Knobloch WH, Moran JA: Retinal pigment epitheliitis. Ann Ophthalmol 1977;9:639-642. 5. Friedman MW: Bilateral recurrent acute retinal pigment epitheliitis. Am J Ophthalmol 1975;79:567-570. 6. Luttrul JK: Acute retinal pigment epitheliitis. Am J Ophthalmol 1997;123 (1) :127-129. 7. Prost M: Long term observations of patients with retinal pigment epitheliitis. Ophthalmologica 1989;199:84-89. 8. Deutman AF: Acute retinal pigment epitheliitis. Ophthalmologica 1975;171:361. 9. Luttrul JK, Chittum ME: Acute retinal pigment epitheliitis. Am J Ophthalmol 1995;120:389-391. 10. Jamison RR: Acute retinal pigment epitheliitis with macular edema. Ann Ophthalmol 1979;11:359. 11. Suzuki R, Suga Y, Teranishi H, et al: Diffuse midperipheral acute retinal pigment epitheliopathy. Ann Ophthalmol 1988;20:17. 12. Schwartz PL, Rosen DA, Lerner DS, et al: Acute retinal pigment epitheliopathies. Ann Ophthalmol 1981;13:1139-1141. 13. Piermarocchi S, Corradini R, Midena E, et al: Correlation between retinal pigment epitheliitis and central serous chorioretinopathy. Ann Ophthalmol 1983;15:425-428. 14. Quillen DA, Zurlo jJ, Cunningham D, et al: Acute retinal pigment epitheliitis and hepatitis C. Am]. Ophthalmol 1994;118:120-121. 15. Tahri H, Chaoui Z, Berbicho, et al: The eye and hepatitis C. J Fr Ophtalmol1997;20(6):453-455. 16. Broekhuyse RM, Huitinga I, Kuhlman ED, et al: Differential effect of macrophage depletion on two forms of experimental uveitis evoked by pigment epithelial membrane protein (EAPU) , and by melanin-protein (EMIU). Exp Eye Res 1997;65(6):841-848. 17. Broekhuyse RM, Kuhlmann ED: Uveitogenic 28/20 kD and 43 kD polypeptides in pigment epithelial membranes of the retina. Ocul ImmunolInflamm 1997;5(1):19-26.

18. Bos PJM, Deutman AF: Acute rnacular neuroretinopathy. Am J Ophthalmol 1975;80:573. 19. Rush JA: Acute macular neuroretinopathy. Am J Ophthalmol 1977;83:490. 20. Priluck IA, Buettner H, Robertson DM: Acute macular neuroretinopathy. Am J Ophthalmol 1978;86:775. 21. Sieving PA, Fishman CA, Salzano T, Rabb MF: Acute macular neuroretinopathy: Early receptor potential changes suggest photoreceptor pathology. Hr J Ophthalmol 1984;68:229. 22. Gass JD: Acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol 1968;80:177. 23. Ryan SJ, Maumenee AE: Acute posterior multifocal placoid pigment epitheliopathy. AmJ Ophthalmol1972;74:1066. 24. Annesley WH, Tomer TL, Shields JA: Multifocal placoid pigment epitheliopathy. Am J Ophthalmol 1973;76:511. 25. Gass JDM: Acute posterior multifocal placoid pigment epitheliopathy: A long term follow-up. In: Fine SL, Owens SL, eds: Management of Retinal Vascular and Macular Disorders. Baltimore, Williams & Wilkins, 1983, pp 176-181. 26. Holt WS, Regan CD, Trempe C: Acute posterior multifocal placoid pigment epitheliopathy. AmJ Ophthalmol 1976;81:403. 27. Savino PJ, Weinberg RJ, Yassin JG, et al: Diverse manifestations of acute posterior multifocal placoid pigment epitheliopathy. Am J Ophthalmol1974;77:659. 28. Damata BE, Nanjiani M, Foulds WS: Acute posterior multifocal placoid pigment epitheliopathy: A follow-up study. Trans Ophthalmol Soc UK 1983;103:517. 29. Jacklin HN: Acute posterior multifocal placoid pigment epitheliopathy and thyroiditis. Arch Ophthalmol 1977;95:995. 30. Fitzpatrick PJ, Robertson DM: Acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol 1973;89:373. 31. Van Buskirk EM, Lessel S, Friedman E: Pigment epitheliopathy and erythema nodosum. Arch Ophthalmol 1971;85:369. 32. Deutman AF, Oosterhuis JA, Boen-Tan TN, et al: Acute posterior multifocal placoid pigment epitheliopathy: Pigment epitheliopathy or choriocapillaritis? Br J Ophthalmol 1972;56:863. 33. Lowes M: Placoid pigment epitheliopathy presenting as an anterior uveitis: A case report. Acta Ophthalmol Scand 1977;55:800. 34. Hedges TR III, Sinclair SH, Gragoudas ES: Evidence for vasculitis in acute posterior multifocal placoid pigment epitheliopathy. Ann Ophthalmol1979;11:539. 35. Priluck IA, Robertson DM, Buettner H: Acute posterior multifocal placoid pigment epitheliopathy: Urinary findings. Arch Ophthalmol 1981;99:1560. 36. Kirkham TH, Ffytche TJ, Sanders MD: Placoid pigment epitheliopathy with retinal vasculitis and papillitis. Br J Ophthalmol 1972;56:875. 37. Isashiki M, Koide H, Yamashita T, Ohba N: Acute posterior multifocal placoid pigment epitheliopathy associated with diffuse retinal vasculitis and late haemorrhagic macular detachment. Br J Ophthalmol 1986;70:255. 38. Frohman LP, Klung R, Bielory L, et al: Acute posterior multifocal placoid pigment epitheliopathy with unilateral retinal lesions and bilateral disk edema. AmJ Ophthalmol 1987;104:548. 39. Jenkins RB, Savino PJ, Pilkerton AR: Placoid pigrnent epitheliopathy with swelling of the optic disks. Arch Neurol 1973;29:204. 40. Kayazawa F, Takahashi H: Acute posterior multifocal placoid pigment epitheliopathy and Harada's disease. Ann Ophthalmol 1983;15:58. 41. Bird AC, Hamilton AM: Placoid pigment epitheliopathy presenting with bilateral serous retinal detachment. Br J Ophthalmol 1972; 56:881. 42. Young NJ, Bird AC, Sehmi K: Pigment epithelial diseases with abnormal choroidal perfusion. AmJ Ophthalmol 1980;90:607. 43. Lyness AL, Bird AC: Recurrences of acute posterior multifocal placoid pigment epitheliopathy. AmJ Ophthalmol 1984;98:203. 44. Lewis RA: Acute posterior multifocal placoid pigment epitheliopathy. A recurrence. Arch Ophthalmol 1975;93:235. 45. Saraux H, Pelosse B: Acute posterior multifocal placoid pigment epitheliopathy: A long term follow-up. Ophthalmologica 1987; 194:161. 46. Smith CH, Savino PJ, Beck RW, et al: Acute posterior multifocal placoid pigment epitheliopathy and cerebral vasculitis. Arch Neurol 1987;40:48. 47. Kersten DH, Lessell S, Carlow TJ: Acute posterior multifocal placoid

CHAPTER 11: ACUTE RETINAL

48.

49.

50.

51.

52.

53.

54. 55. 56. 57.

58. 59. 60. 61.

rn.!IIDVDII::R"lI

pigment epitheliopathy and late-onset meningoencephalitis. Ophthalmology 1987;94:393. Wilson CA, Choromokos EA, Sheppard R: Acute posterior multifocal placoid pigment epitheliopathy and cerebral vasculitis. Arch Ophthalmbl 1987;106:796. Sigelman J, Behrens M, Hilal S: Acute posterior multifocal placoid pigment epitheliopathy associated with cerebral vasculitis and homonymous hemianopia. AmJ OphthalmoI1979;88:919. BullockJD, Fletcher RL: Cerebrospinal fluid abnormalities in acute posterior multifocal placoid pigment epitheliopathy. AmJ Ophthalmol 1977;84:45. Fishman GA, Baskin M,Jednock N: Spinal fluid pleocytosis in acute posterior multifocal placoid pigment epitheliopathy. Ann Ophthalmol 1977;9:33. Dick DJ, Newman PK, RichardsonJ, et al: Acute posterior multifocal placoid pigment epitheliopathy and sarcoidosis. Br J Ophthalmol 1988;72:74. Brown M, Eberdt A, Ladas G: Pigment epitheliopathy in a patient with mycobacterial infection. JPediatr Ophthalmol Strabismus 1973;10:278. Hansen RM, Fulton AB: Cone pigments in acute posterior multifocal placoid pigment epitheliopathy. AmJ Ophthalmol 1981;91:465. Von Graefe A: Ueber centrale recidivierende retinitis. Graefes Arch Clin Exp Ophthalmol 1866;12:211-215.. Bennet G: Central serous retinopathy. Br J Ophthalmol 1995; 39:605-618. Gass JDM: Pathogenesis of disciform detachment of the neuroepithelium. II. Idiopathic serous central choroidopathy. AmJ Ophthalmol 1967;63:587-615. Gass JDM: Stereoscopic Atlas of Macular Diseases. St. Louis, CV Mosby, 1987. Burton TC: Central serous retinopathy. In: Blodi FC, ed: Current Concepts in Ophthalmology, vol 3. St. Louis" CV Mosby, -1972. Edwards TS, Proestly BS: Central angiospastic retinopathy. Am J Ophthalmol 1964;57:9888-9996. . GassJDM, Norton EWD,JusticeJ: Serous detachment of the retinal pigment epithelium. Trans Am Acad Ophl'halmol Otolaryngol 1966;70:990-1015.

62. Gass JDM: Bullous retinal detachment: An unusual manifestation of idiopathic central serous choroidopathy. Am J Ophthalmol 1973;75:810-821. 63. Klein BA: Symposium: Macular diseases, clinical manifestations. 1. Central serous retinopathy and chorioretinopathy. Tr<~ns Am Acad Ophthalmol Otolaryngol 1965;69:614-620. 64. Mitsui Y, Sakanishi R: Central angiospastic retinopathy. Am J Ophthalmol 1956;41:105-114. 65. Straatsma BR, Allen RA, Petit TH: Central serous retinopatl1Y. Trans Pacific Coast Oto-Ophthalmol Soc 1966;47:107-127. 66. Klein ML, van Buskirk EM, Friedman E, et al: Experience witl1 non-treatment of central serous choroidopathy. Arch Ophthalmol 1974;91:247-250. 67. Cohen D, Gaudric A, Coscas G, et al: Epitheliopathie retinienne diffuse et chorioretinopathie sereuse centrale. J Fr Ophtalmol 1983;6:339-349. 68. Gilbert M, Owen SL, Smith PD, et al: Long-term follow-up of central serous chorioretinopathy. Br J Ophthalmol 1984;68:815-820. 69. Spitznas M: Central serous chorioretinopathy. Ophthalmology 1980;87 (8S) :88. 70. Wessing A: Grundsatzliches zum diagnostochen Fortschritt durch die Fluoreszenzangiographie. Ber Zusammenkunft Dtsch Ophthalmol Ges 1973;73:566-568. 71. Yannuzi LA: Type A behavior and central serous chorioretinopathy. Trans Am Ophthalmol Soc 1986;84:799-845. 72. Piccolino FC: Central serous chorioretinopathy: some considerations on the pathogenesis. Ophthalmologica 1981;182(4):204-210. 73. Hayashi M, Yoshimura N, Kondo T: Acute rubella retinal pigment epitheliitis in an adult. Am J Ophthalmol 1982;93(3) :285-288. 74. Fischer DH: Viral disease and the retina. In: Tabarra KF, Hyndiuk RA, eds: Infections of the Eye. Boston, Little, Brown, 1986, 487-497. Alfano JE: Ocular aspects of the maternal rubella syndrome. Trans Am Acad Ophthalmol Otolaryngol 1966;70:235. 76. Wolff SM: The ocular manifestations of congenital rubella. Trans Am Ophthalmol Soc 1972;70:577. 77. Obenour LC: -The electroretinogram in rubella retinopathy. Int Ophthalmol Clin 1972;12:105.

75.

Alejandro Rodriguez-Garcia

Serpiginous choroiditis is a rare, chronic, progressive, and recurrent bilateral inflamlnatory disease involving the retinal pigment epithelium (RPE) , the choriocapillaries, and the choroid.1, 2 The cause of serpiginous choroiditis is unknown. 2-4 The disease is characterized acutely by. irregular, gray-white or cream-yellow subretinal infiltrates at the level of the choriocapillaries and the RPE. 3, 4 These lesions show a propensity for developing near the optic disc, extending centrifugally in a pseudopodial or serpentine fashion. 5 A pattern of inflammatory quiescence followed by recurrence is common,6, 7 with the recurrences appearing at the edges of the atrophic chorioretinal scars from prior attacks, occurring weeks, months, or even years after a prior attack. With time, atrophy of the RPE, choriocapillaries, and overlying retina occurs, leaving scarred tissue in the wake of the lesions.4-6 It is this final serpentine-shaped appearance of extended chorioretinal atrophy that gives this disease its name, serpiginous choroiditis. The disease has also ,been described in the literature a.s helicoid peripapillary chorioretinal degeneration,S geographic choroiditis9 or choroidopathy,4, 10 geographic helicoid peripapillary choroidopathy, 2 macular geographi~ helicoid choroidopathy, 3 choroiditis geographica,l1 and serpiginous choroidopathy. 12

Serpiginous choroiditis was first described in 1932 by Junius,13 who followed a 39-year-old patient for 14 years and described the clinical features that we now recognize as serpiginous choroiditis. He termed the condition peripapillary and central retinochoroiditis. Sorsby14 described a series of patients who appeared to have serpiginous choroiditis in 1939 but classified them as a peripapillary type of choroidal sclerosis. Franceschetti 15 pointed out that there were two groups of diseases that had similar appearances but different clinical courses. One group was probably degenerative in origin, whereas the other was characterized by progressive disease, probably representing serpiginous choroiditis. In his report, Franceschetti collected 16 cases of circumscribed atrophy of the RPE and choroid from his own practice and from previous reports in the literature, and he termed the condition helicoid peripapillary chorioretinal degeneration. 15 In this collection of cases, there was a considerable amount of parity in the clinical course and the probable cause of the disease. Although some patients were shown. to have progressive disease, in others the disorder was static. Some patients were considered to have a primary hereditary degeneration, whereas others were thought to have an inflamlnatory disease. 4 In 1974, Hamilton and Bird4 described a series of patients with serpiginous choroiditis. They emphasized the recurrent and progressive course of the disease, with a final appearance of atrophy of the RPE and choriocapil-

laries in the posterior pole, similar to that described Krill and Archer 16 in 1971. Different reports of small series of patients with serpiginous choroiditis, describing the clinical presentation,1, 3 fluorescein angiographic findings,2, 4 clinical course,5-7 treatment,17-19 and complications2Q-23 of the disease, have sporadically appeared in the literature thereafter.

Serpiginous choroiditis is rare. Of 1237 patients with uveitis referred to the Ocular Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary over a 10-year period, serpiginous choroiditis accounted for only 0.3% of all patients with intraocular inflammation seen and 1.6% of a total of 240 patients with posterior uveitis. 24 The largest series reported to date, by Chishohn, Gass, and Hutton,5 consisted of 20 patients, all of whom were white. In this series, there were 11 men and 9 women, with a mean age at presentation of 47.5 years (range, 29 to 70 years). Other reports have also found a male predominance, with most patients being whites. Schatz and coworkers 2 reported serpiginous choroiditis in seven men and two women with a mean age at presentation of 51.6 years (range, 41 to 68 years). Identical sex distribution was reported by Weiss and coworkers. 7 In their series, the mean age at presentation was 46.0 years (range, 22 to 58 years). In another series of 15 Finnish patients, Laatikainen and Erkkil~6 also found male predominance (eight men and six women) but with a younger mean age at presentation of 35.0 years (range, 20 to 65 years). According to these findings, the clinical presentation of serpiginous choroiditis occurs most commonly between the third and sixth decades of life. Although the great majority of patients reported to have serpiginous choroiditis have been whites,5, 7 the disease has also been noted in Asians,25 blacks,7 and Hispanics. 26

Patients with serpiginous choroiditis typically present with a painless unilateral decrease in central vision, metamorphopsia, and/or small central or paracentral scotomas (Table 72-1). The latter may by either absolute (particularly during the active stage of the disease) or relative, as the acute lesions resolve. 1, 2, 5, 7 Amsler grid testing reveals scotomas that correspond precisely to visible funduscopic lesions. 27 On examination the anterior segment usually appears quiet, although a nongranulomatous anterior uveitis has been described in some cases. 4, 2S A mild vitritis and/or fine pigmented cells within the vitreous have been seen in up to 50% of eyes in some series. 5, 7,29,30 On funduscopic examination, active disease manifests gray-green or cream-colored, deep-within-the-retina lesions with irregular borders involving the RPE and the choriocapillaris. 1,2,7 The overlying retina is usually edema-

CHAPTER 72: SERPIGINOUS CHOROIDITIS TABLE 72-1. CLINICAL DIAGNOSTIC SERPIGINOUS CHOROIDITIS

IN

Demographics Mostly whites Male to female ratio, 1:1 Age at presentation, 30 to 60 years Ocular findings Symptoms: Blurred vision, metamorphopsia, and central or paracentral scotomas Funduscopic appearance: Sharply demarcated gray-green or creamcolored deep-within-the-retina lesions with irregular borders, involving the RPE and choriocapillaris. Lesions extend in a pseudopodial pattern, leaving extensive chorioretinal atrophy. Disease progression: Centripetal (most common), macular (poor prognosis), centrifugal, and isolated peripheral lesions Additional tests Visual fields: Absolute scotomas (active phase), relative scotomas (resolution) corresponding precisely to visible funduscopic lesions Fluorescein angiography Active phase: Early hypofluorescence and late hyperfluorescence (leakage) at borders of lesions. Inactive phase: Mottled hyperfluorescence and late staining of the scar ERG and EOG: Frequently normal, except for patients with extensive disease, particularly if macula is involved (abnormal recordings corresponding to extent of damage) RPE, retinal pigment epithelium; ERG, electroretinogram; EGG, electro-oculogram.

tous and an associated neurosensory retinal detachment may occur2, 4, 5 (Fig. 72-1). The fundus lesions may vary in size ;f1om one to several disc diameters, having variable distribution and shape. 1- 10 Multiple areas of inflammation may be seen, most frequently at the distal edges of inactive scars and extending in a pseudopodial fashion. Noncontiguous "skip" lesions have also been observed and may represent de novo foci of involvement. 2, '1, 5 Involved areas of each eye frequently show different stages of progression. 6, 7 Classically,. as described by Chisholm and colleagues, 5 lesions develop first in the peripapillary area and tend to spread centrifugally2, 4 (Fig. 72-2). In such cases, the cen tral vision is unaffected in the beginning of the

FIGURE 72-1. Serpiginous choroiditis, witll both active and inactive lesions. Note tlle peripapillary involvement, with active foci nasal to tlle disc and the inactive areas of chorioretinal scarring in the macula. (Courtesy of C. Stephen Foster, MD.) (See color insert.)

FIGURE 72-2. Residuum of the earliest lesions of serpiginous choroiditis around the disc. Note, however, tllat the disease is now inactive and tllat the vitreous is crystal clear. (Courtesy of C. Stephen Foster, MD.) (See color insert.)

process, and it is not until the fovea becomes involved that visual acuity diminishes, frequently to counting fingers. I - 5 Weiss and colleagues 7 found a substantial reduction in visual acuity in 15 of 17 eyes affected by serpiginous choroiditis, although in nine of these eyes, visual acuity recovered to variable degrees. Improvement of vision following foveal involvement by an active lesion is variable, with a few patients demonstrating complete recovery and many others showing only partial improvement of one or two Snellen lines of visual acuity. 1, 6. 7 In their series, Laatikainen and Erkkila 1 recorded visual recovery in only 6 of the 18 eyes affected. Hamilton and Bird4 reported a visual improvement from 20/200 to 20/30 in one eye of the five patients they described, and Schatz and coworkers 2 did not find visual improvement in any of the nine patients in their series. Hardy and Schatz,3 and later Mansour and colleagues,26 as well as others,1, 13 have described a series of cases of serpiginous choroiditis in which the disease appeared initially in the macular area; they therefore termed this condition macular serpiginous choroiditis. In Hardy and Schatz's series of 31 patients, eight (11 eyes) had the macular form. 3 This form of the disease may be unilateral, or bilateral and simultaneous. 3 Although the clinical characteristics of eyes with the macular form differ little from those with the typical peripapillary form, patients with the macular form present early in the course of the disease with an acute onset of central visual 10ss.l, 3. 26 Subretinal neovascularization, resulting in further visual loss, is relatively common in this type of serpiginous choroiditis.20, 21 Less frequently, midperipheral lesions, which tend to progress centripetally, may occur. Weiss and colleagues 7 described 3 of 17 eyes in which new lesions appeared in an extrapapillary location and progressed toward the optic disc None of these patients had isolated macular disease. Finally, a few cases of isolated peripheral lesions have also been described. 7 During active disease, the RPE appears edematous and inflamed. 4 Over a 2- to 3-month period, the edema resolves and atrophy of the RPE and choriocapillaris are observed. 2, 5 In time, coarse, irregular clumps of RPE

s

SERPIGINOUS CHIOFlOllorns

hyperpigmentation develop within the lesions, and the large choroidal vessels become increasingly prominent. 5-7 As the disease progresses, large geographic-type or serpentine-shaped areas of chorioretinal atrophy are produced, which extend into the far retinal periph ery6, 7 (Fig. 72-3). Subretinal fibrosis may eventually develop within the atrophic scars in up to 50% of eyes according to one series. 5 Generally, the optic nerve is not affected,5, 6 although Wu and colleagues 31 described a patient with temporal sectorial atrophy of the optic nerve. F"l~isawa and colleagues 25 reported a patient with recurrent disease who developed optic neuritis, and Wojno and Meredith 22 reported two patients with optic disc neovascularization.

PATHOGENESIS/IMMUNOLOGY/ PATHOLOGY The pathogenesis of serpiginous choroiditis is unknown. Although no definitive systemic involvement has been found, there have been reports of the disease in association with neurologic disorders. Richardson and colleagues32 described a patient who had acquired extrapyramidal dystonia and two other cases suggesting a link between serpiginous choroiditis disorders, including a young man with a relative absence of arm swing while walking and another patient whose sister had multiple sclerosis. King and colleagues 33 reported elevated von Willebrand factor VIII (VIII-VWF) antigen in eight patients with serpiginous choroiditis V\1.
fiGURE 72-3. Progressive, active serpiginous choroiditis, which first began in the peripapillary region but now has spread in a serpiginous way superiorly and temporally in this left eye, now involving the macula. (Courtesy of C. Stephen Foster, MD.) (See color insert.)

of infection were initially assumed to be the cause of serpiginous choroiditis byWitmer 36 in 1952 and SchlaegeP7 in 1969. Laatikainen and Erkkila l found two patients with active pulmonary tuberculosis that preceded the appearance of clinical serpiginous choroiditis, and all nine patients in their series had a positive purified protein derivative (PPD) skin test. At that time, these authors suggested that· a tubercular allergic etiology could be a possible mechanism in the pathogenesis of serpiginous choroiditis. In addition to the tuberculosis cases, a patient with viral meningitis, three patients with increased antistreptolysin antibody titers, and single cases of active serpiginous choroiditis with concurrent maxillary sinusitis and influenza have been described by the same investigators. l No subsequent cases of serpiginous choroiditis have been associated with an infectious cause. A11tibody determinations have been performed in patients with serpiginous choroiditis against the following infectious agents, all with negative results: vaccinia virus; herpes simplex and herpes zoster; cytomegalovirus; adenovirus; influenza viruses A and B; parainfluenza viruses 1, 2, and 3; respiratory syncytial virus, rubella and rubeola viruses; reovirus; polioviruses 1, 2, and 3; and coxsackieviruses A7, A9, B5, as well as other microorganisms, such as Toxoplas177,a gondii and Mycoplasma pneumoniae. 34 Maumenee 38 has suggested that the disease is the result of a vascular abiotrophy and therefore could be considered a degenerative disorder. Indeed, the prominent choroidal vascular obliteration initially led to the inclusion of serpiginous choroiditis in the group of choroidal dystrophies. However, the late onset, the acuteness of visual loss, the marked asymmetry, and the absence of familial cases tend not to support this notionY On the other hand, the occasional presence of anterior uveitis, retinal vasculitis, and vitreous cellular reaction in patients with serpiginous choroiditis suggests an inflammatory cause. 7, 23. 28 Jampol and colleagues,20 as well as others,9,37 suggest that an inflammatory process causes a disruption of Bruch's membrane, permitting the development of subretinal neovascularization, a not uncommon cause of visual loss in patients with serpiginous choroiditis. Wojno and Meredith 22 also support the inflammatory hypothesis, noting that optic disc neovascularization and vitritis are more readily explained by this type of mechanism. Erkkila and colleagues 39 have suggested that a localized immune vasculitis induces occlusion of the choroidal vessels. In addition, the demonstration of elevated VIII-VWF by King and colleagues suggests endothelial injury from a vaso-occlusive event, perhaps caused by a vasculitis. 33 In favor. of this hypothesis are the fluorescein angiographic characteristics found in serpiginous choroiditis, in which interference with choroidal fluorescence is apparent, especially during the active phase of the disease. 2, 7, 10 In other areas, however, the l~emaining abnormal choroidal vasculature is visible on fluorescein angiography, indicating loss of integrity of the RPE barrier. 2 This finding, in addition to the lack of choriocapillary flush, suggests that the choriocapillaris is obliterated within the margins of the lesion. The margins become hyperfluorescent from leakage of normal choriocapillaries at the borders. Large

CHAPTER 72: SERPIGINOUS CHOROIDITIS

remaining choroidal vessels within the lesion fill slowly and leak moderately, indicating that these vessels have also lost endothelial integrity.2, 10 Secchi and colleagues 18 have suggested that there is a vascular inflammatory lesion beginning at the choriocapillaris as a focal vasculitis. Type III (immune complex) and type IV (cell-mediated) hypersensitivity reactions may playa role. These authors also believe that in the course of the disease, type II (cytotoxic) reactions may also take place, possibly elicited by autoantibodies to retinal autoantigens (S and interphotoreceptor retinoid binding protein) . Broekhuyse and colleagues 40 found responsiveness to retinal S-antigen by lymphocytes frOlTI patients with serpiginous choroiditis, and they suggested that autoimmune reactivity probably depends on the damage of RPE cells, release of autoantigens, and leakage of S-antigen through the blood-retina barrier at the level of the RPE. According to Nussenblatt and Palestine,12 a possible mechanism for this disease entails abiotrophy with the release of potentially antigenic molecules, which, in genetically susceptible individuals, leads to an inflamlTIatory response. Indeed, a statistically significant increase in the frequency of human leukocyte antigen (HLA)-B7 in 15 patients with serpiginous choroiditis compared with a control Finnish population (54.5% versus 24.3%; P > .95). was found by Erkkila and colleagues~;39 Very few eyes with serpiginous choroiditis have been studied histopathologically. Histologic examination shows extensive loss of the RPE and destruc1ton of the overlying retina. 29 , 31 The choriocapillaris as well as part of the choroid is filled with a mononuclear cell infiltrate, suggesting an inflammatory component to this disorder. A diffuse and focal accumulation of lymphocytes in the choroid has been observed. 31 This accumulation was greatest at the margins of the atrophic scars. Within the scars themselves, the RPE and photoreceptor layers are lost, with focal defects of the underlying Bruch lTIembrane occurring at various sites within the lesIons. Fibroglial tissue is seen at the inner surface of Bruch's membrane, with some migrating through breaks in Bruch's membrane into the choroidY

FIGURE 72-4. Fluorescein angiogram, midphase, in a patient with serpiginous choroiditis. Note the hyperfluorescence around the satellite lesion supratemporal to the macula, along the supratemporal arcade. (Courtesy of C. Stephen Foster, MD.)

a lesion may show spotty hyperfluorescence. The areas of active inflammation eventually stain latein the study.5

During the inactive stage of the disease, the fluorescein angiogram shows mottled hyperfluorescence, the result of pigment clumping with some late staining. 3,lo In early phases of inactive disease, the scars are hypofluorescent because most of the choriocapillaris is absent (Fig. 72-4). As the angiogram proceeds, an increasing hyperfluorescence is seen at the margins of the scar as fluorescein diffuses into the scarred area from the bordering normal choriocapillaris (Fig. 72-5). Late staining of the sclera and fibrous tissue follows. 6, 7

Indocyanine Green Angiography Our experience with indocyanine green (ICG) angiography in serpiginous choroiditis is limited to one patient, in whom we found severe, diffuse atrophy of the choriocapillaris and increased visualization of the large choroidal vessels within the lesions. Middle and large choroidal vessels also appeared narrower and fewer in number (Fig. 72-6).

The diagnosis of serpiginous choroiditis is made mainly on its clinical features in patients between their second and sixth decades of life, with a funduscopic appearance typical of active disease in one eye together with the characteristic bilateral distribution of pre-existing inactive disease.2, 4

Fluorescein Angiography

Active Phase Fluorescein angiography of active lesions shows hypofluorescence during the early phases of the angiogram. The hypofluorescence of the interior lesion represents either blockage by swollen RPE cells or nonperfusion of the choriocapillaris, or both. 26 As the angiogram proceeds, hyperfluorescent borders, representing leakage of fluorescein from the surrounding choriocapillaris, may be seen. 2, 4, 10 Later in the angiogram, the inner portions of

FIGURE 72-5. Fluorescein angiogram, same patient as shown in Figure 72-4, late phase, with late staining of the inactive macular lesion and perilesional halo staining of a mildly active satellite lesion superotemporal to the macula. (Courtesy of C. Stephen Foster, MD.)

r

CHAPTER 72: SERPIGINOUS CHIOftOllOrTiS

of 26 eyes. Only the eye with the most extensive posterior pole involvement showed a marked reduction of the ERG. In their series, the EOG light rise ratio was normal in 17 eyes, moderately abnormal in one eye. (1.45:1.65), and severely abnormal in eight eyes « 1.45). The reduced levels of the EOG appeared to correlate well with the extent of the funduscopic changes. 5 This pattern differs from that seen in hereditary dystrophies, where electrophysiologic abnormalities are frequently found to reflect global pathology, and the degree of dysfunction is often greater than expected from the clinical appearance.'12

DI FIGURE 72-6. ICG angiogram in a patient with serpiginous choroiditis, showing diffuse leakage in the choroid during active inflammation. (Courtesy of C. Stephen Foster, MD.)

Giovannini and colleagues have recently described the ICG findings of patients with serpiginous choroiditis during the acute, subacute, and healed phases of the disease. Early hypofluorescence followed by late staining was observed with acute lesions, similar to that seen on fluorescein angiography. In addition, ICG revealed active choroidal involvement beyond that deliillited by fluorescein angiography or visualized by biomicroscopy, suggesting more widespread ischemic or inflammatory pathology than what was apparent clinicalfy. Healed lesions stain with both ICG and fluorescein angiography in areas of scarring and fibrovascular tissue. As in our patient, choroidal atrophy is sharply circumscribed, with absence of the choriocapillaris. 41

Visual Fields Visual field testing in active serpiginous choroiditis often demonstrates dense scotomas, corresponding in size, shape, and location to active lesions, and less dense scotomas as disease activity subsides. 5 , 7 Frequently, scotomas are not uniformly absolute and may have a dense center with a light surrounding area. 7 The regular use of Amsler grid testing is recommended to follow the central progression of the disease. 3 ,26 Because of the slow and recurrent nature of serpiginous choroiditis, serial fundus photographs are also very helpful in documenting progression of the disease, particularly if this is subclinical. 34

Electrophysiology Electrophysiologic testing is frequently normal in serpiginous choroiditis. Weiss and colleagues 7 performed electroretinogram (ERG) and electro-oculogram (EOG) testing on eight of their nine patients with serpiginous choroiditis, and both tests were' recorded withiIi normal limits for all eyes. Abnormalities may be seen in patients with extensive disease, correlating with the degree of retinal damage. 1, 4, 5 When extensive disease is present, ERG values have been shown to fall to 70% to 80% of normal for total retinal illumination and to 20% to 30% of normal for focal macular illumination. 5 , 9 Chisholm and colleagues5 found that the ERG was abnormal in 3

When serpiginous choroiditis develops in the absence of previous lesions, the diagnosis can be a clinical challenge. A number of infectious, inflammatory, degenerative, and hereditary conditions may produce a clinical picture compatible with a diagnosis of serpiginous choroiditis (Table 72-2) . The differential diagnosis of macular serpiginous choroiditis involves many clinical entities, including agerelated macular degeneration, idiopathic subretinal neovascularization, retinal pigment epitheliitis, presumed ocular histoplasmosis syndrome, multifocal choroiditis and panuveitis (MCP), and acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Other causes of choroiditis, such as tuberculosis, sarcoidosis, Harada's disease, and sympathetic ophthalmia, may also resemble serpiginous choroiditis. 2 The disease most likely to be confused with the initial acute presentation of serpiginous choroiditis is APMPPE, as the acute lesions in APMPPE involve the RPE and choriocapillaris and have a coloration and appearance similar to those of serpiginous choroiditis. Indeed, the fluorescein angiographic findings are similar in both diseases during the acute phase, with early blockage and late staining of the lesions. However, in APMPPE, the disease usually occurs bilaterally and simultaneously. The lesions are discrete, round to oval or placoid, usually confined to the posterior pole, and more randomly distributed; they tend not to coalesce, as do those of serpiginous choroiditis. 43 The lesions of APMPPE regress oVer a period of 1 to 2 weeks, usually with significant visual improvement, leaving scars which, while pigmented, are less atrophic and less destructive to the choroid and overlying neurosensory retina. 43-45 Recurrences, which are

TABLE 72-2. DIFFERENTIAL DIAGNOSIS OF SERPIGINOUS CHOROiDITIS vVhite dot syndromes Acute posterior multifocal placoid pigment epitheliopathy Multifocal choroiditis and panuveitis Presumed ocular histoplasmosis syndrome Acute retinal pigment epitheliitis Infectious diseases Outer-layer retinal toxoplasmosis Tuberculous choroiditis Miscellaneous Sarcoidosis choroiditis Harada's disease Sympathetic ophthalmia

CHAPTER 72: SERPIGINOUS CHOROIDITIS

distinctly unusual in APMPPE, are the rule in serpiginous choroiditis; with resolution of the lesions, there is profound derangement in the RPE, marked choroidal atrophy, and frequently impaired vision, A diagnosis of APMPPE should be questioned in patients with unilateral, recurrent, or progressive macular lesions, especially if visual recovery does not occur. Visual acuity, even following foveal involvement, often recovers dramatically in APMPPE, but recovery is less common in serpiginous choroiditis. 27 Choroidal neovascularization has been reported in both entities but is more common in serpiginous choroiditis.27, 29 Moreover, patients suffering from APMPPE are usually younger, and patients with serpiginous choroiditis are more frequently middle-aged. Despite the clinical differences between APMPPE and serpiginous choroiditis, the recurrent form of APMPPE described by Lyness and Bird46 resembles macular serpiginous choroiditis in its bilateral nature, fluorescein angiographic characteristics, and the resultant pigmentary disturbance. Whether APMPPE and serpiginous choroiditis represent extreme manifestations of a single disease or are in fact separate and distinct entities remains speculative. Patients with MCP differ from those with serpiginous choroiditis in that they are young, mostly female, and frequently have moderate myopia. 47, 48 Choroidal lesions. found in MCP are round, of variable size, more numerous, .and more widely distributed than those seen in serpiginous choroiditis.'17 Vitreous inflammation is prominent in MCP, and late-stage subretif1al fibrosis is quite common. 49 Outer retinal toxoplasmosis may also mimic serpiginous choroiditis. Lesions in this disorder do not coalesce and are virtually always unilateral. Vitreous inflammation usually develops, and the overlying retina eventually becomes involved. 5o , 51 Disseminated tuberculous choroiditis may present with a yellowish gray, round lesion of the choroid with overlying necrotic retina, associated opacities of the vitreous, and, frequently, granulomatous uveitis. 52 Systemic findings include a positive PPD skin test and systemic manifestations of miliary tuberculosis. 1, 30 In serpiginous choroiditis, vitritis is not a prominent feature, nor is it granulomatous in nature. 28 Biopsy-proven sarcoidosis in the clinical form of extensive, confluent choroiditis with RPE changes resembling serpiginous choroiditis has been reported by Edelsten and colleagues53 in two patients. In their report, the patients presented with active lesions on the posterior pole associated with marked RPE changes, with fluOl'escein angiographic features of early masking and late staining of the edges of the lesions. Several systemic diseases may cause choroidal ischemia in the posterior pole. These include hypertensive vascular disease, systemic lupus erythematosus, polyarteritis nodosa, toxemia of pregnancy, disseminated intravascular coagulation, and thrombotic thrombocytopenic purpura. 54-56 The fluorescein angiogram pattern in these conditions may resemble that of serpiginous choroiditis, but the clinical course is different and associated systemic findings are the rule in these cases.54-56 Choroidal neovascularization may be seen with many

inflammatory, degenerative, and neoplastic conditions. Damage to Bruch's membrane with the occurrence of choroidal neovascularization may be seen in degenerative diseases, including angioid streaks, drusen, and myopia; dystrophic diseases such as Best's disease "and fundus flavimaculatus may also produce choroidal neovascularization. 2, 3 Angioid streaks have a distinct funduscopic appearance, including "leopard-skin change" (peau d'orange), hemorrhage, and "salmon spot" changes quite typical for this condition, and together with the not infrequent association with pseudoxanthoma elasticum, they may be easily distinguished from serpiginous choroiditis. 2 In older patients, metastatic tumors, non-Hodgkin's lyJ-nphoma, and choroidal osteoma may mimic the appearance of the acute unilateral le'sion of serpiginous choroiditis. Stepwise progression with severe loss of the RPE and choriocapillaris are unusual in these disorders. 42

Medical Treatment Serpiginous choroiditis is a chronic, recurrent, and progressive disease that is particularly resistant to treatment. Despite the use of a variety of anti-inflammatory and immunosuppressive drugs in the treatment of serpiginous choroiditis, most therapeutic regimens reported thus far do not seem to be totally efficacious in controlling the recurrent and progressive nature of the disease. In their first report on serpiginous choroiditis, Laatikainen and Erkkila1 found a high incidence of active or presumed tuberculosis in their patients and decided to treat most of them with aggressive antituberculous therapy (streptomycin, isonicotinic acid hydrazide, and paraamino salicylic acid), with poor results. The reports on the use of oral or periocular corticosteroids in the treatment of the acute phase or recurrences of serpiginous choroiditis have produced mixed results, with some authors reporting a beneficial effect while others were failing to demonstrate a good therapeutic response. Systemic prednisone at 60 to 80 mg/ day has not been shown to affect the recurrence rate or the long-term outcome of the disease. 1, 7 Moreover, reports advocating corticosteroid therapy have recorded favorable responses over the same 1- to 2-month period as that in untreated lesions in other studies, making the treatment effect difficult to differentiate from the natural history of the lesion. 12 Laatikainen and Erkkila l did not find prednisone to be useful in preventing progression of the disease. Oral prednisone was given as a monotherapy to six patients with serpiginous choroiditis. In three patients, the lesions remained confined, whereas in the other three, considerable progression occurred in spite of therapy. Five of these six patients had one or more recurrences while on therapy. 6 Chisholm and colleagues5 treated 18 serpiginous choroiditis patients with periocular or systemic corticosteroids at some stage of the disease. Even though some patients felt clinical improvement, the authors could not find objective evidence of improvement as a result of the use of corticosteroids. They also noted that in patients

CHAPTER 72:

with foveal involvement, there was no rapid resolution of disease activity with this same therapy.5 On the other hand, Hardy and Schatz 3 noted an apparently favorable response to early treatment with corticosteroids. Of eight episodes of acute disease treated with oral prednisone or sub-Tenon's injection of 40 mg of triamcinolone acetonide, all patients seemed to respond promptly, with resolution of disease activity and preservation or improvement of visual acuity. Treatment of serpiginous choroiditis with cyclosporineA (CsA) as monotherapy has also produced conflicting results. Failure of CsA therapy with respect to both progression of the disease l7 , 57 and induction of disease regression and visual improvement has been observed. IS Secchi and colleagues 1S treated seven patients (seven eyes) with active serpiginous choroiditis with CsA monotherapy at a starting dose of 4 to 7 mg/kg/day for a period of 6 to 21 months (mean duration of therapy, 10 months). Six of the seven eyes studied showed a significant improvement in vis'ual acuity within the first few months of therapy and remained stable during the whole course of treatment. Moreover, four of the seven remaining inactive eyes showed some improvement in visual acuity. The results of this study, in which 80% of patients maintained vision equal to or better than baseline, indicate that CsA compares favorably with corticoste\'oids alone or in combination with immunosuppressive agents, for which the average rate of visual loss reported in the literature is 36%.42 Accordingly, Secchi and colleagues 1S recommended CsA monotherapf as the first line of treatment fOr serpiginous choroiditis, particularly in the active phase of the disease and when the macula was threatened or involved. On the other hand, separate therapeutic regilnens using CsA or azathioprine in combination with prednisone have been tried in small numbers of patients with serpiginous choroiditis with disappointing resultsP Hooper and Kaplan 19 have shown that triple-agent immunosuppression, using azathioprine (1.5 mg/kg/day), CsA (5 mg/kg/ day), and prednisone (1 mg/kg/ day) combined, is effective in controlling disease progression. In their study, patients with serpiginous choroiditis were considered for treatment if visual acuity was reduced to 20/200 or less in one eye, or an active lesion was seen within 500 fJvm of the fovea centralis in the remaining eye. Five patients were treated with this regimen, and active lesions resolved within 2 weeks of therapy in all five patients. Vision remained stable in three eyes and improved in two as edema and subretinal fluid resolved. As the medications were weaned or discontinued, recurrences developed in two patients. Both recurrences responded rapidly to reinstitution of therapy and remained inactive over an 18-month period. These authors also observed less destruction of the RPE and choriocapillaris, with less pigment hyperplasia and intraretinal pigment migration in eyes treated during the active phase of the disease. 19 Despite the apparent therapeutic efficacy shown by triple-agent immunosuppression in this study, there are several uncertainties with respect to this type of regimen: (1) the length of time patients remain relapse free while undergoing therapy; (2) the effect of therapy on the

incidence of malignancy; and (3) the appropriate of time that patients should be treated after "'L()LV~H.~~~.~-­ of disease activity.19 Because of this, the authors .-~.~~;,-..,­ mend this triple-agent therapeutic regimen only for piginous choroiditis patients with bilateral disease who have active lesions that threaten the central vision or do not respond to other forms of therapy.19 Unfortunately, a definitive therapy for serpiginous choroiditis will require a long-term, well-contTolled, prospective study including a large cohort of patients, a goal that seems very difficult if not impossible to accomplish, given the rarity of this disease. Our group at the Massachusetts Eye and Ear Infirmary studied the clinical courses of six patients (12 eyes) with vision-threatening, steroid-dependent/ resistant serpiginous choroiditis treated with the triple-agent immunosuppression regimen (prednisone, CsA, azathioprine) or with cyclophosphamide monotherapy.5s All patients were treated for a minimum of 12 months (range, 12 to 87 months; mean, 43 months), with follow-up of 19 to III months (average, 62 months). All patients were able to successfully taper off from the oral steroids on which they had been dependent, and all were eventually able to taper off and discontinue the immunomodulatory agents as well. Ten eyes had improved visual acuity, none had progressive loss of vision during follow-up, and two with macular scars were stable. Cyclophosphamide was the most effective treatment, enabling long-term remission with much shorter treatment course (12 and 19 months in the two patients thus treated) than that required with combination triple therapy (average, 59 months).

Treatment of Choroidal Neovascularization There are no reports on the therapeutic response of choroidal neovascularization to anti-inflamlnatory treatment in patients with serpiginous choroiditis. 42 On the other hand, subretinal neovascular membranes have been treated successfully with intense argon laser photocoagulation. 20 , 21, 27, 59 Jampol and colleagues 20 were the first to report the successful treatment of subretinal neovascular membranes in serpiginous choroiditis using argon laser photocoagulation. In their report, two of three eyes with choroidal neovascularization in the macular area were photocoagulated with preservation of central vision. The third patient could not be treated because of the proxilnity of the neovascular membrane to the fovea centralis. Laatikainen and Erkkila21 reported on two serpiginous choroiditis patients (three eyes) with subretinal neovascul4rization. One eye was treated with argon laser photocoagulation with recurrence of the neovascular net; the second eye could not be treated because of the subfoveal location of the lesion; and in the third eye, the neovascularization regressed spontaneously without therapy. Recurrence of subretinal neovascularization following argon laser photocoagulation (which was further treated successfully with krypton laser) has also been reported by Mansour and colleagues. 26 An early diagnosis of subretinal neovascularization is critical, because new vessels outside the fovea centralis may be suitable for treatment with laser. 2o ,21 Subretinal neovascular membranes located in the foveal avascular

· CHAPTER 72: SERPIGINOUS CHOROIDITIS

zone of any etiology are now being treated with photodynamic. therapy with verteporfin with promising results.

In earlier reports of serpiginous choroiditis in the literature, the occurrence of subretinal neovascular membranes (choroidal neovascularization) was not observed or was considered to be rare. 4 , 5, 7, 29, 59 Although Gass 29 described one patient with an atypical case of serpiginous choroiditis characterized by subretinal neovascularizatiQn with exudation and hemorrhage, the first report that specifically addressed the occurrence of subretinal neovascularization in patients with serpiginous choroiditis was made by Jampol and colleagues. 2o Since then, choroidal neovascularization with secondary hemorrhage, exudation, or serous retinal detachment has been described to occur in approximately 13% to 20% of eyes with serpiginous choroiditis in long-term studies. 20 , 21, 27, 59 The neovascularization usually develops at the border of an old scar. The development of a subretinal membrane is not easily detectable on funduscopic examination or color fundus photographs. This is because the early formation of a neovascular membrane beside an old scar reselnbles a recurrent serpiginous choroiditis lesion. 20 In this case, the differentiation can best be made by fluorescein angiography findings. 21 Schatz and McDonald 27 emphasized that new lesions in patients with serpigi':: nous choroiditis should be carefully assessed to determine whether they represent an inflammatory recurrence or a choroidal neovascular membrane. Serous retinal detachment during the active phase of the disease has been observed in a few patients with serpiginous choroiditis. 2 , 7 This shallow exudative detachment of the retina eventually resolves as disease activity subsides. 7 , 21 Another serpiginous choroiditis patient experienced an RPE detachment, as described and demonstrated angiographically by Wojno and Meredith. 22 Cystoid macular edema has been demonstrated angiographically by Steinmetz and colleagues 60 in a patient with active macular serpiginous choroiditis. The patient was successfully treated with a significant improvement in visual acuity using 500 mg/day of acetazolamide for 2 weeks. Retinal vasculitis and inflammation of the optic disc during active serpiginous choroiditis have also been described. 1, 5, 7, 28 Branch retinal vein or artery occlusions 23 and neovascularization of the optic disc 2I , 22 have been seen uncomm0l1ry in association with active serpiginous choroiditis.

Between 12% and 38% of eyes suffering from serpiginous choroiditis will end up with a central vision of less than 20/200 to counting fingers. Conversely, fewer than 5% of patients will have a final visual acuity of less than 20/200 in both eyes. 2- 7 If it occurs, visual recovery after foveal involvement in serpiginous choroiditis may be delayed by 1 year or more, and neither correlates with the degree of initial visual loss or with the appearance of the lesion. This notwithstanding, the great majority of affected eyes will end up with a poor central vision following foveal disease. 1, 2, 5-7

The visual prognosis of macular serpiginous choroiditis is less favorable than that of peripapillary serpiginous choroiditis, probably because of early involvement of the macula in the former. 26 In addition, subretinal neovascularization may contribute to further loss of vision. 26 Patients with bilateral macular disease exhibit a tendency toward progression of the disease and recurrence, as well as to the development· of subretinal neovascularization and neurosensory retinal detachment of the macula. 3 On the other hand, Hardy and Schatz 3 found that patients with unilateral macular serpiginous choroiditis have a better visual prognosis and, at least in their series, did not develop macular disease in the uninvolved eye during their entire follow-up (mean, 46.0 months). Long-term follow-up studies of patients with serpiginous choroiditis are necessary to monitor disease activity and to assess the potential for macular involvement. In such cases, serial fundus photographs are very helpful to record progression of the disease. Patients with serpiginous choroiditis should also be instructed to perform selftesting with the Amsler grid to monitor the appearance of metamorphopsia or central scotomas between regular visits to the ophthalmologist.

CONCLUSIONS Serpiginous choroiditis is. a rare, chronic, and recurrent bilateral disease affecting the RPE, the choriocapillaris, and the choroid. The disease occurs more frequently in whites, with both sexes affected in equal proportion. The onset of the disease is between the third and sixth decades of life. The etiology of serpiginous choroiditis is uncertain. Neither has a definitive systemic disease been associated with the disease, nor has an infectious agent been proven to be the cause. The contention that the disease could represent a dystrophy or a degenerative process can be dismissed by the lack of familial cases, the late onset of the disease, and the marked asymmetry observed in most cases. On the other hand, the occasional presence of anterior uveitis, retinal vasculitis, and vitreous cellular reaction in these patients suggests an inflammatory cause. In addition, histopathologic examination of eyes suffering from serpiginous choroiditis has shown the choriocapillaris and part of the choroid filled with a round-cell infiltrate consisting of focal accumulations of lymphocytes. Finally, some patients have been shown to respond to antiinflammatory therapy. Patients with serpiginous choroiditis typically present with painless, unilateral decrease in central vision, metamorphopsia, and/or small central or paracentral scotomas. On examination, the anterior segment and vitreous usually appear quiet, although a nongranulomatous anterior uveitis and mild vitritis may be present. Active disease manifests sharply demarcated, graygreen or cream-colored lesions deep within the retina with irregular borders involving the RPE and the choriocapillaris. The fundus lesions may vary in size from one to several disc diameters, having a variable distribution and shape. Multiple areas of disease activity may be seen, most frequently at the distal edges of inactive scars and

CHAPTER 72: SERPIGINOUS

extending in a pseudopodial fashion, usually from the optic disc. The clinical course of the disease is one of long periods of quiescence, lasting months to years, followed by recurrent episodes of activity. Disease activity may last for 2 to 3 months before resolution. The end stage of the disease is characterized by the formation of a large serpentineshaped area of chorioretinal atrophy, extending into the far retinal periphery. The diagnosis of serpiginous choroiditis is based on clinical grounds. The typical funduscopic appearance of active lesions in one eye, in conjunction with a characteristic bilateral distribution of inactive chorioretinal scars, makes the suspicion of serpiginous choroiditis a very strong one. The fluorescein angiographic appearance of active lesions is typical, showing early hypofluorescence of the lesions and late hyperfluorescent borders, representing leakage of fluorescein from the surrounding choriocapillaris. During the inactive phase of the disease, the fluorescein angiogram shows mottled hyperfluorescence with some late staining of the sclera and fibrous tissue. Serpiginous choroiditis is particularly resistant to treatment. Systemic steroids do not appear to be totally efficacious in controlling the recurrent and progressive nature of the disease. Even the use of oral or periocular OOl"ticOsteroids in the treatment of· the acute phase or recurrences of serpiginous choroiditis is controversial. There are reports showing a beneficial effect, but others fail to demonstrate a good therapeut'!'lc response. Treatment of serpiginous choroiditis with CsA monotherapy has also produced conflicting results. Both failure of CsA therapy with pro'gression of the disease, and inflammatory regression and visual improvement have been observed. Triple-agent immunosuppression using azathioprine, CsA, and prednisone has been shown to be effective in controlling disease progression in a small number of patients. However, this therapeutic regimen has been recommended only for patients with bilateral disease who have active lesions that threaten central vision or those who do not respond to other forms of therapy. Despite the promising results with triple-agent immunosuppression, a definitive therapeutic strategy for serpiginous choroiditis remains elusive and awaits a better understanding of the pathogenesis of the disease.

References 1. Laatikainen L, Erkkila H: Serpiginous choroiditis. Br J Ophthalmol 1974;58:777. 2. Schatz H, Maumenee AE, Patz A: Geographic helicoid peripapillary choroidopathy: Clinical presentation and fluorescein angiographic findings. Trans Am Acad Ophthalmol Otolaryngol 1974;78:747. 3. Hardy RA, Schatz H: Macular geographic helicoid choroidopathy. Arch Ophthalmol 1987;105:1237. 4. Hamilton AM, Bird AC: Geographical choroidopathy. Br J Ophthalmol 1974;58:784. 5. Chisholm H, Gass JDM, Hutton WL: The late stage of serpiginous (geographic) choroiditis. AmJ Ophthalmol 1876;82:343. 6. Laatikainen L, Erkkila H: A follow-up study on serpiginous choroiditis. Acta Ophthalmol 1981;59:707. 7. Weiss H, Annesley WH, Shields JA, et al: The clinical course of serpiginous choroiditis. AmJ Ophthalmol 1979;87:133. 8. Sveinsson K: Helicoidal peripapillary chorioretinal degeneration. Acta Ophthalmol 1979;57:69.

ChIOI~OIIDI'TIS

9. Baarsma GS, Deutman AF: Serpiginous (geographic) choroiditis. Doc Ophthalmol 1976;40:269. 10. Carr RE, Noble KG: Geographic (serpiginous) choroidopathy. Ophthalmology 1980;87:1065. 11. Pham-Duy T, Miszalok V: Choroiditis geQgraphica. Klin Monatsbl Augenheilkd 1983;183:278. 12. Nussenblatt RB, Palestine AG: Serpiginous choroidopathy (choroiditis). In: Uveitis. Fundamentals and Clinical Practice. Chicago, Year Book Medical, 1989, p 309. 13. Junius P: Seltene augenspiegelbilder zum klinischen phanomen del' retinitis exsudativa coats und del' retino-choroiditis "parapapillaris." Arch Augenheilkd 1932;106:475. 14. Sorsby A: Choroidal angio-sclerosis with special reference to its hereditary character. Br J Ophthalmol 1939;23:433. 15. Franceschetti A: A curious affection of the fundus oculi. Helicoid peripapillary chorioretinal degeneration. Its relation to pigmentary paravenous chorioretinal degeneration. Doc Ophthalmol 1962;16:81. 16. Krill AE, Archer D: Classification of the choroidal atrophies. Am J Ophthalmol 1971;72:562. 17. Laatikainen L, Tarkkanen A: Failure of cyclosporine A in serpiginous choroiditis. JOcular Ther Surg 1984;3:280. 18. Secchi AG, Tognon MS, Maselli C: Cyclosporine-A in the treatment of serpiginous choroiditis. Int Ophthalmol 1990;14:395. 19. Hooper PL, Kaplan HJ: Triple agent immunosuppression in serpiginous choroiditis. Ophthalmology 1991;98:944. 20. Jampol LM, Orth D, Daily MJ, et al: Subretinal neovascularization with geographic (serpiginous) choroiditis. Am J Ophthalmol 1979;88:683. 21. Laatikainen L, Erkkila H: Subretinal and disc neovascularization in serpiginous choroiditis. Br J Ophthalmol 1982;66:326. 22. Wojno T, Meredith TA: Unusual findings in serpiginous choroiditis. AmJ OphthalmoI1982;94:650. 23. Friberg TR: Serpiginous choroiditis with branch vein occlusion and bilateral periphlebitis. Arch Ophthalmol 1988;81:481. 24. Rodriguez A, Calonge M, Pedroza-Seres M, et al: Referral patterns of uveitis in a tertiary eye care center. Arch Ophthalmol 1996;114:593. 25. Fl~jisawa C, Fujiwara H, Hasegawa E, et al: The cases of serpiginous choroiditis Uapanese, English abstract]. Nippon Ganka Gakkai Zasshi 1978;82:135. 26. Mansour AM, Jampol LM, Packo KH, et al: Macular serpiginous choroiditis. Retina 1988;8:125. 27. Schatz H, McDonald HR: Geographic helicoid peripapillary choroidopathy (serpiginous choroiditis). In: Ryan SJ, Schachat AP, Murphy RB, Patz A, eds: Retina. St. Louis, c.v. Mosby, 1989, P 705. 28. Masi RJ, O'Connor GR, Kimura SJ: Anterior uveitis in geographic or serpiginous choroiditis. AmJ Ophthalmol 1978;86:228. 29. Gass JDM: Inflammatory diseases of the retina and choroid. In: Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment, 4tl1 ed, vol II. St. Louis, Mosby, 1987, P 710. 30. Jampol LM: The retina: Inflammatory diseases. In: Miller S, ed: Clinical Ophthalmology. Bristol, Wright, 1987, p 186. 31. Wu IS, Lewis H, Fine SL, et al: Clinicopathologic findings in a patient with serpiginous choroiditis and treated choroidal neovascularization. Retina 1989;9:292. 32. Richardson RR, Cooper IS, Smith JL: Serpiginous choroiditis and unilateral extrapyramidal dystonia. Ann Ophtl1almol 1981;13:15. 33. King DG, Grizzard WS, Sever RJ, Espinoza L: Serpiginous choroidopathy associated with elevated factor VIII-von Willebrand factor antigen. Retina 1990;10:97. 34. Bock q, Jampol LM: Serpiginous choroiditis. In: Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology. Philadelphia, W.B. Saunders, 1987, p 517. 35. Mulder Cn, Pena AS, Jansen J, Oosterhuis JA: Celiac disease and geographic (serpiginous) choroidopathy with occurrence of thrombocytopenic purpura. Arch Intern Med 1983;143:842. 36. Witmer R: Fine spezielle Form rezidivierendir choroiditis. Ophthalmologica 1952;123:353. 37. Schlaegel TF: Metastatic nonsuppurative uveitis. In: Schlaegel TF, ed: Essentials of Uveitis. Boston, Little, Brown, 1969, p 77. 38. Maumenee AE: Clinical entities in "uveitis": An approach to the study of intraocular inflammation. XXVI Edward Jackson Memorial Lecture. AmJ Ophthalmol 1970;69:1. 39. Erkkila H, Laatikainen L, Jokinen E: Immunological studies on

72: SERPIGINOUS CHOROIDITIS

iO.

i1.

i2.

:1:3. :1:4.

:1:5. :1:6. :1:7.

:1:8. :1:9.

serplg1l10US choroiditis. Graefes Arch Clin Exp Ophthalmol 1982;219:131. Broekhuyse RM, Van Herck 1\1, Pinckers AJLG, et al: Immune responsiveness to retinal S-antigen and opsin in serpiginous choroiditis and other retinal diseases. Doc Ophthalmol 1988;69:83. Giovannini A, Mariotti C, Ripa E, et al: Indocyanine green angiographic findings in serpiginous choroidopathy. Br J Ophthalmol 1996;80:536-540. Hooper PL, Secchi AG, Kaplan H]: Serpiginous choroiditis. In: Pepose JS, Holland GN, Wilhelmus KR, eds: Ocular Infection and Immunity. St. Louis, Mosby 1996, P 579. Gass JDM: Acute posterior placoid pigment epitheliopathy. Arch Ophthalmol 1968;80:177. Deutman AF, Lion F: Choriocapillaris nonperfusion in acute multifocal placoid pigment epitheliopathy. Am J Ophthalmol 1977;84:652. Ryan SJ, Maumenee AE: Acute posterior multifocal placoid pigment epitheliopathy. AmJ Ophthalmol 1972;74:1066. Lyness AL, Bird AC: Recurrences of acute posterior multifocal placoid pigment epitheliopathy. AmJ Ophthalmol 1984;98:203. Dreye RF, Gass JDM: Multifocal choroiditis and panuveitis. A syndrome that mimics ocular histoplasmosis. Arch Ophthalmol 1984;102:1776. Nozik RA, Dorsch W: A new chorioretinopathy associated with anterior uveitis. AmJ Ophthalmol 1973;76:758. Cantrill HL, FolkJR: Multifocal choroiditis associated with progressive subretinal fibrosis. AmJ Ophthalmol 1986;101:170.

50. Doft BH, Gass JDM: Outer retinal layer toxoplasmosis. Graefes Arch Clin Exp Ophthalmol 1986;224:78. 51. Friedman CT, Knox DL: Variations in recurrent active toxoplasmic retinochoroiditis. Arch Ophthalmol 1969;81:481. 52. Helm C], Holland GN: Ocular tuberculosis. Surv Oph.thalmol 1993;38:229. 53. Edelsten C, Stanford MR, Graham EM: Serpiginous choroiditis: An unusual presentation of ocular sarcoidosis. Br J Ophthalmol 1994;78:70-71. 54. Gaudric A, Coscas G, Bird AC: Choroidal ischemia. Am J Ophthalmol 1982;94:489. 55. Spolaore R, Gaudric A, Coscas G, et al: Acute sectorial choroidal ischemia. AmJ Ophthalmol1984;98:707. 56. Kinyoun JL, Kalina RE: Visual loss from choroidal ischemia. Am J Ophthalmol 1986;101:650. 57. Nussenblatt RB, Palestine AG, Chan CC: Cyclosporine-A therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents. Am J Ophthalmol 1983;96:275. 58. Yang J, Akpek E, Foster CS: Long-term immunosuppressive treatment of serpiginous choroiditis. Ophthalmology. In press. 59. Blumenkranz MS, Gass JDM, Clarkson JG: Atypical serpiginous choroiditis. Arch Ophthalmol 1982;100:1773. 60. Steinmetz RL, Fitzke FW, Bird AC: Treatment of cystoid macular edema with acetazolamide in a patient with serpiginous choroidopathy. Retina 1991;11:412.

Blanca Rojas

DEfiNITION Many inflammatory disorders of the posterior segment of the eye have been described. These include disorders with a known etiology and others in which the etiology has not been established. In general, a specific cause is rarely found in inflammatory disturbances involving retinal pigment epithelium (RPE) or choroid. As a result, classification of these disorders is established on the basis of the clinical course, the ophthalmoscopic appearance, or the angiographic findings. During the inflammatory process, numerous cytokines, growth factors, and other .proteins released by either inflammatory or ocular resident cells influence each other and produce various reactions in the eye. Subretinal fibrosis, a feature that can disrupt the normal intercellular relationship between the photoreceptors and the RPE, l is one such reaction. The subretinal fibrosis and uveitis syndrome (SFU) is a rare clinical entity that presents with a distinctive posterior uveitis and progresses to 'subretinal fibrosis. It belongs to a group of inflammatory conditions characterized by the presence of multif9cal lesions of the RPE and choroid and includes such lntities as punctate inner choroidopathy and recurrent multifocal. choroiditis and panuveitis. Although in some cases steroids have proved beneficial, the syndrome leads to progressive fibrotic subretinal lesions with severe and permanent visual loss.

HISTORY Palestine and coworkers reported an entity characterized by chronic inflammation in the vitreous in association with whitish fibrotic-like subretinal lesions that progressively enlarged and coalesced. 2 They termed that entity progressive subretinal fibrosis and uveitis because the subretinal lesions had an appearance similar to the subretinal fibrosis seen in other retinal diseases such as complications of retinal detachment. The same group3, 4 subsequently described the histopathology and immunohistopathology of this condition. This clinical picture could be the same as that of choroiditis proliferans, a rare disease reported by Fuchs (in 19495, 6), in which large areas of connective tissue formed on the inner side of the choroid and led to a profound loss of vision despite slight changes in the retina. In 1982, Doran and Hamilton 7 reported ophthalmoscopic findings similar to those noted by Palestine and colleagues 2 and called the entity disciform macular degeneration in young adults. Later, Cantrill and Folks reported a series of patients with multifocal choroiditis, uveitis, and progressive subretinal fibrosis; they called the clinical picture multifocal choroiditis with progressive subretinal fibrosis. Based on these reports, it seemed that an unusual form of multifocal choroiditis was preferentially affecting' a group of young, healthy, myopic women. This condition differed

from other multifocal choroidal diseases in that instead of forming chorioretinal scars, the acute lesion healed with the formation of discrete, sharply angulated subretinal scars that could coalesce, forming broad zones of subretinal fibrosis. s Recent reports in the literature refer to this entity as diffuse subretinal fibrosis syndrome (DSF) .9,10 It has been proposed that SFU may simply be a rarely observed late stage of any multifocal choroiditis, rather than being a unique entity.9 Thus, the spectrum of this disease might include an early stage that is seen in reports describing recurrent multifocal choroiditis and panuveitis. This could be the case in the series of Morgan and Schatz,9 who reported 11 cases of an inflammatory disorder involving the RPE and the choroid, characterized by multiple relapses. Cases of progressive subretinal fibrosis have been included in reports of other clinical entities. Dreyer and Gass,11 in a series of 28 patients with multifocal choroiditis and panuveitis, described three patients with "retinal pigment metaplasia" and "large subretinal bands" (cases 7, 9, and 10). Similarly, the report of Watzke and coworkers 12 on punctate inner choroiditis contained one example (case 7) in which hyperplastic scarring developed. Additionally, progressive subretinal fibrosis has been reported in the setting of multifocal inflammatory involvement of the RPE and inner choroid without concomitant vitreous or anterior chamber inflammation. 12- 14 I have observed this same pattern of subretinal fibrosis in patients with sympathetic ophthalmia (Fig. 73-1).

EPIDEMIOLOGY Patients affected by SFU as described by Palestine and colleagues 2 and Cantrill and Folks are predominantly young, otherwise healthy myopic women. Taking ii1to account those cases considered to be early stages of the disease, the patients are usually under 35 years old. 2-'1, S, 9, 11, 13, 15, 6 The youngest reported patient was 6 years old.15 Some reports include patients older than 35. 9, 10, 14, 17 However, two series of patients have been .reported that differ from all previous reports. Gass and coworkers 1s described three elderly patients, two men and one woman, with a mean age of 71 years (range, 69 to 76), with biopsy-proven SFU. Similarly, the report of Matsuo and Matsuo 14 includes a 71-year-old patient. Whether this is an indication that patients of all ages can develop the syndrome, and most patients were younger in previous series by chance, or there truly is a bimodal distribution of ages with both young and old susceptible to the syndrome remains to be seen. 19 The vast majority of patients reported with SFU are women. 2-4, S, 9,11-13,17,20 In some series, most of the patients were myopic. 9, 10, 12, 13 Thus, the 10 patients reported Watzke and associates 12 had a spherical equivalent rang-

'CHAPTER 13: SUBRETINAL FIBROSIS AND UVEITIS SYNDROME

FIGURE 73-1. Soft yellow-white subretinal lesions, at the level of the choroid, of various ages and stages. (Courtesy of C. Stephen Foster, MD.) (See color insert.)

ing from - 3.50 to - 10 diopters. The refractive error of 10 of the 11 patients included in Morgan and Schatz's series ranged from - 2.75 to - 8.50. 9 There appears to be no racial predilection, and most systemic evaluations have been unremarkable. 2-4, 8, 13, 17,18,20 However, positive purified protein derivative test, for tuberculosis,8, 12 histoplasmin skin test positivity,2, 11 anomalies on chest radiograph/I, 12 or the presence of Histoplasma on tissue section 2 have all been described in a few cases. In isolated cases, flulike symptoms .preceded the ons~t of visual complaints.11-13, 15

Patients usually present complaining of acute or progressive unilateral visualloss 2,3, 9-11, 13-15,18.20 or blurred vision. 2, 8,13-15 However, visual acuity may be normal or slightly affected even though the fundus is involved. 2, 8, 9, 11-15, 17 Central or multiple scotomas,8, 12, 13, 15 metamorphopsias,9, 10, 14 and photopsias may also occur. The disease is usually bilateral, although the ocular involvement may be asymmetric. 2, 4, 8, 10-1.5, 17 The fellow eye may be simultaneously affected on clinical examination despite being asymptomatic. 2, 8, 9, 11, 12, 14, 16 Some cases of unilateral disease have been reported. 3,8,11-13,16,17 The degree of visual loss depends on the stage of the disease at which the patient presents. Patients with mild disease can have 20/20 acuity, and severe disease may reduce visual acuity to light perception. Whether a patient has the full clinical picture of SFU or only the early stages of the disease, mild to moderate anterior chamber2, 8,10,11,15,18 and vitreous inflammation 2, 4, 8-11, 15, 17, 18, 20 is present. However, some cases of SFU without concomitant vitreous or anterior chamber inflammation have been reported, including one patient in the series of Cantrill and Folk8 (case 1) and the patients reported by Salvador and coworkers 13 and Matsuo and Matsuo. 14 Occasionally, slit-lamp examination reveals other signs of inflammation, including episcleritis, scleritis, limbal phlyctenula, posterior synechiae, keratic precipitates, or iris atrophy.2, 7-9, 11, 12, 15 In the early stage of the syn.drome, the funduscopic findings consist of multiple small, round, discrete, whitish

yellow, hypopigmented lesions with soft, indistinct borders at the level of the RPE or inner choroid in the posterior pole and midperiphery (see Fig. 73-1). The lesions range in size from 50 to 500 /-Lm in diameter,2, 3, 8, 9, 11-13 and they occur singly, in clumps,12 and in linear clusters. 12 , 15 Lesions showing a swordlike pattern have also been reported. 15 , 16 RPE disturbances at the posterior pole, adopting a crumpled and mottled pattern, may also be seen early in the course of the disease. 8, 14 The evolution of the acute whitish yellow hypopigmented lesions may adopt different patterns. Some lesions may fade over time without any alteration of the RPE, suggesting that they were located beneath the RPE. 8, 12 Others heal, leaving a punched-out atrophy suggesting involvement of the RPE,3, 8,11,13,15 or they become pigmented chorioretinal scars. 2, 3, 8, 9, 12, 15 But what gives distinctiveness to this syn.drome is tlle fact that many of the acute lesions enlarge and coalesce, forming stellate irregular zones of subretinal fibrosis scattered throughout the posterior pole and mid periphery,2, 8-10, 13, 14, 18, 20 occasionally having irregular, slightly pigmented borders (Fig. 73-2) .2,8 The progression to fibrosis may take months to years to occur. The funduscopic appearance may evolve to form radial bands of fibrosis extending peripherally (Fig. 73-3) .3,8 Additional funduscopic findings can be seen in the setting of SFU. Serous detachment may develop with or without cloudy subretinal exudate. 2, 8, 9, 12, 14, 15, 18,20,21 Subretinal neovascular membranes,8-12, 18 cystoid macular edema,2, 8,11,15 and optic disc edema8, 10, 13, 15 have all been reported. Perivascular infiltrate and vascular sheathing were noted in two reports. 2,3

The histopathology and immunohistopathology for patients with SFU have been reported from chorioretinal biopsy in five cases 3, 18, 21 and from enucleation in five cases.'!' 18, 21 Palestine and associates 3 described for the first time the findings in a chorioretinal biopsy taken frOlll a young woman with SFU syndrome who had progressive visual loss despite chronic steroid therapy. The vitreous aspirate contained a few lymphocytes that were identified as being T-helper-inducer lymphocytes and B cells. 3

FIGURE 73-2. Fibrotic scar formation in the area of former soft choroidallesions. (Courtesy of C. Stephen Foster, MD.) (See color insert.)

CHAPTER 73: SUBRETINAL FIBROSIS AND UVEITIS SYNDROME

FIGURE 73-3. Expanding fibrotic bands, now beginning to contract in a patient with SFU. (Courtesy of C. Stephen Foster, MD.) (See color insert.)

The cases reported in the literature all exhibited choroidal inflammation on histopathology. The cellular infiltration of the choroid ral~ged from moderate to marked and consisted of lymphocytes and plasma cells. 3, 17 Retinal involvement varied from scattered infiltration of plasma cells and mostly a normal appearance on routine histologic examination 17 to one in which the RPE was eSsentially replaced by amorphous co'nnective tissue, with lymphocytes extending to Bruch's membrane. 3, 17,21 The white, fibrous-like mate~ial was composed of fibrous amorphous tissue with iSlands of cells that had the histologic characteristics of pigment epithelial cells,3 fibroblasts, and glial cellsP The granulomatous inflammation reported by Kim and colleagues,4 Gass and colleagues,18 and Chan and colleagues 21 differs from the initial case reported by Palestine and associates 3 and those subsequently reported by others,17,21 in which the inflammatory infiltrate was not granulomatous. Kim and associates 4 studied the histopathologic and immunopathologic findings in one eye of a young woman who over a few months developed complete blindness caused by SFU, despite intensive antiinflammatory and immunosuppressive therapy. The pathologic study of the subretinal tissue demonstrated a marked granulomatous reaction consisting of mononuclear cells, plasma cells, and some multinucleated giant cells. 4 In a report by Chan and associates,21 the enucleated eye of a 24-year-old woman with multifocal choroiditis and subretinal whitish lesions that progressed to bilateral blindness in a short period of time despite immunosuppressive treatment, showed a marked gliotic retina and a thick subretinal fibrotic tissue. A diffuse granulomatous and T- and B-Iymphocytic infiltration was present. Additionally, in the report by Gass and coworkers,18 three elderly patients with no evidence of systemic disease experienced ongoing loss of vision associated with multifocal choroiditis and SFU. The disease process resulted in blindness despite systemic corticosteroids and, in one patient, cyclophosphamide. Histopathologic examination of the four blind eyes disclosed findings involving the inner choroid and the outer retina. These included diffuse lymphocytic and plasma cell infiltration of the choroid, multifocal areas of degeneration, and focal de-

struction of Bruch's membrane associated with epithelioid and giant-cell proliferation, widespread destruction of RPE and retinal receptor cells, and multiple large, thick plaques of subretinal fibrosis. In cases 2 and 3,18 there were concerns of the possibility of sympathetic uveitis because of the multiple operative procedures undergone by the patients. However, the histologic findings were not characteristic of sympathetic ophthalmia. Histopathologic findings of cases 1 and 2 18 were similar to those reported by Kim and colleagues. 4 The choroid was infiltrated by a mixture of T and B IYlTIphocytes, with a relative predominance of B cells. 3, '1,17,21 The T-he1perinducer/ suppressor-cytotoxic ratio was 1.8: 1 in the study of Palestine and associates 3 and 4: 1 in the case reported by Kim and coworkers. 4 Occasional monocytes and natural killer cells were also present. 3,4 Immunofluorescence studies revealed complement and IgG deposition above Bruch's membrane 3,17 as well as types I, III, and V collagen. 3 The majority of large cells in the subretinal tissue demonstrated specific antigenic determinants of Mi'tller cells. 3 The islands of cells within the white amorphous fibrous tissue stained with a monoclonal antibody specific for Mi'tller cells. Some cells also stained with phosphatase and alphanapthylacetate esterase, which is a characteristic of RPE and macrophages. 3 In the case reported by Kim and coworkers, 4 Mi'tller cells expressed the· class II antigen of the major histocompatibility complex. Additionally, the interleukin-2 receptor marker (a marker of T-cell activation) was present in the locus of T-cell infiltration. 4 Electron microscopic findings reported by Palestine and colleagues3 disclosed that the subretinal amorphous connective tissue appeared to consist of collagen fibrils. The islands of cells within this amorphous connective tissue were surrounded by a basement membrane and by groups of numerous cells that were closely attached to each other with many desmosomes and tight junctions. 3 Altered pigmented cells were seen by electron microscopy in the fibrotic tissue of the eye studied by Kim and colleagues. 4 Special stains for microorganisms were negative. 4, 17, 18 Electron microscopy disclosed negative results for viral particles.18

In 1975, Mandelcorn and his group22 showed that RPE cells had the ability to form membranes while proliferating. In their experiment, RPE cells from one eye were transplanted into the vitreous cavity of the fellow eye of owl monkeys, where they proliferated and underwent metaplastic changes. They observed long spindle cells forming membranes that resembled fibroblasts, although by electron microscopy these cells retained epithelial characteristics such as basement membranes and cell junctions (fibrous metaplasia). The metaplastic cells looked like pigmented macrophages, membrane-forming fibrocyte-like cells, and frank epithelial cells. The authors hypothesized that pigment epithelial cells could be the source of the intraocular proliferation seen in massive periretinal proliferation. It is now widely believed that both RPE and Milller cells are the principal cell types responsible for the formation of abnormal cellular assemblage or "membranes" in

·CHAPTER 73: SUBRETINAl FIBROSIS AND UVEITIS SYNDROME

the vitreous cavity and the subretinal space. 1 The subreti~ nal membranes grow as sheets with or without pigmentation, depending on derivation from RPE or glial cells, respectively. ~3 The proliferation of astrocytes is a common event in many injuries of the central nervous system. Milller cells are highly specialized astrocytes, and they react to injuries such as retinal detachment. Additionally, one or more localized factors may mediate the proliferative response. A number of growth factors are potential candidates for that role. I It has been reported that all non-neuronal cell types participate in retinal proliferation, including cells associated with the retinal vasculature, glia, and invading and "resident" macrophages (microglia).1 The potential role of microglia in the regulation of the proliferation of other cell types has been suggested. The origin of subretinal fibrosis may lie in the early proliferation of cells in the retina, the migration of some fraction of these cells into the subretinal space, and their subsequent proliferation at those loca. tions. I The cause of SFU, like the causes of many other inflammatory conditions affecting the retina and choroid, is unknown. Histopathologic and immunohistopathologic findings in eyes with SFU seem to indicate that the disease is a result of inflammation leading to RPE destruction and transformation, with consequent fibrotic tissue for-:. mation and participation of Muller cells. An immunemediated response could be involved in the pathogenesis of the disease. Palestine and colleagues3 have postulated an autoimmune cause for SFU. They consider the disease to be an antibody-mediated inflammation in which local antibody production, possibly to the RPE structures, leads to the significant alterations seen. Their theory is supported by the presence of B cells and plasma cells in the inflammatory infiltrate, the deposition of immunoglobulin and complement in the outer subretinal tissue, the absence of circulating antibodies to the retina, and the marked decrease in the electro-oculogram (EOG). The presence of granulomatous inflammation, consisting of a delayed-type hypersensitivity reaction (epithelioid cells, multinucleated giant cells, and fibrosis), supports the idea of an immune-mediated mechanism participating in the pathogenesis of the disease. In the immune response, Fas-FasL interactions induce T-cell apoptosis, thus eliminating the potential autoreactive and activated T cells. Recent studies have indicated that apoptosis plays a role in immune-mediated inflammatory lesions in target organs. 24 ,25 An enucleated eye and a chorioretinal biopsy from patients with SFU were included in the study of Chan and colleagues 21 investigating the expression of apoptotic markers in the eyes of patients with uveitis. The authors found an increased expression of Fas and FasL in the retina, the chorioretinal scars, and choroidal granulomas. Additionally, DNA fragmentation, which labels the particular cells undergoing apoptosis, was present in the gliotic retina, subretinal fibrotic tissue, and chorioretinal scars in eyes with SFU. Chan and colleagues stated that there might be pathologic consequences of Fas-FasL interactions in gliotic and fibrotic tissue, and they proposed that a dysregulation of the Fas-FasL pathway may lead to gliosis and fibrosis. In summary, the fibrous portion of the amorphous

connective tissue observed in the subretinal space of patients with SFU seems to be derived from RPE cells that have proliferated to form membranes. The RPE cell is pluripotent and can have fibroblastic activity when proliferating. 22 ,26 Thus, it may be responding with fibroblastic activity to a yet unknown stimulus causing the subretinal fibrosis. Milller cells expressed class II antigens, which are not expressed by these cells in the normal retina. 4 RPE cells also expressed class II antigen, as it has been observed in other types of uveitisP' 28 The expression of such antigens may indicate that the cells are activated and proliferating, which could result in marked retinal gliosis and subretinal fibrosis formation.

DIAGNOSIS laboratory Investigations Posterior involvement of the eye is considered to be one of the criteria to expand laboratory investigations from the minimal work-up required in a patient with uveitis to a more extensive evaluation. Laboratory and ancillary test selection is based on the diagnosis suggested by clinical examination and a careful review of systems. It is mainly during the early phase of SFU, before subretinal fibrosis is present, that the clinician faces a diagnostic problem, as shown in the differential diagnosis section of this chapter. In that setting, it is essential to exclude treatable infectious (i.e., syphilis, tuberculosis, toxoplasmosis) and noninfectious (i.e., sarcoidosis) causes of choroidal and outer retinal involvement. But it should be kept in mind that, as in many other inflammatory processes involving the retina and choroid, the diagnosis of SFU is essentially based on clinical examination (Table 73-1). Patients with SFU generally have no evidence of systemic disease. 2-4,8-13, 15, 17, 18, 20 However, a flulike illness preceding ocular complaints has been reported in six patients.u, 12 Extensive investigations reported in the literature, including complete blood cell count, erythrocyte sediInentation rate, antinuclear antibodies, complement

TABLE 73-1. SUBRETINAl FIBROSIS AND UVEITIS SYNDROME: DIAGNOSTIC FEATURES Patient characteristics Female Young* Healthy Myopic Early ocular manifestations Acute or rapidly progressive visual disturbances Unilateral symptoms despite bilateral involvement on clinical examination Ocular examination Mild to moderate vitreous and anterior chamber inflammation Whitish yellow lesions (50-500 !-Lm) in the posterior pole and midperiphery affecting RPE or inner choroid Lesions over time Fade without any RPE alteration Leave a punched-out atrophy Enlarge and coalesce, forming stellate zones of subretinal fibrosis Serous detachment, macular edema, disc edema *Elderly patients have been described. RPE, retinal pigment epithelium.

CHAPTER 73: SUBRETINAl

levels, serum protein electrophoresis, rheumatoid factor, angiotensin-converting enzyme, and lumbar puncture, were noncontributory. The chest radiograph was nonnal except for five patients with a positive skin test for histoplasmosis (three of these were from areas endemic for histoplasmosis).l1 A fourth patient showed hilar adenopathy, skin test positivity for histoplasmosis, and Histoplasma organisms on tissue section after Inediastinal biopsy. 2 Serologic tests for syphilis, toxoplasmosis, toxocariasis, cryptococcosis, blastomycosis, coccidioidomycosis, herpes virus, cytomegalovirus, Epstein-Barr virus, Lyme disease, and Histoplasma titers were unrevealing. A histoplasmin skin test and purified protein derivative skin test were negative, except for isolated patients who displayed a positive result. 8, 11, 12 Examination of family Inembers did not reveal any detectable abnormality.13, 15

ru;;B>n.....'.;:DI.::D

AND UVEITIS

SYll\lnROME

field defects involved fixation at some time during the course of the disease in most patients. Enlarged blind spots were less frequent. With treatment, the size of the field defect improved, but it typically worsened with recurrence of inflammation. Other diseases affecting the choroid were included in their study. Overall, visual field defects improved in most patients with multiple evanescent white dot syndrome (MEWDS) and punctate inner choroidopathy (PIC), whereas most patients with multifocal choroiditis and panuveitis (MCP) and DSF did not improve.

Ancillary Tests Unlike patients with other posterior uveitides, these patients did not exhibit in vitro IYlnphocyte proliferation in response to the retinal S-antigen. 2

Angiographic Findings On fluorescein angiography (FA), acute lesions show hyperfluorescence during the' early phase of the angiogram,2,9 with a mottled appearance in smne instances. 8, 13, 14 Late in the course of the angiogram, staining of the lesions with 2,8, 9, 14 or without2, 13 leakage is observed. Late views show staining in the zones of subretinal fibrosis. 8 Resolving lesions show pigment epithelium window defects. 4, 8, 9, 15 The old resolved lesions (scars) demonstliate fluorescein staining. One of the patients reported by Palestine and associates 2 showed blockage of background chorqidal fluorescence. Optic disc leakage and macular edema have also been reported. 8,'!).1 Onoda and colleagues 16 reported the findings on FA and indocyanine-green angiography (ICG) of two young (14 and 18 years) myopic girls with multifocal choroiditis and subretinal fibrosis. On FA, the center of the lesions hypofluoresced and the edges hyperfluoresced. On ICG, the entire lesion hypofluoresced from an early stage and some major choroidal vessels were visible through them. The hypofluorescent areas persisted into the late phase and were larger than those seen in FA and in funduscopy.

Electrophysiology Electrophysiologic features from 29 patients have been reported. 2, 3, 8-11, 13, 15 There were more anomalies in both the electroretinogram (ERG) and the EOG (23 patients) 2, 3, 8, 9, 11, 13 than normal responses (six patients) .9, 10, ]3, 15 One patient in the series of Salvador and colleagues exhibited abnormal pattern ERG with normal EOG.13 Overall, patients with abnormal findings on electrophysiology had subretinal fibrosis on fundus examination,2, 3, 8-11, 13 with a visual acuity of less than or equal to 20/100 2,3,8,13 and chronic requirements or no response to systemic corticosteroids. 2, 3, 8, 11, 13 However, some patients had normal responses 8, 9, 11, 15 despite impaired visual acuity (less than or equal to 20/100)8,15 and diffuse fundus abnormalities, including three patients8, 10 with subretinal fibrosis confined to the posterior pole.

Visual Field Visual field testing sometimes shows marked scotomas that encompass an area somewhat larger than the area of subretinal lesions. 3 In the six patients studied by Reddy and coworkers 10 affected by what they called DSF, visual

FIBROSIS Subretinal fibrosis has been reported in other inflalnmatory conditions, such as the late stage of serpiginous choroiditis,29 systemic lupus erythematosus associated central serous chorioretinopathy,30 and onchocerciasis. 31 A 34-year-old man with acquired immunodeficiency syndrome (AIDS) presented with a choroidal mass, exudative retinal detachment, and vitritis. The patient underwent a choroidal biopsy tC>.elucidate the infectious or malignant nature of the lesion. The specimen showed a subretinal eosinophilic infiltrate and subretinal fibrosis. 32 Of interest are two cases recently reported by Matsuo and Matsuo,H who described two patients with subretinal fibrosis in the setting of rheumatoid arthritis. In both instances, subretinal fibrosis developed in parallel with exacerbation of rheumatoid arthritis and deteriorating renal function. The subretinal fibrosis in the right eye of the first patient developed abruptly in the course of active multifocal choroiditis with serous retinal detachment in both eyes, in parallel with rapid, progressive glomerulonephritis. In contrast, subretinal fibrosis in the second patient developed insidiously in the left eye and there was slowly progressive RPE atrophy in both eyes in the presence of stable, chronic renal failure. Interestingly, a case of progressive subretinal fibrosis with fundus flavimaculatus has been reported. 33 A 20-yearold mildly myopic woman was under ophthalmologic care for fundus flavimaculatus. During 9 years of follow-up, an increasing number of chorioretinal punched-out spots in the posterior pole and midperiphery were noted, with progressive development of subretinal fibrosis. The anterior segment and vitreous were quiet, and systemic evaluation was unremarkable. FA demonstrated hypofluorescence and subsequent hyperfluorescence of the punchedout lesions, and staining of the fibrous tissue. Lersutmikul and colleagues 34 have reported on the presence of subretinal fibrosis in Voght-Koyanagi-Harada (VKH) syndrome. In their retrospective study, 40% of patients (30 of 75) developed subretinal fibrosis defined as a yellow to white linear or polygonal fibrotic tissue at least one quarter of a disc diameter. For those patients having fibrotic lesions, these were located in the peripapillary and macular areas in 80% (22 of 30) of the cases. Subretinal fibrosis was not correlated with the presence

CHAPTER 73: SUBRETINAl fIBROSIS AND UVEITIS SYNDROME

of an exudative retinal detachment but with longer duration of the disease and more severe ocular inflam·mation. Additionally, presence of subretinal fibrosis was associated with a poor visual prognosis, as are choroidal neovascularization and the number of recurrences.

DIAGNOSIS During the early stages of the disease, several entities may be confused with SFU. However, over time, the characteristic subretinal fibrosis helps to differentiate the disease from other conditions, including white dot syndromes, a collection of ocular disorders that share in common the presence of discrete, light-colored lesions in the fundus during at least one phase of the disease. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE), MEWDS, birdshot retinochoroidopathy (BSRC), MCP, the presumed ocular histoplasmosis syndrome (POHS), and PIC35 are the major members of this group of syndromes. Other entities, however, like acute retinal pigment epitheliitis (ARPE) and diffuse unilateral subacute neuroretinitis (DUSN), must also be included in this differential diagnosis (Table 73-2). APMPPE36 is a distinct entity often preceded by a viral illness. The disease is usually bilateral. Vitritis is rare, as are recurrences. Acute lesions consist of multiple yellowwhite placoid or irregular lesions that ar~ predominantly located in the posterior pole. FA features are characterized by early hypofluorescence of the plaques, followed by late hyperfluorescence. The lesions ~~ually resolve, leaving a residual RPE stippling. Vision begins to improve spontaneously a few weeks after the onset of the symptoms; most patients recover 20/40 or better vision. MEWDS9 differs from SFU with respect to the lesions, with discrete white dots (100 to 200 /-Lm) at the level of the outer retina or RPE. MEWDS lesions are mainly located in the macula, and they regress in a few weeks, leaving only very minor RPE defects. A macular granularity is often present. The patients' visual acuity returns to

TABLE 73-2. SUBRETINAl fiBROSIS AND UVEITIS SYNDROME: DiffERENTIAL DIAGNOSIS Of FUNDUSCOPIC APPEARANCE Early phase Infectious Syphilis Tuberculosis Diffuse unilateral subacute neuroretinitis (DUSN) Punctate outer retinal toxoplasmosis -.r oninfectious Acute posterior multifocal placoid epitheliopathy (APMPPE) Multiple evanescent white dot syndrome (MEWDS) Birdshot retinochoroidopathy (BSRC) Multifocal choroiditis panuveitis (MCP) Presumed ocular histoplasmosis syndrome (POHS) Punctate inner choroidopathy (PIC) Acute retinal pigment epitheliitis (ARPE) Acute macular retinopathy Sarcoidosis Myopia ,ate stage Serpiginous choroiditis Age-related macular degeneration (ARMD)

normal or near normal within a few weeks after the onset. Most patients suffering from BSRC37 are human leukocyte antigen (HLA)-A29 positive. BSRC generally appears in middle-aged patients 40 to 60 years old. Multiple.discrete, depigmented, or cream-colored spots in the midperiphery and posterior pole are seen. Most patients have chronic vitritis, papillitis, and retinal vascular leakage that results in macular edema. Problems with night vision and color discrimination are common complaints of patients with BSRC. Patients with MCP9, 11, 15 have numerous presumed ocular histoplasmosis syndrome (POHS)-like lesions, predominantly in the midperiphery of the retina, and vitreous cells are always present. MCP is characterized by bouts of recurrent inflammation, consisting of vitreous and anterior chamber cells and swelling around previously noted lesions. Subretinal neovascularization is common. Early hyperfluorescence on FA is a feature of the diagnosis. POHS is a multifocal choroiditis characterized by atrophic peripheral "histo spots" (200 /-Lm), peripapillary pigmented changes, and a disciform macular scar. 38 Patients with POHS may develop new choroidal lesions, but they do not have an appreciable associated vitritis; they may have pigment cells in the vitreous that can be confustd for "vitritis." PIC12 is characterized by the absence of anterior chamber and vitreous cells. During its acute stage, 100 to 200 /-Lm yellow, well-defined lesions at the level of the RPE or the inner choroid are observed in the posterior pole and midperiphery. Recurrent swelling around old lesions is rare. Patients with PIC do not develop new lesions on prolonged follow-up (Table 73-3). ARPE39 is a benign, self-limiting condition characterized by sudden, unilateral (75%), decreased visual acuity. The fundus picture consists of dark gray spots surrounded by a yellow-white halo without overlying vitritis in the acute stage. The lesions are usually located in the macula and they are smaller and subtler in appearance than those seen in SFU. There is typically complete resolution in 6 to 12 weeks, with a return to normal vision and no recurrences, although enlargement of the blind spot may be permanent. Features of early DUSN4 0 that distinguish it from SFU are diffuse RPE changes between the punched-out lesions, worms or worm tracks, the presence of outer retinal inflammation, vasculitis, vitritis, and papillitis. The biphasic nature of this immune or toxic reaction to worm byproducts leads to a progressive loss of the visual field, optic disc atrophy, and narrowing of the retinal vessels that can be seen late in the course of the disease. The dark gray lesions and their normal or hypofluorescent appearance on FA help to differentiate acute macular retinopathy41, '12 from SFU. The exclusion of a potentially treatable infectious cause of uveitis is essential in any patient for whom systemic steroid therapy is contemplated. Both syphilis and tuberculosis can manifest inflammation involving the vitreous, outer retina, and choroid. Laboratory studies for syphilis and tuberculosis help to exclude these diagnoses, as do signs and symptoms of systemic disease that may coexist with the ophthalmic manifestations. Punctate

CHAPTER 73: SUBRETINAL

rllCln.'4J.;;)B.;;)

AND UVEITIS SYNDROME

TABLE 73-3. PIC, MCp, AND SFU: DU=FE:RENC:ES AND SIMILARITIES PIC

MCP

SFU

Demographics

Young, female, myopic

Young, female, myopic

Location

RPE, choroid; posterior pole and midperiphery

Laterality Symptoms

Bilateral Blurred vision, flashes, central scotomas

Anterior segment Vitritis Acute lesions Evolving lesions

No Rare 100-300 /-1m, yellow, welldefined lesions Atrophic cylindrical scars

Other fundus findings

Serous RD

CNV Chronology Fluorescein angiography Visual field

Rare Unique episode Early hyperfluorescence, late leakage Usually normal

Electrophysiology

Normal

Visual prognosis Treatment

Good unless CNV No

Response to therapy

Poor

Young to adult, female, myopic RPE, choroid; posterior to equator > posterior pole Bilateral Blurred vision, flashes, central scotomas, floaters, metamorphopsias Typically Marked POHS-like lesions, 50-200/-1m Atrophic scars bigger and more pigmented than in PIC CME, serous RD, peripapillary pigmentary changes Common Chronic, recurrent Early hyperfluorescence, fade late Enlarged blind spots, full fields, involving fixation Abnormal-to-extinguished ERG responses Fair Yes: immunosuppressors, laser photocoagulation (CNV) Variable

RPE, choroid; posterior pole and midperiphery Bilateral Blurred vision, flashes, central scotomas, metamorphopsias

Yes Present> > absent 50-500 /-1m white-yellow hypopigmented lesions Irregular zones of subretinal fibrosis CME, serous RD, papillitis

Possible Chronic, recurrent Early hyperfluorescence, late leakage Enlarged blind spots, involving fixation Abnormal ERG/EOG > WNL Poor Yes: immunosuppressors, laser photocoagulation (CNV) Very poor if subretinalfibrosis is present

PIC, punctate inner choroidopathy; MCP, recurrent multifocal choroiditis and uveitis; SFU, subretinal fibrosis and uveitis syndrome; RPE, retinal pigment epithelium; RD, retinal detachment; POHS, presumed ocular histoplasmosis syndrome; CME, cystoid macular edema; ERG, electroretinogram; EOG, electro-oculogram; CNV, choroidal neovascular membrane; WNL, within normal limits.

outer retinal toxoplasmosis 43 is a subset of ocular toxoplasmosis in which patients present with acute, multifocal, gray-white lesions involving the outer retina and RPE, with little or no vitreous involvement. The lesions may recur next to each other in a satellite fashion and slowly resolve with scar formation. Serology for Toxoplasma is positive. Sarcoidosis is a chronic multisystem disease, classically with candle-wax drippings around retinal vessels, retinal hemorrhages, "snowball" vitreous opacities, chorioretinal granulomas, and response to corticosteroid treatment. It must be included in the differential diagnosis of SFU. Although many patients in the reports of SFU are myopic, the SFU differs from pathologic myopia, as there are no staphylomas, lacquer-cracks, straightening of the retinal vessels, or Fuchs' spots. The late stage of SFU has an appearance similar to choroidopathies with subretinal neovascular membranes and disciform scarring, such as serpiginous choroiditis and age-related macular degeneration. Serpiginous choroiditi~ is a progressive disorder that affects the peripapillary RPE, choriocapillaris, and choroid. Lesions consist of large, well-circumscribed areas that extend from the disc in a progressive pseudopodial fashion, The FA pattern is quite characteristic, with hypofluorescence of the acute lesion early in the angiogram and late hyperfluorescence that begins along the margins of the lesion. 9

Although in some cases .systemic corticosteroids may be of benefit during the acute phase of the disease, once the subretinal fibrosis occurs, there appears to be no effective treatment. In one series,9 the nine patients who were treated with systemic and periocular injections of corticosteroids during the acute phase of the disease responded well to treatment. Even a subretinal neovascular membrane regressed with the steroid therapy. Unfortunately, most other studies describe variable responses, with a few patients showing improvement8 , 14,20 and most exhibiting progression of the disease or, at best, questionable results. 2, 3, 8, 10, 11, 13, 17, 20, 21 Similarly, a combination of corticosteroid and therapy with immunomodulators (cyclophosphamide, azathioprine, or cyclosporine-A) has also shown variable benefit, with some cases showing no response 4, 17, 21 and some. others in which the inflammation was controlled. 10 , 17,20 Laser photocoagulation has been attempted to treat neovascular membranes without success. 7 , 11, 12 The visual prognosis of patients with SFU is poor. 20 Impaired visual acuity depends on the presence of subretinal fibrosis, atrophy, or subretinal neovascular membranes affecting the macula. The natural course of the disease consists of numerous bouts of inflammation, typically in

CHAPTER 73: SUBRETINAl FIBROSIS AND UVEITIS

and around previous lesions, with most of the affected eyes developing severe. visual loss over a period of lTIonths 2 , 3, 8, 9,17,18 to years. 4, 13, 21 In some cases, the disease may affect Visual acuity in a short period. The case of a 24-year-old woman with a rapid and severe onset of the disease, which led to no light perception bilaterally in 6 months despite treatment with corticosteroids and cyclophosphamide,4 is illustrative of this rapidly progressive form. Similarly, the case of a 31-year-old woman with visual acuity in her left eye decreasing to counting fingers in 3 weeks and further dropping to hand movements and unresponsive to systemic corticosteroids illustrates the same phenomenon. 13 In most series reported, final visual acuity ranges from 20/200 to no light perception. 2 , 3, 4, 8,10,11,13,17,18,20,21 Reddy and colleagues 10 included in their series patients with MCP, PIC, MEWDS, and what they called DSF. Patients with DSF had the worst initial visual acuity (20/291) in comparison with MCP (20/45),. PIC (20/41), and MEWDS (20/26). Additionally, the group with clinical features of DSF had the worst final visual acuity (20/ 163) in comparison with MCP (20/33), PIC (20/33), and MEWDS (20/20). Similarly, the patients with DSF had the worst visual prognosis of the three groups (the other two being MCP and PIC) in the study of Brown and coworkers. 20

CONCLUSIONS Inflammatory conditions causing multifocallesions of the choroid and pigment epithelium are confusing group of diseases. SFU differs from other multifocal choroidal or RPE diseases in that instead of forming atl~ophic or pigmented chorioretinal scars, the acute lesions heal with the formation of multiple zones of subretinal fibrosis that enlarge and coalesce, forming large placoid lesions with irregular margins. This rare condition usually affects young, myopic, otherwise healthy women, although middle-aged and older patients have been reported. Initially, only one eye may become symptomatic, but bilateral involvement is typical. Symptoms include unilateral visual loss, scotomas, metamorphopsias, and photopsias. Mild vitritis is normally present. In the acute stage, the funduscopic picture consists of multiple, small, white-yellow RPE or choroidal lesions. The visual prognosis is poor and recurrences are COmlTIOn, typically involving previously affected sites. Treatment is controversial, with some authors finding a beneficial effect of early steroids and chemotherapy treatment. The etiology is unknown, but SFU is believed to be a localized autoimmune reaction to the RPE. It may be a COlTImOn response of the retina to different offending stimuli.

a'

References 1. Fisher SK, Erickson PA, Lewis GP, Anderson DH: Intraretinal proliferation induced by retinal detachment. Invest Ophthalmol Vis Sci 1991;32:1739. 2. Palestine AG, Nussenblatt RB, Parver LM, et al: Progressive subretinal fibrosis and uveitis. Br] Ophthalmol 1984;68:667. 3. Palestine AG, Nussenblatt RB, Chan CC, et al: Histopathology of the subretinal fibrosis and uveitis syndrome. Ophthalmology 1985;92:838. 4. Kim MK, Chan CC, Belfort R, et al: Histopathologic and immunohistopathologic features of subretinal fibrosis and uveitis syndrome. Am] OphthalmoI1987;104:15.

5. Fuchs A: Diseases of the Fundus Oculi with Atlas. Philadelphia, Blakiston, 1949, p 125. 6. Calixto N: Histopathologic and immunohistopathologic features of subretinal fibrosis and uveitis syndrome. Am ] Ophthalmol 1988;105:220. . 7. Doran R, Hamilton A: Disciform macular degeneration in young adults. Trans Ophthalmol Soc U K 1982;102:471. 8. Cantrill HL, Folk]C: Multifocal choroiditis associated with progressive subretinal fibrosis. Am] OphthalmoI1986;101:170. 9. Morgan CM, Schatz H: Recurrent multifocal choroiditis. Ophthalmology 1986;93:1138. 10. Reddy CV, Brown], Folk]C, et al: Enlarged blind spot in chorioretinal inflammatory disorders. Ophthalmology 1996;103:606. 11. Dreyer RF, Gass ]DM: Multifocal uveitis and panuveitis. A syn.drome that mimics ocular histoplasmosis. Arch Ophthalmol 1984; 102:1776. 12. Watzke RC, Packer A], Folk]C, et al: Punctate inner choroidopathy. Am] Ophtl1almol 1984;98:572. 13. Salvador F, Garda-Arum! ], Mateo C, et al: Multifocal choroiditis with subretinal fibrosis. Report of two cases. Ophthalmologica 1994;208:163. 14. Matsuo T, Matsuo N: Progressive subretinal fibrosis in patients with rheumatoid arthritis and renal dysfunction. Ophthalmologica 1998;212:289. 15. Nozik RA, Dorsch W: A new chorioretinopathy associated witl1 anterior uveitis. Am] Ophthalmol 1973;76:758. 16. Onoda S, Shibuya K, Miyasaka H, et al: Multifocal choroiditis with subretinal fibrosis. Nippon Ganka Gakkai Zasshi 1997;101:711. 17. Martin DF, Chan CC, Smet MD, et al: The role of chorioretinal biopsy in the management of posterior uveitis. Ophthalmology • 1993;100:705. 18. Gass ]DM, Margo CE, Levy MH: Progressive subretinal fibrosis and blindness in patients witl1 nlultifocal granulomatous chorioretinitis. Am] Ophthalmol 1996;122:76. 19. Kaiser PK, Gragoudas ES: The subretinal fibrosis and uveitis syndrome. Int Ophtlulmol Clin 1996;36:145. 20. Brown], Folk ]C, Reddy CV, et al: Visual prognosis of multifocal choroiditis, punctate inner choroidopathy, and the diffuse subretinal fibrosis syndrome. Ophthalmology 1996;103:1100. 21. Chan CC, Matteson DM, Li Q, et al: Apoptosis in patients with posterior uveitis. Arch Ophthalmol 1997;115:1559. 22. Mandelcorn MS, Machemer R, Fineberg E, et al: Proliferation and metaplasia of intravitreal retinal pigment epithelium cell autotransplants. Am] Ophtl1almol 1975;80:227. 23. Sternberg P, Machemer R: Subretinal proliferation. Am] Ophthalmol 1984;98:456. 24. D'Souza SD, Bonetti B, Balasingam V, et al: Multiple sclerosis: Fas signaling in oligodendrocyte cell death. ] Exp Med 1996; 184:2361. 25. Giordano C, Stassi G, Galluzo A: Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto's thyroiditis. Science 1997;275:960. 26. Machemer R, Laqua H: Pigment epithelium proliferation in retinal detachment (massive periretinal proliferation). Am ] Ophtlulmol 1975;80:1. 27. Chan CC, Hooks.il, Nussenblatt RB, et al: Expression of Ia antigen on retinal pigment epithelium in experimental autoimmune uveoretinitis. Curr Eye Res 1986;5:325. 28. Chan CC, Detrick B, Nussenblatt RB, et al: HLA-DR in retinal pigment epithelial cells ll"Om patients with uveitis. Arch Ophthalmol 1986;104:725. 29. Chisholm IH, Gass ]DM, Hutton WL: The late stage of serpiginous (geographic) choroiditis. Am] Ophthalmol 1976;82:343. 30. Cunningham ET, Alfred PR, Irvine AR: Central serous chorioretinopathy in patients with systemic lupus erythematosus. Ophthalmology 1996;103:2081. 31. Newland HS, White AT, Greene BM, et al: Ocular manifestations of onchocerciasis in a rain forest area of West Mrica. Br] Ophthalmol 1991;75:163. 32. Rutzen AR, Ortega-Larrocea G, Dugel PU, et al: Clinicopathological study of retinal and choroidal biopsies in intraocular inflammation. An1] Ophthalmol 1995;119:597. 33. Parodi MB: Progressive subretinal fibrosis in fundus flavimaculatus. Acta Ophtl1almol 1994;72:260. 34. Lertsumitkul S, Whitcup SM, Nussenblatt RB, Chan CC: Subretinal

CHAPTER 13: SUBRETINAl FIBROSIS AND UVEITIS

35.

36. 37. 38.

fibrosis and choroidal neovascularization in Voght-Koyanagi-Harada syndrome. Graefes Arch Clin Exp Ophthalmol 1999;12:1039-1045. BrownJ, FolkJG: Current controversies in the white dot syndromes. Multifocal choroiditis, punctate inner choroidopathy and diffuse subretinal fibrosis syndrome. Ocul Immunol Inflamm 1998;6:125. Gass JDM: Acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol 1968;80:177. Ryan SJ, Maumenee AE: Birdshot retinochoroidopathy. Am J Ophthillmol 1980;89:31. Gass JMD: Presumed ocular histoplasmosis syndrome. In: Gass JMD, ed: Stereoscopic Atlas of Macular Diseases. Diagnosis and Treatment, 4tl1 ed, voIr. St. Louis, Mosby-Year Book, 1997; p 130.

CVi"UII"'llIDR"'\_

39. Krill AE, Deutman AF: Acute retinal pigment epitheliitis. Am J Ophtl1almol 1972;74:193. 40. Gass JDM, Braunstein RA: Furtl1er observations concerning the diffuse unilateral subacute neuroretinitis syndrome. Arch Ophthalmol 1983;101:1689. 41. Priluck IA, Buettner H, Robertson DM: Acute macular neuroretinopathy. Am J Ophtl1almol 1978;86:775. 42. Gass JMD: Acute macular neuroretinopathy. In: Gass JMD, ed: Stereoscopic Atlas of Macular Diseases. Diagnosis and Treatlnent, 4th ed, vol II. St. Louis, Mosby-Year Book, 1997, P 693. 43. Doft BH, Gass JDM: Punctate outer retinal toxoplasmosis. Arch Ophthalmol 1985;103:1332.

I Carl Ho Park and Michael Bo Raizman

Punctate innerchoroidopathy (PIC) is an inflammatory multifocal chorioretinopathy of unknown cause. It is categorized with other inflammatory chorioretinopathies of unknown etiologies, including acute posterior multifocal placoid pigment epitheliopathy (APMPPE), multiple evanescent white dot syndrome (MEWDS) ,birdshot retinochoroidopathy (BSRC), serpiginous choroiditis, multifocal choroiditis and panuveitis (MCP), and subretinal fibrosis. PIC mainly affects myopic women who present with s}'lnptoms of blurry vision and/or scotoma. As suggested by the name, ophthalmoscopy reveals discrete, white-yellow lesions in the inner choroid, concentrated in the posterior pole. Examination of the eye is otherwise unremarkable, with no evidence of either anterior or posterior uveitis. PIC is thought to be a self-limited process, and the visual outcome is usually good, although it can result in the formation of choroidal neovascular membranes, which can lead to a poor visual outcome.

HISTORY In 1984, Watzke and colleagues presented a series of 10 moderately myopic women (- 3.25 to -10.00 diopters), ranging in age from 21 to 37, who presente¢ with blurred vision, flashes, and paracentral scotomas. 1 Examination revealed small (l00 to 300 /-Lm) yellow-white lesions at the level of the inner choroid, often associated with small serous retinal detachments. Eight of the 10 patients presented with bilateral lesions, and six developed subretinal neovascular membranes. None of the 10 had vitreous or anterior chamber inflammation, and the laboratory evaluation failed to reveal evidence of a microbial cause (including histoplasmosis, blastomycosis, or coccidioidomycosis). The authors suggested that this was a new clinical entity, distinct from other chorioretinal inflammatory diseases, and they proposed the term punctate inner :::horoidopathy. Watzke and colleagues felt that PIC was a distinct entity .n the category of multifocal choroiditis of unknown etiol)gies, or the so-called white dot syndromes. Interestingly, ;everal reports between 1984 and 1986 described other :onditions predominantly affecting myopic women pre,enting with multifocal choroiditis with varying degrees )f uveitis. In 1984, Dreyer and Gass presented 28 cases )f multifocal choroiditis with vitreous inflammation and :horioretinal scars similar to those seen in presumed )cular histoplasmosis (PORS).2 Average age at presentaion was 33 years old, with a 3: 1 female-to-male preponlerance. Anterior chamber inflammation was seen in 12% of the eyes, and vitreous cells were seen in 94% of he eyes. Ophthalmoscopic examinations revealed deep horoidallesions of varying size (50 to 300 /-Lm) located loth in the posterior pole and in the periphery. Choroilal neovascular membranes (CNVM) were observed in 0% of the eyes. Only 5 of 16 patients tested positive on l.e histoplasmosis skin test. Dreyer and Gass2 suggested

that the presence of vitritis (and, in some, anterior uveitis) , the size of the choroidal and retinal pigment epithelimn (RPE) lesions (smaller than seen with paRS), and the lack of evidence for histoplasmosis exposure pointed toward a distinct clinical entity which they called MCP. In 1986, Cantrill and Folk described a case series of five healthy women (ages 14 to 34) who presented with blurred vision or scotomas. 3 Four of the five patients showed no anterior chamber or vitreous inflammation. Funduscopic examination revealed clusters of hypopigmented lesions (l00 to 200 /-Lm) located in the posterior pole. Over time, these lesions faded, leaving either punched-out atrophic lesions or RPE pigment changes. The distinct characteristic of this series of patients was the development of progressive subretinal fibrosis, apparently formed by coalescence and evolution of the acute lesions. The authors reintroduced the term progressive subretinal fibrosis, initially coined by Palestine and coworkers,4 to describe this unique outcome of what appeared to be a rpultifocal choroiditis of unknown etiology in young "'healthy women. Cantrill and Folk suggested that the three entities just described may have a significant overlap in presentation, clinical finding, and clinical course. 3 There is clearly a preponderance of young women in these three series, and in most cases both eyes are affected. All three diseases can present (at least initially) as small, punctate, outer retinal lesions in the posterior pole and the periphery. Serologic and laboratory evaluations are typically negative. The clinical course of these three entities may also share certain features. Cantrill and Folk pointed out that one patient in the Dreyer and Gass series 2 demonstrated "large subretinal bands of metaplastic RPE," consistent with progressive subretinal fibrosis. A case series of Watzke and coworkers 1 included a patient with late formation of "a fibrotic hyperplastic central scar." And all three conditions are associated with formation of CNVM, which can lead to significant visual impairment. These three diseases, PIC, MCP, and progressive (diffuse) subretinal fibrosis, are now thought to be a clinical spectrum of a single disease, a choroiditis that affects the choroid and tlle RPE of (mostly) young healthy women. MCP and subretinal fibrosis and uveitis s}'lldrome (SFU) will be discussed in other chapters. This chapter will focus on the unique presentation and clinical course of PIC, as well as the clinical features shared with the other forms of multifocal choroiditis.

EPIDEMIOLOGY It is difficult to estimate the incidence or the prevalence of PIC or other multifocal choroiditis entities, and good demographic data are also lacking. An estimate can be made from the studies of Brown and colleagues, 5 the largest published series on multifocal choroiditis. Their study reviewed all diagnoses for PIC, MCP, and SFU from 1980 and 1994 at the University of Iowa, a major regional

CHAPTER 74: PUNCTATE INNER

tertiary eye care referral center in the midwestern United States. A total of 161 patients were identified with these three diagnoses in 'a period of 15 years, or approximately 11 cases per year. Assuming that the referral population of 'the University of Iowa is the population of Iowa (2.8 million), then a national incidence of multifocal choroiditis could be about 1000 to 2000 cases per year. Only 16 patients of the 161 case series patients had the diagnosis of PIC (10%). The national incidence of PIC could therefore be estimated as about 100 to 200 cases per year. It should be noted that many cases of PIC may be subclinical (i.e., minimal visual disturbances, lack of central foveal lesions, lack of foveal CNVM), so these numbers may be an underestimate. PIC tends to affect young, apparently healthy women. However, case series of PIC are usually small and there may be a predisposition or bias against diagnosing PIC in men. Brown and colleagues5 presented 16 cases of PIC with only one male patient. The average ages of the patients in the two studies were 27 and 30 years. I,5 No studies (or case series with sufficient numbers) exist that suggest a racial or cultural predisposition for PIC. However, most cases are in white women. 1, 5

CLINICAL CHARACTERISTICS The predominant symptoms at presentation for these young women are blurred central vision or scotomas. Also documented are complaints of flashes, floaters, and photopsias. I, 5, 6 Visual disturbances are usually unilateral, although, as will be described late', funduscopic examinations usually reveal bilateral lesions. 1 There is usually no concurrent or recent systemic illness or viral prodrome, as often documented in cases of APMPPE or MEWDS. The visual acuity at presentation is usually decreased. Reddy and colleagues 6 analyzed 16 patients with PIC (the same group as in the Brown and colleagues series 5 ) and the initial average visual acuity was 20/41 with a range of 20/15 to 20/500. Over 75% of the patients were 20/40 or better. Their analyses of the refractive errors for the different chorioretinitis cases are of interest. PIC had the highest refractive error at - 3.67 diopters, versus - 2.19, -1.25, and -1.25 for MCP, SFU, and MEWDS, respectively. The external examination of patients with PIC is unremarkable. The anterior segment examination is also normal, with a quiet anterior chamber and no stigmata of prior uveitis. The vitreous is clear without inflammatory cells. The lack of vitreous inflammation is a hallmark of PIC, and the presence ofvitritis should suggest a different diagnosis. Fundus examination usually reveals multiple discrete, flat, yellow, round lesions (50 to 300 /-LIn in size) at the level of the RPE and the inner choroid (Figs. 74-1 to 74-4). The number of lesions is variable (12 to 25 in the Watzke and coworkers series I). They are concentrated in the posterior pole, which is in distinct contrast to MCP and SFU, where mid-peripheral lesions are more apparent. Initially, some of these yellow spots may be associated with serous detachment of the neurosensory retina (see Fig. 74-1). Visual disturbances are usually associated with foveal choroidal lesions with or without an associated serous detachment. The acute lesions usually evolve over a few months to become either faded

CHIOFtOIDC~PA:THIY

FIGURE 74-1. Case 1. Thirty-two-year-old white, myopic woman presented with a 2-week history of metamorphopsia OS. Fundus examination revealed several punctate chorioretinal lesions with overlying neurosensory retinal detachments. (See color insert.)

chorioretinal lesions or atrophic chorioretinal scars. Watzke and colleagues 1 found that' some scars became pigmented over a period of years, often resembling old punched-out POHS scars (see Fig. 74-3). An important differentiating feature is the distinct absence of cystoid macular edema or disc edema in PIC as opposed to MCP or MEWDS.I, 5, 6 As previously stated, although visual symptoms are usually unilateral at presentation, fundus abnormalities are usually bilateral. Eight of 10 patients (80%) in the Watzke and coworkers' series l and 14 of 16 patients (88%)in the Brown and coworkers' series 5 had bilateral disease. In comparison, 27 of 41 (66%) patients with MCP, 5 of 5

FIGURE 74-2. Case 2. Twenty-three-year-old white, myopic woman was referred with a 3-month history of c~ntral vision. loss OD. Fundils examination showed numerous punctate, white chorioretinal atrophic lesions in the posterior pole. A fibrovascular CNVM was evident in the macular. (Courtesy ofJay S. Duker, M.D.) (See color insert.)

Bruch membrane interface causes a nondistinct, nonfocal neovascularization to occur. The therapeutic implications of different types of CNVM and its relevance to PIC will be discussed later. The clinical characteristics of PIC are summarized in Table 74-1.

FIGURE 74-3. Case 2. One year later, the patient returned for a follow-up examination. Note that many of the chorioretinal lesions have become pigmented. A new CNVM with an associated subretinal hemorrhage is evident superior to the old macular scar. (See color insert.)

patients with SFU (100%), and only 4 ,of 16 (25%) patients with MEWDs had bilateral fundl~s lesions in the study by Reddy and colleagues. 6 The most significant clinical sequela,,;; of PIC is the formation of CNVM. It is estimated that the 17% to 40% of eyes with PIC lesions will develop CNVM.l, S ·CNVM may be present on the first examination or it may form up to 1 year later. I, S It is the leading cause of poor visual outcome (less than 20/200) in patients with PIc. s It is thought that CNVM arises from focal chorioretinal scars in response to choroidal injury.7 This may be in contrast to the formation of CNVM in age-related macular degeneration, where generalized deterioration of the RPE-

No studies to date have examined the histopathology of the characteristic PIC lesions. U nfortunate1y, little is known about the etiology or pathogenesis of PIC. Watzke and colleagues I were not able to find an infectious cause for their patients with PIC. Their rather extensive evaluation included serologies for fungi (histoplasmosis, blastomycosis, and coccidioidomycosis), toxoplasmosis, herpes virus, and cytomegalovirus without revealing any candidate causative organism. Most patients with PIC have normal systemic studies, including complete blood cell count, erythrocyte sedimentation rate, angiotensin-converting enzyme, and antinuclear antibody titers. I Watzke and colleaguesI have speculated that PIC may be a special and limited spectrum of myopic degeneration. Clearly, most patients with PIC have a history of at least moderate myopia, and many of the PIC lesions appear in a linear configuration, which suggests a pathog~nesis possibly similar to that of the lacquer cracks seen in myopic degeneration. The histopathology of CNVM in PIC is important, as most visual loss from PIC results from the formation of a neovascular membrane. Olsen and colleaguesS examined the clinical course and evolution of CNVM in five patients with PIC. They subsequently examined the surgical specimens following submacular extraction of these neovascular membranes. They described the typical PIC neovascular membranes as "multiple, small «300 /-Lm), yellow-white, or yellow-green foci deep to the retina with pigmented borders and an accompanying shallow overlying neurosensory retinal detachment." They observed that, with time, these smaller CNVMs coalesce to form a larger neovascular membrane with multiple "feeder vessels" from the choroid. These membranes, lying anterior to the RPE and below the neurosensory retina, have been termed type II membranes by Gass. 7 Type II melnbranes are more amenable to surgical removal than type I membranes, which are beneath the RPE as seen in age-related macular degeneration. The anatomic configuration of type II membranes in POHS and PIC may confer a better prognosis following surgical excision. Histopathologic examination showed a fibrovascular tissue bordered by RPE,

TABLE 74-1. CLINICAL CHARACTERISTICS OF PUNCTATE INNER CHOROIDOPATHY

FIGURE 74-4. Case 3. Twenty-four-year-old white, myopic woman was referred,with an 8-month history ofa central scotoma. Fundus examination revealed multiple, punctate perifoveal lesions with a fibrovascular CNVM in the fovea. (Courtesy ofJay S. Duker, M.D.) (See color insert.)

FEATURES

COMMENTS

Female > > male Young, healthy Myopic Unilateral symptoms No anterior chamber reaction No posterior inflammation ·White punctate lesions Choroidal neovascular membranes

93% to 100% female 20-30 years old, no prodrome Average, - 4.00 diopters Bilateral lesions A key element A key element Mostly posterior pole 17% to 40%

CHAPTER 74: PUNCTATE INNER TABLE 74-2. DIFFERENTIAL DIAGNOSIS OF PUNCTATE INNER CHOROIDOPATHY Presumed ocular histoplasmosis syndrome Multiple evanescent white dot s)'lldrome Acute posterior multifocal placoid pigment epitheliopathy Multifocal choroiditis and panuveitis Subretinal fibrosis and uveitis Birdshot retinochoroidopathy Sarcoidosis Myopic degeneration maculopathy Ocular toxoplasmosis Lyme disease Vogt-Koyanagi-Harada s)'lldrome

infiltrated with few lymphocytes. There was no evidence of Bruch's membrane or choriocapillaris. In this manner, the CNVM of PIC may be similar to the CNVM seen in POHS in that the membrane lies anterior to the RPE layer. 7 Surgical specimens from s.ubmacular CNVM extraction in POHS show a similar histology.

DIAGNOSIS The differential diagnosis of PIC is extensive and is summarized in Table 74-2. However, the key element in the diagnosis of PIC, the absence of anterior and posterior segment inflammation, eliminates !il0st of the diagnoses listed, including MFC, SFU, sarcoidosis, BSRC, toxoplasmosis, and Vogt-Koyanagi-Harada. PIC can be differenti-

_Ug_IEll_I~,""'II"!lAT!LII

ated from POHS by . the lack of peripapillary changes. and peripheral retinal lesions. Other retinal white dot syndromes of unknoyvn etiologies must be differentiated from PIC. MEWDS lesions are also concentrated in the posterior pole as in PIC, but the lesions have a less distinct border and do not have an associated serous detachment. 9 Also, patients with MEWDS have the characteristic granular appearance of the macula. APMPPE does not affect women predominantly, and patients with APMPPE may have associated systemic manifestations, including cerebral vasculitis and encephalitis. lo , 11 In contrast to PIC lesions, APMPPE lesions are typically placoid, large, and often confluent to each other. 12 Patients with BSRC have an associated vitritis, and the lesions are typically seen throughout the fundus to the periphery.13,14 Table 74-3 <summarizes the cliriical characteristics of the white dot syndromes, or multifocal choroiditis of unknown etiology. Although the diagnosis of PIC usually can be made based on clinical examination, ancillary testing, including visual field testing and retinal angiography, can be helpful in confirming the diagnosis, following the clinical course of the disease, and making therapeutic decisions. Because patients present with a scotoma, visual field testing may be helpful in documenting and following this symptom. Reddy and colleagues 6 performed visual field testing on 22 eyes with PIC and they were able to document a defect in 12 of the 22 (55%). The predominant finding was an enlarged blind spot, seen in 41 % of patients. Enlarge-

TABLE 74-3. SUMMARY OF WHITE DOT SYNDROMES OF UNKNOWN ETIOLOGIES APMPPEI2-12 Age Sex Viral prodrome Unilateral or bilateral Typical findings

MEWDS9

BSRCI3, 14,22

scn, 24

MCP/PU2. 3, S

PIC'S

20-30

20-40

30-60

20-60

20-60

20-40

M=F Often severe" Bilateral

F»M

F»M

M=F Rarely Bilateral

F»M Not typical Bilateral

F»M Rarely Variable

Iritis, vitritis; peripapillary fibrosis; multiple yellow lesions Early block; late stain; cystoid macular edema Hypo lesions

Multiple punctate, white chorioretinal lesions

Yellow, creamy, flat, placoid lesions

50% Asymmetric

Bilateral

Multiple white lesions at level of RPEor choroidb Early hyper of lesions; disc hyper

Vitritis; crealuy, white lesions entire fundus c Subtle late stain of lesions; disc stain Hypo lesions

Yellow/gray peripapillary lesion; progress in serpentine fashion f Late hyper of lesion; retinal vascular stain Hypo lesions

Rarely

Yes

Yes

Yes

Can be progressive Often decreased

Chronic/ progressive Usually decreased

Can be progressive Variable

Self limited

Fluorescein angiography

Early hypo, then late hyper

Indocyanine green angiography

Hypo lesions

Choroidal neovascularization Recurrent

Rarely

Multiple hypo lesions c Rarely

Rarely

Rarely

Visual outcome

Baseline

Baseline

Early hyper of lesions

Hypo lesions

Usually decreased

RPE, retinal pigment epithelium; hypo, hypofluorescent or hypofluorescence; hyper, hyperfluorescent or hyperfluorescence; APMPPE, acute posterior mUltifocal placoid pigment epitheliopathy; MEvVDS, multiple evanescent white dot syndrome; BSRC, birclshot chorioretinopathy; SC, serpiginous choroiditis; MCP/PU, multifocal choroiditis/panuveitis; PIC, punctate inner choroidopathy. "Associated with cerebrovasculitis; CSF abnormalities "Often disc edema, granular foveal changes 'ERG-;-decreased a-wave amplitude d90% HLA-A29 positive; lymphocyte active against retinal S_AglS eAlso disc edema and cystoid macula edema fOften anterior/posterior inflammation; eventual atrophy of lesions

14:

INNER. CHOR.OIDOPATHY

74-6).1 Older PIC lesions can show transmission defect hyperfluorescence, reflecting the evolution of acute lesions to atrophic chorioretinal scars. . Indocyanine green (ICG) angiography of PIC lesions shows hypofluorescent spots in the posterior pole (Fig. 74-7). These spots may correspond to the areas of visible lesions. Slakter and colleagues have suggested that ICG angiography may be helpful in the diagnosis of MCPP They have shown that in the active phase of MCP, ICG angiography shows hypofluorescent spots in the posterior pole, which gradually resolve with clinical improvement of the choroiditis. The same may perhaps also be true for PIC. FA is invaluable in localizing and characterizing the CNVM seen in PIC. Most CNVM in PIC begins as lTIultipIe, smaller, yellow-green lesions in the deep retina with surrounding pigment changes. s FA of these lesions shows early hyperfluorescence with late leakage. Over time (weeks to months), these lesions coalesce to form a larger CNVM with bridging networks developing between the smaller membranes (see Fig. 74-6) .5, S FIGURE 74-5. Case 3. Early transit fluorescein angiography revealed multiple punctate hyperfluorescent lesions with early staining of the fibrovascular CNVM.

ment of blind spots are well docume11ted in other instances of multifocal choroiditis, such as MEWDS and MCP.g, 15, 16 Fluorescein angiography (FA) of acu& PIC lesions usually shows an early hyperfluorescence in the arteriovenous phase with a variable amount of leakage in the late arteriovenous phase. Some lesions have been shown to block fluorescence in the early arteriovenous phase and stain thereafter. If a serous detachment is present, the spots leak dye into the subretinal space (Figs. 74-5 and

FIGURE 74-6. Case 3: Late-phase fluorescein angiography demonstrated further hyperfluorescence of the fibrovascular CNVM. The branched out configuration of this older, evolved CNVM with the small "bridging vessels" (armw) is typical for PIC.

No treatment is advised for the majority of patients withput evidence of CNVM, as patients without CNVM have excellent visual outcomes. 1, 5 However, corticosteroids may be considered in some patients who present with poor initial visual acuity (less than 20/200) with an abundance of acute PIC lesions (with or without an associated serous detachment) concentrated in the fovea. There are two rationales for treating acute foveal PIC lesions. First, it may be possible that corticosteroids can limit the extent of RPE disturbance and choroidal scar formation following the insult of the acute PIC lesions. Significant RPE disturbances and scar formation in the fovea lTIay lead to a relatively poor visual outcome when compared to eyes without extensive foveal changes. Second, it is thought

FIGURE 74-7. Case 3. Indocyanine green angiography demonstrated multiple perifoveal and peripapillary hypofluorescent lesions.

CHAPTER 74: PUNCTATE INNER ...... "".....,If.......,.

that most CNVMs arise from evolved PIC lesions and scars. Because theformation of a foveal CNVM portends a poor visual outcome, it may be possible to reduce the incidence of neovascularization by limiting foveal scar formation. These are theoretical arguments, and no studies have been performed to test the hypothesis that there is a benefit of corticosteroid use in treating acute PIC lesions without evidence of CNVM, and other immunosuppressive therapy has not been tried in the treatment of PIC. However, if the acute lesions are inflammatory (and we believe they are), and if CNVM generally results from inflammatory damage to an area (as in POHS) , then anti-inflammatory therapy may prevent such damage and thereby reduce the likelihood of CNVM formation, provided such therapy is instituted at a time and at a dose that could reasonably be expected to rapidly reverse the inflammation. Testing this hypothesis in a rare disorder will be very difficult at best. The treatment of CNVM probably represents the most significant challenge in the management of patients with PIC. The three available treatment modalities include laser photocoagulation, corticosteroids, and subfoveal surgery. Most clinicians would choose to treat the extrafoveal (greater than 200 j.1m from the foveal avascular zone [FAZ]) CNVM and the juxtafoveal (from 20 to 200 j.1m from the FAZ) CNVM with laser photocoagulation. Reports by Brown and colleagues and Watzke and colleagues demonstrate favorable regression response from laser photocoagulation of extrafoveal and juxtafoveal CNVM.l,5 No prospective studi~s have cOlnpared laser treatment with observation of these lesions or treatment with sub-Tenon's or systemic steroid for that matter. The outcome studies of the Macular Photocoagulation Study Group 1S showing a favorable response in the POHS subgroup may be extrapolated to the laser treatment of the CNVM associated with PIC, as much similarity exists (clinically, surgically, and histologically) between these two types of neovascular membranes. Patients with subfoveal CNVM represent the greatest therapeutic challenge. Flaxel and colleagues have examined the use of oral corticosteroids in the treatment of subfoveal CNVM in patients with either PIC or MFC.l9 They treated 10 patients (12 eyes) with oral prednisolone at 1 mg/kg for 3 to 5 days with a gradual taper. hi. 10 eyes, the vision improved or stabilized, and in nine eyes, the authors were able to demonstrate resolution of the CNVM on FA. Brown and colleagues found that corticosteroids (oral and sub-tenon) may be helpful in slowing the growth of smaller CNVMs (less than 200 f-Lm) associated with PIC and MCP.5 Although these studies are of interest, they did not include control groups and may not be better than the natural history of the disease. Hence, well-designed comparative studies are needed. A trial of oral corticosteroids may be reasonable in PIC patients with a smaller (around 100 j.1m) subfoveal CNVM or an actively growing subfoveal CNVM. In the near future, the best treatment for the larger subfoveal CNVMs in PIC may be submacular surgery. Although the technology and techniques of submacular surgery are currently state of the art and the early results are promising, especially in the subgroup of patients with POHS, and more recently in patients with PIC, more j

long-term follow-up data are needed to assess this modality for these diseases. S, 20 This is especially true in the light of recent data that were presented by Matt Thomas at the American Academy of Ophthalmology in October, 1998, in which he reported that the visual acuity outcome following macular surgery for POHS trend back toward baseline over 3 years of follow-up and a staggering 56% recurrence rate. The anatomy and the histopathology of the CNVM of POHS and PIC (see pathophysiology sec.. tion) may be more favorable for surgical extraction than the CNVM of age-related macular degeneration. s Olsen and colleagues performed subfoveal CNVM extractions on six eyes in five patients with PIC, and they were able to show visual improvements in all six eyes. s However, the rate of recurrence was high (six events in four eyes), often requiring a repeat surgical or laser procedure.

COMPLICATIONS Complications of the medical or surgical therapies for PIC are not unique to this disease. Vision loss and recurrence of the CNVM are complications of laser photocoagulation of CNVM in PIC. Complications of steroid therapy can be local (ocular hypertension and cataract) or systemic (e.g., hyperglycemia, immunosuppression, weight gain, peptic ulcer disease). The general health of the patient should be carefully reviewed prior to initiation of systemic corticosteroid therapy. As most patients with PIC are young and healthy, a course of corticosteroids is usually safe. Although Olsen and colleagues did not report serious postsurgical complications, subfoveal surgery can result in macular hemorrhage, retinal tears, retinal detachment, scar formation, cataracts, epiretinal membrane, and endophthalmitis.20, 21

Many patients with PIC will have a visual outcome of 20/40 or better. The case series of Brown and colleagues showed. that 77% of the eyes with PIC had a visual acuity of 20/40 or better, 5 and Watzke and colleagues showed a similar outcome. l The main reason for poor vision was the formation of CNVM within the macula. Other causes for poor vision in PIC include extensive foveal RPE changes or scar formation, complications of the therapy, and late recurrences of the CNVM.

PIC is a relatively recently described condition characterized by discrete, posterior pole lesions in otherwise healthy, myopic women. The cause of PIC is unknown and the pathophysiology is poorly understood. Many clinicians believe that PIC is a subset of the broader spectrum of diseases including MCP and SFU. The visual outcome can be good unless complicated by the formation of CNVM. Treatment of subfoveal CNVM is controversial, although steroids and subfoveal surgeries may help to improve visual outcome. However, a prospective, randomized trial is needed, comparing the different treatment options (observation, corticosteroids, laser and subfoveal surgery) for subfoveal CNVM in PIC and other inflammatory chorioretinal diseases to allow for rational therapeutic decisions.

CHAPTER

PUNCTATE INNER CHOROIDOPATHY

1. Watzke RC, Packer AJ, FolkJC, et al: Punctate inner choroidopathy. AmJ Ophthalmol 1984;98:572-584. 2. Dreyer RF, Gass JDM: Multifocal choroiditis and panuveitis: A syndrome that mimics ocular histoplasmosis. Arch Ophthalmol 1984;102:1776-1784. 3. Cantrill HL, FolkJC: Multifocal choroiditis associated with progressive subretinal fibrosis. AmJ Ophthalmol 1986;101:170-180. 4. Palestine A, Nussenblatt R, Parver L, I(.l1oX D: Progressive subretinal fibrosis and uveitis. Br J Ophthalmol 1984;68:667-673. 5. Brown J Jr, Folk JC, Reddy CV, Kimura AE: Visual prognosis of multifocal choroiditis, punctate inner choroidopathy, and the diffuse subretinal fibrosis syndrome. Ophthalmology 1996;103:11001105. 6. Reddy CV, Brown J Jr, Folk JC, et al: Enlarged blind spots in chorioretinal inflammatory disorders. Ophthalmology 1996; 103:606-617. 7. Gass JDM: Biomicroscopic and histopathologic consideration regarding the feasibility of surgical excision of subfoveal membranes. AmJ Ophthalmol 1994;118:285-298. 8. Olsen TW, Capone A Jr, Sternberg P Jr, et al: Subfoveal choroidal neovascularization in punctate inner choroidopathy. Ophthalmology 1996;103:2061-2069. 9. Jampol LM, Sieving PA, Pugh D, et al: MLlltiple evanescent white dot syndrome. 1. Clinical findings. Arch Ophthalmol 1984;102:671-674. 10. Fishman GA, Baskin M,Jednock N: Spinal fluid pleocytosis in acute posterior multifocal placoid pigment epitheliopathy. Ann Ophthalmol 1977;9:36-46. 11. Weinstein JM, Bresnick GH, Bell CL, et al: Acute posterior multifocal placoid pigment epitheliopathy associated with cerebral vasculitis. J Clin Neuroophthalmol 1988;8:195-201. 12. Gass JDM: Acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol 1968;80:177-185.

13. Kaplan HJ, Aaberg TM: Birdshot retinochoroidopathy. Anl J Ophthalmol 1980;90:773-782. 14. Ryan SJ, Maumenee AE: Birdshot retinochoroidopathy. Am J Ophthalmol 1980;89:31-45. 15. Hamed LM, Glaser JS, Gass JDM, et al: Protracted eqlargement of the blind spot in mUltiple evanescent white dot syndrome. Arch OphthalmoI1989;107:194-198. 16. Khorram KD, Jampol LM, Rosenberg MA: Blind spot enlargement as manifestation of multifocal choroiditis. Arch Ophthalmol 1991;109: 1403-1407. 17. Slakter JS, Giovannini A, Yannuzzi LA, et al: lndocyanine green angiography of multifocal choroiditis. Ophthalmology 1997; 104:1813-1819. 18. Macular Photocoagulation Study Group. Argon laser photocoagulation for ocular histoplasmosis. Results of a randomized clinical trial. Arch Ophthalmol 1983;101:1347-1357. 19. Flaxel CJ, Owens SL, Mulholland B, et al: The use of corticosteroids for choroidal neovascularization in young patients. Eye 1998;12:266-272. 20. Thomas MA, Dickinson JD, Melberg NS, et al: Visual results after surgical removal of subfoveal choroidal neovascular membranes. Ophthalmology 1994;101:1384-1396. 21. Thomas MA, Grand MG, Williams DF, et al: Surgical management of subfoveal choroidal neovascularization. Ophthalmology 1992;99:952-968. 22. Nussenblatt RB, Mittal KK, Ryan S, et al: Birdshot retinochoroidopathy associated with HLA-A29 antigen and immune responsiveness to retinal S-antigen. Am J Ophthalmol 1982;94: 147-158. 23. Chisholm lH, Gass JD, Hutton WL: The late stage of serpiginous (geographic) choroiditis. AmJ Ophthalmol 1976;82:343-351. 24. Jampol LM, Orth D, Daily MJ, et al: Subretinal neovascularization • with geographic (serpigil(ous) choroiditis. Am J Ophthalmol 1979;88:683-689.

Helen Wu

DEFINITION

CLINICAL

Acute zonal occult outer retinopathy (AZOOR) is a syndrome characterized by rapid loss of retinal function in one or more regions, photopsias, mild vitritis, electroretinographic (ERG) abnormalities, an enlarged blind spot on visual field testing, and minimal initial ophthalmoscopic changes with late development of retinal degenerative changes. Similar findings have been seen in patients with multiple evanescent white dot syndrome (MEWDS), acute idiopathic blind spot enlargement syndrome (AIBSES), multifocal choroiditis and panuveitis (MCP, or pseudo-presumed ocular histoplasmosis syn.drome), and acute macular neuroretinopathy (AMN). It has been suggested that these diseases are not separate entities, but rather constitute a spectrum of a single disorder. However, we believe this is probably not a correct notion because the natural histories and responses to treatment differ among these disorders. The etiology of AZQOR is unclear.

A significant percentage of patients with AZOOR may have flulike symptoms before the onset of ocular symptoms. Interestingly, two patients in Gass' original report were diagnosed with infectious mononucleosis 2 years prior to developing AZOOR. Photopsia and visual field loss in one or both eyes are the predominant presenting ocular symptoms of AZOOR. The photopsias have often been described as multicolored and are associated with shimmering or ameboid micromovements. The photopsias and scotomata may be exacerbated by bright light, exercise, stress, and fatigue. Early in the course of the disease, the majority of eyes have 20/30 or better visual acuity. The visual field defects are most commonly noted in the superior and temporal quadrants, and they often include enlargement of the blind spot. The visual field loss is usually asymmetric. Typically, the scotomata increase in size within days to weeks, although progression of visual field defects has been documented up to 6 months after the onset of symptoms. The fundus appears normal in a majority of patients on presentation. Subtle pigment epithelial changes may be seen initially; depigmentation of the RPE layer corresponds to the areas of visual field loss in the later stages of the disease (Fig. 75-1). Retinal vessels may narrow in the areas of atrophy. Late pigment migration into the overlying retina can mimic the bone spicule appearance of retinitis piglnentosa. Focal perivenous infiltration or sheathing of the retinal vessels may occur. Several of Gass' original 13 patients had leakage at the optic nerve and macula on fluorescein angiography. In four of these patients, no funduscopic changes were found throughout the course of the disease, despite the presence of dense scotomata.

HISTORY Although MEWDS, AIBSES, MCP, and AMN have been described as independent entitiel l - 7 there have been reported cases in which certain features of these syn.dromes overlap,8-12 prompting Gass to suggest that they are related diseases. 13 He reported on 13 young white adults, predominantly females, with acute loss of outer retinal function in one or more large retinal zones. Two of these patients had fundus lesions typical of both MEWDS and MCP. He proposed the term acute zonal occult outer retinopathy (AZOOR) to describe the findings in these 13 patients, and speculated that all of these seemingly heterogeneous disorders are closely related or perhaps manifestations of the same disorder. In 1995, Gass reported on a patient he had previously diagnosed with acute progressive zonal inner retinitis and degeneration. 14 The patient had presented with an acute scotoma associated with a gray intraretinal ring corresponding to the scotoma. Mter years of follow-up, the patient was found to have depigmentation and migration of pigment epithelium into the overlying retina, similar to the earlier 13 patients with AZOOR. Gass termed this condition acute annular outer retinopathy and speculated that it was most likely a variant of AZOOR. He also presented another possible variant of AZOOR in 1997,15 in which patients demonstrated acute disruption of the retinal pigment epithelium (RPE) and whitening of the outer retina and RPE. Other published reports suggest that the full clinical spectrum of AZOOR may not yet be established. In 1994, Holz and colleagues presented a case of AZOOR associated with multifocal choroidopathy.16 In 1996, Jacobson presented an atypical case of AZOOR with macular involvement, recurrences, and central nervous system inflammationY

FIGURE 75-1. Patient with AZOOR. Status postresolution of the acute phase. Note the zone of RPE disturbance extending inferiorly from the disc.

CHAPTER 75: ACUTE ZONAL OCCULT OUTER RETINOPATHY

Vitritis, which is present in approximately half of the cases, is generally mild, The degree of vitritis· appears to be related to the degree of visual field loss. A relative afferent pupillary defect occurs in approximately half of reported cases. Optic disc swelling was seen in only one patient, although its appearance did not change over years. Opticatrophy has not been reported in any patient. Other ocular manifestations may include retinal lesions similar to those of MEWDS, AMN, or MCP.13, 15, 16 Choroidal neovascularization has been observed in two patients, who subsequently developed impaired central vision. 16 Cystoid macular edema has also been reported. 13

the most recently affected area of the retina, or by an immune reaction at the junction between normal vascularized inner retina and the leading edge of the infected outer avascularized retina. 15 The presence of iritis in some, but not all, of the affected patients suggests that inflammation Inay be secondary to the underlying disease process. Patients with greater degrees of visual field loss appear to have associated iritis more often. One can speculate that vitl-itis occurs in response to factors released by damaged RPE and receptor cells.

In the acute annular outer retinopathy variant of AZOOR, photopsias may not be a presenting symptom. In the first published case, the patient experienced sudden onset of a scotoma. A circular ring of gray-white retinal opacification was seen in the superotemporal fundus of the left eye, with narrowing of the retinal vessels within the ring. 14 The ring slowly' enlarged over a period of several weeks and then disappeared. Pigmentary changes characteristic of AZOOR then occurred over months, demonstrating that the receptor cells and the RPE were the damaged layers. It is interesting to note that, in this index case, visual acuity remained 20/20 throughout, and the initial relative afferent pupillary defect vanished over the 6-year follow-up period. In otb.er' cases, RPE disruption occurred earltin the course of the disease, with variable degrees of whitening of the outer retina and RPE. 1'1 Although antecedent systemic diS'~ase is not uncommon in patients with AZOOR, concomitant systemic inflammation is rare. One patient was reported to have cerebrospinal fluid pleocytosis and multiple brain magnetic resonance imaging (MRI) signal abnormalities. 17 She subsequently developed an acute cervical myelopathy, which resolved after intravenous steroid therapy. Her ocular course was also unusual, with central macular involvement and recurrent bouts of an AZOOR picture over several years. It is unclear whether this case represents a true association between AZOOR and central nervous system (CNS) inflammation, a chance occurrence of AZOOR and possible multiple sclerosis, or an ocular problem that was not AZOOR to begin with.

The characteristic history of photopsias and the rapid onset of one or more large peripheral scotomata suggest the diagnosis of AZOOR. Funduscopic findings may be normal or subtle initially, and vitritis mayor may not be present. Over time, characteristic pigmentary changes in the outer retina and RPE substantiate the diagnosis. In the acute phase, however, ERG abnormalities are essential to confirm the diagnosis and avoid additional unnecessary neurologic testing. In some patients, a focal ERG may be required to detect the abnormalities. Multifocal ERG19 and scanning laser ophthalmoscopy20 have also been used as adjunctive tools to confirm the diagnosis of AZOOR.

The etiology of AZOOR is unclear but it is presumed to be of inflammatory origin. Although patients with MEWDS, AIBSES, AMN, and MCP all share the COlnmon feature of occult visual field loss secondary to receptor cell and RPE damage, there is no known cause for these disorders. Because many of these patients are young women, who are more likely in general to have autoimmune disorders, it is tempting to propose an autoimmune etiology for AZOOR. Currently, there is no evidence for autoantibodies to any retinal cell· type in any of these patients. IS Gass speculates that in AZOOR, a viral infection latent in a region of the outer retina is activated, causing acute retinal dysfunction and death of the retinal receptors with no effect on retinal transparency or the outer and inner blood-retinal barrier in the early stages of disease. The ring seen in acute annular outer retinopathy may be caused either by the loss of transparency of

Laboratory Investigations A laboratory work-up should be performed in all suspected AZOOR patients to rule out infectious etiologies, such as syphilis and Lyme disease. Noninfectious etiologies, including retinitis pigmentosa and cancer-associated retinopathy (CAR), should be considered. Medical and neurologic consultation should be obtained. Before the initiation of systemic therapy, the following tests should be obtained: complete blood count with differential, fluorescent treponemal antibody absorption and rapid plasma reagin tests, chest x-ray, blood urea nitrogen (BUN), and creatinine, and skin testing for anergy. Serologic titers for Epstein-Barr virus, herpes simplex virus, varicella zoster virus, and Lyme disease may be helpful. Testing for retinal antigens, including the CAR antigen, may be obtained. An MRI of the brain may be necessary to rule out CNS inflammation or a compressive mass lesion. If CAR is strongly suspected, further imaging of the chest, abdomen, and pelvis may be required to rule out a malignancy.

fluorescein Angiography Fluorescein angiography is typically normal in the acute phase of AZOOR, but it may show an increase in retinal circulation time in the affected area. 13- 15 , 20, 21 One patient demonstrated evidence of juxtapapillary choroidal neovascularization 4 weeks after the onset of symptoms. 16 Mter several months, fluorescein angiography demonstrates hyperfluorescence corresponding to the choriocapillaris underlying areas of depigmented RPE. Narrowing of the retinal vessels may occur in these areas as well, particularly when the affected region is large and peripheral in location. In contrast, in patients with fundus lesions typical of MEWDS, fluorescein angiography shows early pinpoint

g

CHAPTER 75: ACUTE ZONAL OCCULT OUTER RETINOPATHY

hyperfluorescence and late staining of the lesions, with staining of the optic disc. 13

Electrophysiology Electroretinographic changes show dysfunction of the photoreceptors, which are patchy in distribution, with mildly to moderately decreased rod and cone amplitudes in most cases. 13 , 15, 16, 18-21 In the initial report by Gass,13 the ERG was extinguished in only one patient who later displayed some evidence of cone function by ERG testing. The cone responses were affected to a greater extent than the rod responses in the less-affected eyes, whereas the opposite was found in severely affected eyes. Overall, 81 % of eyes had ERG abnormalities. Electro-oculography showed a reduced or absent response in all three eyes tested in this study. Two of 11 eyes had visual evokedresponse abnormalities as well. In one study that analyzed ERG changes in 24 patients with AZOOR, almost one third had normal ERG results in both eyes but showed abnormal interocular differences for some of the measured parameters. 18 Full-field ERG was typically adequate for detecting the abnormality in most patients with AZOOR. More than half of the patients tested had abnormalities 10 months to 20 years after the onset of symptoms, suggesting persistent r~tinal damage. The ERG is not only important in the diagnosis of AZOOR; it may also have a, role in monitoring both the course of the disease and the outcomes of therapeutic intervention. Multifocal ERG, which records primarily cone responses, was used in one published case to further define the exact topographic distribution of the retinal dysfunction in a patient with AZOOR 19 The study confirms that the visual field defect in AZOOR results from outer retinal dysfunction, predominantly in the cones. The standard ERGs in that patient showed impairment of almost all cones and slight rod impairment, but they could not detect the precise location of the defect. The multifocal ERG demonstrated recordable responses only from the central macular area.

Ancillary Tests Visual field testing should be performed in all suspected AZOOR patients; it generally shows temporal and superior field defects, with involvement of the blind spot. Visual field testing should be repeated regularly to monitor the course of the disease. Color vision testing using the Farnsworth D-15 color panel was abnormal in 25% of patients in Gass' initial reportY Scanning laser ophthalmoscopy with a 514-nm wavelength laser performed in a single reported case 20 demonstrated retinal abnormalities undetectable by fundus examinations, fluorescein angiography, and computed tomography. The 630-nm wavelength laser was unable to demonstrate any abnormalities. This result' localizes damage to the retinal layer because the 514-nm laser shows primarily the retinal layer, and the 630-nm laser visualizes the choroidal layer. Furthermore, the laser was able to demonstrate abnormal retinal lesions in the asymptomatic eye as well.

The differential diagnosis of patients with acute visual loss and visual field defects includes retrobulbar neuritis, pituitary tumors, and other intracranial lesions. Although the absence of local neurologic signs or symptOllls may be reassuring, an MRI of the brain is frequently performed in this clinical setting to rule out these potentially devastating possibilities. The presence of cone or rod dysfunction on ERG testing, however, points to the diagnosis of AZOOR. In patients who manifest abnormal cone function on ERG testing, the diagnoses of acquired cone dystrophy and paraneoplastic retinopathy, including CAR and melanoma-associated retinopathy (MAR), should be considered in addition to AZOOR. Patients with paraneoplastic retinopathy may present with photopsias, visual field defects, color vision abnormalities, or nyctalopia. These patients may experience visual symptoms prior to the discovery of the carcinoma, which is most frequently a small-cell carcinoma of the lung. Paraneoplastic disorders have also been found in patients with other types of neoplasia, including melanoma and cervical, colon, prostate, and breast cancer. Most patients with CAR develop bilateral, progressive retinal degeneration with significant arteriolar narrowing. 22 ,23 Vision loss is thought to be secondary to a cancer-evoked autDimmune retinopathy~ Serum antibodies to a specific 23-kd retinal antigen (CAR antigen) have been identified, and the retina-specific immunologic reaction is located within the retinal receptors. 24-26 Patients with MAR may have acute nyctalopia, associated with anterior and posterior uveitis, depigmentation of the choroid, vitiligo, and dysacusis. Vision loss may be severe. Patients with MAR generally have central vision loss, as opposed to the ring scotomata seen witl1 CAR and the peripheral vision field defects seen in AZOOR. The ERG early in the course of MAR does not show evidence of photoreceptor dysfunction, which is typically seen in CAR and AZOOR Bilateral diffuse uveal melanocytic proliferation associated with systemic occult carcinoma may also cause loss of retinal receptor function. Metastatic cutaneous melanoma and retinitis pigmentosa may also milllic the retinal changes seen in patients with the late stage of AZOOR, but the clinical course of the entities is much different from that of AZOOR A variety of diseases may produce white dots in the retina that may resemble those seen in some reported cases of AZOOR. Diffuse unilateral subacute neuroretinitis (DUSN) and the ocular histoplasmosis syndrome may produce white dots in the retina, resembling those seen in MEWDS or MCP. DUSN is caused by subretinal nematodes and may present with visual loss, vitritis, papillitis, retinal vasculitis, and gray-white outer retinal lesiDns early in the course of the disease. Later, patients may show diffuse RPE degeneration, with progressive visual loss, retinal vessel narrowing, and optic atrophy. This syndrome is always unilateral, however. Syphilis and tuberculosis may also produce chorioretinitis and vitritis. In patients with luetic chorioretinitis, migration of pigment into the overlying retina may produce a bone-spicule pattern, similar to that seen in retini-

75:

ZONAL OCCULT OUTER RETINOPATHY

tis pigmentosa or AZOOR. Generally, the acute pattern of inflammation is quite different from that of patients with AZOOR, and geographic pale chorioretinal lesions are frequently confluent in the posterior pole and the mid-periphery of the fundus. Sarcoidosis may produce retinal vasculitis, as well as vitritis and choroidal granulomata. Other white dot syndromes to be distinguished from MEWDS and MCP include punctate inner choroidopathy (PIC) and acute posterior multifocal placoid pigment epitheliopathy (APMPPE).

TREATMENT Treatment is based on the patient's medical history, review of systems, and the presence or lack of inflammation. In general, patients with severe vitritis have been treated with systemic corticosteroids. Although inflammation has been resolved in all cases, it is unclear whether the treatment alters the course of the disease. The visual field defects have persisted in many patients despite therapy. Several patients have been treated with oral acyclovir, with mixed results. One patient was treated with ceftriaxone sodium and vancomycin hydrochloride because of suspected Lyme disease, with stabilization of the visual fields.

NATURAL HISTORY AND PROGNOSIS For most patients with AZOOR, the visual prognosis appears good. All 13 patients in Gass' ini,tial series maintained 20/25 or better visual acuity in at least one eye. One patient, however, is legally blind froD;). a severe visual field defect. No progression of visual field defect was noted after 6 months in the original series, but the patient with combined ocular and CNS symptoms has had recurrences over several years. Other patients had more severe visual loss, with deterioration of ERG findings over time. I6 The photopsias may be chronic in some patients. In all reported cases, inflammation of the vitreous resolved over time. Cystoid macular edema may persist for months. I3 Permanent central visual loss may occur in cases with associated choroidal neovascularization. I6

CONCLUSION Acute zonal occult outer retinopathy (AZOOR) is a syndrome characterized by rapid loss of one or more broad zones of retinal function; it is associated with the acute onset of photopsias and scotomata. The ERG abnormalities are critical to an early diagnosis. Because these clinical and ERG findings may be seen in several other syndromes, such as MEWDS and MCP, Gass has coined the term AZOOR to describe this disease and postulates a possible common etiology of these clinical entities. The natural history of this disorder generally is one of stabilization of the visual field defects within days to weeks, with preservation of good central visual acuity. Treatment should be based on the patient's medic<:ll history and a review· of systems. Systemic corticosteroids may be used to treat patients with severe vitritis; resolution of inflammation and stabilization of the visual field defects result in most cases. It is unclear, however, whether systemic treatment alters the course of the disease. Further work needs to be done to elucidate the etiology of this interesting and poorly understood syndrome.

References 1. Jampol LM, Sieving PA, Pugh D, et al: Multiple evanescent white dot syndrome. I. Clinical findings. Arch Ophthalmol 1984;102:671-674. 2. Sieving PA, Fishman LA, Jampol LM, et al: Multiple evanescent white dot syndrome: II. Electrophysiology of the phdtoreceptors during retinal pigment epithelial disease. Arch Ophthalmol 1984;102:675-679. 3. Fletcher WA, lInes RK, Goodman D, et al: Acute idiopathic blind spot enlargement: a big blind spot syndrome without optic disc edema. Arch Ophthalmol 1988;106:44-49. 4. Nozik RA, Dorsch W: A new chorioretinopathy associated with anterior uveitis. Am J Ophthalmol 1973;76:758-762. 5. Bos PJM, Deutman AF: Acute macular neuroretinopathy. Am J Ophthalmol 1975;80:573-584. 6. Dreyer RF, Gass JDM: Multifocal choroiditis and panuveitis; a syndrome that mimics ocular histoplasmosis. Arch Ophthalmol 1984;102:1776-1784. 7. Tessler HH, Deutsch TA: Multifocal choroiditis (inflammatory pseudo-histoplasmosis). In: Saari KM, ed: Uveitis Update: Proceedings of the First International Symposium on Uveitis, May 16-19, 1984, Hanasaan, Espoo, Finland. Amsterdam, Excerpta Medica, 1984, pp 221-226. 8. Gass JDM, Hamed L: Acute macular neuroretinopathy and MEWDS occurring in the same patient. Arch Ophthalmol1989;107:189-193. 9. Hamed LM, Glaser JS, Gass JDM, et al: Protracted enlargement of the blind spot in multiple evanescent white dot syndrome. Arch Ophthalmol1989;107:194-198. 10. Khorram lID, Jampol LM, Rosenberg MA: Blind spot enlargement as a manifestation of multifocal choroiditis. Arch Ophthalmol 1991;109:1403-1407. 1L Singh K, de Frank M, Shults WT, et al: Acute idiopathic blind spot enlargement: a spectrum of disease. Ophthalmology 1991;98:497502. 12. Callanan D, Gass JDM: Multifocal choroiditis and choroidal neovascularization associated with the multiple evanescent white dot and acute idiopathic blind spot enlargement syndrome. Ophthalmology 1992;99:1678-1685. 13. Gass JDM: Acute zonal occult outer retinopathy. J Clin Neuroophthalmol 1993;13:79-97. 14. Gass JDM, Stern C: Acute annular outer retinopathy as a variant of acute zonal occult outer retinopathy. Am J Ophthalmol 1995; 119:330-334. . 15. Gass JDM: Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment, vol 2, 4th ed. St. Louis, CV Mosby, 1997, pp 682-687. 16. Holz FG, Kim RY, Schwartz SD, et al: Acute zonal occult outer retinopatllY (AZOOR) associated with multifocal choroidopathy. Eye 1994;8:77-83. 17. Jacobson DM: Acute zonal occult outer retinopathy and central nervous system inflammation. J Neuroophthalmol1996;16:172-177. 18. Jacobson SG, Morales DS, Sun XK, et al: Pattern of retinal dysfunction in acute zonal occult outer retinopathy. Ophthalmology 1995;102: 1187-1198. 19. Arai M, Naoi N, Sawada A, et al: Multifocal electroretinogram indicates visual field loss in acute zonal occult outer retinopathy. AmJ Ophthalmol 1998;126:466-469. 20. Nishio M, Suzuki T, Chikuda M, et al: Scanning laser ophthalmoscopic findings in a patient with acute zonal occult outer retinopathy. AmJ Ophthalmol1998;125:712-715. 21. Lee AG, Prager TC: Acute zonal occult outer retinopathy. Acta Ophtllalmol Scand 1996;74:93-95. 22. Thirkill CE, Roth AM, Keltner JL: Cancer-associated retinopathy. Arch Ophtllalmol 1987;105:372-375. 23. Thirkill CE: Cancer associated retinopathy: the CAR syndrome. J Neuroophthalmol 1994;14:297-323. 24. Thirkill CE, FitzGerald P, Sergott RC, et al: Cancer-associated retinopatllY (CAR syndrome) witll antibodies reacting with retinal, optic-nerve, and cancer cells. N Engl J Med 1989;321:1589-1594. 25. Thirkill CE, Keltner JL, Tyler NK, et al: Antibody reactions with retina and cancer-associated antigens in 10 patients with cancerassociated retinopatllY' Arch Ophthalmol 1993;111:931-937. 26. Thirkill CE, Tait RC, Tyler NK, et al: Intraperitoneal cultivation of small-cell carcinoma induces expression of the retinal cancerassociated retinopatllY antigen. Arch Ophthalmol 1993;111:974978.

I

I I

Shawkat Shafik Michel and C. Stephen Foster

The terms phacogenic uveitis and lens-induced uveitis (LIU) will be used synonymously and interchangeably in this chapter for all cases of uveitis caused by lens material. Previously, these cases were called phacolytic, phacotoxic, or phacoantigenic uveitis, or endophthalmitis phacoanaphylactica. The old terms are not accurate and can be confusing. Now it is well established that anaphylaxis 1 is mediated by immunoglobulin E (IgE) antibodies attached to high-affinity receptors on the surface of basophils and mast cells. Cross-linking of these antibodies by a specific antigen leads to activation of mast cells and basophils. Activated mast cells secrete certain cytokines (interleukins 4 and 5 [IL-4 and IL-5]) and also release their stored and newly formed granules (degranulation). The result of this type of reaction (type I hypersensitivity reaction) is typically an acute eosinophil-rich inflammation. It is clear that phacogenic uveitis is completely different from the aforementioned mechanism, without participation of IgE, basophils, mast cells, or eosinophils. Additional confusion rather, than enlightenment Cleveloped in the medical literature regarding the terminology of phacogenic uveitis as a consequence of descriptive histopathology of LIU and otqer related or unrelated entities, including sympathetic ophthalmia, phacolytic glaucoma, and infectious postoperative endophthalmitis (e.g., secondary to Propionibacterium acnes). Thus, although earlier authors described the pathologic picture of zonal granulomatous inflammation around lens capsule ruptures and called it endophthalmitis phacoanaphylactica,2,3 more recently some ophthalmologists suggested the use of the term phacoanaphylactic endophthalmitis for cases showing a preponderance of polymorphonuclear leukocyte infiltration, and the term phacolytic uveitis for cases. showing a predominance of macrophage infiltration. 4 We suggest (and choose this approach here) the term phacogenic or lens-induced as a more simplified approach to the matter. We believe that the uveitis that develops as a consequence of mature cataract leakage, or residual cortex following cataract surgery, or lens material lost into the vitreous is caused by the presence· of the lens material. Removal of this lens material is curative. The details, both clinical and histopathologic, may differ between cases, but the cause, mechanism, and cure are the same. Although lens-induced or phacogenic uveitis is a curable type of uveitis, it is a frequently missed diagnosis. 5 Many of the cases mentioned in the literature have been histologically6' 7 confirmed in eyes that had been enucleated for being blind and painful. If the diagnosis is missed and proper treatment not initiated, the condition usually progresses to secondary glaucoma, and ultimately the eye must be removed because of intractable pain. The resurgence of extracapsular cataract extraction and phacoemulsification should heighten the ophthalmologist's

awareness of the possibility of this condition as a cause of protracted, sometimes stormy, postoperative uveitis. 8, 9

HISTORY Phacoanaphylactic endophthalmitis was initially recognized as a distinct entity by Straub in 1919. The nature of the process was further clarified by Verhoff and Lemoine 1922. 2 The clinical picture of phacolytic glaucoma was first described by Gifford as early as 1900, but the term phacolytic was coined by Flocks and coworkers 10 in 1955.

EPIDEMIOLOGY There are no estimates for the incidence and prevalence of LIU in the medical literature. When compared with other causes of anterior uveitis (e.g., human leukocyte antigen B27-associated), phacogenic uveitis is not common, but it is an important and a frequently missed type of uveitis. Phacogenic uveitis is expected to be more prevalent in developing countries where cataract is the leading cause of blindness. 11 , 12 The relationship between cataract (hypermature and mature) and phacogenic uveitis is well established. Uveitis as a cause of blindness is underestimated in developing countriesY· 12 All.d in developed countries, where extracapsular cataract extraction is now the most common technique for cataract surgery, it may be expected that the incidence of phacogenic uveitis will increase. Regrettably, the diagnosis will probably often not be suspected. In a retrospective study13, 14 of 144 eyes that were characterized histopathologically, it was found that only 5% of cases had been clinically suspected. It was also found that the age range was between 60 and 70 years, with a peak corresponding to the most frequent time of cataract surgery. Men were slightly more prone to LID than WOlnen, probably related to an increased history of trauma. But 20% of cases had neither history of trauma nor histopathologic evidence of a penetrating wound; 5% of the cases were shown to have gram-positive organisms in the histopathologic sections, raising the possibility, at least in this small number of cases, that a microbial adjuvant14 effect with the lens material may enhance the possibility of escape from tolerance and development of an inflammatory immune response to lens protein.

PATHOGENESIS Until the 1970s, it was taught that the lens proteins are sequestered 15 within the lens capsule with no opportunity to be recognized as self proteins by the cells of the immune system. Consequently, leakage of lens proteins was believed to result, essentially, in a foreign body reaction as a consequence of these proteins being recognized as foreign by cells of the immune system. During the 1970s,16-18 it was shown that lens proteins are neither organ- nor species-specific and that the lens proteins leak into the aqueous humor even under normal conditions (i.e., a clear lens with an intact capsule). Lens

76: LENS-INDUCED UVEITIS

proteins, especially the soluble proteins, have been experimentally shown to be weak antigens (a- and f3-crystallins) or to be frankly nonalitigenic (jI-crystallin). Additional experiments showed that some animals were more tolerant than others to injected lens material. It is possible that differences in the immune response (Ir), or the imlllune-associated (Ia) f3 genes (various alleles of the major histocompatibility complex I and II molecules 1 account, at least in part, for this individual susceptibility to an inflammatory response to lens material in the anterior chamber. Although the exact mechanism is not yet known, it is generally agreed that LID is a localized form of autoimmune disease. Ii maybe that tolerance to lens protein is lost or altered as a result of excessive leakage of lens material, and possibly as a result of some other factors, with IgG lens autoantibodies or autoreactive T cells initiating the inflammation. Anterior chamber-associated immune deviation (ACAID; see Chapter 5: Inflammation/Immunology) plays the impor'tant role of protecting the eye from the damaging effect of delayed-type hypersensitivity and complement-fixing antibodies. What role ACAID plays, or fails to play, in the pathogenesis of phacogenic uveitis is still to be answered.

Triggering Factors Typically phacogenic uveitis is seen;·in the setting of trauma or mature cataract (also hypermature cataract); both of these conditions can be associated with rupture of the lens capsule~ The trauma may be s1!t.rgical (following cataract or glaucoma surgery), or nonsurgical, following blunt or penetrating trauma. . There have even been reports from pathologically examined eyes that phacogenic uveitis may occur in developmentally abnormal eyes (e.g., microcornea or persistent hyperplastic primary vitreous).14 There are no associated systemic conditions.

PATHOLOGY The characteristic histol ogy13, 14, 19 of phacogenic uveItIs consists of zonal inflammation in and around the lens (Fig. 76-1), especially at the area of capsular rupture. The inflammatory cells are composed of lymphocytes, neutrophils, macrophages, epithelioid cells, and giant cells (Fig. 76-2). Eosinophils may be seen, but rarely. In severe, neglected cases,6,7 as seen in badly damaged enucleated eyes, granulation tissue (newly formed blood vessels and fibroblasts) is seen in the center of the damaged lens. The iris and ciliary body are moderately to densely infiltrated by lymphocytes, plasma cells, and macrophages; nongranulomatous lymphocyte infiltration may be found in the limbus. Peripheral anterior synechiae, pupillary membranes, cyclitic membranes, glaucomatous optic atrophy, and other complications of the initial trauma, or of phacogenic uveitis, may be seen in such cases.

FIGURE 76-1. A case of phacogenic uveitis showing lens material in the anterior chamber. The uveitis in this patient did not respond to topical steroids but dramatically improved after complete surgical removal of lens material. (See color insert.)

of trauma, physical composItIOn of the lens, degree of immunologic presensitization, amount and period of antigen liberation, vascularization), but also genetic and individual factors (e.g., age, degree of immunologic respon'siveness) contribute to the individual response. A history of a recent or old trauma to the eye, whether blunt or penetrating, is usually elicited from a patient with LID. Similarly, a history of prior cataract or glaucoma surgery may be obtained. Phacogenic uveitis reportedly can develop between 24 hours and 59 years 13 , 14 after the causative event. The clinical picture is that of anterior uveitis, which may be granulomatous or nongranulomatous, depending on severity. It is usually associated with keratic precipitates (KPs), which may be small and white in the early stage but coalesce into large mutton-fat KPs in severe granulomatous inflammation. The anterior chamber usually shows thick flare and abundant cells. Hypopyon or pseudohypopyon (admixed with lens material) may be seen; here the horizontal fluid level is usually absent (Fig.

CLINICAL Clinically, a spectrum of different disease patterns can be seen after lens damage. The particular reaction appears to be determined by multiple factors, many of which are largely unknown. 19 Clinical observations and experimental evidence show that not only local factors (e.g., kind

FIGURE 76-2. Pathology of phacogenic uveitis: zonal inflammation around the lens especially at the site of capsular rupture. Mononuclears are seen together with epithelioid cells and giant epithelial cells. (See color insert.)

CHAPTER 16: LENS-INDUCED

FIGURE 76-4. Significant amount of residual lens matter following extracapsular cataract extraction with lens implantation. Tl~is patient is at higher risk of developing phacogenic uveitis. (See color msert.) FIGURE 76-3. Pathology of phacogenic uveitis: epithelioid and multinucleated giant cells engulfing lens material. (See color insert.)

76-3). The anterior lens surface may appear ragged (i.e., irregular anterior lens capsule), and the lens is always opaque. The intraocular pressure is usually elevated. Vitreous inflammatory cells are the rule rather than the exception, especially in longstanding cases; this has been confirmed in enucleated eyes. For this reason, phacogenic uveitis is appropriatelyoiclassified as ~n interm~di­ ate uveitis. Although the anterior segment InflammatIOn and the opaque lens may obscure the view of the vi~reou~, ophthalmologists should be aware of accomp~nYl:ng Vltritis. Phacogenic uveitis caused by lens matenal In the vitreous cavity following extracapsular cataract extraction may be associated with an especially intense vitritis.

DIAGNOSIS The history and clinical features of phacogenic uveitis are characteristic (some published data clearly indicate that the diagnosis of LID is often missed5- 7 , 13, 14). In case of doubt, anterior chamber tap may be diagnostic. Giant macrophages full of lens material will confirm the diagnosis. The aspirated aqueous can also be examined bacteriologically and with polymerase chain reaction to exclu~e the possibility of any microbial infection. The dramatIc resolution of the inflammation following surgical removal of all lens material would also confirm the diagnosis. A- and B-scan ultrasonography9 are valuable tools for confirming the diagnosis when phacogenic uveitis is caused by lens material in the vitreous cavity, as may occur following extracapsular cataract extraction.

DIFFERENTIAL DIAGNOSIS Phacogenic uveitis should not be difficult to diagnose in most cases. But apparently it continues to this day to escape the notice of many ophthalmologists. Thach and colleagues,14 for example, found that only 5% of the cases in their study had been suspected as being LID clinically. The main differential diagnosis in cases following trauma is sympathetic ophthalmia. 2o- 23 In cases following extracapsular cataract extraction, the main differential diagno-

sis is postoperative endophthahnitis, caused by P acnes. 23- 25 As a cause of anterior and intermediate uveitis, phacogenic uveitis should be differentiated from other causes of anterior and intermediate uveitis. Syrnpathetic ophthalmia follows penetrating trauma or intraocular surgery in one eye. It is always a bilateral disease: Both eyes are usually affected at the same time, or within a short time interval. Phacogenic uveitis usually follows trauma to the eye, but it may also occur in nontraumatic mature cataract. Phacogenic uveitis is usually a unilateral disease; occasionally it is bilateral, as when it follows extracapsular cataract extraction or cases of trauma to both eyes. Extra attention to complete removal of all lens material should attend cataract surgery in a patient who has. had phacogenic uveitis in the opposite eye (Fig. 76-4). Whereas syrnpathetic ophthalmia cau~es panuveitis, phacogenic uveitis typically causes anten?r and intermediate uveitis. Lens material may be seen In the anterior chamber of patients with phacogenic uveitis but not in sympathetic ophthalmia. Phacogenic uveitis is

TABLE 16-1. DiffERENTIAL DIAGNOSIS: PHACOGENIC UVEITIS AND SYMPATHETIC OPHTHALMIA SYMPATHETIC OPHTHALMIA

Always bilateral and simultaneous or within a short interval (days or a few weeks)

Panuveitis Always follows a penetrating trauma or an intraocular surgical procedure No lens fragments in anterior chamber Relapses are characteristic

Antigenic reaction to photoreceptor protein

PHACOGENIC UVEITIS

Usually unilateral. When it follows extracapsular extraction, care should be taken when removing the cataract in the other eye AIlterior uveitis Usually but not always

Usually lens fragments in anterior chamber No relapses once the lens is completely removed from the eye Antigenic reaction to lens protein

TABLE 76-2. CHARACTERISTIC FEATURES OF EACH OF THE CAUSES OF ANTERIOR UVEITIS HISTORY

CORNEA

A.C.

Idiopathic HLA-B27 ass.

Trauma, surger~ or cataract ·Acute, recurrent Acute, recurrent

Fine or mutton fat KPs Fine KPs Fine KPs

Giant cells, pseudohypopyon Cells Cells

JRA assoc.

Chronic, quiet eye

Flare and cells

Fuchs

Present late with cataract or glaucoma

Band-shape keratop. Small-medium size KPs all over, specially inferior

Minimal inflammation

Heterochromia, prominent vessels, neovessels

Herpetic

± Preceding

± Corneal

Cells

Syphilis

corneal involvement Sexual transmission

Transillumination defects, sector atrophy Roseata

Tuberculosis

LID

Intraocular lens induced Posner Schlossman Traumatic

anesthesia Cells

± Exposure to

Fine or mutton fat KPs Mutton fat KPs

disease Surgery

KPs KPs, edema

Cells, ± IOL, ± hyphema 1-2 + cells

Fine KPs

Cells, hyphema

Acute, recurrent, self-limited History

Cells

IRIS

LENS

± PS ± PS

Cataract, ragged or Inflammatory ruptured capsule infiltrates Pigment on lens, PS Pigment Cataract Cataract (posterior subcapsular, progresses quickly)

VITREOUS

Inflammatory exudates Cells and debris

. Exudates

Nodules (granulomas)

Exudates IOL

± Lacerations

± Cataract

± Hemorrhage

ASS. DIS.

OIAG.

None

Clinical features; A.G tap By exclusion HLA-B27

None Spondyloarthropathies JRA None

ANA on 2 substrates Clinical

None

Sector atrophy, transillumination

Secondary or late latent ± Tuberculosis

FTA-ABS test

Glaucoma

Clinical

High lOT

Clinical

None

Clinical

+PPD

A.C., anterior chamber; Vit., vitreous; Ass. Dis., associated disease; FTA-ABS, fluorescent treponemal antibody-absorption test; HLA-B27 ass., HLA-B27 associated; IOL, intraocular lens; lOT, intraocular tension; JRA-assoc., juvenile rheumatoid arthritis associated; KPs, keratic precipitates; PPD, purified protein derivative; PS, posterior synechia; ± ,lnay be associated with.

CHAPTER 76: LENS-INDUCED

cured once the lens material. is completely removed from the eye; sympathetic ophthalmia is characterized by frequent relapses and, if not properly diagnosed and treated, may ultimately lead to significant visual loss or complete blindness. In some cases, both phacogenic uveitis and sympathetic ophthalmia occur in the same eye 23 (Table 76-1). p. acnef 3- 25 is one cause of chronic infectious postoperative endophthalmitis. It usually occurs 3 months or more after extracapsular cataract extraction. It causes a granulomatous uveitis (mutton-fat KPs), small hypopyon, mild vitritis, and characteristic plaques on the posterior capsule. Residual lens material may be seen in the capsular bag. P. acnes in vitro culture may require up to 2 weeks of incubation under anaerobic conditions; samples of vitreous and posterior capsule should be obtained for such culture. Other causes of chronic infectious postoperative endophthalmitis include Staphylococcus epidermidis (between 2 and 6 weeks) and fungus (usually Candida, 1 to 3 months). Steroid-resistant or persistent postoperative inflammation is clearly an indication for aqueous and vitreous specimen harvesting for microbiologic stains and cultures. Other causes of anterior uveitis that might, in very rare instances, be confused with phacogenic uveitis are shown in Table 76-2.

TREATMENT Phacogenic uveitis typically responds completely to removal of all lens material. Rerrroval of the inciting lens material is the prescribed treatment. Adjunctive therapy may include systemic and topical steroid and cycloplegics. If phacogenic uveitis follows extracapsular extraction, steroid treatment might be sufficient if the residual cortex is minimal; treatment should continue until all lens material is resorbed. Lens material that is unlikely to be quickly resorbed must be removed surgically. Surgical removal of lens material will be either through a limbal approach (when the residual material is in the anterior chamber) or a three-port pars plana vitrectomy (for lens material in the vitreous cavity). Pars plana vitrectomy is also the best way, of course, to obtain vitreous material for culture purposes. Failure of the uveitis to respond completely to surgical removal of all lens material should alert the clinician to the possibility of sympathetic ophthalmia or another coexistent disorder (e.g., infectious endophthalmitis).

COMPLICATIONS If the lens is not promptly removed from an eye sUffering from phacogenic uveitis, the following complications may occur: glaucoma, pupillary membrane, cyditic membrane, hypotony, corneal edema, macular edema or scarring, and even retinal detachment secondary to contraction of the cyclitic membrane. Ultimately, the eye may be blind and painful, eventually becoming phthisis bulbi.

CONCLUSION Phacogenic uveitis is an important but frequently missed cause of uveitis. It should be suspected in all cases of traumatic or postoperative uveitis and in cases associated

with mature or hypermature cataract. Once the lens material is completely removed from the eye, the inflammation resolves. Failure to remove the lens material from the eye may lead to serious complications and total loss of useful vision. The resurgence of extracapsular cataract extraction may be accompanied by a corresponding increase in cases of phacogenic uveitis.

References 1. Abbas AK, Lichtman AH, Pober JS: Cellular and Molecular Immunology, 3rd ed. Philadelphia, WE Saunders, 1997. 2. Verhoff FH, Lemoine AN: Endophthalmitis phacoanaphylactica. Proceedings of the International Congress of Ophthalmologists 1922;1:234-284. 3. Irvine SR, Irvine AR: Lens-induced uveitis and glaucoma. Part I: Endophthalmitis phacoanaphylactica. Am J Ophthalmol 1952;35:177-186. 4. Khalil MK, Lorenzetti DW: Lens-induced inflammation. Can J Ophthalmol 1986;21:96-':'102. 5. Chandler P: Problems in the diagnosis and treatment of lens-induced uveitis and glaucoma. Arch Ophthalmol 1958;60:828-841. 6. deVeer A: Bilateral endophthalmitis phacoanaphylactica. Arch Ophthalmol 1953;49:606-632. 7. Easom HA, Zimmerman LE: Sympathetic ophthalmia and bilateral phacoanaphylaxis. Arch Ophthalmol 1964;72:9-15. 8. Irvine WD, Flyll.n HW, Murray TG, et al: Retained lens fragments after phacoemulsification manifesting as marked intraocular inflammation with hypopyon. AmJ Ophthalmol 1992;114:610-614. 9. Hodes BL, Stern G: Echographic diagnosis of phacoanaphylactic endophthahnitis. Ophthalmic Surg 1976;7:60-65. 10. Flocks M, Littwin CS, Zimmerman LE: Phacolytic glaucoma. Arch Ophthalmol 1955;54:37-45. 11. Ronday MJH, Stilman JS, Rothova A, et al: Blindness from uveitis in a hospital population in Sierra Leone. Br J Ophthalmol 1994;78:690-693. 12. Ronday M: Uveitis in Africa with emphasis on toxoplasmosis. Netherlands Ophthalmic Research Institute of the Royal Netherlands Academy of Arts and Sciences, Dept. of Ophthalmology, Amsterdam, 1996. ISBN 90-393-1467-5. 13. Marak G: Phacoanaphylactic endophthalmitis. Surv Ophthalmol 1992;36:325-339. 14. Thach AB, Marak GE, McLean IW, et al: Phacoanaphylactic endophthalmitis: A clinicopathologic review. Int Ophthalmol 1991;15:271279. 15. Law F: Ocular reaction to lens protein. Br J Ophthalmol 1953;37:157-164. 16. Rahi AHD, Misra RN, Morgan G: Immunopathology of the lens. I. Humoral and cellular immune responses to heterologous lens antigens and their roles in ocular inflammation. Br J Ophthalmol 1977;61:164-176. 17. Rahi AHD, Misra RN, Morgan G: Immunopathology of the lens. II. Humoral and cellular immune responses to homologous lens antigens and their roles in ocular inflammation. Br J Ophthalmol 1977:61 :285-296. 18. Rahi AHD, Misra RN, Morgan G: Immunopathology of the lens. III. Humoral and cellular immune responses to autologous lens antigens and their roles in ocular inflammation. Br J Ophthalmol 1977;61:371-379. 19. Muller-Hermelink HK: Recent topics in the pathology of uveitis. In: Kraus-Mackiwe E, O'Connor GR, eds: Uveitis: Pathophysiology and therapy. Stuttgart, Thieme, 1986, pp 155-203. 20. Blodi FC: Sympathetic uveitis as allergic phenomenon. Trans Am Acad Ophthalmol Otolaryngol 1959;63:642-656. 21. Easom HA, Zimmerman LE: Sympathetic ophthalmia and bilateral phacoanaphylaxis. Arch Ophthalmol 1964;72:9-15. 22. Allen JC: Sympathetic ophthalmia and phacoanaphylaxis. Am J Ophthalmol 1967;63:281. 23. Meisler AM, Mandelbaum S: P aGnes associated endophthalmitis after extracapsular cataract extraction. Ophthalmology 1989;96:5661. 24. Winward KE: Postoperative P aGnes endophthalmitis. Treatment strategies and long-term results. Ophthalmology 1993;100:447-451. 25. Zambrano W: Management options for P aGnes endophthalmitis. Ophthalmology 1989;96:1100-1105.

I .Will Ayliffe

Retinal vasculitis is a sight-threatening inflammatory eye disease involving the retinal blood vessels. 1, 2 The terms retinal vasculitis and retinal perivasculitis are used interchangeably as clinical descriptions of the funduscopic sign of exudative gray-white sheathing of the retinal blood vessels (Fig. 77-1A).3 Most frequently, the retinal veins are involved and. the term retinal periphlebitis is used to describe this condition. Retinal vascu:Iitis may occur as a primary syn.drome called idiopathic retinal vasculitis, which affects the eye vasculature without any evidence of any systemic or other eye disease. More commonly, retinal vasculitis is seen as a manifestation of systemic diseases including sarcoidosis, collagen-vascular autoimmune disorders, malignancy, neurologic conditions, and systemic infections. 4 ,5 It also occurs in ocular inflammatory conditions such as pars planitis or birdshot retinochoroidopathy, as well as in infections of the eye (Table 77-1). The clinically observable signs of retinal vasculitis are caused by inflammation in or around the walls of retinal blood vessels. 1, 4 Vasculitis in other orgaii systems is confirmed and classified on histopathologic findings. This is not routinely possible for eye disease, so retinal vasculitis is a diagnosis made by ophthalmoscopic'l/observation of sheathing of the retinal vessels. Often this is a correct supposition and pathologic examination of the few enucleated eyes from patients with retinal vasculitis has confirmed leukocytic infiltration of the vessel walls and surrounding tissues. 1, 6-8 However, there are noninflammatory causes of retinal vessel sheathing. 1, 9 These sclerotic changes do not cause

leaking or staining of the vessel wall and are not associated with inflammatory changes in the vitreous. Perivascular sheathing that is not associated with angiographic evidence of leakage may merely represent long-term changes of blood vessels, which can develop following a variety of pathologic changes including vascular occlusion, atherosclerosis, and even previous vasculitis. Inflammatory sheathing often occurs as focal fluffy cuffing with diffuse edges enveloping the vessel, contrasting with the well-defined long segments of sheathing seen as a consequence of noninflammatory vascular disease. The term perivascular cuffing, indicating inflammatory retinal vasculitis, may therefore be a more accurate term than sheathing to describe foci of active retinal vasculitis. The clinical diagnosis of retinal vasculitis· is supported by evidence of inflammation in the anterior chamber or vitreous and leakage or staining of the vessel wall seen by fluorescein angiography (Fig. 77-1 B) .5,10 In addition to ophthalmoscopic observation of perivascUlar cuffing, many other fundal changes can also be seen. These include retinal hemorrhage, branch retinal vein occlusion, neovascularization, and vitreous hemorrhage. 4 ,II

HISTORY The clinical picture of retinal periphlebitis was first described in 1887 by Wadsworth in a discussion of a case report on recurrent retinal hemorrhages by Theobald. I2 However, Perls had already performed histologic examination of periphlebitis in a case of tuberculosis (TB) affecting the eyes in 1873.13 Even earlier, the dramatic

FIGURE 77-1. A) Red-free photograph of the left eye of a patient with retinal vasculitis. There are multiple foci of sheathing around the veins, periphlebitis. These are caused by inflammatory cells within and around the vessel giving the appearance of cuffing. B) Fluorescein angiogram of the same eye as in Figure 77-1A, showing leakage of dye from the inflamed vessel segments. Areas that are not apparently sheathed in Figure 77-1A are revealed by fluorescein angiography to be involved. For example, staining of tlle vessel wall and dye leakage is seen in a clinically normal portion of the inferior arcade.

CHAPTER 77: RETINAL TABLE 77-1. DISORDERS VASCULITIS

_..,.;;»...,_.. D_

WITH

Ocular disorders Idiopathic retinal vasculitis Eales' disease Idiopathic retinal vasculitic aneurysms and neuroretinitis (IRVAN) Bilateral iridocyclitis with retinal capillaritis (BIRC) Acute multifocal hemorrhagic retinal vasculitis Frosted branch angiitis Idiopathic recurrent branch retinal arteriolar occlusion Pars planitis Primary ocular disease Birdshot retinochoroidopathy Sympathetic ophthalmia Vogt-Koyanagi-Harada syndrome Neurologic disorders Multiple sclerosis Microangiopathic encephalopathy, hearing loss, and retinal arteriolar occlusions Isolated central nervous sy'stem angiitis Systemic autoimmune diseases Sarcoidosis Adamantiades-Beh<;:et's disease Buerger's disease Crohn's disease Rheumatoid disease Human leukocyte antigen B27-associated uveitis Sjogren's syndrome A antigen Retinal vasculopathy in systemic vasculitis Systemic erythematosus Wegener's granulomatosis Polyarteritis nodosa Infections associated with retinal vasCl~litis Tuberculosis Syphilis Borreliosis (Lyme disease) Whipple's disease Brucellosis Cat scratch disease Rickettsia Toxoplasmosis Herpes virus Cytomegalovirus HIV Human T-cell lymphoma virus type 1 Rift Valley fever virus Retinal periphlebitis and uveitis 'with viral-like upper respiratory disease Epstein-Barr virus Candidiasis Endophthalmitis Drug-induced retinal vasculitis Retinal vasculitis secondary to malignancy Miscellaneous causes of retinal vasculitis

complication of recurrent vitreous and retinal hemorrhages had previously brought the condition of retinal vasculitis to the attention of ophthalmologists using the first ophthalmoscopes. The observation by van Trigt in 1852 was followed by numerous subsequent descriptions in the literature 12 , 14 and in several 19th century textbooks and atlases such as McKenzie's Practical Treatise on Diseases of the Eye, 4th edition, 1854. 1 The first attempt to describe the syndrome was by Henry Eales in 1880. 15 He associated epistaxis and constipation with recurrent vitreous hemorrhage and, in a later paper, excluded known systemic diseases including diabetes, clotting abnormalities, blood dyscrasias,. and syphilis. 16 In 1887, a 52-year-old. nondiabetic woman with recur-

rent retinal hemorrhages was noted to have disc neovascularization. 12 Subsequently, the presence of periphlebitis in cases of recurrent vitreous hemorrhage was noted. 14 A possible relationship with TB was suggested at the beginning of this century. In India, Mycobacterium tuberculosis is still believed to be the etiologic agent or involved by hypersensitivity in Eales' diseaseP Duke-Elder regarded Eales' disease as a clinical manifestation of inflammatory retinal vein occlusion or periphlebitis. 1 This accords with the modern view of many authorities not recognizing the eponymous condition as a distinct clinical entity. However, the disease is uncommon in the western hemisphere, and clinicians in areas where Eales' disease occurs frequently, s\lch as in India, find it helpful to distinguish this condition frOlll other types of retinal vasculitis. 17 The association of l:etinal vasculitis with systemic disease became' increasingly recognized in the middle of the 20th century. Retinal venous sheathing was observed in some patients with multiple sclerosis. IS Subsequently, many more conditions, from eye infections to systemic inflammatory diseases, were found to be associated with retinal vasculitis. 1, 2, 4

IOlOGY In a prospective epidemiologic study in Savoy, France, the prevalence of uveitis was 38 per 100,000 with an annual incidence of 17 per 100,000 per year. 19 Only 13% of these cases were retinal vasculitis, giving an estimated incidence of 2 per 100,000 per year, which is similar to that in other areas. 5 So, primary retinal vasculitis is rare and always has been. In the year 1980 to 1981, no cases of primary retinal hemorrhage were identified in the 12,000 eye patients who were treated at the Birmingham and Midland Eye Hospital in England. 16 More recently, the diagnosis was made in 25 patients seen at the National Eye Institute (NEI), Bethesda, between 1984 and 1994. 20 Retinal vasculitis affects young adults and there may be female preponderance, although not all studies agree. In a series of 150 patients with retinal vasculitis seen over 10 years at St. Thomas' Hospital in London, the disease was confined to the eye in 40% of cases. lO Most of these patients with primary retinal vasculitis were between 15 and 40 years of age and there was a female-to-male ratio of 4:2.7. A similar age distribution of 14 to 52 years but with an equal female-to-male ratio was found. in. the NEI group.20 However, retinal vasculitis is seen more commonly as a manifestation of ocular infections or systemic disorders such as Adamantiades-Belwet's Disease (ABD) ,4,5 and the incidence of these diseases varies throughout the world. Therefore, data from centers with a predominantly white population do not reflect the incidence of retin'at vasculitis in other regions such as Brazil or Japan.

Symptoms Inflammation of the peripheral retinal vessels may be completely asymptomatic even in those patients with asso-

ciated systemic disease. 4 ,21 However, patients with retinal vasculitis often complain of painless blurring or loss of vision. Large scotomata corresponding to areas of ischemia may also be noticed.' These symptoms may be accompanied by floaters. Some patients, particularly those with Eales' disease, may present with sudden loss of vision due to vitreous hemorrhage. Symptoms and signs suggestive of systemic involvement should be identified. These include, but are not limited to, orogenital ulceration, arthritis, skin rashes, thrombosis, and neurologic and respiratory symptoms. It is often helpful to ask the patient to complete a standard uveitis questionnaire, and further inquiry with respect to positive ahswers enables the ophthalmologist to focus on specific systemic entities. Visual acuity is variably affected. In the St. Thomas study, two thirds of patients had an acuity of 6/18 in at least one eye, and only 22% had bilateral acuities of less than 6/18. 10 Similarly, the NEI group reported a median visual acuity of 20/63 (range, 20/16-light perception) at the time of referral. 20 The diseas'e affected both eyes in all cases.

Signs Slit-lamp examination of the anterior segment is useful to detect anterior uveitis, which is found in about one third of cases. IO Occasionally, evaluation of associated scleritis is required. Cellular infiltration of the vitreous is present in nea.rly all patients and it can be severe. Collections of inflammatory cells,. or snowballs, are typically found in the inferior vitreous cavity, and ~ posterior vitreous detachmept is usually present. The striking vascular changes are the hallmark' of retinal vasculitis. During the active phase, sheathing of the vessels occurs, which is seen by ophthalmoscopy as focal fluffy-white cuffing, in approximately two thirds of patients (Table 77-2).10, 20 The sheathing may develop around long stretches of the vessel or it may occur as skip lesions. The sheathing is most often seen around retinal veins but can also affect arteries. Some authors have attempted to differentiate sheathing, seen in peripheral

TABLE 11-2. POSTERIOR FINDINGS AT PRESENTATION IN 25 PATIENTS FINDINGS Vascular sheathing Arteries and veins Arteries Veins Not specified Neovascularization Intraretinal hemorrhage Sclerotic!attenuated vessels Vitreous hemorrhage Vascular occlusion Cystoid macular edema Branch retinal vein occlusion Optic atrophy Retinal detachment

retina and not necessarily associated with fluorescein leakage, from periphlebitis, identified as cuffing of retinal veins, with leakage of fluorescein at these sites. lo This fine distinction may help to separate active disease from chronic changes, but it is not universally recognized, and we regard perivascular exudates or cuffing as active vascular disease. 3 An extreme form of exaggerated sheathing of the vessels gives a clinical picture that resembles tree branches in winter. This sign is called frosted branch angiitis. 22 As well as vasculitis, other perivascular changes may occur in certain conditions. These need to be differentiated from true retinal vasculitis. For example, in some patients with sarcoidosis, discrete waxy nodules may be seen adjacent to the retinal vessels. 23 These yellow perivenous exudates, originally described by Walsh in 1939, were likened to candle wax drippings and called taches de bougie by Franceschetti and Babel in the French literature. 7,23 This change represents perivascular granulomatous tissue with associated exudation. 7 It is seen in eyes with sarcoidosis but it is not necessarily pathognomonic for that condition. Likewise, characteristic gray-white granular deposits are seen on the retinal vessels in human T-cell lymphoma virus type-l (HTLVI) -associated uveitis, and if recognized they may help establish the diagnosis. 2'1 · Retinal vascular occlusions are particularly associated with ABD,lO but they are also seen in other types of retinal vasculitis. 20 Occlusive vasculopathy leads to retinal hemorrhage, cotton-wool spots, and pallor in areas of retinal ischemia. The vessels in these areas eventually become sclerotic and attenuated,20 with large areas of capillary nonperfusion and retinal ischemia. Subsequent retinal neovascularization, occurring in 16% to 40% of all cases of retinal vasculitis, may develop, along with vitreous hemorrhage. Alterations in the vascular architecture have also been described. These develop just temporal to the macula and include arteriolar-venous anastomoses and traversing of retinal vessels across the horizontal raphe. 4 In addition to vascular changes, retinal pathology may also occur. Retinal edema is common and may precede vascular cuffing. 4 Deep retinal infiltrates are seen in some patients with ABD, and atrophic retinal pigment epithelial lesions may be seen in patients with isolated retinal vasculitis. 10

NUMBER OF PATIENTS (%) 16 (64) 4 (16) 2 (8) 1 (4) 9 (36) 10 (40) 9(36) 8 (32) 6 (24) 5 (20)

4 (16) 2 (8) 2 (8) 1 (4)

Modified from George T, Walton Re, Whitcup SM: Primary retinal vasculitis: Systemic associations and diagnostic evaluation. Ophthalmology 1996;103:384389.

Fluorescein Angiographic Findings Diffuse capillary leakage is a common finding in patients with idiopathic retinal vasculitis. lo Macular ischemia is most readily identified on fluorescein angiography, and it is important to recognize, particularly in patients whose visual acuity fails to improve despite aggressive medical therapy and inflammatory control. Late staining of vessels occurs in two thirds of patients, and it affects arteries, veins, or both (Fig. 77-2). Patients with ischemic disease have retinal capillary closure and nonperfusion. 20 When this affects the macula, it causes an enlarged or irregular foveal avascular zone. 25 Using fluorescein angiography to separate patients into ischemic and nonischemic groups has been shown to predict the visual outcome. 25 -

CHAPTER 77: RETINAL

detail in other chapters. The purpose of this survey is to highlight the retinal vascular changes and diagnosis of patients who have retinal vasculitis.

Retinal Vasculitis in Ocular Disease

The disorders associated with retinal vasculitis are multiple and diverse. A summary of the main diseases is found in Table 77-1. Many of the conditions are dealt with in

Primary retinal vasculitis is a rare disease but it affects young adults and can cause blindness. 2o , 25 It is a clinical diagnosis based on the ophthalmoscopic findings of sheathing of the retinal vessels and vitritis. The diagnosis is supported by fluorescein angiography, which may also reveal areas of clinically invisible disease (Fig. 77-4). In the absence of systemic clinical findings by history and examination, an extensive laboratory investigation is not required. 20 In these cases, investigation can be limited to a full blood count and sedimentation rate, serology for syphilis, and a chest radiograph. However, in those patients with symptoms or signs indicating an underlying systemic condition, a work-up tailored to the suspected diagnosis is required. The visual outcome is variable and depends on the presence of retinal ischemia. 25 The ischemic group fared less well over a 5-year follow-up, with 34% having vision of 6/60 or worse compared to only 6% of the eyes deemed to be nonischemic at the start of the study.25 Although retinal vasculitis may appear to be confined to the eye at presentation, it must be remembered that serious systemic illness may subsequently develop in some of these patients. In a retrospective study of 67 patients with at least 5 years follow-up, those with ischemic retinal vasculitis had a 59% chance of developing systemic disease. Over half of these had a major vascular event such as cerebrovascular accident or stroke. 26 This is of some consequence because these patients are young. So, although intensive investigations are not required to pursue a diagnosis in patients with isolated retinal vasculitis,20 it is prudent to pay attention to cardiovascular risk factors including blood pressure, lipids, and particularly smoking. 26

FIGURE 77-3. Fluorescein angiogram of retinal neovascularization in a patient with retinal vasculitis. Scars from laser that had been previously applied on the adjacent retina can be seen superiorly. The photograph is of the right eye of the same patient as in Figure 77..:..1 and was taken on the same day.

FIGURE 77-4. Fluorescein angiogram of the midperipheral fundus in another patient with retinal vasculitis revealing active disease in small vessels that was not detectable by ophthalmoscopy.

FIGURE 77-2. Late-phase fluorescein angiogram demonstrating staining of blood vessel walls.

Neovascularization is identified in 12% to 16% of patients with idiopathic retinal vasculitis. 20 The new vessels are flat and sometimes difficult to detect clinically. They leak fluorescein profusely and are readily detectable by fluorescein angiography, providing that peripheral. areas of the fundus are imaged (Fig. 77-3). It is found more frequently in those patients with retinal vasculitis as~oci­ ated with sarcoid or uveomeningitis. lO Neovascularization may often develop as a cons~quence of inflammatory mediators rather than of retinal ischemia, which is found in only one third of cases. 10

DISORDERS ASSOCIATED WITH VASCULITIS

17: RETINAL VASCULITIS

A syndrome of recurrent retinal and vitreous hemorrhage in young men, associated with constipation and epistaxis, was first·· de,<;;cribed by Henry Eales in 1880 15 and was later shown to be associated with retinal periphlebitis. Classically, this entity manifests as an obliterative periphlebitis, anterior to the equator, involving multiple quadrants, with progression posteriorly. Neovascularization elsewhere (commonly occurring at the border between perfused and nonperfused retina), neovascularization of the disk, and rubeosis iridis may occur with or without vitritis. 5 While these changes may simulate those seen in idiopathic branch retinal vein occlusion, the retinal vascular changes associated with Eales' disease do not commonly occur at arteriovenous crossing sites and may or may not be associated with extensive cotton-wool spots. In addition to the retinal venous changes, choroidal inflammation develops under inflamed vein segments, and anterior, posterior, or intermediate uveitis may be present. 17 Eales' disease typically presents in young, healthy adult men between 30 and 40 years of age. It is most prevalent in India, Pakistan, and Mghanistan. 27 In India it is common, with an incidence of 1:200 ophthalmic patients. 17 In that subcontinent, the disease is associated with TB, and concomitant therapy with oral steroids and antitubercular chemotherapy is recommended if evidence of this infection is found. In other. patients, the disease responds to oral steroids with sector laser panretinal ablation or cryotherapy to areas ofnonperfused retina in the presence of neovascularizatio~ involving the retinal periphery or posterior pole. Some· investigators have recommended full panretinal photocoagulation and early vitrectomy, in an effort to improve the visual prognosis in patients with Eales' disease. 28 Vitreoretinal surgery is necessary in cases with prolonged vitreous hemorrhage or complications arising from vitreoretinal traction (Fig. 77-5). The diagnosis of Eales' disease is essentially one of exclusion. Fluorescein angiography is extremely valuable in revealing the degree of retinal capillary nonperfusion and the presence of neovascularization, and as a guide to laser photocoaglllation for sector ablation. The strong association of Eales' disease with purified

FIGURE 77-5. Recurrent vitreous hemorrhage in a patient with periphlebitis Eales' disease. (See color insert.)

protein derivative skin positivity,29 and the demonstration of circulating immune complexes in these patients 30 suggests that Eales' disease is an immune-driven process. However, it is hard to reconcile this theory with the relative paucity of this disease in populations who are immunized with Bacille Calmette-Guerin vaccine. A longterm follow-up study of patients with Eales' disease found that a proportion developed vestibuloauditory dysfunction. 31 This complication occurs in other idiopathic retinal vasculitis subgroups,32 which suggests that Eales' disease may in fact be a part of a spectrum of related conditions. Indeed, it is debatable whether Eales' disease represents a separate condition or is merely part of a spectrum of retinal vasculitis. The condition is probably identical to ischemic idiopathic retinal vasculitis,25 and the eponym is less frequently used in the modern literature.

Idiopathic Retinal Neuroretinitis

Va~~ClJrlltjs anjQ,rBlI"\I~Int'll~

Two patients with bilateral retinal arteritis, multiple microaneurysms, neuroretinitis, and uveitis were described in 1983. 33 Ten more cases were subsequently described, in more detail, and the name idiopathic retinal vasculitis aneurysms and neuroretinitis (IRVAN) was proposed. 34 The distinctive retinal findings are numerous aneurysmal dilations (75 to 300 /-1m in'. diameter) of the retinal and optic nerve head arterioles. The sight-threatening complications are exudative retinopathy and peripheral capillary nonperfusion, leading to neovascularization and vitreous hemorrhage. Neuroretinitis (manifested by late diffuse staining of the optic nerve head) and retinal vasculitis (staining of the vessel walls seen in the late stages of the angiogram) were used as inclusion criteria for the study. Despite the apparently inflammatory nature of this syndrome, steroids had little effect on the degree of uveitis or retinal ischemia. 3'l Retinal photocoagulation is recommended if neovascularization or rubeosis iridis develops. The condition is limited to the eye and inappropriate investigation can be avoided by tailoring the work-up to the review of systems. In addition to causing inflammation in arterioles and veins, retinal vasculitis can affect the capillary bed. A group of 18 juvenile patients with bilateral granulomatous uveitis and retinal capillaritis has been described. 35 The patients with this disease were between 9 and 17 years of age and presented with red eyes and photophobia. Examination revealed a variable extent of cloudy edematous retina. Fluorescein dye leakage and pooling from the retinal capillaries underlying the. cloudy retina was the characteristic finding on angiography. Leakage from arterioles and veins was not observed, and this helped to distinguish the condition from other causes of retinal vasculitis associated with uveitis. Although leakage restricted to the retinal capillaries has been described in acute tubular interstitial nephritis, none of the patients with bilateral iridocyclitis with retinal· capillaritis (BIRC) had any evidence of systemic disease. The condition was associated with human leukocyte antigen (HLA)-DR6 alld

CHAPTER 77: RETINAL

HLA-Cw7, but HLA-B27 was not found in any of the patients and there was no increased incidence of HLADR8, which is associated with juvenile rheumatoid arthritis. Retinal vasculitis associated with seronegative spondyloarthritis also presents with diffuse capillary leakage and macular edema. lO The .capillaries and postcapillary venules are the preferential sites for inflammation in these patients.

Acute Multifocal Hemorrhagic Retinal Vasculitis In 1988, a group of seven patients with acute bilateral loss of vision, retinal vasculitis (predominantly venular), variable retinal hemorrhage, posterior retinal infiltrates, vitritis, and papillitis was described. 36 The vasculitis was predominantly an occlusive phlebitis. These patients were otherwise fit and well. Treatment with oral prednisone was of some benefit but acyclovir was ineffective. Five of the patients developed neovascularization of the posterior pole and required laser photocoagulation. The major differential diagnostic considerations were acute retinal necrosis, sarcoidosis, toxoplasmosis, and ABD, all of which were excluded. This condition, like Eales' disease, appears to be yet another presentation of idiopathic retinal vasculitis, but whether it truly represents a distinct pathologic process is far from c~ear. j

Frosted Branch Angiitis In some patients with retinal vasculitis, the sheathing of the blood vessels is so extensive 'hat the underlying vessels are obscured. This clinical picture, which looks like the branches of trees in winter, was first reported in a healthy 6-year-old Japanese boy and was called frosted branch angiitis. 22 Although initially described as affecting both arteries and veins, it predominantly involves the veins. 37 Patients report with acute decrease in visual acuity. On examination, cells are detected in the anterior chamber and vitreous. Prominent sheathing of retinal veins is the hallmark of this condition, but in younger patients, the arteries may also be involved. In severe cases, macular edema develops. No clinical or laboratory evidence of systemic disease is detected. Treatment is with systemic steroids. The condition resolves with treatment over 2 to 3 weeks, and most patients return to 20/20 acuity. The initial cases were idiopathic, but subsequently cases have been described in patients with acquired immunodeficiency disease (AIDS) and early cytomegalovirus (CMV) retinitis. 3s After anti-CMV treatment is started, the sheathing resolves in 2 weeks, before the retinal opacification clears. The need to add steroid is debatable. Frosted branch angiitis is a clinical sign representing an exaggerated sheathing of retinal vessels. It will probably be reported to occur in many other conditions that cause retinal vasculitis such as sarcoidosis, in infectious disorders,39 and even in neoplastic disease. 4o

Idiopathic Recurrent Branch Retinal Arteriolar U(:ClllISlon A small number of reports have described healthy middleaged patients who developed recurrent branch retinal

artery occlusions of unknown cause in one or both eyesY These patients do not have underlying inflmnmatory disease or evidence of embolism. Ophthalmoscopy reveals focal periarterial sheathing, and fluorescein angiography shows multiple segments of arteriolar staining, suggesting that arteritis is the cause of the obstructions. Preretinal neovascularization occurs in areas of ischemia, but the prognosis for vision is generally good. Although no systemic cause was found, 50% of the· patients had vestibuloauditory or transient sensorimotor symptoms or both. 32 It has been suggested2 that these patients may have a partial manifestation of the microangiopathic syndrome of encephalopathy, hearing loss, and retinal arteriolar occlusions. 42 However, patients with the microangiopathic syndrome do not show evidence of true retinal vasculitis.

Pars Planitis Pars planitis is a type of intermediate uveitis characterized by vitritis and snowballs, peripheral retinal vasculitis, and exudate at the pars plana. Although initially described as inflammation of the ora serrata, the term pars planitis was subsequently more commonly adopted. 43 The disease is usually bilateral at presentation and can vary from a mild inflammation, requiring no treatment, to a severe blinding condition. The pars plana exudate is composed of collapsed vitreous, blood vessels, fibroglial tissue, and infiltrating lymphocytes. Pathologically, the exudates are collections of multinucleated giant cells and epithelioid cells. It remains uncertain whether the disease is primarily a retinal vasculitis, with the associated features being a consequence of the blood-retinal barrier breakdown, or whether it is a vitritis.

Primary Ocular Diseases Retinal vasculitis, primarily affecting the retinal venules, is a prominent and consistent feature of birdshot retinochoroidopathy. Birdshot retinochoroidopathy may present as idiopathic retinal vasculitis with the development of the characteristic focal cream-colored lesions. 44 ,45 Sympathetic ophthalmia also has striking choroidal changes (Dalen-Fuchs nodules) with panuveitis. Some patients also have retinal vasculitis. 46 In.Vogt-Koyanagi-Harada syndrome, retinal periphlebitis47 and peripapillary venous sheathing are occasionally seen. 4S All these conditions are described in detail in other chapters.

Retinal Vasculitis as a Manifestation Neurologic Disease

Multiple Sclerosis A variety of ocular inflammatory signs have been described in patients with multiple sclerosis (MS), including iritis, intermediate uveitis, posterior uveitis, periphlebitis, and optic neuritis. 49 The association of retinal venous sheathing and MS was first reported by Rucker, who found the sign in 20% of patients. IS The reported incidence of retinal periphlebitis in MS varies from 8.5% of eyes at autopsy,50 to 33% of patients with MS undergoing ophthalmic examination. 51 In most cases, the periphle- . bitis is subtle, peripheral, and of no visual consequence. It is also transient, explaining the wide variability of its

77: RETINAL VASCULITIS

reported incidence. However, in other patients the periphlebitis can be severe, leading to occlusive vasculitis, ischemia, and retinal neovascularization. 49 Patches of fluffy perivascular cuffing represent areas of active disease, whereas sclerotic whitening of the venular wall with no leakage is probably a chronic change. The periphlebitis consists of a lyrnphoplasmacytic .infiltrate, occasionally with a granulomatous component. 50 The changes are similar to those seen in the brain of MS patients, which suggests that the finding of retinal vasculitis might have important implications. In a study of 54 patients with pars planitis, 22% developed MS or optic neuritis after a 7.5-year follow-up.52 The presence of retinal vasculitis at the time of diagnosis was associated with earlier onset of MS or optic neuritis. The presence of retinal periphlebitis might also be an indicator of active neurologic disease. In a study of 282 patients with MS, retinal vasculitis was found in 43% of those with active disease compared to 25% of the group in remission. 53 In contrast, a more recent study did not find this correlation with disease activity.54 The relationship between MS and retinal vasculitis is therefore complex. About 25% of patients with retinal vasculitis or pars planitis will develop MS, particularly if they are female and carry the HLA-B7 or HLA-DR2 alleles. About 15% of patients with MS will have asympto-matic retinal vasculitis, and 25% will d~velop a symptomatic uveitis.

A Microangiopathic Syndrome of '1j E.ncephalopathy, Hearing Loss, and Retinal Arteriolar Occlusions This occlusive arterial disease affecting the brain, inner ear, and retina affects young women. 42 Patients present with encephalopathy manifesting as behavioral change and memory disturbance with hearing loss and tinnitus. Eye examination reveals bilateral retinal arterial occlusions and retinal infarctions. Although the arterioles are occluded with white matter, there is no clinical or angiographic evidence of vasculitis, and brain biopsies show multiple noninflammatory arteriolar occlusions. The disease may therefore not be a true retinal vasculitis, as is also the case for many patients with cerebral lupus. and "retinal vasculitis. "55

in 25% to 50% of patientsY Although anterior uveitis is the most common eye association, retinal vasculitis is a characteristic feature of sarcoidosis. It is nearly always a retinal periphlebitis, and retinal arteries are only rarely involved. It is the most common fundal finding and occurs in 10% to 45% of patients with active disease. 58 The involvement of vessels is discontinuous, and this appears clinically as skip lesions. It may be mild and associated with peripheral retinal and focal vitTeal infiltrates indistinguishable from idiopathic intermediate uveitis. Indeed, pars planitis may be the presenting sign in patients who develop sarcoidosis many years later. In other patients, a more severe periphlebitis develops (Fig. 77-6). In the acute stage, this can be accompanied by retinal hemorrhage and edema. Retinal pigment epithelial atrophy may subsequently develop under the sites of periphlebitis. lo , 58 With systemic corticosteroid treatment, periphlebitis resolves, but some residual sheathing can persist. Yellow perivenous exudates, described as taches de bougie (candle wax drippings), are also sometimes seen. 8 They are not, however, pathognomonic for sarcoidosis. Neovascularization develops in 20% of cases lO and may lead to vitreous hemorrhage or retinal detachment. It is often associated with ischemia and responds to panretinal la~er photocoagulation.

Adamantiades...Beh~et's Disease ABD is a multisystem inflammatory illness presenting with recurrent orogenital ulceration, skin lesions, and intraocular inflammation. It is the leading cause of endogenous uveitis and acquired blindness in Turkey and Japan, and it is associated with HLA-B51. 4 Retinal vasculitis is a major cause of visual loss in this multisystem disease, and it is difficult to treat. Relapses are frequent, leading eventually to a final stage of retinal and optic disc atrophy, variable chorioretinal and retinal pigment epithelial change, sheathed vessels, and chronic mild vitritis. The acute stage of retinal vasculitis is associated with yellow-white retinal infiltrates. lo Recurrent branch retinal vein occlusions are more common in ABD than in any

Isolated Central Nervous System Angiitis This rare disorder can affect all age groups. It is characterized by granulomatous inflammation of intracerebral and leptomeningeal vessels. 56 The disease may be a nonspecific immunopathologic response to a variety of antigens. It has been reported to occur in some patients with malignant lymphoma and in patients with varicella zoster virus infections. 49 Some patients with isolated central nervous system (eNS) angiitis have occlusive retinal vasculitis. 49

Retinal Vasculitis in Association with Systemic Autoimmune Disease Sarcoidosis Sarcoidosis is a granulomatous disease of unknown origin that affects many organs. Ophthalmic involvement occurs

FIGURE 77-6. The fundus of a patient with sarcoidosis and retinal vasculitis showing creamy white sheathing of the retinal veins. (See color insert.)

CHAPTER 77: RETINAL '(f_.;;Il""~Jil-m

other type of retinal vasculitis. lO Capillary closure causes macular ischemia and, if extensive, can lead to neovascularization of the retina, disc, and iris. Arteriolar sheathing and .occlusion may also develop. The vascular events are accompanied by vitritis, diffuse capillary leakage, macular edema, and optic disc swelling.

Buerger's Disease Thromboangiitis obliterans (Buerger's disease) is an inflammatory obliterative vascular disease of unknown etiology that preferentially affects male smokers. The arterial lesions are segmental. The arterial wall is infiltrated with polymorphonuclear leukocytes and lymphocytes, and the inflammation extends into the surrounding tissues involving the veins. Fibrosis and proliferation of the intima follows and the lumen becomes obliterated with thrombus. 59 The disease follows a relapsing course with paroxysmal episodes of pain, cyanosis, and even gangrene. Ocular involvement may be preceded by a prodromal phase of visual obscurations that may result in complete blindness. The periarteritis of the retinal vessels results in obliterative endarteritis with thrombosis. The vessels eventually become densely sheathed, appearing as white strands. Occlusion of the central retinal artery is rare. Retinal vein occlusions and recurrent hemorrhages also occur. 60

Crohn's Disease Crohn's disease is a focal granulomatous disease affecting any part of the alimentary trac~. Systemic vasculitis can occur in inflammatory bowel disease and several organs including the eyes may be affected. Uveitis occurs in 2% to 9% of patients with inflammatory bowel disease. 61 Retinal vasculitis associated with Crohn's disease is rare. In a study of 17 patients with uveitis and inflammatory bowel disease, a pars plana exudate occurred in one patient and retinal vasculitis was found in two (11 %).61 However, the retinal disease can be severe, affecting both retinal arteries and veins. 62 ,63 Treatment may require both systemic corticosteroids and cyclophosphamide. 62

Rheumatoid Disease Rheumatoid arthritis is the most common rheumatic disorder and affects 1% to 2% of the adult population. Although it is recognized as a symmetric deforming polyarthritis, extra-articular manifestations are common and affect a variety of tissues. Retinal vasculitis is rarely associated with rheumatoid arthritis, but several cases have been reported. 64 However, it may occur more frequently than is suspected by clinical examination alone. It has been found by fluorescein angiography to affect 17 patients with rheumatoid arthritis, even if no ophthalmoscopic signs were present. 65 Retinal vasculitis has also been reported in juvenile rheumatoid arthritis and in severe seronegative arthritis, although it is a very rare complication. lO

H LA-B11-Assodated Uveitis Although acute iritis is the most common manifestation of HLA-B27-associated uveitis, retinal vasculitis may occur. 66 It may be overlooked on clinical examination and detected only by fluorescein angiography. Some patients

have more severe vasculitis, with multiple retinal infarcts, intraretinal hemorrhage, disc swelling, vitritis, and macular edema. 21

Sjogren's Syndrome A Antigen Sjogren's syndrome is a multisystem disease that is often overlooked. Some of these patients are at risk of severe systemic manifestations, which may require immunosuppression. In a study of eight patients with primary Sjogren's disease and uveitis, four had pars planitis and one had a history of retinal periphlebitis and branch retinal vein occlusion. 67 Patients with antibodies to Sjogren's syndrome A (SSA) antigen, who may have mild or presumptive systemic lupus erythematosus (SLE), can also develop peripheral retinal vasculitis (arteriolitis) and neovascularization. 68 It seems that retinal vasculitis (arteriolitis) is more commonly seen in lupus-like illnesses if SS-A antigen is present. It is important to recognize the existence of this syndrome to prevent confusing the neurologic manifestations of Sjogren's disease with MS. In addition, primary Sjogren's syndrome is associated with malignancy, and there are other aspects of this autoimmune disease that may require attention.

Retinal Vasculopathy in Systemic Vasculitis

Systemic Lupus E.rythematosus Retinopathy is the most frequent ocular complication of SLE, occurring in 7.5% of well-controlled patients. 69 The majority of these patients have mild small-vessel disease manifesting as multiple cotton-wool spots and intraretinal hemorrhages. The cotton-wool spot is the hallmark of the classic retinopathy of SLE. In contrast to hypertension and diabetes, arteriolar dilation, rather than constriction, may be observed. In some patients with SLE, especially those with elevated antiphospholipid antibodies, severe retinal vaso-occlusive disease may develop with occlusion of both arterioles and venules, causing retinal ischemia and proliferative retinopathy.70 The vessel occlusion may be caused by true vasculitis with perivascular inflammatory sheathing. 49 However, the retinopathy is more commonly not a true vasculitis but is caused by nonvasculitic occlusion, which is not associated with an inflammatory cell infiltrate, and is seen clinically as multiple cotton-wool. spots.55 The cause of these noninflammatory microvascular occlusions is contentious. A study in mice with lupus-like diseases suggests that occlusion of capillaries is by large immune complexes. 71 If these complexes are able to penetrate the vessel wall as in the choroid, then an intense in.flalumatory reaction will occur. It is suggested that the tight endothelial barriers in the retinal vasculature prevent either. egress of the complexes or ingress of the leukocytes, and therefore inflammation is not initiated.55 The cause of occlusions in larger vessels is also uncertain but they may be initiated by lUpus anticoagulant, anticardiolipin antibodies, or antiendothelial antibodies. Occlusion of capillaries and small to medium-sized

CHAPTER 77: RETINAL VASCULITIS

arteries and veins may lead to proliferative retinopathy.'19 Proliferative lUpus retinopathy may progress despite absent antinuclear antibody and normal serum complement levels. There does not have to be serologic evidence of active SLE for neovascularization to develop, particularly in the presence of retinal ischemia. Regression can be induced by panretinal scatter laser photocoagulation. 49 , 70

Wegener's Granulomatosis Wegener's granulomatosis is a granulomatous, necrotizing, vasculitic condition that primarily affects the upper and lower respiratory tract and the kidneys. Ocular manifestations are common and may precede involvement of other organs. 72 Ophthalmic disease is the presenting feature in 8% to 16% of cases, and it may eventually develop in up to 87% ofpatients. 73 The eye disease mostly affects the orbits, causing proptosis, and the anterior segment, causing necrotizing sclerokeratitis. 74 Vitritis and optic nerve vasculitis occasionally develop.74 Surprisingly, retinal vasculitis is an extremely uncommon manifestation of Wegener's granulomatosis. 73 The cytoplasmic pattern of the antineutrophil cytoplasmic antibody (cANCA) is highly specific for this disease. 75

Polyarteritis Nodosa Polyarteritis nodosa has protean manifestations depending on the site of vasculitis. There are disseminated inflammatory lesions involving medium and small-sized arteries, commonly affecting the heart, kidneys, liver, gastrointestinal tract, and CNS. Ocular in~olvement is infrequent, affecting 10% to 20% of patients and typically involving the choroidal arteries. 76 Retinal arteritis can occur and patients may present initially with uveitis. 76

Relapsing Polychondritis Relapsing polychondritis is a rare connective tissue disease characterized by inflammatory episodes involving the cartilage of the nose, ears, larynx, and trachea, together with an inflammatory arthritis. In a review of 112 patients, ocular disease was noted in 21 patients at the time of diagnosis, with episcleritis and scleritis being the most common manifestations. Retinal vasculitis, often associated with retinal vascular occlusion, was noted in 9% of the patients. 77

Infections Associated with Retinal Vasculitis

Bacterial TUBERCULOSIS

TB of the retina occurs via hematogenous spread from infections elsewhere, which may be occult. Choroiditis is the most frequent ocular feature of TB,78 but periphlebitis is the most common retinal sign and, rarely, it can be the presenting sign of disseminated TB.79, 80 There is usually associated vitritis and retinal hemorrhage. 79 Branch or central retinal vein occlusion luay occur, and this causes peripheral capillary closure. Neovascularization and vitreous hemorrhage may then develop. This infection must be considered when evaluating patients with idiopathic retinitis. In India, the infection

or hypersensitivity to Mycobacterium, antigens can cause a clinical picture identical to that of Eales' disease. 17 The diagnosis is often difficult because it is hazardous to obtain biopsy material from these inflamed eyes. Smears and cultures from aqueous and vitreous have a low yield of positive results. 78 Polymerase chain reaction to amplify Mycobacterium DNA from intraocular fluids can be used. Most often, the diagnosis of intraocular TB is presumed in indirect evidence even in the presence of systemic disease. A 2-week trial of antitubercular drugs without steroids is recommended by some authors in cases of retinal vasculitis with a high sedimentation rate and a positive Mantoux reaction or suspicious chest radiographic findingsY However, single-agent treatment with isoniazid is not advised because of the risk for development of drug-resistant organisms. Neovascularization of the disc and retina can be treated with panretinal scatter photocoagulation. SYPHILIS

Because syphilis can mimic a variety of eye diseases, the infection should be excluded in any patient with retinal vasculitis. Syphilis causes vitritis, chorioretinitis, venous and arterial occlusions, retinal vasculitis, neuroretinitis, optic neuritis, subretinal neovascularization, and exudative retinal detachments. 81 Syphilitic retinal vasculitis is 'rare and is usually an arteritis, but isolated periphlebitis can also occur. 82 Spirochetes cannot be routinely isolated, so the diagnosis is made by clinical history, examination, and laboratory tests, including the Venereal Disease Reference Laboratory (VDRL), fluorescent treponemal antibody absorption (FTA-ABS), and micro hemagglutination T pallidum tests. The uveitis may occur late in the course of the disease and the VDRL can be negative, so confirmatory FTA-ABS and microhemagglutination assay- T pallidum should be performed. 2 BORRELIOSIS (LYME DISEASE)

Lyme disease is caused by the tick-borne spirochete Borrelia burgdorferi. It is transmitted to humans via the bite of an infected tick, whose normal hosts include deer, birds, and field mice. The acute stage of Lyme disease is a localized annular skin rash with influenza-like symptoms. If left untreated, a variety of systemic symptoms may develop over the subsequent few weeks, affecting the integumentary, cardiovascular, musculoskeletal, and neurologic systems. Eventually, chronic arthritis and neurologic symptoms develop. The patients susceptible to arthritis have the HLA-DRb1 *0401 allele, which is also found in rheumatoid arthritis. This allele binds a peptide derived from an outer surface protein of Borrelia called protein A. This peptide shows sequence homology with a human protein (LFA-1) and this may generate an autoimmune T-cell response to the self antigen. Posterior uveitis occurs in the disseminated and chronic phases. Pars planitis, vitritis, choroiditis, exudative retinal detachment, branch retinal artery occlusion, and retinal vasculitis have all been described. 83 Retinal vessel sheathing and occlusion may lead to disc or retinal neovascularization and vitreous hemorrhage. The diagnosis is made with the clinical history and

77: RETINAL

serologic evidence of B. burgdorferi infection. Cytologic examination of the vitreous may reveal the organism. 84 Serologic tests including immunofluorescence and enzyme·:1inked immunosorbent assay have limited sensitivity, but a rising titer of immunoglobulin G (IgG) supports the diagnosis of active disease. Western blot assay of vitreous specimens may also be helpful.

Retinal vasculitis is not typically associated with cat scratch disease, although a few cases are being recognized. 88 The role of antibiotic treatment for the systemic disease is controversiaP7 It is advisable to treat the posterior segment manifestations with antibiotics to lninimize visual loss from retinal and optic nerve damage, and ciprofloxacin has been used to treat retinal vasculitis and pars planitis with· good effect.88

WHIPPLE'S DISEASE

Whipple's disease is a multisystem chronic inflammatory disorder that mainly affects men in their fifth decade. It causes fever, arthralgia, weight loss, anemia, diarrhea, and abdominal pain. An infectious cause is supported by histopathology demonstrating macrophages containing gram-negative bacilli that stain intensely with periodic acid-Schiff reagent. Intraocular involvement is rare, but uveitis, retinal vasculitis, retinal hemorrhage, .capillary nonperfusion, vitreous hemorrhage, and papilledema have all been described. 85 These intraocular complications may occur in the absence of CNS disease. Treatment is with oral tetracycline or intravenous chloramphenicol to eradicate the bacterium. BRUCELLOSIS

Brucellosis is a zoonotic systemic infection caused, by members of the bacterial genus Brucella. It was first identified in British soldiers serving . on the Mediterranean island of Malta. The infection is transmitted by direct contact with infected animals bU1fl..,mostly by consumption of unpasteurized dairy products. Brucellosis presents acutely with fever, .fatigue, weight loss, abdominal pain, and arthralgia. If not treated, it enters a chronic phase with arthritis, sacroiliitis, and neurologic complications. Many other synlptoms and signs can also occur. The eye may be involved in either the acute or the chronic phase, and uveitis is the most common manifestation. Inflammation may cause granulomatous or nongranulomatous anterior uveitis, vitritis, retinitis, and choroiditis. 86 Retinal vasculitis may also occur. The diagnosis is easily overlooked in patients with chronic uveitis, and this condition remains an important health hazard in many developing countries. 86 CAT SCRATCH DISEASE

Cat scratch disease is a zoonotic infection with Bartonella henselae (formerly classified under the genus Rochalimaea) , a small gram-negative rod of the Rickettsiaceae family of the Proteobacteria. It causes asymptomatic bacteremia in domestic kittens. Infection in humans is nearly always a mild self-limiting condition 87 ; it is considered to be the most common cause of chronic regional lymphadenopathy in children and young adults. A local papule or vesicle occurs at the inoculation site, followed in a few weeks by a tender regional lymphadenopathy that resolves over several months. Extranodal dissemination causes severe and sometimes widespread complications. Primary infection affecting the ocular surface causes Parinaud's syndrome. More severe eye sequelae include neuroretinitis, optic neuritis, uveitis, retinitis, and focal choroiditis. 87

ROCKY MOUNTAIN SPOTTED FEVER

Rickettsia rickettsii, the cause of Rocky Mountain spotted fever, is transmitted to humans by the bite of an infected tick. It is the most common rickettsial disease in the United States, with up to 12,000 reported cases annually, the majority of which are from North Carolina. 88 Retinal involvement is uncommon and includes vascular occlusions, retinal edema, multiple cotton-wool spots, hemorrhages, vitritis, and retinal vasculitis. 89 The condition responds to intravenous doxycycline.

Protozoal TOXOPLASMOSIS

The major features of toxoplasmosis chorioretinitis are described in detail elsewhere (see Chapter 33). As well as retinal and choroidal inflammation, retinal vascular involvement occurs, observed ophthalmoscopically as perivascular sheathing. The retinal veins may show continuous sheathing over long segments, with narrowing near acute lesions or segmental cuffing. Vessels adjacent to areas of active retinitis may be involved, but vessels at remote locations may also be sheathedYo Periarteritis may also be seen and it occasionally occurs without associated periphlebitis. 91 The perivasculitis is believed to be caused by an Arthus-type reaction. 92 Locally produced antigens diffuse into the vessel walls where they react with circulating antibodies, activate complement, and thereby recruit inflammatory cells that form a cuff of lllononuclear cells around and in the vessel wall. 92 Focal periarterial exudates or plaques, called Kyrieleis arteriolitis, are not associated with vessel leakage or obstruction, and their pathogenesis is unknown. 3 The vasculitis resolves quickly with resolution of the disease and disappearance of the antigen.

Viral CYTOMEGALOVIRUS

CMV retinitis is a common ocular infections in AIDS patients. Since the introduction of highly active antiretroviral therapy (HAART) with a combination of reverse transcriptases and protease inhibitors, -the incidence of CMV retinitis is falling. Most patients are asymptomatic in the early stages. CMV causes fluffy white necrotic lesions along the vascular arcades of the posterior pole. The lesions have discrete edges. Retinal hemorrhages and vessel sheathing are also seen. 93 The vasculitis is caused by perivascular neutrophil infiltration of both the arteries and veins. There is usually little vitritis associated with CMV retinitis, but in HAART-treated patients inflammation is a prominent feature. . Treatment is with antiviral drugs ganciclovir, cidofovir,

CHAPTER 71: RETINAL VASCULITIS

or foscarnet. Lifelong maintenance therapy is required to prevent .recurrence of retinitis, but it may be possible to discontinue this in some patients on HAART who have had prolonged remission, CD4 + counts above 100 cells/ mm 3, and negative CMV plasma load. A recent report described CMV causing peripheral necrotizing retinitis, occlusive retinal vasculitis, and panuveitis in an immunocompromised patient. 94 This clinical picture is called acute retinal necrosis and is usually caused by herpes virus infection in immunocompetent individuals. HERPES VIRUS

Retinal infections with herpes simplex or zoster viruses result in necrotizing retinitis, vasculitis, and retinal hemorrhage. 93 Acute retinal necrosis occurs in healthy people but has also been described in immunocompromised patients. A peripheral full-thickness necrotizing retinitis with a marked vitreal inflammatory reaction is associated with a severe occlusive vasculitis affecting arteries in the retina and choroid. The causative organism can be detected from intraocular fluids. Retinal detachment is a common late complication. A severe, rapidly progressive form of herpetic retinopathy, progressive outer retinal necrosis, occurs in AIDS patients. 93 The retinal necrosis develops in multiple patches in the posterior pole and, in contrast to acute retinal necrosis, there is not a prominent vitritis. Retinal arteritis is not a prominent feature, although vessel sheathing occurs in and adjacent to areas f»f retinal necrosis. Severe periphlebitis similar to frosted branch angiitis is seen in immunocompromised patients with CMV or herpes simplex virus infections. It may also occur as a finding in immunocompetent patients with herpes simplex infection. In this instance, polymerase chain reaction analysis of intraocular fluids is helpful in identifying the correct diagnosis. 39 HUMAN IMMUNODEFICIENCY VIRUS

Retinal vasculopathy occurs in up to 50% of patients with AIDS. It is usually a microvasculopathy with cotton-wool spots and retinal hemorrhages, but, particularly in Mrican patients, isolated retinal vasculitis can occur. 95

scattered on the vessel wall was seen in 13 of the 32 cases. In addition, some patients had more classic retinal vasculitis consisting of perivascular sheathing associated with dye leakage and staining on fluorescein angiography. RIFT VALLEY FEVER VIRUS

Rift Valley fever is an arthropod-borne RNA-virus disease of livestock that is widespread in eastern and southern Mrica. Humans are infected by handling diseased and dead animals or their products. Epidemics affecting humans occasionally occur. From 1977 to 1978, an outbreak in Egypt killed 600 people. 98 In humans, the disease is an acute febrile illness with biphasic temperature elevations mimicking dengue fever. There are lTIUScle and joint pains, headache, and nausea. Conjunctivitis and photophobia are common in the early phase. Visual loss develops some days or weeks after subsidence of the fever. Ophthalmoscopy reveals acute necrotizing retinitis with cotton-wool spots, retinal hemorrhages, retinal edema, and occlusive retinal vasculitis. 98 ACUTE RETINAL PERIPHLEBITIS AND UVEITIS ASSOCIATED WITH VIRAL-LIKE UPPER RESPIRATORY DISEASE

Following an upper respiratory or flu-like illness, some patients develop panuveitis and retinal periphlebitis. Patients complain of blurred' vision, which usually resolves over a fortnight. The fundal and angiographic changes revert to normal appearance. An adenovirus has been cultured from the throat of one 9-year-old boy who had this presentation in association with pleocytosis in the cerebrospinal fluid. 3

Drug-Induced Retinal Vasculitis Retinal vasculitis has been reported in association with inhalation of methamphetamine,99 rifabutin treatment, 100 and with intravenous immunoglobulin therapy.10l, 102 The latter association is of concern because intravenous immunoglobulins have been suggested as a treatment for refractory uveitis.

Retinal Vasculitis Secondary to

8V1lA"IIUt.rll"lld'1ll1"11d"'\1

CANCER-AssOCIATED RETINOPATHY HUMAN T-CELL LYMPHOMA VIRUS TYPE I

This retrovirus causes two systemic diseases. One is adult T-cell malignancy, and the other is a chronic progressive neurologic disease called HTL\T-1-associated myelopathy or tropical spastic paraparesis. 24 The virus is widespread and endemic in the Caribbean, South America, Central Mrica, and southwestern Japan. It is also found in immigrants from these areas. In a report of 12 female patients with adult-onset, slowly progressive myelopathy and anti-HTLV-l antibodies, three were found to have peripheral retinal phlebitis. 96 More recently, HTLV-1 antibodies were found in 44% of patients with idiopathic endogenous uveitis. 97 This incidence of seropositivity was much higher than that in the general population. In these patients with anterior uveitis, vitreous opacities were common. A mild retinal vascular change consisting of punctate white or yellow deposits

Cancer-associated retinopathy is an uncommon paraneoplastic condition that develops in patients with neoplasia remote from the eye, typically small cell lung cancer. Patients present with visual loss and progressive night blindness, and examination reveals attenuated retinal vessels. Retinal phlebitis and vitritis have been reported in a Japanese man with small cell lung cancer. 103 However, despite sheathing of retinal veins and staining of the vessel walls on fluorescein angiography, no inflalTImatory cells were identified in the retinal vessels at autopsy 6 months later. This may have been because of resolution of the vasculitis with systemic prednisolone therapy. Another case with dramatic fluorescein angiographic evidence of retinal vasculitis was reported in a woman with .lung cancer. 104 She had an antibody to a 62-ill bovine retinal protein but no reactivity to 23-kD retinal protein (recoverin).

11: RETINAL VASCULITIS

Cancer-associated retinopathy is probably an autoimmune condition, and circulating antibodies to retinal cells and retinal antigens including recoverin have been identified in most of these patients. 105 OCULAR LYMPHOMA

In elderly patients, ocular lymphoma presents as chronic uveitis, which is poorly responsive to steroid therapy.l06 Manifestations are variable and include subretinal plaques, retinal infiltrates, and hemorrhage. It may present as retinal vasculitis,107 and subretinal pigment epithelial infiltrates, retinochoroiditis, and vasculitis were found in 60% patients who underwent vitrectomy for intraocular lymphoma. lOS Retinal vasculitis leads to vitritis, vessel sheathing, and perivascular exudates that can mimic frosted branch angiitis. The tumor cells are clustered in the perivascular regions of the retina, and there is destruction of pigment epithelium and Bruch's membrane. l09 ACUTE LEUKEMIA

Some patients with acute leukemia have retinal sheathing that can be extensive, presenting as acute unilateral frosted branch angiitis. 40

Miscellaneous Causes of Retinal Vasculitis Retinal vasculitis has been described in association with a variety of conditions. These include IgA nephritis,l1O uveitis associated with particular HLA phenotypes (HLAB5 and HLA-DR4),111 hemifaci/Jl atrophy,112 and adult Kawasaki disease. 113

The complications of retinal vasculitis are diverse (Table 77-2) .10, 20 Neovascularization occurs in about 10% to 15% of patients with retinal vasculitis. lO The new vessels are sometimes associated with capillary closure identified by fluorescein angiography (see Fig. 77-3) .25 It is believed that angiogenic factors are released from the ischemic retina. These factors induce blood vessel growth, which is the cause of ischemic diabetic eye disease. 114 In contrast, some eyes with retinal vasculitis and neovascularization do not show vessel closure, and fluorescein angiography reveals diffuse capillary leakage. 11 Thus, new vessels may develop perhaps as a response to hypoxia, or possibly from stimuli derived from inflalued retina or inflammatory cells. l l In such cases, neovascularization may be seen to involute with anti-inflammatory therapy alone. In addition to new vessels, arteriolar-venular anastomoses and other vascular architectural changes can also occur, often just temporal to the macula. 4 Macular ischemia due to closure of perifoveal capillaries is seen in some patientsY5 Fluorescein angiography, which reveals an enlarged and· irregular foveal avascular zone, confirms the diagnosis. This complication should be considered if vision remains poor despite adequate immunosuppression. Severe ischemic disease may also lead to rubeosis of the iris and subsequent glaucoma. Untreated new vessels in the disc and retina bleed easily, and vitreous hemorrhage is an important cause of visual loss in patients with

retinal vasculitis (see Fig. 77-5) .II' 20, 25 The hemorrhage absorbs without the tendency to tractional retinal detachments seen in diabetic maculopathy. This may be because of the posterior vitreous detachment that occurs in eyes with vitritis. Retinal detachment is a rare complication. However, when it develops, it is accOlupanied by severe proliferative vitreoretinopathy, particularly in eyes with active inflammation. Perioperative systemic corticosteroids are therefore recommended. 116 Those patients who have retinal vasculitis as part of a systemic condition may also have nonophthalmic complications of their systemic disease. However, it must be remembered that sometimes the retinal vasculitis may precede the onset of systemic disease by many months or years, as in MS and sarcoidosis. These patients will be initially diagnosed as having idiopathic retinal vasculitis. The amount of investigation required to exclude systemic disease in patients presenting with retinal vasculitis is controversial. ;Recent evidence suggests that those patients without! any relevant systemic history or clinical signs suggesti~e of an underlying disease do not require an extensive laboratory work-up.20 The patients who do have clinical evidence suggesting systemic illness should have investigations tailored to those symptoms and signs. This approach is unlikely to miss serious disease and will prevent the expensive, sometimes misleading and occasionally dangerous, overinvestigation of patients who will not necessarily benefit from it. Appropriate investiga.,. tions can be performed at any time if suggestive features develop. Even those patients with true idiopathic retinal vasculitis without any evidence of any systemic disease are at increased risk of developing serious systemic morbidity, including stroke and myocardial infarction at a relatively young age. 26

PATHOPHYSIOLOGY Retinal vasculitis is believed to be an immunologically mediated condition. Direct evidence to support this proposition in humans is scarce, as biopsy in eyes with potentially useful vision is not practicable and peripheral blood investigations are not helpful in patients without systemic disease. However, isolated pathologic reports of eyes with retinal vasculitis in sarcoidosis 117 and ABD6, 7, lIS have provided some valuable insight. Most of these eyes were removed because of secondary complications such as phthisis, pain, or glaucoma. The results therefore reflect end stages of the disease. Some studies have examined eyes obtained after the death of the patient. 6 Although the inflammation will have been modulated by immunosuppressive treatment, these reports may more accurately reflect the pathology than studies of enucleated eyes. The evidence of an autoimmune pathogenesis for retinal vasculitis is derived from experimental work in animals and indirectly from clinical studies. 119 The retina contains a number of tissue-specific antigens, one of which is retinal S-antigen. Experimental autoimmune uveoretinitis can be produced by immunizing animals with S-antigen. 120 The ocular inflammation induced by S-antigen is a marked retinal vasculitis accompanied by focal mononuclear cell infiltrate and necrosis of the

CHAPTER 11: RETINAL VASCULITIS

photoreceptor cell layer. Interestingly, patients with retinal vasculitis also develop autoilllmunity to this molecule.120, 121 Patients who have a systemic inflammatory disease could develop retinal vasculitis. because of the presence of circulating immune complexes, non-organ-specific autoimmunity, or abnormal white cell functionOU 9 On the other hand, isolated retinal vasculitis Illay be an organspecific autoimmune disease of the retina. In either case, the disease responds to immunosuppressive therapy. The major component of the iIllmune response is cellmediated immunity, with cell adhesion molecules playing a critical role in recruiting leukocytes to the site of inflammation. Humoral immunity may also be an impOl'tant component, but its role may be that of immunomodulation. 121

the patient had been heavily immunosilppressed at the time of death. 6 CDS + T cells were not found in the uvea or vasculitic lesions. 6 , 118 A few cells in the hyalinized vessel walls were positive for the macrophage primary antibody but neutrophils were not present. 6 The presence of CD4 + T cells as the predominant cell in the vascular lesions of the eye supports the assumption that retinal vasculitis is a cell-mediated condition. The absence of B cells and neutrophils is evidence that humoral immunity does not play a major role in the tissue damage. However, one study of five eyes found infiltrating B cells but only infrequently.7 A more recent report on an enucleated eye from a patient with ABD identified focal clusters of CD 19 + B cells in the uvea and retina. 118

Adhesion Molecules Cell-Mediated Immunity The cause of idiopathic retinal vasculitis is probably a disorder of immunity, which generates self-reacting T cells. It has been known for some time that patients with the clinical features of retinal perivasculitis have lymphocytes infiltrating in and around the retinal veins. 122 These lymphocytes are predominantly T cells 6 , 117 of the CD4 + subtype. 7, 118 In one study a proportion of these T cells were found to be activated, expressing interleukin (IL)-2 receptors, which is remarkable considering that

Cell adhesion molecules of the selectin, integrin, and immunoglobulin supergene families play an essential role in the development of inflammation. To produce vasculitis, circulating leukocytes must be recruited to the site of inflammation, where their speed is curbed by tethering of selectin molecules to carbohydrate moieties. The leukocytes move toward the vessel walls and begin to roll along the endothelium. This enables adherence to the vascular endothelium, and activation of the leukocyte. The sequential interactions of leukocyte adhesion IIIole-

Endothelium

red blood cells

FIGURE 77-7. The cellular process involved in retinal vasculitis. A, Recruitment of inflammatory cells from the circulation. Endothelium

Extracellular matrix

A

Initial adhesion by selectins and carbohydrates slows the leukocytes. Once tethered the leukocytes begin to roll on the surface of the endothelium. The arrested leukocytes are to respond to cytokines and endothelial cell surface molecules.

CHAPTER 77: RETINAL

cules with their receptors on the blood vessel wall are involved in each of these steps. Local action of chemokines also plays an important role (Fig. 77-7) .123

Tethering and Rolling The initial adhesion of leukocytes to the vascular endothelium is mediated by lectin-carbohydrate interactions (see Fig. 77-7 A). The leukocyte L-selectin (CD62L) interacts with. carbohydrates called addressins, which are present on the cell surface of vascular endothelial cells and are involved with cell trafficking in lymph nodes. These carbohydrate lllolecules are also induced at other sites during inflammation. Activated vascular endothelium expresses P-selectin (CD62P) and later E-selectin (CD62E). Interaction of these selectins with carbohydrate moieties on the leukocyte, such as the sialyl Lewis-X carbohydrate associated with CD15 present on many leukocytes, slows their speed. Initial adhesion is followed by rolling of the white cells along the vascular endothelium. 124 Expression of P-selectin is up-regulated by inflammatory mediators including histamine. E-selectin is a cell surface glycoprotein that predominantly binds neutrophils. It is not normally expressed by vascular endothelilllll or ocular tissues. However, certain cytokines, including IL-1, interferon gamma,

'11_..;1, .... "'"

and tumor necrosis factor alpha (TNF-ex), induce expression of this molecule. In the rat endotoxin-uveitis lllodel, E-selectin is up-regulated on corneal endothelilull and vascular endothelium of the ciliary body within 12 hours and precedes the binding of neutrophils to inflamed tissues. 125 It is expressed· only transiently and is mainly involved in the initial phases of leukocyte recruitment. Eselectin was not found in human eyes with chronic posterior uveitis except in the choroidal vasculature of one patient with sympathetic ophthahllia that exhibited choroidal neutrophil infiltration. 126

latching and Activation Stronger attachment of the leukocytes then occurs via the [32 integrin family of adhesion molecules (see Fig. 777B). The integrins are composed of an ex and a [3 subunit, which are each recognized by different antibodies. Thus, the CD 11a antibody is directed against the ex subunit and CD18 antibody against the [3 subunit of lymphocyte function-associated adhesion molecule-1, abbreviated LFA-1 (CD11a/CD18). LFA-1 (CD11a/CD18) binds to an endothelial cell ligand called intercellular adhesion molecule-1 (ICAM-l [CD54]).LFA-1 also binds to ICAM-2 (CD102) and ICAM3 (CD50), so antibodies against all three ligands are

Endothelium

red blood cells

LFA-1

FIGURE 77-7 Continued. B, Adhesion and activation of lymphocytes. Illustration continued on following page

Endothelium

Extracellular matrix Firm adhesion of the leukocyte, by interaction of its integrin receptors with members of the immunoglobulin supergene family on the endothelium, latches the cell to the vessel wall.

B

Activation of the leukocyte then occurs and it flattens onto the endothelium. The affinity of the leukocyte integrins is upregulated and expression of late binding proteins occurs. Binding to the cell adhesion molecules on the endothelium initiates migration.

CHAPTER 77: RETINAL VASCULITIS

Endothelium

red blood cells LFA-1

FIGURE 77-7 Continued. C, Transmigration of lymphocytes through the vascular endothelium and formation of perivascular inflammatory cell cuffing.

Endothelium

Extracellular matrix

c

Cells migrate through the endothelium and basement membrane to form a perivascular cuff of inflammatory cells. Lymphocytes interact with the extracellular matrix using ~-integrins (VLA antigens).

required to completely block LFA-l-dependent, antigenspecific, T-cell responses. However, antibodies blocking LFA-l or lCAM-l alone are able to prevent lymphocyte proliferation in vivo and they also prevent lymphocyte homing and migration into the eye. 124 lCAM-l is constitutively but weakly expressed by retinal vascular endothelium. 127 However, lCAM-l is strongly expressed by retinal vascular endothelial cells in animals with experimental autoimmune uveitis. 124 Retinal and ciliary body vessels express lCAM-l 7 days after immunization with uveitogenic antigen, and this precedes retinal inflammatory cell infiltration. LFA-l + leukocytes are subsequently recruited into the eye but are not observed for 9 days.124 Furthermore, antibodies against 132 integrins prevent the development of endotoxin-induced uveitis. 12s Similarly, lCAM-l is strongly expressed on the vascular endothelium of retinal and choroidal blood vessels in patients with active posterior uveitis 126 ; furthermore, the retinal cellular infiltrate is limited to those sites where lCAM-l was expressed. ICAM-l has also been demonstrated on the vascular endothelium of human eyes with retinal vasculitis.u s Other adhesion lllolecules are also important, particularly in chronic disease. Those ex-

pressed in the later phases of lymphocyte activation are called very late antigens (VLA) and include VLA-4 (CD49d), which interacts with vascular cell adhesion molecule-I (VCAM-l [CDI06]). The expression of supergene family members by the vascular endothelium, lCAM-l and VCAM-l, is up-regulated by inflammatory cytokines, TNF-a, interferon gamma, and IL_l.12s TNF-a is found in human eyes with posterior uveitis localized to the areas of inflammation, and it may increase lCAM-l expression by adjacent vascular endotheliumP6

Migration Mter passing through the vascular endothelium, the leukocytes lose L-selectin by enzymatic cleavage and begin to express the 131 family of integrins (the 13-chain common to all of this family is recognized by anti-CD29). These receptors are the VIA, expressed only in the late stages of lymphocyte activation. They interact with collagen (VLA-2, VIA-3), laminin (VIA-3, VIA-6), and fibronectin (VIA-3, VIA-4, VIA-5) of the extracellular matrix. The migrated leukocytes form a cuff of cells around

CHAPTER 77: RETINAL

the vessel wall, which is visible ophthalmoscopically (see Fig 77-7C). This evidence from animals and humans emphasizes the important role of CAMs for the recruitInent of lymphocytes into the eye. It also suggests the therapeutic possibility of using antibodies against these molecules to treat retinal vasculitis.

Humoral Immunity and Immune Complexes The role of antibodies and immune complexes in retinal vasculitis remains controversial, although type III hypersensitivity is a mechanism of tissue damage in systemic vasculitides. Antiretinal antibodies are found in 3.8% of normal individuals. 121 The prevalence of these autoantibodies is very much higher in patients with retinal vasculitis. In a large study of 150 patients with retinal vasculitis, antiretinal autoantibodies were found in 58% of patients. 121 It had previously been reported that patients with isolated retinal vasculitis who had more severe disease also had high levels of serum antiretinal antibodies. 1l9 These same patients were also investigated for the presence of circulating immune complexes. Serum from patients with retinal vasculitis and systemic inflammatory disease (other dlan ABD) had elevated imm:une· complexes and antiretinal antibodies. 121 Interestingly, these patients had lower disease severity scores, suggesting that immune complex formation may be a protective measure that mops up potentially dangerous antiretinal antibodies: Their presence may be the response to the inflammation, not the cause. Furthermore, those patients with ABD and sarcoidosis who had antiretinal antibodies but no immune complexes had the more severe disease. The affinity of anti-S-antigen antibodies in patients with retinal vasculitis is lower than that of these antibodies when found in healthy control subjects. 129 It was suggested that high-affinity antibodies, which are also found in immune complexes, may be protective, and that patients who make low-affinity antibody are at increased risk of developing retinal vasculitis. Thus, although overlooked in the presence of a dominating CD4 + T-cell response, retinal vasculitis may also have a humoral response, and this may have an immunoregulatory function perhaps influenced by immune complex formation.

TREATMENT Historically, the treatment of retinal vasculitis has included -deliberate infection with malaria, intravenous injection of milk or diphtheria proteins to induce shock, removal of teeth or appendectomy to clear possible infective foci, and paracentesis or deliberate injection of blood into the eye to introduce antibodies. 5 The introduction of steroids in the 1950s changed the management of uveitis. Oral corticosteroids remain the main therapeutic drugs, but other immunosuppressive agents have an increasing role. Not all patients with retinal vasculitis require treatment. Treatment is indicated for cystoid macular edema, for severe vitritis affecting vision, for severe ischemia identified by fluorescein angiography as large areas of capil-

lary drop-out, or if capillary destruction is identified around the foveal avascular zone. . It is. important to ~lave assessed the patient for infectIOn wIth a carefL~1 hIsto.ry and eye and physical exams. Labo~atory tests In~ludlllg serology, chest radiograph, and, If necessary, Vitreous humor analysis are tailored, according to any findings on history and examination. 20 If infection is identified, appropriate antimicrobial or antiviral therapy is mandatory before attempting immunosuppression. Likewise, identification of any underlying systemic disease is important, not only to help direct therapy for the ocular inflammation but also to control life-threatening complications of autoimmune diseases. Thrombophilic abnormalities are present in about one third of patients with retinal vasculitis. 130

Observation If the patient has only mild vascular changes with little vitritis and no cystoid macular edema, then careful clinical observation is often all that is required. At all times the risks of systemic treatment must be borne in mind; because most patients will require treatment for years and be put at risk of developing iatrogenic complications, treatment may be unnecessary. There is an increased risk of cardiovascular events in patients with retinal vasculitis. It is therefore important to minimize the impact of other risk factors for cardiovascular disease, even in patients who are not being treated, by checking for hypertension, hyperlipidemia, and diabetes. Patients should also be advised to stop sInoking.

Medical Therapy Several immunosuppressive drugs are available to the physician to modulate the inflammatory response in retinal vasculitis. No formal randomized controlled trials have been conducted on these treatments for retinal vasculitis because of the rarity of the conditions and the variety and complications of associated systemic diseases, which may also direct treatment choices. However, literature on series of cases exists and extrapolation of data from controlled trials for the treatment of panuveitis enables rational decisions to be made in treating patients with retinal vasculitis.

Corticosteroids The choice of drug to use has traditionally centered on corticosteroids as the first line of therapy. They may be administered topically to control anterior uveitis, regionally (as sub-Tenon's or peribulbar injections) for mild unilateral disease, or systemically, usually by mouth but also by intravenous pulse therapy. Oral corticosteroids have been shown to be an effective treatment for retinal vasculitis. 131 Treatment was initiated in a high dose: 80 mg of prednisolone for 4 days, then 60 mg for 4 days, followed by 40 mg for 1 month, tapering thereafter according to clinical response. Myles 132 felt that the failure to control retinal vasculitis was commonly caused by instituting therapy at too Iowa dose. However, steroid treatment is potentially dangerous, and the incidence of serious side effects of high-dose or long-term treatInent is frequently underestimated. For example, the main cause of death and morbidity in pa-

· CHAPTER

RETINAL VASCULITIS

tients with giant cell arteritis is the corticosteroid treatment. I33 An excellent summary of complications of steroid therapy in the treatment of inflammatory eye disease has recently been published. I33 In the United Kingdom, the expert working group of the Medicines Control Agency and the Committee on Safety of Medicines. has revised their guidelines for the use of systemic steroids. It now recommends that patients should be given treatment for the shortest time at the lowest dose that is clinically necessary.134

Immunosuppressive Drugs Because of these concerns, many uveItIs specialists are moving away from systemic steroids, or at least they use protocols that minimize dose and duration of treatment. 135 To reduce the total steroid dose, or in cases where retinal vasculitis is poorly controlled, steroid-sparing immunosuppressive drugs are required. Furthermore, steroids alone are insufficient treatment for certain specific conditions, and other immunosuppressive drugs are required to control both the ocular inflammation and the systemic manifestations of the disease. 136 However, the potentially serious side effects and bewildering array of immunosuppressive drugs have limited their use despite the undoubted benefits of immunosuppression in inflammatoryeye disease, including retinal vasculitis. Much light has been shed on the issue with ,reviews from Bos:' ton136 and more recently from Aberdeen135 that have described clear guidelines for the use of immunosuppression in ocular inflammatory disease an~posterior uveitis. Following early trials that demonstrated its efficacy in high doses,137 low-dose cyclosporine A has become the most common steroid-sparing agent for the treatment of retinal vasculitis. 135, 138 The starting dose is 2.5 to 5 mg/ kg/day, usually given as a twice-daily regime. The major side effects include nephrotoxicity, hypertension, hirsutism, and gum hypertrophy.133, 135, 136 However, a plethora of other problems may occur, including elevated serum levels of cyclosporin A caused by drugs or dietary grapefruit juice and the ominous possibility of increasing the risk of skin or lytnphoid tumors in the distant future. For patients who are unable to tolerate cyclosporine, tacrolimus (formerly known as FK506) is a good alternative with a similar mode of action. 139 Other immunosuppressive agents, including methotrexate, azathioprine, colchicine, chlorambucil, and cyclophosphamide, are used in treating retinal vasculitis. These agents also have a role in managing ABD.136 More recently, mycophenolate mofetil (CellCept) has become available. It is rapidly hydrolyzed in vivo by plasma esterases to mycophenolic acid, the active molecule, which inhibits inosine monophosphate dehydrogenase. This inhibition of the de novo pathway of purine synthesis is relatively selective to lytnphocyte proliferation, sparing other cells such as neutrophils, which can use an alternative salvage pathway to obtain purines. 14o It is also useful in some patients with autoimmune disease, in whom it has been used to treat cases of refractory uveitis, intermediate uveitis, and ABD panuveitis. 141, 142 It has a particular use for patients who fail to respond, have toxicity, or are intolerant of cyclosporin. 141 Systemic vasculitis is sometimes treated using intrave-

nous immunoglobulin. I43 If it is administered within 10 days of onset of Kawasaki disease, the incidence of coronary aneurysms is reduced. Intravenous immunoglobulins may also be helpful for treating the occasional patient with intractable retinal vasculitis. The mode of action is incompletely understood. It may act by directly bonding autoantibody, blocking crystallizable fragment (Fc) receptors, modulating cytokine interactions, and inhibiting complement. I43 Potential toxicity, the possibility for transmission of viruses, and reports of retinal vasculitis associated with this therapy limit its widespread use. I02 PlasIna exchange has been used to interrupt the acute inflammatory activity of retinal vasculitis in cases of ABD.I44 However, it does not prevent relapse, and the long-term prognosis in the four patients in that study was poor. Plasma exchange is also expensive and invasive, so it is not recommended for routine use.

Immunoregulation More specific immunoregulation of autoimmune disease is becoming a reality with the advent of specific monoclonal antibodies (mAb) against lytnphocytes and cytokine receptors. 145 , 146 Another approach, based on successful experiments in animals, is to use retinal antigens to induce tolerance in the recipient. 147 These methods are l;:>eing adapted to treat inflammatory eye disease including retinal vasculitis. A panlytnphocyte mAb, Campath 1H, controlled retinal vasculitis that had been refractory to all prior treatments. 148 Long-term benefit resulted from the short-term treatment, suggesting that modulating the immune system in this fashion could potentially induce tolerance. TNF plays a crucial role in inflammation. Recently, the use of anticytokine therapy in Crohn's disease and rheumatoid arthritis has shown potential. 149 Two approaches are being used. One uses a human-mouse chimeric antibody, called infliximab, directed against TNF-a. The other uses a soluble TNF receptor called etanercept. Infliximab combined with methotrexate prevents antibodies against infliximab being formed and produces significant clinical benefit. Etanercept is a fusion protein made up of two recombinant p75 TNF receptors fused with the Fc portion of human IgGl. It binds both TNF-a and TNF-~ (lytnphotoxin). Again, impressive results in patients with rheumatoid arthritis have been reported. It seems very likely that blocking adhesion molecules, antilytnphocyte, or anticytokine therapy will also have a role for patients with refractory retinal vasculitis. In the future, it may be possible to make the patient tolerant to retinal autoantigens given by mouth or intranasally. Inhibition of experimental autoimmune uveitis can be achieved by feeding animals S-antigen orally.149 Tolerance to an autoantigen can spread to other antigens because of the local release of suppressor cytokines (such as transforming growth factor-~, IL-4, IL-10). Therefore, although many potential retinal autoantigens are involved in producing retinal vasculitis, immunization against one or a few may be enough to prevent disease. On this basis, a randomized, masked trial of oral tolerance has been conducted, with demonstration of an effect with an absence of side effects. 150 Although not statistically significant, the results are promising, but they must be interpre-

CHAPTER 77:

ted cautiously because of the late stage of disease treated. Furthermore, the confounding effect of concurrent immunosuppressive'therapy could easily influence the active mechanism by which tolerance is produced.

laser Treatment The use of laser photocoagulation in retinal vasculitis is controversial. It is rarely required for treating retinal vasculitis, and the main indication is for persistent neovascularization causing recurrent vitreous hemorrhage, and less frequently for treating rubeotic glaucoma. 5, 11 Retinal neovascularization associated with ocular inflammation is quite different from other proliferative retinopathies. First, the visual prognosis is better in patients with retinal vasculitis, possibly because of the associated posterior vitreous detachment, which removes the scaffold for elevated new vessels. In addition, new vessels regress with medical treatment in many casesY There is a high incidence of macular edema developing after laser treatment in retinal vasculitis. Laser tr'eatment is therefore reserved to treat those eyes with recurrent vitreous hemorrhage once adequate immunosuppressive treatment has been used. 11 In contrast to these recommendations, other authorities suggest that aggressive retinal laser should be used more frequently, even in those patients without neovascularization. 4 However, there is a risk of provoking further inflammatory episodes ,with retinal photocoagulation. In India, laser treatment of retinal vasculitis is used more commonly, often as a priJIlary therapy to manage the complications of Eales' disease. l51 Photocoagulation of proliferative retinopathy in Eales' disease has been used for over 30 years. Meyer-Schwickerath used xenonarc light photocoagulation in a series of 176 eyes with Eales' disease and proliferative retinopathy.152 Of the treated eyes, 124 remained symptom free over the followup period of 1 to 8 years. Eales' disease mainly affects the peripheral retina, and xenon-arc is not an ideal method of photocoagulation. Laser photocoagulation has therefore become the treatment of choice for the proliferative phase of Eales' disease,l51 but it is not useful for controlling the inflammatory phase. Laser burns are placed in areas of retinal neovascularization, capillary nonperfusion, microaneurysms, and arteriovenous shunt vessels (Fig. 77-8) .151 Direct treatment of flat retinal neovascularization is performed with argon laser spots of moderate intensity (2 to 500 /-Lm diameter and 0.1 sec duration). Elevated new vessels are treated by coagulation of their feeder vessels. Panretinal photocoagulation is required if there are disc new vessels. Spot size is 500 /-Lm for 0.1 sec duration and 1500 to 2000 burns are applied over two or three treatment sessions.

Vitrectomy Recurrent vitreous hemorrhage is a major cause of visual loss in retinal vasculitis, and this is particularly the case for patients with Eales' disease. The first vitreous hemorrhage usually settles inferiorly with gravity and is absorbed over a few weeks or months, with restoration of central vision. Recurrent vitreous hemorrhages are a greater problem and lead to traction bands and membranes in the vitreous, which cause further complications. 151 The

FIGURE 77-8. Sector retinal laser burns on an area of capillary nonperfusion and previous neovascularization in a patient with retinal vasculitis.

objective of surgery is to remove the vitreous opacity and the posterior vitreous face. Other surgical procedures are often required at the same sitting, including lensectomy to enable a clear view. Epiretinal Inembrane removal, endolaser, and cryotherapy with scleral buckling are frequently required. 151 ,153 The prognosis following surgery is generally good, and most patients can expect to have a significant improvement of vision. Patients who have had fewer episodes of recurrent hemorrhage of shorter duration and who have had laser photocoagulation prior to vitrectomy fare better than patients with longstanding vitreous hemorrhage. 15l

PROGNOSIS The diagnosis of retinal vasculitis has implications for general health as well as for sight. Appropriate counseling and management is therefore important to prevent complications or at least to minimize their impact. To a large extent, the prognosis for the health of patients who have apparently isolated retinal vasculitis depends on whether an associated systemic disease subsequently develops. An extended 6-year follow-up study of 67 patients who had retinal vasculitis and intermediate uveitis found significant systemic morbidity.26 These patients were divided on the basis of fluorescein angiography into two groups: ischemic, or nonischemic and leaky. Of the 45 patients in the nonischemic group, 28% subsequently developed MS. Most of these were women with HLA-B7. No patients in the ischemic group developed MS, but a third developed premature cardiovascular disease including stroke and myocardial infarction. Thus, even retinal vasculitis that is not associated with systemic autoimmune disease may still affect the prognosis for the patient's general health or longevity. This is important to recognize, as patients with retinal vasculitis are usually young.lO, 20 More recently, studies of soluble ICAM-1 and IL-8 in the serum of patients with intermediate uveitis have been correlated with a predisposition to developing an associated systemic disease. 154 Using such tools will help to limit

CHAPTER 77: RETINAL VASCULITIS

expensive and invasive diagnostic tests to those patients who are most likely to benefit from them. Other patients develop retinal vasculitis as a component of a preexisting generalized disease. In such cases, the management of their systemic condition largely determines the prognosis for health. The prognosis for sight varies among many different diseases, with most patients who have mild peripheral retinal phlebitis retaining good vision, often without treatment. In contrast, those patients with ABD often have a dire long-term prospect for sight despite aggressive immunosuppression. Visual prognosis in retinal vasculitis also depends on whether there is ischemia noted on fluorescein angiography. A retrospective study of 54 patients found that 24% of patients with ischemic disease had a visual acuity of less than 6/60 at presentation. The percentage increased to 34% of patients over a mean follow-up period of 8.2 years. 25 In contrast, only 10% of the nonischemic group had a visual acuity of less than 6/60 and this percentage did not increase over the follow-up. Thus, patients with ischemic disease have a much poorer visual outcome because of cystoid macular edema, recurrent vitreous hemorrhage, and branch retinal vein occlusions. The worst visual outcome occurred despite aggressive immunosuppression, which suggests that other treatment, in-cluding anticoagulation, might also be ineededin these patients. Interestingly, smoking was more prevalent in the ischemic group. It was postulated that von Willebrand's factor and fibrinogen, which are elevaf~d in smokers, could put them at particular risk of capillary closure if they develop retinal vasculitis. 131 However, smokiIlg also damages vascular endothelium directly and this mechanism could also be involved.

CONCLUSIONS Retinal vasculitis is an important condition that is a component of many systemic inflammatory and infectious diseases. Idiopathic retinal vasculitis is uncommon in the western hemisphere,but Eales' disease (a type of retinal vasculitis associated with capillary shut-down and neovascular proliferation) occurs more frequently in India.

Whom to Investigate Although retinal vasculitis can occur as part of a systemic disease, extensive investigation to uncover occult disease is not often required. A careful history, physical, and ocular exam will usually indicate which patients require a more extensive work-up.20 Those with systemic disease need assessment for treatment, which often requires a multidisciplinary team approach for the best outcome. The role of the ophthalmologist is to preserve sight and to highlight the importance of tlle eye as a major target for organ damage.

Exclude Infection Retinal vasculitis commonly occurs in toxoplasmosis and in posterior segment infections caused by viruses. If infection is identified, appropriate antimicrobial therapy is instituted, often with steroids to reduce the collateral damage from the inflammatory response.

Recommended Treatment Protocol Patients with isolated retinal vasculitis do not necessarily require treatment. Those with sight-threatening complications are started on a regime designed to minimize the total dose of steroids. 135

1. The acute stage. Systemic steroids are started at a dose of 0.5 to 1.0 mg/kg/day. Occasionally, intravenous pulse methylprednisolone 1 g/day for 3 days is required. 2. Long-term control. To allow steroid dosage to be reduced, low-dose cyclosporin therapy 5 mg/kg/day is also given. Mter 3 to 6 weeks, when control has been achieved, the dose of systemic steroid is tapered and if possible discontinued. Monotherapy with cyclosporin or combination therapy with low-dose steroid can be continued for months or years if necessary. 3. Additional immunosuppression. Other drugs are required if inflammation persists despite cyclosporin and lowdose steroid. A variety of agents can be used in combination or as alternatives to the maintenance regime. In certain special instances, patients with specific diagnoses such as Wegener's disease will require additional immunosuppression to control the life-threatening complications of their systemic disease. Patients who are not responding to therapy also require the attention of specialists to exclude rare infections or malignancy. This may require unusual investigations that are not routinely available.

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77: RETiNAL VASCUliTIS 76. Morgan C, Foster CS, D'Amico DJ, et al: Retinal vasculitis in polyarteritis nodosa. Retina 1986;6:205-209. 77. Isaak BL, Liesegang TJ, Michet CJ: Ocular and systemic findings in relapsing polychondritis. Ophthalmology 1986;93:681. 78. Helm C, Holland G: Ocular tuberculosis. Surv Ophthalmol 1993;38:229-256. 79. Rosen P, Spalton D, Graham E: Intraocular tuberculosis. Eye 1990;4:486-492. 80. Shah S, Howard RS, Sarkies NJ, et al: Tuberculosis presenting as retinal vasculitis. J R Soc Med 1988;81:232-233. 81. Margo C, Hamed A: Ocular syphilis. Surv Ophthalmol 1992;37:203-220. 82. Lobes L, Folk J: Syphilitic phlebitis simulating branch vein occlusion. Ann Ophthalmol 1981;13:127-135. 83. Karma A,Seppala I, Mikkila H, et al: Diagnosis and clinical characteristics of ocular Lyme borreliosis. Am J Ophthalmol 1995;119:127-135. 84. Schubert H, Greenbaum E, Neu HC: Cytologically proven seronegative Lyme choroiditis and vitritis. Retina 1994;14:39-42. 85. Avila M, Jalkh AE, Feldman E, et al: Manifestations of Whipple's disease in the posterior segment of the eye. Arch Ophthalmol 1984;102:384-390. 86. Tabbara K, Al-Kassimi H: Ocular borreliosis. Br J Ophthalmol 1990;74:249-250. 87. Ormerod L, Skolnick KA, Menosky MM, et al: Retinal and choroidal manifestations of cat-scratch disease. Ophthalmology 1998;105:1024-1031. 88. Soheilian M, Markomichelakis N, Foster CS: Intermediate uveitis and retinal vasculitis as manifestations of cat scratch disease. Am J Ophthalmol 1996;122:582-584. 89. Duffey R, Hammer M: The ocular manifestations of Rocky Mountain spotted fever. Ann Ophthalmol 1987;19:301-313. 90. Pavesion C, Lightman S: Toxoj)lasma gondii and ocular toxoplasmosis: Pathogenesis. Br J Ophthalmol 1996;80:1099-1107. 91. Schwartz P: Segmental retinal periarteritis as a complication of toxoplasmosis. Ann Ophthalmol 1977;9:157-1.,(}2. 92. O'Connor G: The influence of hypersensitivitY on the pathogenesis of ocular toxoplasmosis. Trans Am Ophthalmol Soc 1970;68:501-547. 93. Yoser S, Forster D, Rao N: Systemic viral infections and their retinal and choroidal manifestations. Surv Ophthalmol 1993;37:313-352. 94. Akpek E, Kent C, Jakobiec F, et al: Bilateral acute retinal necrosis caused by cytomegalovirus in an immunocompromised patient. AmJ Ophthalmol 1999;127:93-95. 95. Kestelyn P, Lepage L, Perre PV: Perivasculitis of the retinal vessels as an important sign in children with the AIDS-related complex. AmJ Ophthalmol 1985;100:614-615. 96. Sasaki K, Morooka I, Inomata H, et al: Retinal vasculitis in human T-Iymphotrophic virus type-1 associated myelopathy. Br J Ophthalmol 1989;73:812-815. 97. Nakao K, Ohba N: Clinical features of HTLV-1 associated uveitis. Br J Ophthalmol 1993;77:274-279. 98. Siam A, Meegan H, Gharbawi K: Rift Valley fever ocular manifestations: Observations during the 1977 epidemic in Egypt. Br J Ophthalmol 1980;64:366-374. 99. Shaw H, LawsonJ, Stulting R: Amaurosis fugax and retinal vasculitis associated with methamphetamine inhalation. J Clin Neuroophthalmol 1985;5:169-176. 100. Arevalo J, Russack V, Freeman W: New ophthalmic manifestations of presumed rifabutin-related uveitis. Ophthalmic Surg Lasers 1997;28:321-324. 101. Ayliffe W, Haeney M, Roberts SC, et al: Uveitis after antineutrophil cytoplasmic antibody contamination of immunoglobulin replacement therapy. Lancet 1992;339:558-559. 102. Vogele C, Andrassy K, Schmidbauer JM, et al: Retinal vasculitis and uveitis-An adverse reaction to intravenous immunoglobulins. Nephron 1994;67:363. . 103. Ohnishi Y, Ohara S, Sakamoto T, et al: Cancer associated retinopathy with presumed periphlebitis. Br J Ophthalmol 1993;77:795798. 104. Suzuki T, Obara Y, Sato Y, et al: Cancer-associated retinopathy with presumed vasculitis. AmJ Ophthalmol 1996;122:125-126. 105. Keltner J, Thirkill CE, Tyler NK, et al: Management and monitoring of cancer-associated retinopathy. Arch Ophthalmol 1992; 110:48-53.

106. Ridley M, McDonald HR, Sternberg P, et al: Retinal manifestations of ocular lymphoma (reticulum cell sarcoma). Ophthalmology 1992;99:1153-1161. 107. Brown S, Jampol L, Cantrill H: Intraocular lymphoma presenting as retinal vasculitis. Surv Ophthalmol 1994;39:133-140. 108. Akpek EK, Al1med I, Hochberg FH, et al: Intraocular central nervous system lymphoma: Clinical features, diagnosis and outcomes. Ophthalmology 1999;106:1805-1810. 109. Barr C, Green WR, Payne jW, et al: Intraocular reticulum-cell sarcoma: Clinicopathological study of four cases and review of the literature. Surv Ophthalmol 1975;19:224-239. 110. O'Neill D, Brown C: Retinal vasculitis and uveitis in IgA nephritis. Eye 1994;8:711-713. Ill. Wakefield D, Lane J, Penny R: Retinal vasculitis associated with HLA DR4. Brief definitive report. Hum Immunol 1985;14:11-17. 112. Ong K, Billson FA, Pathirana DS, et al: A case of progressive hemifacial atrophy with uveitis and retinal vasculitis. Aust N Z J Ophthalmol 1991;19:295-298. 113. Jackson J, Kunkel MR, Libow L, et al: Adult: Kawasaki disease. Report of two cases treated with intravenous gamma globulin. Arch Intern Med 1994;154:1398-1405. 114. Jampol L, Ebroon D, Goldbaum M: Peripheral proliferative retinopathies: An update on angiogenesis, etiologies and management. Surv Ophthalmol 1994;38:519-540. 115. Bentley C, Stanford MR, Shilling JS, et al: Macular ischemia in posterior uveitis. Eye 1993;7:411-414. 116. Brockhurst R, Schepens C: Uveitis 4: Peripheral uveitis: The complication of retinal detachment. Arch Ophthalmol 1986;80:747753. 117. Chan C, Wetzig RP, Palestine AG, et al: Immunopathology of ocular sarcoidosis. Arch Ophthahnol 1987;105:1398-1402. 118. George R, Chan CC, Whitcup SM, et al: Ocular immunopathology of Behl;et:'s disease. Surv Ophthalmol 1997;42:157-162. 119. Dumonde D, Kasp-Grochowska E, Graham E, et al: Anti-retinal autoimmunity and circulating immune complexes in patients with retinal vasculitis. Lancet 1982;2:787-792. 120. Rao N, Wacker W, Marak G: Experimental allergic uveitis: Clinicopathological features associated with varying doses of S-antigen. Arch Ophthalmol 1979;97:1954-1958. 121. Kasp E, Graham EM, Stanford MR, et al: A point prevalence study of 150 patients 'ivith idiopathic retinal vasculitis: 2. Clinical relevance of antiretinal autoimmunity and circulating immune complexes. Br J Ophthalmol 1989;73:722-730. 122. Ballantyne A, Michaelson I: A case of perivasculitis retinae associated with symptoms of cerebral disease. Br J Ophthalmol 1937;21:22. 123. Whitcup S: Involvement of cell adhesion molecules in the pathogenesis of experimental autoimmune uveoretinitis. Ocul Immunol Inflamm 1995;3:53-56. 124. Whitcup S: Endothelial leukocyte adhesion molecule-1 in endotoxin-induced uveitis. Invest Ophthalmol Vis Sci 1992;33:26262630. 125. Whitcup S, Chan CC, Li Q, et al: Expression of cell adhesion molecules in posterior uveitis. Arch Ophthalmol 1992;110:662666. 126. Hill T, Stanford MR, Graham EM, et al: A new method for studying the selective adherence of blood lymphocytes to the microvasculature of human retina. Invest Ophthalmol Vis Sci 1997;38:26082618. 127. Whitcup S, Hikita N, Shirao M, et al: Monoclonal antibodies against CD54 (ICAM-1) and CD11a (LFA-1) prevent and inhibit endotoxin-induced uveitis. Exp Eye Res 1995;60:597-601. 128. Springer T: Adhesion receptors of the immune system. Nature 1990;346:425-434. 129. Kasp E, Whiston R, Dumonde D, et al: Antibody affinity to retinal S-antigen in patients with retinal vasculitis. Am J Ophthalmol 1992;113:697-701. 130. Palmer H, Jurd KM, Hunt BJ, et al: Thrombophilic factors in ischemic and non-ischemic idiopathic retinal vasculitis. Eye 1995;9:507-512. 131. Howe L, Stanford MR, Edelsten C, et al: The efficacy of systemic corticosteroids in sight threatening retinal vasculitis. Eye 1994;8:443-447. 132. Myles A: Polymyalgia rheumatica and giant cell arteritis (letter). Br MedJ 1995;311:1232.

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,Albert T. Vitale, Manfred Zierhut, and C. Stephen Foster

The term intermediate uveitis (IU) was suggested by the International Uveitis Study Group (IUSG) to denote an idiopathic inflammatory syndrome, mainly involving the anterior vitreous, peripheral retina, and ciliary body, with minimal or no anterior segment or chorioretinal inflammatory signs. I Other names previously used in the literature to describe this entity include chronic cyclitis, peripheralJweitis, vitritis, cyclochorioretinitis, chronic posterior cyclitis and peripheral uveoretinitis. IU mayor may not be associated with specific infections (LYIne disease, toxocariasis, Whipple's disease, cat-scratch disease) and noninfectious diseases (multiple sclerosis and sarcoidosis). The term pars planitis has been retained and used to describe the characteristic exudates that can be seen on the pars plana in some patients with IU, and may or Inay not represent a distinct clinical entity.

Patients with IU often present with minimal symptoms, which may include floaters or blurred vision, but no pain, photophobia or obvious external inflammation. In more severe cases, floaters aggregate and visual acuity may be significantly reduced. Sometimes, patients present with abntpt loss of vision owing to acute vitreous hemorrhage or retinal detachment. Clinical signs of anterior segment inflammation may be present or absent. There may be mild anterior chamber cells, keratic precipitates, and even rarely posterior synechiae. The less-than-thorough clinician may simply treat these anterior findings, without performing a dilated, depressed peripheral retinal examination, thereby missing the diagnosis. Band keratopathy has been reported in children with IU, as may occur in uveitis of nearly any chronic kind in children. Autoimmune endotheliopathy has been reported by Khodadoust and colleagues 2S in four of 10 patients with HISTORY Hars planitis. He described peripheral corneal edema The first description of what· probably was IU was re:with keratic precipitates that were arranged linearly on ported by Fuchs in 1908. 2 At that time, ;heused the term the border between edematous and normal cornea, sug3 chronic cyclitis. Schepens described the disease entity of gesting that IU may also be an autoimmune disease-like peripheral uveitis in 1950, which captured most of the transplant rejection. Similar findings have been described classic clinical characteristics of IU. S~bsequently, his by other authors,29, 30 and we, too, have observed this. group reported different aspects of this disease,'J.-7 includVitreous cells are the most characteristic sign for IU ing peripheral vascular abnormalities and exudation (Fig. 78-1), ranging from 1 + to 4 + cellsY In severe S along the pars plana. In 1960, Welch and associates cases, the cellular infiltration is so dense· that it may coined the term pars planitis. In 1987, the IUSG adopted obscure the view of the retina, and it is impossible for the term IU as a part of its anatomic classification scheme one to exclude the diagnosis of posterior uveitis. Vitreal for intraocular inflammation. I yellowish white aggregates, the so-called snowballs, are typical and are mostly found in the inferior periphery EPIDEMIOLOGY (Fig. 78-2). Signs of vasculitis are seen in 10% to 32% of IU has been reported in 8% to 22% of uveitis patients. s- Is patients,lO, 32-34 depending on the method of diagnosis There is only one report published regarding its inci- (Fig. 78-:-3). This includes vascular venous sheathing dence and prevalence. Vadot I7 found an incidence of (periphlebitis), probably leading to occlusion 35 and some1.4/100,000 (0.64 to 2.64 confidence intervals) in a pro- times peripheral retinal neovascularization (Fig. 78-4). spective epidemiologic study of 215 uveitis patients in Savoy, France. The prevalence was estimated to be 5.9/ 100,000. Of 1237 patients with uveitis referred to the Immunology and Uveitis Service of the'Massachusetts Eye and Ear Infirmary over a 10-year period, 162 (13.0%) were classified as IU.I5 The disease seems to affect patients primarily from childhood through the founhdecade, but it has also been reported in older patients. There seems to be no clear gender or race predilection. Good epidemiologicstudies that include a few hundred patients with IU are still lacking. Approximately 70% to 90% of cases are bilateral, albeit 'asYInmetric, with symptoms frequently being confined to one eye. IU is not a hereditary disorder. However, there have been some reports (thus far approximately a'dozen cases) of IU occurring in families. 19- 27 Human leukocyte antigen (HLA) studies in these families have not shown comlnon HLA haplotypes, except for one report concerning two FIGURE 78-1. Vitreous inflammation, with dense vitreal cellular infilaffected brothers with identical HLA-type. 26 trate seen on slit lamp biomicroscopy. (See color insert.)

CHAPTER 78:

FIGURE 78-2. Vitreal cellular aggregates anterior to the retina ("snowballs"). (See color insert.)

In addition, frank exudates on the pars plana can be found. The acute stage of the disease is characterized by white exudations, whiclli may become extensive and confluent. In the later stages, the stimulation of collagen production results in the formation of the so-called snowbank. Snowbanks can be found mostly inferiorly, but.may also extend to encompass 360. degrees of the retinal periphery. Their presence seems to be associated with worse visual outcome. 36 ,37 Much confusion and loose usage have evolved regarding the t~ms snowballs and snowbank; because of this, we generally eschew the usage of these terms, preferring more precise language. We know of those who use the term snowbank to denote confluent pars plana exudates, which is present during active pars planitis, and also use the same term to describe the white collagen band (Fig. 78-5) at the pars plana seen chronically in some patients, even during periods of quiescence. Clearly, it is clinically useful to be more precise than this. We suggest that one simply say what one sees, in an effort to be precise. For example, if we observe a white, sharp-edged band at the pars plana in the absence of cells or exudates indicative of active inflammation, we

FIGURE 78-3. Vasculitis of peripheral retinal vein in a patient with intermediate uveitis. (See color insert.)

FIGURE 78-4. Neovascularization after occlusive vasculitis in intermediate uveitis. (See color insert.)

speak of finding pars plana fibrosis,38 rather than of a snowbank. Conversely, if we discover vitreal cells surrounding collections of exudates on the pars plana or on an area of pars plana fibrosis, we speak of active pars planitis, with pars plana exudates and vitreal cells. A thorough peripheral retinal examination with scleral depression is an important exercise in the evaluation of all patients with ID.

COMPLICATIONS Despite the fact that many studies have suggested that ID tends to be one of the most benign forms of uveitis, severe complications secondary to chronic, indolent inflammation may arise, which may eventuate in bliridness. Even those authors who emphasize the generally good prognosis of this disease admit that 20% of patients have visual acuity of less than 20/40. Deane and Rosenthal36 showed that only 63% of the 86 eyes followed for a mean of 48 months had a visual acuity of 20/20 or better. Ocular hypertension, sometimes leading to glaucoma, has been reported in approximately 8% of patients with ID. In most cases, this ocular hypertension seems to be corticosteroid induced. 7, 16, 35 Interestingly, most studies have not reported on elevated intraocular pressure. 39

FIGURE 78-5. White collagen band at pars plana. (See color insert.)

CHAPTER 78: INTERMEDIATE UVEITIS

In contrast, cataract formation is found in approximately 50% of patients with IU. Previous studies suggest that cataract formation tends to be less severe in patients who have been treated early with immunosuppressive drugs, rather than corticosteroids. * Macular edema and maculopathy are the most common causes of severe visual loss in IU. The incidence may range from 12% to 50%t (Fig. 78-6) and seelns to increase with severity and duration of inflamInation. 40-42 Retinal vasculitis is a frequent finding in many patients. Sometimes, this problem may induce neovascularization (5% to 15%)41,43 and cyclitic membrane formation. Although vitreous hemorrhages may occur in patients with peripheral neovascularization, it seems to be uncommon, occurring in 3% to 5% of patients. 7 , 42 Shields and associates 44 described 113 vasoproliferative tumors of different origin. Of these, the underlying ocular disease was IU or pars planitis in 15 eyes. Retinal detachment may occur in patients with IU. Characteristically, inflammation in IU may lead to exudative retinal detachment (Fig. 78-7) in 5% to 17% of patients,10, 33, 41, 42 a finding uncommonly seen in other uveitic entities except for Vogt-Koyanagi-Harada syndrome. Vitreoretinal traction, reported in 3% to 22% of patients, may lead to retinal breaks, and combined rhegmatogenous-tractional retinal detachments. 5, ~6 Brockhurst and Schepens7 described four types of rhegmatogenous retinal detachment in patients with IU, the complexity of which varied directly with the duration and severity of the inflammatory disease. <1Jf'ype I detachments are low lying, chronic, associated with demarcation lines, and may resolve spontaneously. They occur iIi patients with a benign course and are secondary to small breaks near the ora serrata associated with exudate. Type II detachments resemble large dialyses at the posterior edge of the pars plana exudate. Similarly, these breaks are usually slowly progressive and may resolve spontaneously if vitreoretinal exudation occludes the break. Such detachments are seen in patients with a mild chronic inflammatory course. Type III detachments are rapidly progressive *See references 3, 7, 10, 16, 24, 25, 36, 40, and 4l. tSee references 7, 10, 25, 33, 36, 41, and 42.

FIGURE 78-7. Exudative retinal detachment in intermediate uveitis, demonstrated by fluorescein angiography. (See color insert.)

due to large breaks associated with neovascularization of the vitreous base and circumferential pars plana exudation. These detachments are associated with severe, chronic uveitis. Type N detachments are associated with anterior proliferative vitreoretinopathy associated with 'vascular cicatricial tissue, which produces circumferential traction, fixed folds extending from the periphery to the optic nerve, and total retinal detachment. The breaks in such eyes are difficult to visualize, because they are covered by the extensive pars plana exudate. These detachments occur in patients with the rapidly progressive form of IU, are extremely difficult to repair, and have an extremely poor functional and anatomic prognosis. Malinowski and coworkers41 recently reported an 8.3% rate of retinal detachment in 54 patients with pars planitis followed for slightly more than 7.5 years. Optic nerve involvement is not uncommon in IU. Disc edema is present in 3% to 20% of eyes. 10, 25, 33 It is less common in adult patients with IU,lO, 24, 25,33,45 and it is observed much more often in children. 46 In these cases, disc edema, rarely optic atrophy, and optic disc neovascularization arising from profound retinal ischemia have been reported. Optic neuritis, with or without associated multiple sclerosis (MS), has been reported to develop in 7.4% of 54 patients with pars planitisY

ETIOLOGY

FIGURE 78-6. Macular eden::.a in a patient with intermediate uveitis.

The etiology of IU remains unclear. As with many other forms of uveitis, IU may be initiated by an antigen (probably of infectious origin) leading to a uniform clinical picture with vasculitis and vitreous cells. Probably multiple stimuli can finally lead to the same clinical picture ofIU. The hypothesis now widely accepted is that some cases of IU may represent an autoimmune disorder of the eye. The initiating antigen may be of infectious origin. Only a few infectious agents have been described that lead to the clinical picture of IU, notably Lyme disease, syphilis, and cat-scratch disease. But for the most part, the nature of the antigen remains unclear. The hypothesis of autoimmune disease is supported by the fact that IU is some-

CHAPTER 78: INTERMEDIATE UVEITIS

times associated with MS and with sarcoidosis. Furthermore, IU appears to be a T-cell-mediated disease, because it can be reproduced in experimental models and responds well to immunosuppressive treatment. And finally, Opremcak has shown that lymphocytes frOlll patients with IU but not from patients with other uveitis respond in vitro to exposure to type II collagen, with proliferation and cytokine production, suggesting that type II collagen, richly present in the vitreous, may be an autoantigen in some patients with IU.47 Various studies have looked for a predominant association to an HLA antigen. Most of these studies have used serologic tests only. Recently, Martin and associates 48 reported that 28% of their patients with IU were HLA-A-28 positive, compared with 8.1 % of their healthy control population and 8.6% of patients with posterior uveitis. These findings have not been confirmed by others. Tang and colleagues 49 found a positive, significant association of pars planitis to HLA-DR15, concluding that these patients have a higher risk for the development of systemic diseases. Two years later, researchers at The Johns Hopkins University School of Medicine confirmed these observations, suggesting that HLA-DR15 or some closely linked gene may play a role in both multiple sclerosis and pars planitis. 50 In an ongoing study with 150 patients, we were not able to find a predominant HLA class lor class II-antigen associatiOli' using molecular biology approaches. . Recently, Bora and coworkers51 , 52 described a protein from the serum of patients witli' active IU that may serve as a marker for, and playa potential role in the etiology of this disease. It may become possible in the future to subdivide IU further concerning its etiology. Today, we do not have enough data for such a subdivision.

PATHOGENESIS AND PATHOLOGY The pathogenesis of IU remains unclear. Because of improved treatment modalities, very few eyes have been enucleated, extending our knowledge regarding the pathogenesis and pathology of this disease. 25 , 26, 38, 53-56 Additionally enucleated eyes are mostly blind eyes with longstanding, severe disease, hampering histologic and immunohistologic investigation such that predominant findings are limited to secondary changes, masking the primary pathologic mechanisms. Various anatomic studies of the pars plana region show that this region is characterized·· by relatively low oxygen tension. In case of retinal hypoxia and ischemia, such findings may be relevant with respect to the initiation of inflammation at the pars plana. In addition, there is evidence to suggest that the venules in the pars plana region may be modified in active disease in such a way as to promote lymphocyte trafficking. These venules are characterized by isolated, enlarged endothelial cells, a specialized modification known as high endothelial venule. 56 In one of the few histologic studies, Pederson and colleagues 38 demonstrated that pars plana exudates appear to consist of a loose fibrovascular layer containing occasional fibrocyte-like cells and scattered mononuclear inflammatory cells adjacent to the hyperplastic nonpigmented epithelium of the pars plana.

The fibroglial tissue consists of vitreous collagen and probably fibrous astrocytes, producing larger diameter collagen fibers. Lymphocyte infiltration of retinal veins leads to the clinical signs of vasculitis, but histologically, arterioles are not involved. Choroidal involvement has been demonstrated only in severe cases. 53 These findings clearly demonstrate that IU is not a primary chorioretinal disease. Active vitreal inflammatory cell exudates, which are highly characteristic for IU, were found to be composed of epithelioid cells and multinucleated giant cells. 53 Wetzig and associates 26 found extensive MHC class II antigen expression on vascular epithelium. This could be part of the initiating· process in the recruitment of activated T cells to stimulate a local vasculitis, leading to vitreal inflammation. T cells have been shown to be the predominant cell type in the vitreous in IU, ranging from 11 % to 95% of all vitreous cells. 26 ,57 CD4-positive T cells account for 5% to 75% of all T cells. In the study by Davis and coworkers 58 involving three human vitreous biopsy specimens, the authors found similar results: 35% to 90% CD4-positive cells and 5% to 15% CD8-positive T cells. Macrophages were found to be the second most important cell type. The role of B cells remains unclear. Although Nolle and Eckardt57 were able to demonstrate B cells only rarely, they were the dominant cells in the study of Kaplan and coworkers. 59 Studies of the blood of patients with IU have not extended our knowledge of the pathogenesis of IU. Although the number of T lymphocytes and B lymphocytes in the peripheral blood was normal, an increased ratio of CD4lymphocytes to CD8 IJlllphocytes wasfound in six patients with pars planitis. 60 <X2-Microglobulin, 132-microglobulin, and complement components were also normal, but serum IgD levels and antiganglioside antibodies 61 were elevated. Klok and associates 62 have shown elevated interleukin (IL) 8 levels in the serum of patients with active IU, concluding that elevated IL-8 may predispose these patients to the development of associated systemic disease. Increased levels of soluble IL-2 receptors 63 and inte~Tel­ lular adhesion molecule 1 (ICAM-1)64 have been found in the serum of patients with IU. BenEzra and colleagues 65 recently demonstrated that serum IL-1-receptor antagonist levels in patients with active pars planitis do not differ from those of control patients. In several studies, a search for an antibody response against ocular antigens was' performed. Antibodies against Mueller cells were present in 10% of patients with IU but in only 2.3% of healthy controls and in 7.4% of patients with other autoimlllune disorders. 66 Serum immunoglobulin has been found to bind frozen human retinal sections of patients with IU in 8 of 12 cases of IU,67 whereas staining of retinal vessel walls was demonstrated in 5 of the 12 patients. 67 Antibody production against retinal S-antigen did not differ from normal controls. 68 Using the lymphocyte proliferation test, cellular il1l111 unity against retinal-S and interphotoreceptor-retinoid-binding protein (IRBP) was demonstrated in 22% to 43% of patients with IU, which is less frequerit than

CHAPTER 18: INTERMEDIATE UVEITIS

that which has been shown for posterior uveitis patients. 68-70 Previous studies from our group, investigating a cluster of autoalltib6dies nonspecific for the eye, disclosed typical patterns for acute anterior uveitis (antibodies against sarcolemma 59%, sinusoids 18%, laminin 41 % and microsomes 59%) and posterior uveitis (antibodies against endothelial cells 33% and microsomes 33%) but only a very low production of any of the investigated autoantibodies in patients with IU. 71 To study the pathology and immunohistology of uveitis, experimental models have clearly improved our knowledge. Using retinal S-antigen or IRBP, it is possible to induce a model that is very similar to clinical IU. Vasculitis of retinal vessels with vitreous inflammation is produced. The disadvantage of these models is that IU seems to be only a dose-dependent subgroup of panuveitis, implying that the detectable effects are nonspecific manifestations of inflammation. An IU-like model can also be induced in monkeys after intravitreal il~ection of hyaluronic acid. 72 Experimental models have shown the importance of T cells and the influence of drugs like cyclosporine A on the course of disease, findings that have been verified in clinical IU.

DIAGNOSIS The diagnosis of IU is based on clinical findings. The absence of chorioretinal infiltration, together with vitreous cells that outnumber anterior chamber cell infiltraf1( tion, vitreous snowballs, and the presence of pars plana exudation, suggest IU. Laboratory and ancillary tests are not necessary to establish the diagnosis; however, together with a careful review of systems, laboratory studies may be able to exclude an associated disorder, including Lyme disease, tuberculosis, syphilis, cat-scratch disease, multiple sclerosis, and sarcoid.

Review of Systems The patient's history should concentrate on the duration of symptoms, the number of recurrences, and findings that might be associated with systemic disorders. Fever, fatigue, or night sweats are typical signs of sarcoidosis and tuberculosis, whereas loss of sensitivity or paresthesias of the hands, arms, or legs are suggestive of possible multiple sclerosis. Signs of dermatitis may point to Lyme disease, tuberculosis, or syphilis, whereas arthritis of the knee may suggest the possibility of Lyme disease, and contact with cats may raise the possibility of Bartonella infection. '

Clinical Investigation In addition to the measurement of visual acuity and slitlamp biomicroscopy, measurement of the intraocular pressure and fundus examination with scleral depression is mandatory in patients with uveitis. The Amsler grid has been shown to mirror the presence of macular edema quite well, and we always suggest the grid to patients for self-monitoring.

'Chest X-ray Studies Chest x-ray studies may disclose findings indicative of sarcoidosis or tuberculosis.

Serology

laboratory Testing

In cases of IU, only· a few laboratory and serologic tests are necessary. These tests include determination of the angiotensin-converting enzyme (ACE) level.73. 74 ACE is Inainly produced by granuloma-forming epitheloid cells and is elevated in 60% to 90% of active sarcoid patients and rarely in other lung disorders. It should be remelnbered that ACE in children, as well as in smokers, is nearly always higher than in normal adults. Steroids can suppress elevated ACE activity. Elevated lysozyme levels are also found in the serum of patients with granulomatous disorders like sarcoid, tuberculosis, and leprosy. Serologic testing for cat-scratch disease, syphilis, and Lyme disease should be seriously considered in cases of IU.

Gallium-Scan and Chest Computed Tomography Scan Subclinical pUlmonary sarcoidosis, undetectable by chest x-ray study, may be detected via computed tomography (CT) of the chest or by gallium scan, or both. Abnonnalities discovered through these modalities may be biopsied for definitive diagnosis. A positive gallium scan of the lacrimal gland is found in 60% to 75% of all sarcoid patients. 75 Studies from our group have shown that the combination of serum ACE level and whole-body gallium s'can increases the diagnostic specificity without affecting sensitivity in patients with clinically suspicious ocular sarcoidosis who have normal or equivocal chest radiographs. Although the sensitivity of an elevated ACE in diagnosing sarcoidosis was found to be 73% and the specificity was 83%, the combination of a positive gallium scan and an elevated ACE raised the specificity for diagnosis to 100%, whereas the sensitivity remained unchanged at 73%.76 Furthermore, elevated ACE levels were found in patients with uveitis due to diseases other than sarcoidosis, including Adamantiades-Beh~etdisease, HLA-B27-associated uveitis, syphilis, systemic lUpus erythematosus, juvenile rheumatoid arthritis, tuberculosis, sympathetic ophthalmia, acute retinal necrosis, intraocular lymphoma, birdshot retinochoroidopathy, Lyme disease, Vogt-KoyanagiHarada syndrome, and Wegener's granulomatosis.

fluorescein Angiography Fluorescein angiography can illustrate the extent ofvasculitis and disclose areas of retinal nonperfusion and neovascularization.16, 33, 34, 45 One can see staining of major veins, segmental hyperfluorescence, optic disc hyperfluorescence, and leakage of veins or venules in 40% to 50% of the eyes. In addition to the Alnsler grid, fluorescein angiography is the definitive way to detect cystoid macular edema (CME); however, CME is usually apparent and is diagnosed on biomicroscopic examination of the macula.

Echography In cases of typical pars planitis or IU, echography adds no information to the above-mentioned evaluation. However, severe vitreous infiltration, retinal detachment, posterior scleritis, Toxocara canis granuloma, and intraocular tumors can be excluded by this modality. Using ultrasound biomicroscopy (UBM) , it is possible to demonstrate pars plana exudates and even inflammatory cell aggregates in the vitreous. 77

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Electrophysiology Only a few electrophysiologic studies concerning IU have been published. 78-81 Cantrill and colleagues 78 found mild changes, especially supernormal B-wave implicit times on the electroretinogram (ERG), followed by absence or reduction of scotopic B-wave oscillations in most patients. In mild disease, the B-wave amplitude was found to be increased,81 which may indicate active retinal inflammation or improvement of the inflammation under therapy. Electrophysiology is not a routinely recommended study in the diagnostic work-up of patients with IU.

Diagnostic Vitrectomy Diagnostic vitrectomy is appropriate only in cases with severe vitreal infiltration when posterior uveitis, retinitis, endophthalmitis, or tumors cannot definitely be excluded and when the response to medical therapy is refractory.

ers'll reported a 14.8% incidence of MS in 54 patients with pars planitis who were followed for a little over 7.5 years. Moreover, periphlebitis at the time of diagnosis of pars planitis appeared to be associated with an increased risk of developing MS or optic neuritis, or both. 41 Most recently, Raja and colleagues reported their findings of a long-term follow-up (mean 2 years) study of 53 patients with pars planitis. 50 Of 37 pars planitis patients who had had medical or neurologic follow-up evaluation, six (16.2%) developed MS. Moreover, the HLA-DRI5 allele, coding for one of the two HLA-DR2 subtypes (a phenotype known to be linked to multiple sclerosis), was associated with pars planitis. These findings, together with the previous demonstration of the presence of HLA-DR2 in a homogeneous population of pars planitis patients by Malinowski and coauthors, further support an association between pars planitis and MS, implicating the BLA-DR locus in the pathogenesis of both entities. 88 We recommend that, if symptoms or clinical signs are suggestive for MS on the patient's review of systems and examination, an magnetic resonance imaging (MRI) scan should be performed. This study may· be followed by referral to a neurologist for evaluation, including examination of the cerebrospinal fluid.

The differential diagnosis of IU includes many causes of vitreous inflammation. It is imperative to exclude infectious causes, because specific treatment is indicated and may be curative. Infectious entities in the differential diagnosis include Lyme disease, toxocariasis, Whipple's disease, tuberculosis, syphilis, hUluan T-cell leukeluia vi- Sarcoidosis rus type 1 (HTLV-l), Epstein-Barr virus, and cat-s<;:ratch Landers89 described three of 13 patients with sarcoidosis disease. Equally important is the association of IU with who developed IU. Similarly, Crick90 reported the develunderlying systemic diseases, particularly intraocular lym- opment of IU in all 13 of his patients with sarcoidosis. phoma, sarcoidosis, and MS, because timely diagnosis Conversely, Chester and colleagues 85 studied the inciimpacts not only ocular mor~idity but also quality of dence of sarcoidosis in a group of 51 pars planitis patients life. and potentially mortality. Finally, some other ocular and found it to be only 2%. On the other hand,Jabs and diseases may be difficult to differentiate from typical IU, Johns 91 studied 183 patients with known sarcoidosis, and especially if the patient has already commenced treat- they found 26% with ocular involvement. Eleven of those ment or is in the beginning stage of the disease, or if patients had ID. Other studies have shown that 2% to vitreous inflammation prevents examination of the fun- 10% of patients with IU have sarcoidosis. dus to exclude chorioretinal disease. In their study of 62 patients with pars planitis, Zierhut and Foster86 found six cases of biopsy-proven sarcoid; an Sclerosis additional nine patients were suspected of having sarcoidBreger and Leopold 82 prospectively reported on 14 of 52 osis because of elevated ACE levels. The onset of sarcoidMS patients who developed pars planitis. Giles 83 described osis had begun with pars planitis in two patients, with three patients with MS who later developed pars planitis. one patient developing pulmonary sarcoid 4 to 5 years Porter84 found only two cases of pars planitis in 60 pa- after the onset of the pars planitis. On comparing the tients with MS. Conversely, Chester and associates 85 stud- typical ocular findings seen in pars planitis patients, such ied the incidence of MS developing in patients with pars as CME, optic disc swelling, periphlebitis, and retrobulbar planitis and found that 4 of 51 patients with pars'planitis optic neuritis, the IU patients with sarcoid did not show developed MS. Zierhut and Foster 86 confirmed these significant differences from IU patients without sarcoid. findings in their study, which included 62 patients with In contradistinction to patients with IU, those with pars planitis. Seven of these patients had MS, ranging sarcoid uveitis have a different demographic: There is a from 17 years before the onset of pars planitis to 7 years slight female preponderance, an older age group, and a after the development of pars planitis. Three additional different racial predilection (blacks), at least in the patients (19%) were MS suspects. In their study, they United States. Furthermore, anterior uveitis is more comadditionally compared the incidence of CME, optic disc mon than posterior involvement, with more pronounced swelling, periphlebitis and retrobulbar neuritis in patients anterior segment pathology. Chorioretinitis is a distinctive with pars planitis, with or without MS. Only retrobulbar feature of posterior segment disease in ocular sarcoidosis. neuritis was found to be significantly greater in the MS As intraocular inflammation may precede by many years the onset of syst'emic disease in sarcoidosis, complete group compared with the control group without MS. The association between MS and IU was studied by periodic examinations may be of value. Engell, who positively correlated the level of clinical severity of MS with the presence of vascular sheathing. 87 All but one of these patients had active disease, with vascular sheathing being present in 43% of patients having a rapid Infection with Mycobacterium tuberculosis can induce a cliniprogression of disease. Indeed, Malinowski and cowork- cal picture similar to that of IU. It should be excluded by

CHAPTER 78: INTERMEDIATE UVEITIS

accurate history and review of systems, chest x-ray study, and skin testing. Nodules of the iris or granulomata of the choroid are distinctive findings that may lead to a higher suspicion for tuberculosis.

Syphilis Infection with Treponema pallidum is known to mimic various ocular disorders and to affect nearly every ocular structure. 92 IV seems to be only rarely imitated by syphilis. History and systemic and ocular examinations, together with serologic testing (Venereal Disease and Research Laboratory [VDRL] and fluorescent treponemal antibody absorption [FTA-ABS]), should exclude the diagnosis of syphilis. The VDRL test is not used as the screening test, because 30% of patients with latent secondary syphilis associated with uveitis are VDRL negative but are FTAABS positive. Therefore, the FTA-ABS test is an essential part of the laboratory evaluation.

Lyme Disease

Epstei n-Sarr Zierhut and Foster,86 in their series of 62 patients with pars planitis, found one patient with acute Epstein-Barr virus (EBV) infection, one with serology suggestive for an old EBV infection and findings consistent with sarcoidosis, and one with serology suggestive for an old EBV infection and retinitis pigmentosa. The relevance of EBV in IV remains unclear at the present time.

Intraocular lymphoma

IV can be the first sign of intraocular lymphoma. lo2 If the vitreous inflammation becomes more dense, the chorioretinal lesions may not be visible. A poor or partial response to therapy (corticosteroids or immunosuppressive treatment) should alert the ophthalmologist to consider intraocular lymphoma, a disorder that mostly affects older patients but that has been described in younger patients as well. The diagnostic procedures of choice are vitreal biopsy, careful neurologic history, cerebrospinal fluid investigations, and brain MRI scanning if there is any evidence of a central nervous system (CNS) abnormality.

Lyme disease has been described as causing IV in a small number of studies. 93-96 The history of a tick bite (often unknown to the patient), erythema migrans, or migratory arthralgias (especially involving the knee) in an individual Anterior Uveitis living in an endemic area, with or without neurologic ,Anterior uveitis, by definition, has the predominance of symptoms (eighth cranial nerve palsy ()r chronic meningi- inflammatory activity confined to the anterior chamber, tis), strongly implicates infection with' Borrelia burgdorferi. with minimal vitreous reaction. If patients with severe The diagnosis may be supported by serologic testing; anterior uveitis have been treated aggressively with topical however, such studies are not without problems, especially corticosteroids, the anterior chamber cells may have with respect to false-negative and falsJ-positive findings. cleared, leaving the anterior vitreous with residual spillMter the first several weeks of infection, IgG. and IgM over inflammatory cells, presenting the illusion of IV for antibodies as detected by enzyme-linked immunosorbent the moment. If the history is not typical for acute anterior assay (ELISA) should be positive. However, falsely nega- uveitis (e.g., the presence of pain, photophobia, or red tive cases of Lyme disease, in which the antigen has been eye), one probably must observe the course of the disisolated later, have been reported. False-positive results, ease, because a clear differentiation to IV may be impossiespecially with IgM, may occur in healthy subjects and in ble at that moment. Although posterior syn.echiae are not patients with a variety of other diseases, including syphilis. proof of anterior uveitis, cellular aggregates in the vitreous are found much more often in IV, only rarely in iridocyclitis, and never in iritis. Pars plana exudation is Human T-Cell Leukemia Virus Type I Infection with HTLV-1 has been shown to induce IV. 97 ,98 pathognomonic for pars planitis,. completely excluding Similar to sarcoidosis, HTLV-1 uveitis may lead to granulo- anterior uveitis. matous uveitis with iris nodules, vitreous exudates, and periphlebitis. Differentiating between sarcoid and HTLV- Other Uveitic Syndromes 1 virus uveitides may be difficult. HTLV-1 antibody pro- In certain instances, typical posterior uveitic entities must duction is found in serum and also ~n the aqueous humor be differentiated from IV. In cases of severe vitreous and in cerebrospinal fluid. Although HTLV-1 is endemic infiltration, chorioretinitis may be overlooked, and so inJapan and Haiti, the relevance of this microbe in other toxoplasmosis, toxocariasis, and also endogenous enparts of the world is unclear. dophthalmitis must be excluded. On the other hand, mild vi.tritis seen in conjunction with subtle chorioretinal Cat-Scratch Disease involvement in Vogt-Koyanagi-Harada syndrome, arterioCat-scratch disease has been described by Soheilian and lar vasculitis in Adamantiades-Behc,;:et's disease, and occluassociates99 as causing IV with focal vasculitis. The disease, sive vasculopathy in Eales' disease may rarely simulate IV. caused by Bartonella, typically leads to conjunctivitis and The history, review of systems, ocular examination, and neuroretinitis. loo Laboratory tests may identify Bartonella clinical context serve to differentiate these entities. Chester and associates,85 in his report of 51 patients directly from primary inoculation site, lymph nodes, or blood, or by detecting antibodies lol against Bartonella. with pars planitis, described six as having retinitis pigThe skin test from which antigen is prepared from the . mentosa. One additional patient was reported by Zierhut purulent aspirate of a lymph node from a patient with and Foster. 86 This young female patient, who also had proven cat-scratch disease, has a sensitivity of 79% to serology suggestive of previous EBV infection, developed 100% with a specificity of 90% to 98% and negative IV that evolved years later to retinitis pigmentosa, which had been previously diagnosed in her sister. The relepredictive values of 78% to 100%.

CHAPTER 78: INTERMEDIATE UVEITIS

vance of these findings remains unclear at the present time. Recently, a patIent with tubulointerstitial nephritis with uveitis (TINV) syndrome was reported to develop IV, not the anterior uveitis, which is more typically reported in patients with TINV.103 Dann and coworkers 104 have reported a patient with Gaucher's disease, a sphingolipidose defect syn.drOlne, who developed IV and showed good response to alglucerase substitution therapy. Ormerod and associates 105 reported a patient with pars planitis after cataract surgery. Proprionibacterium acnes was isolated from the vitreous.

TREATMENT The rationale for treatment of IV is slightly different from that of most other uveitic entities. Before commencing therapy, one must have a clear idea of the best indication for treatment and, later, to decide if medication or surgery is the wiser approach in the patient with chronic disease.

Indication for Treatment Whether acute IV should be treated depends on the presence of inflammation, the extent of vasculitis, coexisting macular edema, and finally, the degree of pars plana infiltration. Although the current consensus is that inflammation producing a decrease in visual acuIty to 20/ 30 (some have suggested 20/40 as the point to begin therapy) is an indication for treatment,46,106 we do not subscribe to this view. It has b'een our experience that treating inflammation early and aggressively, rather than an arbitrary level of visual acuity, is more effective in both the short term and in the long run in preserving those ocular structures (the macula and optic nerve) that are critical for good visual function. We have pointed out that a significant number (20%) of patients with IV, who are allowed to lose vision to the 20/40 level before being offered treatment, are never able to recover normal vision even with treatment. Therefore, we believe that it is not reasonable to deny therapy to patients with IV with active inflammation who have lost smne vision. The treatment itself carries some risk; however, given our philosophy of a limit to the total amount of steroid used for any individual, and given our belief that we personally would want treatment if we had IV and lost vision to the 20/30 level, we offer treatment to such patients. We also treat patients with a large extent of vasculitis, for example, involving more than 270 degrees of the retinal circumference, and patients with acute infiltration of the pars plana. If the macula is already involved, immediate and aggressive treatment seems to be the only way to prevent progressive visual loss. Having excluded treatable infectious and noninfectious entities that may simulate or present a clinical picture of IV, we follow a modification of the four-step approach initially described by Kaplan. 107 In this regimen, a series of periocular steroid injections is recommended, followed by oral prednisone for those individuals who continue to experience recurrence of uveitis as the effect of each steroid injection declines, followed by vitrectomy or immunosuppressive drugs. We have modified this to a five-step program, because observing that some individu-

als, treated with oral nonsteroidal anti-inflammatory drugs (NSAIDs) during the administration of a series of periocular steroid injections and continued indefinitely thereafter, will remain relapse free. We also have suggested relatively strict limits to the total amount of steroid therapy: No more than six periocular steroid injections, and no more than 3 months of a tapering oral steroid regimen. Our approach is to commence therapy with (1) topical corticosteroids in the presence of anterior segment inflammation, together with regional corticosteroid injections (triamcinolone, 40 mg); (2) oral NSAIDs, should inflammation recur following the third injection, and topical NSAIDs in the presence of CME; (3) a short course of systemic corticosteroids should inflammation persist or recur despite the previous interventions; (4) peripheral retinal cryopexy or indirect laser photocoagulation should pars planitis recur following the sixth regional steroid injection; and (5) offer therapeutic pars plana vitrectomy (PPV) versus immunosuppressive chemotherapy should inflammation be recalcitrant to the preceding modalities. Cyclosporin A (CSA) and methotrexate are the immunosuppressives of choice at present, whereas mycophenolate mofetil appears to be a promising drug. Azathioprine generally is the second choice, whereas cyclophosphamide and chlorambucil are the drugs of last resort. Although some centers prefer to perform vitrectomy before immunosuppressive treatment, various reports show longlasting improvement after therapy with imlnunosuppressants, reserving vitrectomy for cases of intolerable side effects or nonresponsiveness. We are flexible on this point and are conducting a randomized study comparing therapeutic PPV with low-dose once-weekly methotrexate for pars planitis. There have been no controlled randomized studies assessing the efficacy of various immunosuppressive drugs or for vitrectomy in the treatment of IV. Most have been small retrospective reports, making comparison between treatment modalities nearly impossible owing to the heterogeneity of the uveitis populations, the nonuniformity of diagnostic criteria and treatment protocols, and because frequently, immunosuppressive therapy was terminated too early in the course of the disease, before a remission could have developed.

Drug Therapy

Corticosteroids Corticosteroids are still the mainstay of therapy for patients with IV and pars planitis. Although topical corticosteroids may be effective in some aphakic eyes, generally peribulbar or systemic corticosteroids are required. The optimal dosage is still unknown, but triamcinolone periocularly (40 mg every 3 to 5 weeks) seems to be effective,35, 108 as is prednisolone orally for systemic administration (75 mg daily for 5 days followed by 50 mg for one week and reduced by 10 mg weekly thereafter).108, 109 Our preference is to commence systemic steroid therapy at 1 mg/kg daily, with the initiation of tapering after 2 weeks of treatment, and guided thereafter by the clinical response. Treatment is rarely extended beyond 3 months.

78: INTERMEDIATE UVEITIS

When macular edema is present, we also add acetazolamide (250 bid for 3 to 6 weeks), and very slowly taper over a period of months and on a systemic NSAlD, such as diflunisal, 500 mg PO bidYo Even using this regimen, recurrences are common. Godfrey and associates 35 found a greater effect on CME in patients with IU after periocular corticosteroid injections (71 %) than after systemic treatment (41 %).

Nonsteroidal Anti-inflammatory Drugs Although the efficacy of NSAlDs in uveitic disease has not been firmly established, we have em.ployed systemic NSAIDs successfully in our patients with pars planitis in an effort to spare the total amount of corticosteroids used and to maintain inflammatory remission. In addition, a variety of studies have shown reduced ocular inflammation following cataract extraction, a salutory effect on CME, and improvement in other forms of inflammation with the use of these agents. l l l

Cyclosporine A Reports on the use of CSA for the treatment of IU, or comparison of its use for IU versus other forms of uveitis, are few. Schlote and colleagues 1l2 reported good results for uveitis in childhood. Similar positive results were obtained by Walton and coworkers,113 who treated severe sight-threatening uveitis in children and adolescence, some of whom had IU. They concluded that CSA was a safe and effective therapy for this grol.}f of patients. CSA has also been the preferred immunosuppressive at the National Eye Institute for adults with IU who are intolerant of, or do not respond to, corticosteroid therapy. It should be pointed out that the dosage that is used in uveitis has been reduced from 5 to 10 mg/kg of body weight daily, down to 2 to 5 mg/kg of body weight daily, in an effort to curtail the nearly uniform occurrence of hypertension and renal side effects seen at the higher dosesY4 However, this dosage reduction has also resulted in dilninished anti-inflammatory efficacy compared with that initially claimed for higher dosage regimens.

./ Methotrexate

exploited in the management of a variety of ocular inflammatory disorders, with favorable results. 11 8-120

Azathioprine

N ewell and Krill 121 employed azathioprine in the treatInent of 20 patients with uveitis of various etiologies and found visual improvement in all treated eyes. Apparently, the drug was most effective in those patients with pars planitis. We use azathioprine as a second-line drug, mainly as a steroid-sparing agent.

Cyclophosphamide, 6-Mercaptopurine Cyclophosphamide and chlorambucil are both alkylating agents. Although they are highly effective in vasculitic diseases such as Adamantiades-Beh<,;:et's disease and Wegener's granulomatosis, these drugs carry the potential for serious toxicity and have been used in the therapy of IU only occasionally. GillS 122 described beneficial results after cyclophosphamide treatment in eight patients. Chlorambucil was used successfully by Godfrey and associates,123 who achieved improvement in 10 of 31 patients with intractable uveitis. Likewise, 6-mercaptopurine was employed by Newell and Krill,l21 with improvelnent in four of five cases. Alopecia, bone marrow toxicity, sterility, and · increased risk of malignancy late in life must taper one's enthusiasm for the use of alkylating agents in the care of patients with a disorder (e.g., IU) that carries a relatively good prognosis.

New Drugs A new agent with significant therapeutic promise, a very low toxicity profile and virtually no mutagenic potential is mycophenolate mofetil (CellCept). This drug has been used in uncontrolled, open-label studies, at a dose of 1 g twice daily, in conjunction with corticosteroids as a steroid,..sparing agent or as an adjunct to a pre-existing immunosuppressive regimen (CSA) , with improvement in sYlnptoms and reduction in inflammation in a variety of uveitic entities, including at least one patient with pars planitis. 124, 125 Masked, controlled, randomized clinical trials are required to evaluate the full potential of this drug, as compared with other immunosuppressive agents.

Concerns regarding adverse side effects of methotrexate may have limited its use in the management of uveitis. In their initial reports, Wong and Hersh reported favorable Surgical responses in nine of 10 patients with steroid-resistant Cryotherapy and scatter laser photocoagulation of the uveitis, including IU, who were treated with high-dose peripheral retina, as well as PPV with or without pars (25 mg/m 2 body surface area) intravenous methotrexate plana lensectomy (PPL) , have been shown to be effective every 4 hours for 6 weeks. Although few serious adverse in the treatment of IU. Likewise, visual rehabilitation reactions occurred, inflammatory symptoms recurred in through cataract extraction with intraocular lens implanmore than half of the patients when therapy was discon- tation is a safe and effective procedure, provided vigilant tinued.1l5-117 Lazar and associates 101 obtained similarly perioperative control of inflammation is achieved. encouraging results in 14 of 17 patients with various steroid-resistant uveitides, including four with sympa- Cryotherapy thetic ophthalmia who were treated with intravenous Patients in whom drug therapy has failed or who exhibit methotrexate. However, this success was associated with recurrent inflammation despite the administration of topsignificant drug-induced toxicity, including gastrointesti- ical, regional, and systemic· steroids, or NSAIDs, as prenal complications, secondary infections, and laboratory' viously outlined, may require cryotherapy or laser photoevidence of liver damage. 101 More recently, the reduced coagulation in order to control the disease. These frequency and severity of adverse reactions reported with patients have developed neovascularization of the vitreoral or intramuscular low-dose, pulsed (weekly) metho- ous base, which, although frequently obscured by pars trexate therapy and folic acid supplementation have been plana exudation and vitritis, can sometimes be appreci-

CHAPTER 78:

ated as thick, ropy vessels extending over the ora serrata on scleral depression. The rationale for both cryotherapy and for laser photocoagulation is to induce regression of this vitreous base neovascularization and consequently to stabilize inflammation. In two separate reports, Aaberg and colleagues 126, 127 demonstrated the efficacy of cryotherapy, with 35% of eyes showing complete inflalnmatory quiescence, with an additional 57% achieving marked reduction in inflammatory activity. Subsequently, Devenyi and associates 128 and MieleI' and Aaberg 129 recommended cryotherapy for neovascularization of the vitreOllS base in patients with pars planitis following their experience in achieving inflammatory quiescence in 24 of 30 eyes (80%), with 67% enjoying visual improvement. However, six eyes (20%) required vitreous surgery following cryotherapy, with two developing a retinal detachment. Similarly favorable results were reported by Oldnami,130 with 61 % regression of inflammation after one cryotherapy treatment, and from Berg and Kroll,131 who, despite a 48% improvement of visual acuity, also reported a 39% relapse rate over a period of 1.2 years. In a small randomized study in which cryotherapy was compared with corticosteroids, cryotherapy was superior. 132 Favorable results notwithstanding, cryotherapy may produce significant adverse sequelae, including epiretinal membranes, cataract formation, exacerbation of macular edema, and retinal detachment. 106, 130 Although r~tinal detachment is observed as a part of the natural history of IV, and the incidence of retinal detachment seems no higher with cryotherapy than '¢thout it,130 it is thought that cryotherapy causes more disruption of the bloodocular barrier and adjacent inflammation, and may induce vitreous gel contraction, possibly accelerating the rate of retinal detachment in a predisposed eye. Our technique is to apply a double row, single freeze, of cryopexy applications to the pars plana and posterior to it, extending one clock hour to either side of all areas affected by the inflammation.

Scatter Laser Photocoagulation Recently, panretinal photocoagulation (PRP) has been shown to be effective in the treatment of peripheral neovascularization associated with IV. 133 , 134 Park and colleagues demonstrated regression of neovascularization with stabilization of inflammation, reduction in CME, and improvement in visual acuity il~ ~ight of 10 eyes followil)g PRP alone or in combination with PPY. Advantages of laser photocoagulation include ease of treatment delivery, fewer complications, and reduced ocular. morbidity as compared with cryotherapy. This modality is obviously limited by the extent of vitreous opacification, but appears to be a safe and effective alternative to cryotherapy and is an especially useful adjunctive procedure when applied during therapeutic pars plana vitrectomy.

V,ir
CME, and may ultimately alter the natural history of the disease. Diamond and Kaplan 13.5 were the first to demonstrate beneficial effect of PPV and PPL in patients with uveitis: Specifically, three of four IV patients achieved a visual acuity of 20/40 or better. Subsequently, MieleI' and coworkers,136 Heimann and associates,137 and Eckardt and Bacskulin138 reported the use of PPV with or without PPL for the treatment of vitreous and lenticular opacification, vitreous hemorrhage, tractional retinal detachment, and epiretinal membrane formation complicating pars planitis, and they demonstrated significant improvement in visual acuity. In addition, inflammatory recurrences were reduced with respect to both frequency and severity in 88% of patients,138 preoperative hypotony was normalized in eight patients,138 and CME regression was noted in 14 of 17 patients, while one patient experienced new postoperative CME. 136 The presence of active neovascularization of the vitreous base was associated with a poorer outcome, whereas preoperative cryotherapy appeared to improve the prognosis. 136 Likewise, a large retrospective review by Heiligenhaus and colleagues 60 included 16 patients with IV who underwent PPV with or without PPL. In this review, not only were the frequency and severity of inflammatory episodes reduced but GIVIE was seen to resolve in three eyes. In addition, all six patients requiring prednisone preoperatively to achieve inflammatory quiescence were able to stop taking this medication during the postoperative period. Dugel and colleagues 139 reported visual acuity iInprovement and attenuation of CME in the majority of 11 eyes of nine patients who underwent PPV for CME and intraocular inflammation unresponsive to corticosteroids. Of the six eyes with pars planitis specifically, however, only three were among those noted to improve. Indeed, Schonfeld and coworkers 140 reported a visual acuity of 20/200 in 75% of their patients with IV undergoing pars plana vitrectomy, suggesting that pre-existing macular pathology limited the visual outcome. The efficacy of PPV, with or without PPL, in the treatment of uveitis in general and specifically with respect to IV, remains an open question, especially considering that many of the aforementioned studies were uncontrolled, comparisons were frequently only made between preoperative and postoperative visual acuities, observation times were short, and sample sizes were small. The potential risks of PPV, including epiretinal gliosis, retinal detachment, and cataract, are also not to be trivialized, and hence the folly of being fixed in opinion on the matter of "vitrectomy versus immunomodulation" for any given patient. Definitive efficacy awaits randomized controlled study in a homogeneous population of uveitic patients.

Cataract Surgery Cataract formation is one of the most significant complications of IV. Generally, it appears that cataract extraction is a safe procedure if any active inflammation is controlled with corticosteroids or immunosuppressives for a minimum of 3 months before surgery.141 Cataract extraction can be achieved through PPL, in combination with PPV,l3.5 but also through extracapsular cataract tech. nique 141 or phacoemulsification with consecutive intraocular lens implantation. Cataract extraction can also be

. CHAPTER

INTERMEDIATE UVEITIS

followed by PPV in a single or two-step procedure. 142 , 143 Fourteen of 17 eyes (88%) of patients with pars planitis reported by Kaufman and Foster 144 achieved a visual acuity of 20/40 or better following cataract extraction, for those in whom active inflammation had been suppressed before surgery for a minimum of 3 months. Most eyes underwent intraocular lens implantation, and those with significant vitreous opacification also had PPV performed. Problems may arise if ocular inflammation is not completely controlled preoperatively.144 Indeed, in one series of 15 eyes of eight patients with pars planitis who underwent extracapsular cataract extraction with intra.:. ocular lens implantation, two eyes required lens explantation and five eyes required multiple laser or surgical procedures to clear posterior capsular membranes. Postoperatively, severe inflammation may lead to additional complications such as lens dislocation, symblepharon formation, or even phthisis. Despite these complications, 60% of eyes achieved a postoperative visual acuity of 20/ 40 or better. 143

Alternative Therapies In addition to drugs and surgical procedures, a few interesting alternatives have been suggested for the treatment ofIU. PLASMAPH ERESIS Brunner and associates 145 compared plasma exchange treatment with (25 patients) or without (24 patients) infusion of preserved serum in patien;s with IU. Additional corticosteroid pulse therapy was given to five patients in each group. The authors showed that in both groups, reduction of inflammatory signs was achieved. There was no control group. TOLERANCE INDUCTION

We recently published our first results 146 using oral administration of retinal autoantigens in a phase I and II randomized masked trial. Sixteen of the 45 patients had IU. Patients who were dependent on immunosuppressive agents were assigned to one of four groups: Some patients received retinal-S antigen alone (10 patients); a second group received retinal-S antigen in a mixture of soluble retinal-S antigens (10 patients); a third group received a mixture of soluble retinal-S antigen alone (10 patients); and a fourth group received a placebo (15 patients). Although not statistically significant, the group receiving the purified S-antigen alone were able to be tapered off their immunosuppressive medications more successfully than were the other groups tested. Because of the small sample size, the authors did not show whether patients with IU responded differently from the other patients with uveitis.

NATURAL

AND PROGNOSIS

IU is often considered one of the most benign forms of uveitis. But Brockhurst and Schepens7 described four different groups as defined by clinical course. A mild course was seen in 31 % of patients, a mild chronic course in 49%, a severe chronic course in 15%, and a relentlessly progressive course in 10%. Smith and colleagues 16 found 19% to have mild, 42% moderate, and 39% severe in-

flammation in their group of patients with IU who were studied more than 10 years later. Obviously, such percentages depend greatly on the patient characteristics and referral patterns to a tertiary eye care center, where severe cases will be overrepresented. At the moment, there are no well-defined parameters to predict the natural course of the disease. The presence of a pars plana exudate may have poor prognostic significance. 36,37 Other studies have shown that the severity of inflammation is more important for the visual outcome than the duration of the disease. Smith and associates 16 found a 5% remission rate after a follow-up of 4 to 26 years. It seems that in most patients, the disease goes into remission after 10 to 15 years. The presence of periphlebitis at the time of diagnosis of pars planitis appears to be associated with an increased risk of developing multiple sclerosis or optic neuritisY Moreover, there appears to be a clinically significant association between MS and pars planitis, a link strengthened by common tissue typing to HLA-DR2, and, by implication, a possible shared pathogenesis. 41 , 50 Regarding the prognosis of IU, no truly excellent studies are available. At presentation, approximately 50% of patients have a visual acuity of 20/30 or better. 37 More recent follow-up studies have shown that the majority of patients maintain their good initial visual acuity,41 with up to 90% retaining a visual acuity of 20/40 or better over 2 years in one study. 50 Nevertheless, as previously mentioned, Smith and colleagues observed significant visual disability in over one third of their patients, and it is likely that, with more long-term follow-up, patients described in more recent studies will manifest visually limiting sequela. The clinician must ask the question, "Would I find such sequela acceptable for myself?" Aggressive treatment, before ocular complications arise, is a rational approach to this problem; however, the identification of patients who would benefit most from this approach remains to be determined with more certainty. This conundrum is underscored by the fact that, to date, no controlled data have been gathered to suggest which of the many therapeutic options, either medical or surgical, are most appropriate, impacting positively on the prognosis and natural history of the disease.

CONCLUSIONS Patients with IU represent approximately 10% to 20% of all uveitis patients. Typical vitreous infiltration with cellular exudates and, in cases of pars planitis, pars plana exudates, are found. Potentially blinding complications include glaucoma, cataract, CME, and maculopathy. IU probably represents an autoimmune disease in most cases. Although the initiating antigen may be a microbial agent, its nature remains unknown. In the pathogenesis, CD4 + T-cells seem to playa major role. The diagnosis is based on clinical findings. Associated systemic disorders, such as sarcoid, multiple sclerosis, and infectious diseases . including syphilis, Lyme disease, and tuberculosis, must be excluded. For the treatment of severe IU, a modified five.:.step approach has proven to be effective: (1) topical and periorbital steroids; (2) oral NSAIDs; (3) systemic corticosteroids; (4) cryotherapy or scatter laser photocoagulation; and (5) immunosuppressive chemotherapy or

CHAPTER. 78: INTER.MEDIATE

PPV, with or without PPL. First-choice iInmunomodulators include CSA and methotrexate. Visual rehabilitation through cataract" surgery with intraocular lens implantation, with or without PPV, appears to be safe, provided that proper patient selection and vigilant control of preoperative and postoperative inflammation are exercised. The visual prognosis is, in general, quite good; however, significant visual debility can result. Aggressive treatment of intraocular inflammation may be important in improving the prognosis. There appears to be a clinically significant association between IV and multiple sclerosis.

27. 28. 29. 30. 31.

32.

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CHAPTER 18: INTERMEDIATE UVEITIS 57. Nolle B, Eckardt C: Cellular phenotype of vitreous cells in intermediate uveitis. Dev Ophthalmol 1992;23:145-149. 58. Davis JL, Solomon D, Nussenblatt RB, et al: Immunocytochemical staining ofvit.reous cells: Indications, techniques, and result.s. Ophthalmology 1992;99:250-256. 59. Kaplan HJ, Waldrep JC, Nicholson JKA, Gordon D: Immunologic analysis of intraocular mononuclear cell infiltrates in uveit.is. Arch Ophthalmol 1984;102:572-575. 60. Heiligenhaus A, Bornfeld N, Foerster MH, Wessing A: Long term results of pars plana vit.rect.omy in the management of complicat.ed uveitis. Br J Ophthalmol 1994;78:549-554. 61. Yokoyama MM, Matsui Y, Yamashiroya HM, et al.: Humoral and cellular immunity studies in patients wit.h Vogt.-Koyanagi-Harada syndrome and pars planit.is. Invest Ophthalmol Vis Sci 1981;20:364-370. 62. Klok AM, Luyendijk L, Zaal MJ, et al: Elevated serum IL-8 levels are associated with disease activity in idiopat.hic int.ermediat.e uveitis. Br J Ophthalmol 1998;82:871-874. 63. Murray PI, Young DW: Soluble interleukin-2 receptors in retinal vasculitis. Curl' Eye Res 1992;11 (Suppl): 193-195. 64. Arocker-Mettinger E, Steurer-Georgiew L, Steurer M, et. al: Circulat.ing ICAM-1 levels in serum of uveitis patients. Curl' Eye Res 1992;11 (Suppl) :161-166. 65. BenEzra D, Maftzir G, Barak V: Blood serllm interleukin-1 receptor antagonist in pars planitis and ocular Beh<;:et disease. Am J Ophthalmol 1997;123:593-598. 66. Nolle B: Antiretinal autoant.ibodies in intermediate uveitis. Dev Ophthalmol 1992;23:94-98. 67. Davis JL, Chan CC, Nussenblatt RB: HLA in int.ermediat.e uveitis. Dey Ophthalmol 1992;23:71-85. 68. Doekes G, vanderGaag R, Rothova A, et al: Humoral and cellular immune responsiveness to human S-ant.igen in uveitis. Curr Eye Res 1987;6:909-919. 69. DeSmet MD, Yamamoto JH, Mochizuki M, et. al: Cellular immune responses of patient.s wit.h uveitis t.o retinal antigens and their fragments. AmJ Ophthalmol 1990;110:135-14" 70. Nussenblatt RB, Salinas-Carmona M, Leake W, Scher I: T lymphocyt.e subset.s in uveitis. AmJ Ophthalmol 1983;95:614-621. 71. Zierhut M, Klein R, Berg P, et al: Augenunspezifische Aut.oant.ikorper bei Uveitis. Fortschr Ophthalmol 1989;86:482-485. 72. Hultsch E: Peripheral uveitis in the owl monkey. Mod Probl Ophthalmol 1977;18:247-251. 73. Lieberman J: Enzymes in sarcoidosis: Angiotensin converting enzyme (ACE). Clin Lab Med 1989;9:745. 74. Zierhut M: Uveitis, VoIr. Different.ial Diagnosis. Buren, Netherlands, Aeolus Press, 1995. 75. Weinreb RN, Yavitz EQ, O'Connor GR, Bart.h RA: Lacrimal gland upt.ake of gallium cit.rate Ga 67. AmJ Ophthalmol 1981;92:16-20. 76. Power~, Neves RA, Rodriguez A, et al: The value of combined serum angiot.ensin-convert.ing enzyme and gallium scan in diagnosing ocular sarcoidosis. Ophthalmology 1995;102:2007-2011. 77. Haring G, Nolle B, Wiechens B: Ultrasound biomicroscopic imaging in intermediate uveitis. Br J Ophthalmol 1998;82:625-629. 78. Cantrill HL, Ramsay RC, Knobloch WH, Purple RL: Electrophysiologic changes in chronic pars planitis. Am J Ophthalmol 1981;91:505-512. 79. Ortega C, Jimenez JM, Arellanes L, Angel E: Electrophysiologic changes in chronic pars planitis. Invest. Ophthalmol Vis Sci 1992;33:743. 80. Tetsuka S, Katsumi 0, Mehta MC, et al: Electrophysiological findings in peripheral uveitis. Ophthalmologica 1991;203:89-98. 81. Zimmerman MD, Dawson 1,VW, Fitzgerald CR: Part I: Elect.roretinographic changes in normal eyes during administrat.ion of prednisone. Ann Ophthalmol 1973;5:757-765. 82. Breger BC, Leopold IH: The incidence of uveitis in multiple sclerosis. AmJ Ophthalmol 1966;62:540-545. 83. Giles CL: Peripheral uveit.is in pat.ients wit.h mllltiple sclerosis. Am J Opht.halmol 1970;70:17-19. 84. Porter R: Uveit.is in association with multiple sclerosis. Br J Ophthalmol 1972;56:478-481. 85. Chester GH, Blach RK, Cleary PE: Inflammation in the region of the vitreous base: Pars planitis. Trans Ophthalmol Soc UK 1976;96:151-197. 86. Zierhut M, Fost.er S: MUltiple sclerosis, sarcoidosis and other diseases in patients wit.h pars planit.is. Dev OphthalmoI1992;23:41-47.

87. Engell T: Neurological disease act.ivity in mUltiple sclerosis pat.ient.s wit.h periphlebit.is retinae. Acta Neurol Scand 1986;73:168-172. 88. Malinowski SM, Pulido JS, Goeken ME, et al: The association of HLA-B8, B51, DR2, and multiple sclerosis in pars planitis pat.ients. Ophthalmology 1993;100:1199-1204. 89. Landers PH: Vitreous lesions in Boeck's sarcoid. AmJ Ophthalmol 1949;32:1740-1741. 90. Crick RP: Ocular sarcoidosis. Trans Ophthalmol Soc UK 1955;75:189-206. 91. Jabs DA, Johns CJ: Ocular involvement in chronic sarcoidosis. Am J Ophthalmol 1990;102:297-301. 92. Tamesis RR, Fost.er CS: Ocular syphilis. Ophthalmology 1990;97:1281-1287. 93. Breeveld J, Rot.hova A, Kuiper H: Intermediate uveit.is and Lyme borreliosis. Br J Opht.halmol 1992;76:181-182. 94. Guex-Crosier Y, Herbort CP: Maladie de Lyme en Suisse: Att.eint.es oculaires. Klin Monatsbl Augenheilkd 1992;200:545-546. 95. Nolle B: Serological evidence of an association between Lyme borreliosis and intermediat.e uveitis. Dev Opht.halmoI1992;23: 115117. 96. Winward KE, Hamed LM, Glaser JS: The spectrum of optic nerve disease in human immunodeficiency virus infection. Am J Ophthalmol 1989;107:373-380. 97. Mochizuki M, Watanabe T, Yamaguchi K, et. al: Uveit.is associat.ed with human T-cell lymphotropic virus type 1. Am J Ophthalmol 1992;114:123-129. 98. Mochizuki M, Watanabe T, Yamaguchi K, T
CHAPTER 78: INTERMEDIATE UVEITIS 116. Wong VG, Hersh EM: Methotrexate in the treatment of cyclitis. Trans Am Acad Ophthalmol Otolaryngol 1965;69:279-293. 117. Wong VG: Methotrexate treatment of uveal disease. Am] Med Sci 1966;251 :239-241. 118. Holz FG, Krastel H, Breitbart A, et £11: Low-dose methotrexate treatment in noninfectious uveitis resistant to corticosteroids. German] Ophthalmol1992;1:142-144. 119. Shah SS, Lowder CY, Schmitt MA, et £11: Low-dose methotrexate therapy for ocular inflammatory disease. Ophthalmology 1992;99: 1419-1423. 120. Dev S, McCallum RM, Jaffee GJ: Methotrexate treatment for sarcoid-associated panuveitis. Ophthalmology 1999;106:111-118. 121. Newell FW, Krill AE: Treatment of uveitis with azathioprine (Imuran). Trans Ophthalmol Soc UK 1967;87:499-511. 122. Gills ]P, Durham NC: Combined medical and surgical therapy for complicated cases of peripheral uveitis. Arch Ophthalmol 1968;79:723-728. 123. Godfrey WA, Epstein WV, O'Connor GR, et £11: The use of chlorambucil in intractable idiopathic uveitis. Am ] Ophthalmol 1974;78:415-428. 124. Kilmartin D], Forrester]V, Dick AD: Rescue therapy with mycophenolate mofetil in refractory uveitis. Lancet 1998;352:35-36. 125. Larkin G, Lightman S: Mycophenolate mofetil-a useful immunosuppressive in inflammatory eye disease. Ophthalmology 1999;106:370-374. 126. Aaberg TM, Cesarz T], Flickinger RR: Treatment of peripheral uveoretinitis by cryotherapy. Am] Ophthalmol 1973;75:685-688. 127. Aaberg TM, Cesarz T], Flickinger RR: Treatment of pars planitis. Cryotherapy. Surv Ophthalmol 1977;22:120-130. 128. Devenyi RG, Mieler WF, Lambrou FH, et £11: Cryopexy of the vitreous base in the management of peripheral uveitis.. Am1 Ophthalmol 1988;106:135-138. 129. Mieler WF, Aaberg TM: Further. observations on cryotherapy on the vitreous base in the management of peripheral uveitis. Dev Ophthalmol 1992;23:190-195. 130. Okinami S, Sunakawa M, Arai 1, '~t £11: Treatment of pars planitis with cryotherapy. Ophthalmologica 1991;202:180-186. 131. Berg P, Kroll P: Cryotherapy in uveitis. Dev Ophthalmol, Basel, Karger, 1992;23:219-225.

132. Verma L, Kumar A, Garg S, et ~l: Cryopexy in pars planitis. Can] Ophthalmol 1991;26:313-315. 133. Franklin RM: Laser photocoagulation of retinal neovascularization in intermediate uveitis. Dev Ophthalmol 1992;23:251-260. 134. Park WE, Mieler WF, Pulido ]S: Peripheral scatter photocoagulation for neovascularization associated with pars planitis. Arch Ophthalmol 1995;113:1277. 135. Diamond ]G, Kaplan HJ: Lensectomy and vitrectomy for complicated cataract secondary to uveitis. Arch Ophthalmol 1978;96:1798-1804. 136. Mieler WF, Will BR, Lewis H, Aaberg TM: Vitrectomy in the management of peripheral uveitis. Ophthalmology 1988;95:859864. 137. Heimann K, Schmanke L, Brunner R, et £11: Pars plana vitrectomy in the treatment of chronic uveitis. Dev Ophthalmol 1992;23:196203. 138. Eckardt C, Bacskulin A: Vit:rectomy in intermediate uveitis. Dev Ophthalmol 1992;23:232-238. 139. Dugel PU, Rao NA, OzIer S, et £11: Pars plana vitrectomy for intraocular inflammation related to cystoid macular edema unresponsive to corticosteroids: A preliminary study. Ophthalmology 1992;99:1535-1541. 140. Schonfeld CL, Weil3schadel S, Heidenkummer HP, Kampik A: Vitreoretinal surgery in intermediate uveitis. German] Ophthalmol 1995;4:37-42. 141. Foster CS, Fang LP, Singh G: Cataract surgery and intraocular lens implantation in patients with uveitis. Ophthalmology 1989;96:281-287. 142. Fogla R, Biswas], Ganesh SK, Ravishankar K: Evaluation of cataract surgery in intermediate uveitis. Ophthalmic Surg Lasers 1999;30:191-198. 143. Michelson ]B, Friedlaender MH, Nozik RA: Lens implant surgery in pars planitis. Ophthalmology 1990;97:1023-1 026. 144. Kaufman AH, Foster CS: Cataract extraction in patients with pars planitis. Ophthalmology 1993;100:1210-1217. 145. Brunner R, Borberg H, Kadar ], et £11: Plasma exchange and immunoglobulins in the treatment of intermediate uveitis. Dev Ophthalmol 1992;23:275-284. 146. Nussenblatt RB, Gery I, Weiner HL, et £11: Treatment of uveitis by oral administration of retinal antigens: Results of a phase I/II randomized masked trial. Am] Ophthalmol1997;123:583-592.

-I

I

Margarita Calonge

Medication-induced or drug-induced uveitis is a well-described and yet uncommon adverse reaction to medications. Under this designation, intraocular inflammation (cells and flare in the anterior chamber or vitreous cavity, or both) induced not Jllst by medications but also by vaccines, toxins, or other substances is also included, regardless of the route of administration. 1, 2 There are many medications that Inay cause uveitis (Table 79-1) .1-3 These medications have been reported to cause intraocular inflammation when injected into the anterior chamber or the vitreous cavity, or both. In addition, many of the substances and drugs mentioned in Table 79-1 are only possibly associated with uveitis, and because their causality in the production of uveitis is so weak, they will not be mel~tioned in this review. This chapter addresses uveitis caused by medications administered systemically or topically for which a cause-and-effect relationship with intraocular inflammation is proven or, at least, probable. These medications include systemic biphosphonates (pamidronic acid), intravitreous and systemic cidofovir, topical corticosteroids, topical latanoprost and metipranolol, systemic rifabutin, and systemic sulfonamides. 1 , 2 A brief description of uveitis reported for many other agents that Inay possibly cause uveitis is listed in Table 79-1.

There are many reports in the ophthalmic literature over the past 35 years that have implicated medications, drugs, and vaccines as causes of intraocular inflammation. I - 3 Despite this fact, however, medication-induced uveitis is usually neglected in the differential diagnosis of uveitis. Of late, there is an increasing interest in the putative role of drugs as causes of intraocular inflammation because of reports of uveitis in patients with the acquired immunodeficiency syndrome (AIDS) receiving rifabutin and glaucoma patients treated with the recently marketed topical latanoprost. Most reports of drug-induced uveitis are Inerely clinical observations with no histopathologic proof, and therefore, it is difficult to attribute causality of the inflammation to one particular drug or medication. In 1981, Naranjo and colleagues'! proposed seven criteria to help establish causality of adverse events by drugs. Recently, Moorthy and associates 2 , 5 applied these criteria to some drugs that the authors believed to be the cause of uveitis to evaluate causality; they found that it is rare that drugs

implicated in the induction of uveitis meet all of those criteria.

Because medication-induced uveItIs is an adverse drug reaction, it may be considered an iatrogenic eye disease. 6 Iatrogenic illness in general is a relevant problem, because it affects as many as one third of all hospitalized patients, and 3% to 7% of hospitalizations are attributable to adverse reactions to medications. 7 Drug-induced uveitis, however, seems. to be a rare event: Fraunfelder and Rosenbaum 1 recently reported an incidence of less that 0.5% in their patient database. There is, however, an unavoidable bias because this figure refers to patients cared for in a tertiary referral Uveitis Clinic, while many patients with medication-induced uveitis are likely to go to general ophthalmology clinics or to AIDS and glaucoma specialists. In general, there does not seem to be an age or sex predilection, and no HLA association has been described for any drug-related uveitis.

Drugs implicated in the induction of uveitis include systemically administered drugs, topically applied medications and substances injected intraocularly. Intradermal vaccines, such as those used for influenza, hepatitis B, and bacille Calmette-Guerin (BCG) have been implicated in producing uveitis, as has skin testing with tuberculin protein (see Table 79-1).1-3 It is far from clear, however, that all of these agents are the real cause of the uveitis. Many of the reports are merely clinical observations without confirmation. In this sense, Naranjo and colleagues'! proposed the following seven criteria, which should be fulfilled to attribute causality of adverse effects by drugs: 1. The adverse reaction should be a frequently described event and hence be well documented. 2. Recovery should occur on withdrawal of the drug. 3. Other possible causes for the event should be excluded. 4. The event should become more severe with increased dosage of the drug. . 5. The adverse reaction should be documented byobJective evidence. 6. The patients should experience a similar effect with similar drugs.

79: MEDICATION-INDUCED UVEITIS TABLE 79-1. DRUGS

_.;;».;;»_"'-11',,\1

WITH INTRAOCULAR INFLAMMATION AND TYPE OF UVEITIS INDUCED

MEDICATION

UVEITIS CHARACTERISTICS/OTHER FINDINGS

SYSTEMIC DRUGS (ORAL, INTRAVENOUS, SUBCUTANEOUS)

Antiproteases (ritonavir, indinavir, saquinavir) Biphosphonates* (pamidronate, risedronate, alendronate) Chlorpromazine Cidofovir* Cobalt Contraceptives (oral) Diethylcarbamazine Hydralazine Ibuprofen Interleukin-3/interleukin-6 Nitrogen mustard Procainamide Quinidine Rifabutin* Streptokinase Sulfonamides* Trimethoprim

Anterior Anterior, mild-severe/episcleritis, scleritis, general symptoms Anterior, mild/lens pigment deposits Anterior, mild-moderate/hypotony Anterior, mild-moderate Anterior, retinal vasculitis, papilledema Anterior, chorioretinitis Lupus-like syndrome with episcleritis and retinal vasculitis Anterior, mild/aseptic meningitis Anterior, moderate-intense Necrotizing uveitis with retinal vasculitis Lupus-like syndrome with episcleritis Anterior, mild-moderate An.terior, moderate-severe, hypopyon, vitritis/retinal vasculitis, general symptoms Anterior/ serum sickness Anterior/systemic findings Retinal hemorrhages

TOPICAL OCULAR DRUGS

Amphotericin B Anesthetics (topical) (benoxinate, butacaine, dibucaine, dyclonine, phenacaine) l3-blockers (other than metipranolol) (betaxolol, levobunolol, timolol) Cholinesterase inhibitors· (diisopropyl fluorophosphate, phospholine iodide, isoflurophate (demecarium bromide, echothiophate) Corticosteroids* Latanoprost* Metipranolol* Mitomycin C Thiotepa

Anterior, mild Anterior, mild An.terior, mild Anterior mild • Anterior, Anterior, Anterior, Anterior, Anterior,

mild-moderate, after withdrawal mild-moderate, predisposed eyes/cystoid macular edema moderate, granulomatous mild mild

INTRAOCULAR DRUGS/SUBSTANCES FOR SURGERY

Anesthesics (local) (bupivacaine, chloroprocaine, etidocaine, lidocaine, mepivacaine, prilocaine, propoxycaine) Antibiotics (amphotericin B, bacitracin, tetracycline, chlortetracycline, colistin, erythromycin, neomycin, penicillins, polymixin B, streptomycin, chloramphenicol) Cidofovir* Urokinase

Air Perfluorocarbons Silicone oil Alpha-chymotrypsin

Anterior, mild to severe Anterior, mild-moderate

Anterior, mild to moderate/hypotony Sterile hypopyon, vitreous hemorrhage Anterior, mild Anterior, severe An.terior, mild to moderate Vitritis, severe

VACCINES

Bacille Calmette-Guerin (BCG) Influenza Hepatitis B Purified protein derivative (PPD) skin test

Anterior, retinal pigment epithelium anomalies/iris atrophy Anterior, vitritis/optic neuritis, scleritis Acute multifocal placoid epitheliopathy Anterior, vitritis, multifocal choroiditis, serous retinal detachment

OTHER

Petty spurge sap (Euphorbia pejJlus) Skin tattoos

Anterior/keratitis Anterior, mild to moderate/skin granuloma

*Drugs associated with uveitis. These are the only drugs that probably cause uveitis. The remainder drugs are possibly related to uveitis, reported in single case reports and/or that causation has not been proven.

7. The event should recur on rechallenge with the suspected drug. Using these criteria, Fraunfelder and Rosenbaum consider that medications reported to cause uveitis are the probable cause if many of the above-mentioned criteria are met, whereas the remainder of the medications that do not fulfill many of those criteria can possibly have a causative effect. I Moorthy and associates consider a prob-

able cause of uveItIS those drugs meeting at least five criteria. 2 For these authors, only systemic biphosphonates (pamidronic acid) and topical metipranolol fulfill all seven criteria, whereas systemic sulfonamides, rifabutin, and topical corticosteroids meet at least five criteria; the remaining drugs meet less than five. These authors did not include topicallatanoprost in their initial evaluation} although later they believed that this drug is also a probable cause of medication-induced uveitis. 5

CHAPTER 19: MEDICATION-INDUCED

All authors agree that the most convincing criterion to be met is that the adverse event recurs on rechallenge. The main drHgs and substances reported to have caused intraocular inflammation are listed in Table 79-1. Some of them produced uveitis primarily, because confounding variables were eliminated and double-blind randomized rechallenge testing was performed. Some other drugs reported to have caused uveitis in single case reports lack accurate documentation or causation cannot be fully attributed.

of both is an impairment of melanin's capacity as a scavenger of free radicals, thus potentiating these drugs' toxicity and that from other sources of free radical production, with the induction of intraocular inflammation being the eventual consequence. Alternatively, if a combines with melanin, the intrinsic uveitogenicity of pigment may be enhanced. 2, S

PATHOGENESIS

Drug-induced uveitis usually causes mild to moderate symptoms such as a mild decrease in visual acuity (in the range of 20/50 to 20/40, provided there was a previous good visual acuity). Some drugs, however, such as oral rifabutin, can cause severe uveitis if high doses are used (especially in combination with drugs that increase rifabutin's blood levels) and if the drug is not discontinued. 9- 11 Uveitis induced by drugs is characterized by cellular infiltration in the anterior chamber and, more infrequently, the vitreous. Inflammation in the anterior chamber may range from mild to intense, and it is usually nongranulomatous. Occasionally, posterior synechiae develop and hypopyon can also be seen. 10- 12 In the vitreous, the cell reaction is usually mild, although some cases of severe vitritis, mainly attributed to oral rifabutin, have been reported. 9- 11 There is usually an absence of retinal or choroidal lesions with a few exceptions. 13 Drugs inducing uveitis by systemic routes can produce both unilateral or bilateral inflammation. Obviously, topicalor intraocular drugs produce uveitis only in the targeted eye. There is no recurrence of inflammation when the uveitis is purely due to a drug adverse effect, provided such drug is discontinued. Therefore, complications are not usually encountered and prognosis is favorable. Yet, uveitis can recur, either in the previously affected eye or in the contralateral one if the drug is not stopped. In these cases, involvement of all structures of the eye may occur, developing into a sterile endophthahnitis or panophthalmitis. This is a rare event, however, and has only been reported in oral rifabutin-induced cases. 9 , 11, 12 Usually, drug-induced uveitis has no systemic associations, although some drugs have been described to produce extraocular manifestations, such as the arthralgias or arthritis syndrome produced by high doses of rifabutin 14 or the mild general malaise associated with systemic biphosphonates. 15

Many of the adverse reactions to medications are idiosyncratic, unexpected, or unavoidable. But others result from medications used incorrectly or prescribed inappropriately. Just as uveitis has multiple causes, so, too, multiple mechanisms could account for drug-induced uveitis. In most cases, the pathogenesis of the drug-induced intraocular inflammation is unknown or ill understood owing in part to the absence of histopathologic specimens. Although the described mechanisms that produce drug-induced ocular toxicity may well be involved in drug-induced uveitis, there is no convincing evidence so far to demonstrate that drugs may induce uveitis by any of these reported multiple mechanisms. s Therefor~, the pathogenic mechanisms menti.Qned later remaitl speculative and have not been fully proved to produce uveitis. At least from a theoretical point of view, medications and other substances can cause.,jntraocular inflammation by direct or indirect mechanisms, as recently pointed out by Moorthy and associates. 2 A direct mechanisln, meaning that the drug must enter the eye, can usually be implicated for those drugs topically applied or intraocularly injected, and the inflammation usually develops soon after drug delivery. The drug can cause direct toxicity by itself or through its metabolites. s In general, topical drugs and those injected into the anterior chamber appear to induce uveitis by a direct disruption of the blood-aqueous barrier, whereas drugs applied intravitreally can cause a breakdown of both blood-aqueous and blood-retinal barriers. 2 A drug can also cause uveitis by several indirect mechanisms, mainly by stimulation of the immune system via different routes. 2 First, the drug either by itself or combined with tissue or serum proteins may stimulate the production of antidrug antibodies. Thus, immune complexes may form and deposit in uveal blood vessels, producing uveitis weeks or even months after initial contact with the drug. Second, it is possible that the drug nonspecifically stimulates the immune system acting as an adjuvant. For example, secondary immunologic mechanisms can be enhanced by drugs, causing death of microbes located in the eye if antigens are released. The subsequent immune reaction can produce uveitis in the first 24 hours, but sometimes the process can take longer. 2 Third, melanin-related mechanisms, although more speculative, are also possible causes of inflammation weeks or months after drug exposure. There are certain drugs that, in addition to having an intrinsic high affinity for melanin, can also induce the release of toxic free radicals, which are partly detoxified by melanin. The consequence

Common Clinical Features

Distinct Clinical Pictures The clinical picture of drug-induced uveitis can logically be different depending on the offending drug. A general overview is given in Table 79-1, and a more extensive review is given below only for those medications whose association with uveitis is proven or probable, but not for those with a possible association.

Biphosphonates (Pamidronate, Biphosphonates (alendronate, clodronate, etidronate, pamidronate, risedronate) are inhibitors of bone resorption that are used in the management of Paget's disease

· CHAPTER 19: MEDICATION-INDUCED UVEITIS

of the bone, metastatic bone pain, tumor-induced hypercalcemia, and osteoporosis. 15 Two of these agents, oral risedronate and especially intravenous pamidronate, have been associated with anterior uveitis. The majority of those cases have been reported by Macarol and Fraunfelder,15 who analyzed 23 reports of suspected ocular adverse reactions associated with the use of intravenous pamidronate disodium in a review from the Ciba-Geigy Central Epidemiology and Drug Safety Center. 16-21 Thirteen patients had nonspecific transitory conjunctivitis, three cases involved episcleritis or scleritis, and seven patients developed anterior uveitis. Most of the reported cases developed within the first 24 to 48 hours, and the severity ranged from mild (either clearing spontaneously or with topical corticosteroids) to severe, recurring when steroids were tapered. 15- 21 More recently, three cases of alendronate-associated scleritis with possible contiguous myositis and orbital inflammation have been reported. 22 The uveitis usually recurs when patients are rechallenged with the same or a similar' biphosphonate. 15 , 20 There are, however, two of these compounds that have not been associated with uveitis (disodium clodronate and disodiumetidronate), which may be alternative therapies for patients developing uveitis after treatment with pamidronate or risedronate .15, 20 The acute ocular inflammatory response has also been associated in some patients with transient fever and a flulike episode, and it seems not to be related with the route of administration, the dosage or the activity of the baseline disease. 15 'I( The mechanism by which these biphosphonates cause anterior uveitis is not known. The precipitation of a type III hypersensitivity reaction by the drug has been hypothesized by some authors,15 reasoning that these compounds are known to release interleukin 1 and 6, which can cause lymphocyte proliferation and enhancement of immune complex disease.

Cidofovir Studies on cidofovir, a nucleotide analogue that inhibits viral DNA polymerase, have demonstrated its efficacy and safety when used intravenously for the treatment of both previously untreated 23 and treated but relapsing 24 cytomegalovirus (CMV) retinitis in patients with the AIDS. Uncontrolled case series have shown that intravitreous cidofovir seems to also be effective in preventing the relapse of CMV retinitis. 25- 27 Anterior uveitis hypotony has been described in patients receiving intravenous and intravitreal cidofovir from the initial use of this drug and it seems to be independent of whether patients were or were not on immunodeficiency virus protease inhibitor therapy.23-38 Anterior nongranulomatous uveitis associated with intravitreal cidofovir il~ections ranges from mild to moderate, and its frequency seems to be dose dependent. The initial injections of 100-/-1g and 40-/-1g doses were always associated with uveitis and severe hypotony associated with loss of vision. 32 Consecutive series showed that a 20/-1g dose of cidofovir (with concomitant oral probenecid) was highly effective but still produced uveitis in 14% of injections 26 , 27 and in 23% to 32% of patients after the first injection. 29 , 33, 34 Severe hypotony with irreversible

visual loss also occurred in 1% of injections and 3% of eyes, and transient hypotony with recoverable visual loss in 14% of eyes. 34 Iritis accompanied all cases of transient and chronic hypotony, but there were instances of iritis with no hypo tony, 34 A first episode of uveitis seems to facilitate subsequent episodes with a second injection in the same or in the contralateral eye. 29 Kersten and coworkers 31 have found that 15 /-1g was effective but still found iritis and hypotony in 25% of eyes. Although 10/-1g injections produced fewer side effects, with only a 2.2% frequency of iritis, this dose was less effective. 33 Intravenous cidofovir produces a similar intraocular inflammatory response in 26%30 to 59% of patients,38 which occurs after 5 days, following four doses and may be bilateral. The reported rate of hypotony with visual consequences is similar to that reported for intravitreal injections.28, 30 Cidofovir seems to cause hypotony by damaging the nonpigmented epithelium of the ciliary body,34, 39 with the subsequent possibility of ciliary body atrophy,40 although the exact cause of iritis and its relation to hypotony is not well understood. Iritis accompanied all transient and chronic hypotony cases after both intraocular and intravenous cidofovir, but there were cases of iritis with no hypo tony. 30, 34 However, intraocular pressure in eyes with iritis after a first injection of cidofovir was lower than in eyes with no anterior uveitis. 40 Oral probenecid has been shown to reduce the incidence of uveitis effectively after the first injection from 71 % to 18%. The explanation given is that this drug reduces the absorption of cidofovir into the ciliary body, thus decreasing the chance of developing uveitis. 29 Most uveitis cases attributed to cidofovir have resolved within 2 weeks with frequent administration of topical corticosteroids and cyc1oplegics,29 but some cases recurred, necessitating cidofovir discontinuation. 37 Topical steroids, however, have not been effective in preventing iritis after cidofovir injections of 20 /-1g. 29 Posterior synechiae, cataract, and hypotonous maculopathy cystoid macular edema (CME) vitritis have all been described as longterm sequelae of the uveitis. 29 , 31, 34, 36, 37 In summary, anterior uveitis and hypotony are common complications after cidofovir therapy. These complications may not preclude the use of this drug, because the response to topical treatment is usually rapid and satisfactory. However, if inflammation recurs or hypotony persists, cidofovir may have to be discontinued.

Corticosteroids It is often difficult to ascertain whether uveitis reported to be induced by topical corticosteroids is, in fact, due to the use of these drugs because these agents are so widely used for the treatment of uveitis and for many other ocular inflammatory conditions. Nonetheless, there seems to be strong evidence that nongranulomatous anterior uveitis can be elicited on withdrawal of topical steroids. 41 -45 This observation was first made by Krupin in 1970,42 who published two cases of ipsilateral anterior uveitis found in a population of 2000 patients who were receiving topical dexamethasone sodium phosphate to test the response of their intraocular pressure (lOP) to topical steroids. In these two patients, topical steroid

CHAPTER 79: MEDICATION-INDUCED

therapy was discontinued after 30 days because of a decrease in lOP and periocular pain. Two to five days later, anterior uveitis was diagnosed, which responded well to cycloplegics and intensive topical treatment with dexamethasone, the same agent that presumably had provoked the inflammation. Four years later, Martins and associates43 reported 16 cases out a population of 621 patients who developed mild anterior uveitis after 2.5 to 6 weeks of treatment with dexamethasone sodium phosphate (except one patient, who received topical triamcinolone acetonide) and 1 to 16 days after topical corticosteroids had been stopped. Inflamlnation vanished within 3 to 10 days with cycloplegics and with no steroid treatment. One case was rechallenged with prednisolone acetate 1 % for 15 days, and inflammation recurred 2 days after drops were discontinued because of steroid-induced pressure elevation, whereas no recurrences were observed upon rechallenge with the vehicles. Similar experiences reported in three more publications 41 , 44, 45 allow one to conclude that withdrawal of different corticosteroids drops may produce a subsequent episode of uveitis, fulfilling five of the seven criteria of Naranjo and associates to attribute causality.4 There is not enough information in the cases reported as to whether corticosteroids were discontinued abruptly or slowly tapered, but abrupt stoppage is presumed in mgst €ases because it is not specified otherwise. 41 -45 Most cases reported occurred in patients with glaucoma and ocular hypertension while they were being screened for steroid-induced lOP elevation,41-45 but there seems not to be an association between lOP responsiveness and the development of uveitis. 43 The incidence of uveitis was similar in men and wOlnen,43 and no special HLA locus for corticosteroid-induced uveitis was found. 45 Interestingly, four sisters out of seven black siblings developed uveitis when they were tested with dexamethasone to determine the response of their lOP to topical steroidsY No details were provided on age, duration of treatment, or whether uveitis occurred while these· four patients were on treatment or after discontinuation. Whether this familial occurrence represents an inherited or a shared acquired tendency to develop corticosteroidinduce uveitis remains unknown. It has been speculated that the development of corticosteroid-induced uveitis might correlate with a high prevalence of positive fluorescent treponemal antibody absorption test (FTA-ABS) ,45 but there is not proof of such an assertion. In most cases of corticosteroid-induced uveitis that have been reported, other causes of intraocular inflammation were excluded and some authors believe that corticosteroids could have increased ocular susceptibility to an already pre-existing latent intraocular inflammation or infection. 1, 42 Additionally, melanin might have a role, because cases reported are far more frequent in black patients.43 In summary, uveitis elicited after corticosteroid withdrawal is anterior, nongranulomatous, and usually mild, responding to cycloplegics. Only if inflammation is more severe, corticosteroids must be resumed until inflammation subsides and then the steroid should be slowly tapered.

LATANOPROST

Latanoprost, a new prostaglandin F2a analogue, has been shown to be a safe and efficacious hypotensive agent in phase III clinical trials. 46-48 Adverse side effects reported with use of latanoprost include facial rash, conjunctival hyperemia, blurred vision, choroidal effusion, eye irritation, darkening of the iris color, iris cyst, hypertrichosis and hyperpigmentation of eyelashes. 46 , 49-51 Corneal toxicity associated with latanoprost use ranges from not clinically significant superficial punctate keratopath y 46 or pseudodendrite formation,52 to stimulation of recurrence of herpes simplex keratitis. 53 ,54 It seems that uroprostone, another commercially available prostaglandin analogue, has the same adverse effect profile, but with more corneal toxicity.55 Two more probable side effects of latanoprost therapy have been reported lately: cystoid macular edema51 , 56-66 and anterior uveitis. 66, 67 Although rare cases of anterior chamber flare and cells were documented after 12-month therapy with latanoprost in 1996,47,48 the first case reports of uveitis in patients treated with latanoprost were not published until 1998. 66 , 67 Warwar and associates 66 first reported six cases of uveitis in a series of 94 patients (163 eyes) using latanoprost therapy. Uveitis was anterior and mild, and appeared within 1 day to 6 months after starting latanoprost. Inflammation resolved within 1 week after latanoprost discontinuation in three cases and with concurrent steroids drops in the remaining three patients. Three of the six patients with anterior uveitis were rechallenged, and two of them had a recurrence, which cleared solely with cessation of latanoprost. All six of these patients had had previous intraocular surgeries in the eye that developed uveitis. Two additional patients in this series receiving latanoprost bilaterally developed CME, one in both pseudophakic eyes and the other patient in the pseudophakic eye but not in the fellow phakic eye. Fechtner and colleagues 67 have also reported four patients (five eyes) who developed iritis associated with latanoprost use. Four of five eyes had a history of prior inflammation or intraocular surgery and the fifth eye had had uncomplicated focal laser applied to· the retina 5 years before. Uveitis developed within 1 day to 3 weeks, and its intensity ranged from mild to moderately severe ( + 3 cells in anterior chamber). In all cases, iritis improved after cessation of the drug and topical steroid therapy. All of these patients were rechallenged, and iritis recurred in all eyes within 3 days to 6 weeks. No adverse sequelae were produced by uveitis in any patient. An interesting recent report describes a frequency for latanoprost-induced uveitis of 1.0% in glaucoma patients with no previous history of uveitis, 23.1 % for patients with prior uveitis but inactive at the time of the study, and 0% of worsening for glaucomatous eyes with active uveitis, the drug having no effect on intraocular pressure in this group. In all cases, intraocular anterior inflammation was mild (trace to + cells).68 The explanation given for these two side effects, uveitis and CME, is a breakdown of the blood-ocular barrier by latanoprost in predisposed eyes in which coexisting ocular conditions associated with an altered blood-ocular barrier had previously occurred.50, 56-66 Whether latano-

CHAPTER 79: MEDICATION-INDUCED UVEITIS

prost can also produce this disruption in normal eyes is yet unknown. At least in the development of CME, it seems that the elapsed time between surgery and the onset of treatment with latanoprost could be determinant. One study has demonstrated that the initiation of latanoprost at least 3 months after incisional surgery seems not to cause angiographic CME,61 whereas another study demonstrated CME 5 weeks after surgery when latanoprost was given before surgery and during the five subsequent weeks. 62 Therefore, it seems that latanoprost therapy should be avoided at least during the first 5 weeks after surgery. Most CME cases reported resolved or improved after cessation of drug and concurrent use of steroidal or nonsteroidal anti-inflammatory agents. 51, 55-66 Conversely, elapsed time between previous surgery and latanoprostrelated uveitis does not seem to be relevant. All cases reported by Flechtner and colleagues had surgery at least 4 years before,67 and no information in this regard is provided by Warwar and coworkers. 66 _. Taken together, the published data 66 , 67 indicate that latanoprost meets five of the seven criteria described by Naranjo and coworkers4 to attribute causality of medication-induced uveitis to latanoprost but only in predisposed patients who have had previous episodes of intraocular inflammation or previous incisional ocular surgery.5, 69 Although some authors disagree with the probable association of latanoprost and induction of uveitis and CME,70-72 it may be wise not to choose this hypotensive agent in patients with a history of .i;ncisional sursery or intraocular inflammation. !VJETIPRANOLOL

\1etipranolol, a nonselective [3-blocker that lowers lOP by ;uppressing aqueous humor production, was introduced n the United Kingdom (UK) in 1986 to treat glaucoma ll1d was marketed in three strengths: 0.1 %, 0.3%, and ),6%. The first cases of anterior granulomatous uveitis vere reported in 1991, 15 patients (26 eyes) by Alzingbelin and Villada73 and eight by Kinshuck. 74 By the end of hat year, more than 60 cases had been reported in the JK, with an incidence of 0.38% for metipranolol 0.6% olution and 0.11 % for the 0.3% solution 73 ; therefore, lle multidose preparation of metipranolol was withdrawn ~om the market in the UK. The incidence of metiprano)l-related uveitis seems to be less in the United States, nd Melles and Wong75 calculated an incidence of 0.49% )r patients taking the 0.3% strength of metipranolol for lOre than 6 months at their institution. The etiology of uveitis induced by metipranolol relains unknown. The fact that the incidence in the -nited States seems to be less has been explained by ifferences in the commercial preparation 76 or the rength, or both. 77 Metipranolol is marketed in the nited States in a 0.3% concentration. It contains less ~nzalkonium chloride (0.044%), and bottles are preired in a sterile fashion, whereas in the UK, the 0.6% rength was more commonly used, benzalkonium chlo::le concentration was 0.1 % and bottles were sterilized gamma radiation. 76 r

The uveitis caused by metipranolol is anterior and anulomatous, with prominent mutton fat keratic pre-

cipitates,73-75 although a case has been reported as mild nongranulomatous in a patient being treated with 0.3% metipranolo1. 78 It has been more commonly reported in women, usually starting after 7 to 31 months of metipranolol treatment and causing elevation of lOP in about half of the patients,73-75,78 possibly explained by a decrease in outflow facility. Rechallenge with metipranolol in eyes that previously developed metipranol-induced uveitis caused a recurrence of the inflammation within 4 to 14 days in all cases. 75 , 78, 79 All uveitis reactions reported have resolved after withdrawal of the drug plus additional topical steroids in some. 73- 75 , 78, 79 Metipranolol fulfills the seven criteria proposed by Naranjo and coworkers,4 and therefore its causality in the production of uveitis can be considered as certain. However, metipranolol-induced uveitis seems to be an uncommon reaction,80 and in fact, single-dose units are still available in the UK and multidose preparations are also available in the United States, in some European countries, and in some other countries. 81 Although there are rare descriptions of uveitis caused by other [3-blockers such as timolo1 82 or betaxolol,83 causality has not been demonstrated; therefore, these agents remain as only a possible rare cause of uveitis. I, 80 RIFf.\BUTIN

Rifabutin-induced intraocular inflammation is perhaps the best-documented form of uveitis among all drugrelated types of uveitis. Rifabutin is a macrophage-penetrating lipophilic semisynthetic derivative of rifamycin and rifampin used as oral prophylactic treatment for disseminated Mycobacterium avium complex (MAC) infection in patients with AIDS. Other approved uses include treatment of refractory cases of pulmonary tuberculosis and inflammatory bowel disease. As early as 1990, Siegal and colleagues ll described a reversible syndrome of arthralgia and arthritis in 10 of 16 patients with AIDS treated with more than 1000 mg daily of oral rifabutin, two of whom developed uveitis. The uveitis was unilateral and mild in the first patient, although this increased to severe panophthalmitis on resuming rifabutin treatment at higher doses. The second case had a bilateral anterior uveitis. Both cases resolved with corticosteroid therapy after 6 to 10 weeks of permanent discontinuation of rifabutin and were thought to be caused by the high doses employed. When rifabutin was found to be efficacious in the prophylaxis against MAC infection in AIDS patients at lower maintenance dosages (300-600 mg/day) 3 years later, 84 more uveitis cases were reported.9, 10, 12, 85-92 The use of 600 mg of rifabutin daily in combination with other drugs has been reported to produce uveitis in 8% ofpatients. 93 In this same report, a diffuse polyarthralgia syndrome occurred in 19%, gastrointestinal sYJ-uptoms in 42%, abnormal liver enzymes in 12%, and reduction in the total blood cell count in 100% of patients making rifabutin-related adverse effects quite frequent, occurring in 77% of patients. Uveitis induced by rifabutin develops sometimes in combination with arthralgia, arthritis, jaundice, pseudojaundice, and a transient rash. H ,92 In 1996, Shafran and coworkers 93 reported an incidence of uveitis of 5.6% for doses of 300 mg/day and a

CHAPTER 79: MEDICATION-INDUCED

fourfold increase in the incidence when doses were 600 mg daily. A case-control study published by the same authors in 199894 found that baseline body weight predicted the development of uveitis, with an incidence of 14%, 45%, and 64% in patients weighing more than 45 kg, 55 to 65 kg, and less than 55 kg, respectively. The most frequent rifabutin-induced uveitis type reported is mild-to-moderate unilateral anterior uveitis with concomitant mild vitritis, developing after 2 weeks to even 9 months of treatment. 85 , 91, 92, 95, 96 Severe hypopyon uveitis and bilateral cases have also been reported. 10- 12 Occasional reports have found vitreous opacities, developing sometimes into a pars planitis-like syndrome 10, 86 or even dense vitritis obscuring fundus visualization and mimicking infectious endophthalmitis or panophthalmitis if rifabutin had not been stopped. 9- 11 In general, no chorioretinal involvement has been reported, although Arevalo and associates 13 described a patient with retinal vasculitis while being treated with rifabutin. An.other rare event recently reported is bilateral corneal endothelial peripheral deposits in the absence of uveitis, found in 15% to 24% of children infected with the human immunodeficiency virus (HIV) and prophylactically treated with rifabutin 97, 98; this event seelllS to be independent of the CD4 counts and the concomitant presence of cytomegalovirus retinitis, uveitis, and other medicatio'ns. 98 Rifabutin associated uveitis has· also been reported in a nonimmunosuppressed patient who did not have AIDS with a pulmonary infection caused by MAC99 and in immunosuppressed patients due tt> transplantation antirejection medication. 10o , 101 However, uveitis did not develop in 25 patients followed for 2 years in whom 300 mg daily of rifabutin were administered because of inflammatory bowel disease. 102 It seems clear now that uveitis is a dose-related toxicity of rifabutin therapy. The adverse reactions probably depend on the dose, metabolism, and excretion of the drug, and inhibition of cytochrome P450 seems to be an important mechanism. 14

Using rifabutin at doses of 300 mg daily, the risk of uveitis is markedly reduced. l l , 94 Interactions with azoles and macrolides increase blood levels of rifabutin and can lead to the development of uveitis in patients with low doses of rifabutin in whom concomitant medications, especially fluconazole or clarithromycin, or both, are often used and so contribute to enhanced rifabutin ocular toxicity. 11, 103 For this reason, rifabutin is recommended not to be used at doses greater than 300 mg/day in multidrug regimens that include a macrolide, whereas it is less clear whether the same precaution needs to be taken when rifabutin is combined with fluconazole; in spite of being a drug known to raise rifabutin serum concentration, this combination has not been associated with increased incidence of uveitis in one study.94 It seems unlikely that the immune status or concomitant MAC infection plays a role in the pathogenesis of rifabutin-induced uveitis, because it has also been described in patients who did not have AIDS and who were treated with rifabutin for other indications and in the absence of MAC infection.100-102 No etiologic infectious agent has ever been isolated from any patient, and only

acute infllammatory cells have been identified in vitreous cytology specimen. 13 , 95 Although its pathogenic mechanism remains unknown and keeping in mind the present information about rifabutin-induced uveitis, a working hypothesis for the production of uveitis is that the drug kills the mycobacteria present in the eye, and that the dead bacteria might elicit an immune response similar to that produced by complete Freund's adjuvant (enhancer of the illlmune response consisting of dead mycobacteria in a water in oil emulsion). The greater incidence in patients with AIDS could be explained by increased rifabutin serum levels provoked by the azoles and macrolides that these patients usually receive concomitantly. Rifabutin-induced uveitis responds rapidly to drug discontinuation, resolving within 1 to 2 months. Topical corticosteroids and cycloplegics are often used, leading to resolution, provided the drug is stopped. 95 In those cases that develop into panophthalmitis, systemic corticosteroids are required,u In general, if uveitis develops, rifabutin treatment must be discontinued promptly, because the inflammation is usually refractory to treatment if rifabutin is continued. In addition, recurrences are common in the first affected eye or in the contralateral eye if the drug is not stopped. SULFONAMIDES

Systemic sulfonamides are antimicrobial drugs used for the treatment of many gram-positive and some gramnegative bacteria. In addition, the combination trimethoprim-sulfamethoxazole (TMP-SMX) is frequently used for ocular toxoplasmosis, cat-scratch disease, and is also the best prophylaxis for Pneumocystis carinii infection in HIVinfected patiet;lts. In general, adverse reactions to sulfonamides are frequently reported, but because these drugs are so commonly prescribed, adverse effects, including uveitis, may in fact be uncommon. 1, 2 There are about 15 cases reported in the literature of sulfonamide-induced uveitis. Fourteen cases were collected by Tilden and associates and reported in 1991. 104 Twelve of those were treated with TMP-SMX, one with sulfacytine and one with an unspecified sulfonamide. Uveitis was always anterior, developed within 1 to 8 days, and it was bilateral in six cases. All patients developed acute bilateral iritis 24 hours after rechallenge with TMPSMZ, which constitutes strong evidence that systemic sulfonamides are a cause of uveitis. Another case of bilateral anterior uveitis has been recently reported in association with the use of TMP-SMZ and TMP alone, in addition to retinal hemorrhages after the use of TMP alone.105-107 The mechanism by which sulfonamides cause uveitis remains speculative and could be the result of the development of a systemic vasculitis, similar to that produced in drug-induced Stevens:Johnson syndrome or as the result of direct immunogenicity of sulfonamides. 2 The majority of the reported cases had been associated with the frequently prescribed fixed cOlllbination TMP-SMZ, and because TMP alone can also be a possible cause of ocular toxicity,105-107 the contribution of each component of the combination to the development of uveitis can be difficult to ascertain.

79: MEDICATION-INDUCED UVEITIS

It is important to be aware that medications and other substances can be a cause of intraocular inflammation. This usually makes the physician confront the dilemma as to whether the inflammation is caused by inadequate or insufficient therapy, or is actually caused by the therapy itself. It helps to be familiar with the main drugs that have historically been associated with uveitis l - 3 (see Table 79-1) and compare this list with the patient's medications and possible recent vaccinations. It is also advisable to record the patient's habits that might be associated, such as skin tattoos, for instance (see Table 79-1). When possible, the drug in question must be stopped and the patient rechallenged later when all inflammation has disappeared. Should inflammation recur, the suspected drug is most likely to be the cause. 4 It must be considered, however, that in many instances, the reported association may not necessarily mean that the patient developed uveitis because of the medication taken. Only well-controlled, large-scale epidemiologic studies can firmly establish a cause-and-effect relationship.6 In principle, even if the patient is highly suspected of having a drug-induced uveitis, he or she should undergo the same diagnostic approach followed for any other uveitis: a detailed clinical history, a uveitis questionnaire,a careful review of systems, and ancillary tests and consultations dictated by the differential diagnosis elaborated for that particular case. Exclusion of other possible causes of uveitis is, in fact, one of the seven cri&ria required by Naranjo and associates4 to establish causality. This is most important, because the physician needs to be aware of all medications and putative toxins to which the patient has been or is currently being exposed. In addition, some drugs may produce pathology extraocularly, which may be unknown to the patient. Moreover, clinical history and examination may prove that the initially suspected medication-induced uveitis has in fact a different origin.

Treatment of drug-induced uveitis begins with recognition of a drug-related event and usually, subsequent avoidance of the drug. Patients respond promptly to the classic topical treatment of uveitis (corticosteroids and cycloplegics) provided discontinuation of the causative medication is accomplished. I, 2

PROGNOSIS In general, drug-induced intraocular inflammation is mild to moderate and causes no recurrence provided the drug is discontinued. Therefore, complications are not usually encountered and consequently the prognosis is favorable. In the few early cases of rifabutin-induced uveitis in which high doses were used, severe inflammation did occur, and recurrences were observed, sOlnetimes developing into severe inflammation. Even in these less favorable cases, uveitis responded well to treatment and discontinuation of the drug. 9- 11 The key point then, to ensure a good prognosis in medication-induced uveitis is to stop the offending drug.

Uveitis has been associated with a number of systemic and topical medications, and may also occur after vaccination and the use of other substances. However, druginduced uveitis is a relatively rare event. Only a few drugs have been proven to cause uveitis, whereas many others may not represent a direct causal effect relationship. Anterior uveitis is the most common clinical presentation, and therefore, patients with a new onset anterior uveitis should be asked whether they have recently started any new medications. These patients need to undergo the same diagnostic protocol followed for any uveitis case. Drug-induced uveitis is almost always reversible within weeks of cessation of the medication and the institution of topical treatment of the inflammation.

References 1. Fraunfelder FW, Rosenbaum JT: Drug-induced uveitis. Incidence, prevention and treatment. Drug Saf 1997;17:197. 2. Moorthy RS, Valluri S, lampol LM: Drug-induced uveitis. Surv Ophthalmol 1998;42:557. 3. Fraunfelder FT, Grove lA, eds: Drug-Induced Ocular Side Effects and Drug Interactions. Philadelphia, Williams and Wilkins, 1996. 4. Naranjo CA, Busto U, Sellers EM, et al: A method for estimating the probablity of adverse drug reactions. Clin Pharmacol Ther 1981;39:239. 5. Moorthy RS, Valluri S, lampol LM: Latanoprost-induced uveitis. Surv Ophthalmol 1999;43:466. 6. Rosenbaum IT: Drug-indu~ed uveitis: Reporting inflammation while avoiding inflammatory reports. Am 1 Ophthalmol 1994;118:805. 7. Justiniani FR: Iatrogenic disease: An overview. Mount Sinai] Med 1984;51:210. 8. Koneru PB, Lien El, Koda RT: Oculotoxicities of systemically administered drugs. J Ocul Pharmacol 1986;2:385. 9. Akduman L, Del Priore LV, Kaplan Hl, et al: Rifabutin induced vitritis in AIDS patients. Ocul Immunol Inflamm 1996;4:219. 10. Schimkat M, Althaus C, Becker K, et al: Rifabutin-associated anterior uveitis in patients infected with human immunodeficiency virus. Ger 1 Ophthalmol 1996;5:195. 11. Siegal FP, Eilbott D, Burger H, et al: Dose-limiting toxicity of rifabutin in AIDS-related complex: Syndrome of arthralgia/ arthritis. AIDS 1990;4:433. 12. Saran BR, Maguire AM, Nichols C, et al: Hypopyon uveitis in patients with acquired immunodeficiency syndrome treated for systemic Mycobacterium avium complex infection with rifabutin. Arch Ophthalmol 1994;112:1159. 13. Arevalo IF, Russack V, Freeman WR: New ophthalmic manifestations of presumed rifabutin-related uveitis. Ophthalmic Surg Lasers 1997;28:321. 14. Lowe SH, Kroon FP, Bollemeyer lG, et al: Uveitis during treatment of disseminated Nlycobacteria avium-intracellulare complex infection with the combination of rifabutin, clarithromycin and ethambutol. Nethl Med 1996;48:211. 15. Macarol V, Fraunfelder FT: Pamidronate disodium and possible ocular adverse drug reaction. Aml Ophthalmol 1994;118:220. 16. Adami S, Zamberlan N: Adverse effects of biphosphonates. A comparative review. Drug Saf 1996;14:158. 17. De S, Meyer P, Crisp AJ: Pamidronate and uveitis. [Letter.] Br 1 OphthalmoI1995;34:479. 18. Ghose K, Waterworth R, Trolove P, et al: Uveitis associated with pamidronate. [Letter.] Aust N Zl Med 1994;24:320. 19. O'Donnel NP, Rao GP, Aguis-Fernandez A: Paget's disease: Ocular complications of disodium pamidronate treatment. Br 1 Clin Pract 1995;49:272. 20. Siris ES: Biphosphonates and iritis. Lancet 1993;342:436. 21. Stewart GO, Stuckey BG, Ward LC, et al: Iritis following inu-avenoilS pamidronate. Aust N Z 1 Med 1996;26:414. 22. Mbekeani IN, Slamovits TL, Schwartz BH, Sauer HL: Ocular inflammation associated with alendronate therapy. Arch Ophthalmol 1999;117:837. 23. Studies of Ocular Complications of AIDS Research Group, AIDS

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·CHAPTER 79: MEDICATION-INDUCED UVEITIS 77. Akingbehin AO: In discussion: O'Connor GR. Granulomatous uve" itis and metipranolol. Br J Ophthalmol 1993;77:536. 78. Patel NP, Patel KH, Moster MR, et al: Metipranolol-associated nongranulomatous anterior uveitis. Am J Ophthalmol 1997;123:843. 79. Akingbehi~l T, VilladaJR, Walley T: Metipranolol-induced adverse reactions: 1. The rechallenge study. Eye 1992;6:277. 80. Beck RW, Moke P, Blair RC, et al: Uveitis associated with topical beta-blockers. Arch Ophthalmol 1996;114:118l. 81. KeBler C: Possible bilateral anterior uveitis secondary to metipranolol (OptiPranolol) therapy. Arch Ophthalmol 1994;112:1277. 82. Zimmerman TJ, Baumann JD, Hetherington J: Side effects of timolol. Surv Ophthalmol 1983;28:243. 83. Jain S: Betaxolol-associated anterior uveitis. Eye 1994;8:708. 84. Nightingale SD, Cameron DW, Gordin FM, et al: Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. N Engl J Med 1993;329:828. 85. Becker K, Schimkat M,Jablonowski H, et al: Anterior uveitis associated with rifabutin medication in AIDS patients. Infection 1996;24:34. 86. Chaknis MJ, Brooks SE, Mitchell KT, et al: Inflammatory opacities of the vitreous in rifabutin-associated uveitis. Am J Ophthalmol 1996;122:580. 87. Fuller ID, Stanfield LED, Craven DE: Rifabutin prophylaxis and uveitis. [Letter.] N EnglJ Med 1994;330:1315. 88. Havlir D, Torriani F, Dube M: Uveitis associated with rifabutin prophylaxis. Ann Intern Med 1994;121:510. 89. Jacobs DS, Piliero PJ, Kuperwaser MG, et al: Acute uveitis associated with rifabutin use in patients with human immunodeficiency virus infection. AmJOphthalmol1994;118:716. 90. Karbassi M, Nikou S: Acute uveitis in patients with acquired immunodeficiency syndrome receiving prophylactic rifabutin. Arch Ophthalmol 1995;113:699. 91. Shafran SD, Deschenes J, Miller M, et al: Uveitis and pseudojaundice during a regimen of darithromycin, rifabutin, and ethambutol. [Letter.] MAC Study Group of the Canadi~n HIV Trials Network. N Engl J Med 1994;330:438. 92. Shafran SD, Singer J, Zarowny DP, et al: A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: Rifabutin, ethambutol, and darithromycin versus rifampin, ethambutol, dofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group. N Engl J Med 1996;335:377. 93. Griffith DE, Brown BA, Girard WM, et al: Adverse events associated with high-dose rifabutin in macrolide-containing regimens for the

94.

95.

96. 97.

98.

99.

100.

101.

102. 103,.

104.

105.

106. 107.

treatment of Mycobacterium avium complex lung disease. Clin Infect Dis 1995;21:594. Shafran SD, SingerJ, Zarowny DP, et al: Determinants ofrifabutinassociated uveitis in patients treated with rifabutin, darithromycin, and ethambutol for lV1ycobacterium avi1l1n complex bacteremia: A multivariate analysis. Canadian HIV Trials Network Protocol 010 Study Group.J Infect Dis 1998;177:252. Nichols CW: Mycobacterium avium complex infection, rifabutin, and uveitis: Is there a connection? Clin Infect Dis 1996;22(Suppl 1):S43. Tseng AL, Walmsley SL: Rifabutin-associated uveitis. Ann Pharmacother 1995;29:1149. Smith JA, Mueller BU, Nussenblatt RB, et al: Corneal endothelial deposits in children positive for human immunodeficiency virus receiving rifabutin prophylaxis for lVIycobacterium avi1l1n complex bacteremia. AmJ Ophthalmol 1999;127:164. Holland JP, Chang CW, Vagh M, Cartright P: Corneal endothelial deposits in patients with HIV infection or AIDS: Epidemiologic evidence of the contribution of rifabutin. Can J Ophthalmol 1999;34:204. Ramon PM, Tillie-Leblond I, Labalette P, et al: Uveitis, arthralgia and pseudojaundice in a HIV seronegative patient due to rifabutin. Rev Mal Respir 1998;15:204. Jewelewicz DA, Schiff WM, Brown S, et al: Rifabutin-associated uveitis in an immunosuppressed pediatric patient without acquired immunodeficiency syndrome. AmJ Ophthalmol 1998;125:872. Ng P, McCluskey P, McCaughan G, et al: Ocular complications of heart, lung, and liver transplantation. Br J Ophthalmol 1998;82:423. To KW, Tsiaras WS, Thayer WR: Rifabutin use in inflammatory bowel disease. Arch Ophthalmol 1995;113:1354. Hafner R, BethelJ, Power M, et al: Tolerance and pharmacokinetic interactions of rifabutin andc;larithromycin in human immunodeficiency virus-infected volunteers. Antimicrob Agents Chemother 1998;42:631. Tilden ME, RosenbaumJT, Fraunfelder IT: Systemic sulfonamides as a cause of bilateral, anterior uveitis. Arch Ophthalmol 1991;109:67. Arola 0, Peltoner R, Rossi T, et al: Arthritis, uveitis, and StevensJohnson syndrome induced by trimethoprim. Lancet 1998;351:1102. Gilroy N, Gottlieb T, Spring P, et al: Trimethoprim-induced aseptic meningitis and uveitis. Lancet 1997;350:112. Kristinsson JK, Hannesson OB, Sveinsson 0, et al: Bilateral anterior uveitis and retinal haemorrhages after administration of trimethoprim. Acta Ophthalmol Scand 1997;75:314.

I

Note: Page numbers followed by the letter f refer to figures; those followed by the letter t refer to tables.

A ABD. See Adamantiades-Beh<;:et's disease (ABD). Abdominal pain in polyarteritis nodosa, 654 Absorptiometry for rheumatoid arthritis, III ACAID. See An.terior chamber-associated immune deviation (ACAID). Acanthamoeba keratitis, 412 Accommodation, 10-11 ACE. See Angiotensin-converting enzyme (ACE). Acetaminophen, 29t, 167t Acetazolamide for intermediate uveitis, 852 Acetonide, 28t aJ-Acid protein in uveitis testing, 95t, 96 Acid-fast staining and culture for tuberculosis, 267 Acneiform eruptions in AdamantiadesBeh<;:et's disease, 632. See also Adamantiades-Beh<;:et's disease. Acquired immunodeficiency syndrome (AIDS). See also Human immunodeficiency virus (HIV). acute retinal necrosis in, 319 bartonella in, 261 cryptococcosis in, 377 cytomegalovirus in, 323 necrotizing herpetic retinopathy in, 318 PneLl1nocystic carinii choroidopathy in, 425 toxoplasmosis in, 390-391 Whipple's disease in, 289 Acquired measles, 336-338 Acquired rubella, 345-346 Acquired toxoplasmosis, 389-390 diagnosis of, 398-400 Acrodermatitis chronica atrophicans in Lyme borreliosis, 247 Activation proteins in multiple sclerosis, 704 Acute glomerulonephritis in AdamantiadesBeh<;:et's disease, 636 Acute idiopathic blind-spot enlargement syn.drome (AIBES), 767 zonal occult outer retinopathy and, 813816 Acute inflammation, 17 Acute leukemia in retinal vasculitis, 833 Acute lymphocytic leukemia (ALL), 506-509, 507f Acute macular neuroretinopathy (AMN) retinal pigment epitheliitis versus, 781-782, 783t, 784t zonal occult outer retinopathy and, 813816 Acute macular retinopathy, 802, 802t Acute multifocal hemorrhagic retinal vasculitis, 827 Acute myelocytic leukemia (MIL), 506-509, 507f

Acute nonsuppurative inflammation, 87-88, 88t Acute papular onchodermatitis (APOD), 446, 447f Acute periphlebitis in Adamantiades-Beh<;:et's disease, 637 Acute posterior multifocal placoid pigment epitheliopathy (APMPPE), 20, 772-779 angiography in, 121, 122f associated diseases of, 777 birdshot retinochoroidopathy versus, 736t, 737 clinical characteristics of, 772-774, 773f776f definition of, 772 diagnosis of, 79, 777 differential diagnosis of, 777 diffuse unilateral subacute neuroretinitis versus, 477 epidemiology of, 772 history of, 772 multifocal choroiditis and panuveitis versus, 762 pathogenesis of, 776-777 pathophysiology/immunology/pathology of, 774-776 retinal pigment epitheliitis versus, 782-783, 783t, 784t serpiginous choroiditis versus, 791-792 subretinal fibrosis and uveitis syndrome versus, 802, 802t summary of, 809, 809t treatment of, 777-778 Acute postoperative endophthalmitis, 528, 528t. See also Endophthalmitis. Acute retinal necrosis (ARN) glaucoma surgery and, 228, 228f in herpes simplex virus clinical characteristics of, 317-318, 318f diagnosis of, 320-321 pathogenesis of, 319-320 treatment of, 321-322 Acute retinal pigment epitheliitis (ARPE), 20, 780-786 clinical features of, 780-781, 780f complications of, 781 definition of, 780 diagnosis of, 780f, 781£, 782, 783t differential, 781-784, 783t, 784t epidemiology of, 780 etiology, pathogenesis, and pathology of, 781 history of, 780 natural history and prognosis for, 784-785 subretinal fibrosis and uveitis syndrome versus, 802, 802t treatment of, 784

Acute tubulointerstitial nephritis (ATIN), 726. See also Tubulointerstitial nephritis and uveitis (TINU) syndrome. Acute zonal occult outer retinopathy (AZOOR),813-816 Acyclovir for acute retinal necrosis, 321 for iridocyclitis and trabeculitis, 321 mycophenolate mofetil and, 190 Adamantiades-Beh<;:et's disease (ABD) , 632-652 acute retinal necrosis versus, 321 angiography for, 127, 128f azathiopline for, 188 chlorambucil for, 183-184 clinical features of, 633-638 diagnostic system in, 633-634, 633t nonocular, 634-636, 634f, 635f oculal~ 636-638, 637f-639f colchicine for, 208 complications of, 646-647 cyclophosphamide for, 181 cyclosporine A for, 194 definition of, 632 diagnosis of, 641-642, 641£, 642f imaging for, 112 epidemiology of, 24, 632-633, 633t extraocular examination in, 94 history of, 632 in children, 638 in pregnanc~ 638-639 multiple sclerosis and, 706 pathogenesis and immunology of, 639-640 pathology of, 640-641 prognosis for, 647 retinal vasculitis in, 828-829 treatment of, 642-646, 643f, 644f Whipple's disease versus, 293 Adenopathy, hilar, 109 Adhesion molecules, 42t in retinal vasculitis, 834, 834f-836f Adjuvants to immunosuppressive therapy, 204-209 a-Adrenergic agonists, 159 Adrenergic mydriatics, 159 Adrenocorticotropic hormone (ACTH) for multiple sclerosis, 'ro6 introduction and history of, 142 Adventitia proper, 6 Advil. See Ibuprofen (Advil, Motrin, Nuprin, Rufen). Africa, onchocerciasis in, 443, 444£, 445t African Americans, uveitis in, 88 African tick-bite fever, 298, 298t clinical characteristics of, 301 t epidemiology of, 299 African trypanosomiasis, 420. See also Trypanosomiasis.

Age in uveitis diagnosis, 88 Age-related degenerative retinoschisis, 539 Age-related vitreous liquefaction, 539 Ahmed valve implantation in glaucoma, 227, 227f AIBES. See Acute idiopathic blind-spot enlargement syndrome (AIBES). AIDS. See Acquired immunodeficiency syndrome (AIDS). AION (anterior ischemic optic neuropathy), 620-621, 621£ Alaria mesocercaria in neuroretinitis, 477 Albendazole for ascariasis, 441, 441 t for cysticercosis, 471 for loiasis, 466 for toxocariasis, 434 Alcon. See Maxidex (Alcon); Vexol (Alcon). Alendronate, uveitis induced by, 860t, 861-862 Alkylating agents, 179t, 180-185 chlorambucil as, 178t, 183-185, 183f cyclophosphamide as, 177f, 180-183, 180f dosage and route of administration of, 30t, . 178t side effects of, 31 ALL. See Acute lymphocytic leukemia (ALL). Allelic exclusion, 48 Allergic alveolitis, 719, 719t Allergy, in Wegener's granulomatosis, 666 Allograft, corneal, 72-73 Allopurinol azathioprine and, 188, 1~9 cyclophosphamide and, 183 Alopecia from methotrexate, 187 in Vogt-Koyanagi-Harada syndrome, 749 Alpha herpesvirus retinitis, 321 Alpha melanocyte stimulating hormone (XMSH), 18-19, 19t Amaurosis fugax in optic neuropathy, 620 Amblyopia in toxocariasis, 432 Amebas, 411-416. See also Free-living amebas. Amenorrhea from cyclophosphamide, 182 American College of Rheumatology criteria for giant cell arteritis, 624, 624t for Wegener's granulomatosis, 668 American Journal of Ophthalmology, 30-31 American Rheumatic Association criteria for systemic lupus erythematosus, 601, 60lt American Uveitis Society, 27 on Vogt-Koyanagi-Harada syndrome, 751 Americas, onchocerciasis in, 443, 444f, 445t Amino terminus, 49 pam-Aminophenols, 29t, 167t AML (acute myelocytic leukemia), 506-509, 507f AMN. See Acute macular neuroretinopathy (AMN). Amoxicillin, for Lyme borreliosis, 253 Amphotericin B for candidiasis, 368 for coccidioidomycosis, 374, 375 for endophthalmitis, 534 for presumed ocular histoplasmosis syndrome,360 for sporotrichosis, 383 Amsler's sign in Fuchs' heterochromic iridocyclitis, 694 Amyloidosis in Adamantiades-Beh\:=et's disease, 636 Anaphylactoid reaction in ophthalmia nodosa,488 Anaprox. See Naproxen (Anaprox, Naprosyn). ANAs. See Antinuclear antibodies (ANAs). ANCAs. See Antineutrophil cytoplasmic antibodies (ANCAs).

Ancillary tests for acute zonal occult outer retinopathy, 815 for birdshot retinochoroidopathy, 736 for multiple sclerosis, 705 for subretinal fibrosis and uveitis syndrome, 801 Anemia, from dapsone, 203 Anergy clonal,66 cutaneous, 716-717 Aneurysms, in Adamantiades-Beh\:=et's disease, 635 Angiography fluorescein. See Fluorescein angiography (FA). for subretinal fibrosis and uveitis syndrome, 801 for systemic lUpus erythematosus, 607 indocyanine green. See lndocyanine green (ICG) angiography. magnetic resonance, 106 for Takayasu's arteritis, 112 retinal, 137 Angioid streaks, in presumed ocular histoplasmosis syndrome, 355 Angiomatosis, bacillary, 261 Angiotensin-converting enzyme (ACE) in intermediate uveitis, 848 in sarcoidosis, 718-719, 719t diagnostic imaging for, 109 in uveitis testing, 9!'it, 96Angiotensin-converting enzyme (ACE) inhibitors, 189 Angle hypopyon in Adamantiades-Beh\:=et's disease, 636, 637, 637f Ahgle-closure glaucoma in retinoblastoma, 514 in systemic lupus erythematosus, 603 mydriatic-cycloplegic agents and, 163-164 Anicteric leptospirosis, 273 An.kylosing spondylitis (AS), 581-584, 582f, 583t in Adamantiades-Beh\:=et's disease, 636 juvenile, 592 Annelida in neuroretinitis, 476 Ansaid. See Flurbiprofen (Ansaid). Antacids, 191 Anterior chamber immunomodulatory properties of, 18 in ameba infection, 412-413 in clinical examination, 91-92, 91t in cysticercosis, 472 in Fuchs' heterochromic iridocyclitis, 694695 in human immunodeficiency virus, 498 in lens-induced uveitis, 818, 818f in sympathetic ophthalmia, 742, 743f paracentesis of, 215-216, 216f Anterior chamber tap for candidiasis, 367 for endophthalmitis, 530, 533 Anterior chamber-associated immune deviation (ACAID), 70 definition of, 18, 19 in sympathetic ophthalmia, 745 Anterior ischemic optic neuropathy (AION), 620-621, 621£ Al1.terior segment in Adamantiades-Belwet's disease, 636-637, 637f in birdshot retinochoroidopathy, 732 in cysticercosis, 470 in leukemia, 508 in loiasis, 464t, 465 in polyarteritis nodosa, 654-655, 655f

Anterior segment (Continued) in sarcoidosis, 712-713, 712f, 713f Anterior uveitis classification of, 82, 82t, 83f anatomic, 19, 19t differential diagnosis of, 79, 80t, 581, 581t epidemiology of, 21, 22, 22f, 22t from cidofovir, 862 from latanoprost, 863-864 in ai1kylosing spondylitis, 582-583, 582f in inflammatory bowel disease-associated arthritis, 589, 590 in juvenile rheumatoid arthritis, 595 in onchocerciasis, 449, 449f in psoriatic arthritis, 588 in Reiter's syndrome, 585-587 in rickettsial diseases, 302 initial work-up for, 93, 94t intermediate uveitis versus, 850 prevalence of, 581 syphilitic, 238-239, 238t Toxoplasma, 396 Antiamebic agents, 414 Antibiotics dosage and route of administration of, 30t, 178t for brucellosis, 282-283 for endophthalmitis, 534 for immunosuppressive chemotherapy, 191204 cyclosporine as, 191-196. See also Cyclosporine A (CSA). dacliximab as, 201-202 dapsone as, 202-204, 202f etanercept as, 200-201 FK 506 and sirolimus as, 196-200 for Lyme borreliosis, 253 for relapsing fever, 256 for Whipple's disease, 293-294 Antibody (ies) in antiphospholipid syndrome, 687 in B-Iymphocyte responses, 45-50 determination of, 48-50, 49f regulation of, 48, 48f sources of, 47-48 structure and organization of, 46-47, 46f-48f in candidiasis, 367 in loiasis, 466 in onchocerciasis, 453, 454 in scleroderma, 614 in systemic lupus erythematosus, 607 in uveitis testing, 95t, 96 injury mediated by, 57-62 type I reactions in, 57-60, 57f, 58f, 58t, 60t type II reactions in, 60-61, 61£ type III reactions in, 61-62, 62f to Brucella, 279 Anticardiolipin antibodies (aCL), 687 Anticholinergic agents overdosage of, 164 pharmacology of, 159 clinical, 160-162, 160t Anticoagulant, lupus, 687 Antiendothelial cell antibodies in polyarteritis nodosa, 656 Antigen(s) B-Iymphocyte responses to, 51-52, 52f in candidiasis, 367 in corneal transplantation, 71-72 in immune response regulation, 65 in loiasis, 466 in onchocerciasis, 454 in toxocariasis, 430 induction of immunity to eye-derived, 70

Antigen(s) (Continued) presentation of, 43, 43f T cell recognition of, 53 T-lymphocytes activation by, 54 Antigen-activated T-cell responses, 54-55 Antigen-presenting cells (APes), 18, 34-36 Antihepatitis B antibodies, in polyarteritis nodosa, 656 Anti-herpes antibody measurement, 215 A.l1tihistamines, for loiasis, 466 AIlti-inflammatory effects, of corticosteroids, 144 Anti-inflammatory therapy, for acute retinal necrosis, 321-322 An.timetabolites, 178t, 179t, 185-191 azathioprine as, 178t, 179t, 185f, 187-189 dosage and route of administration of, 30t, 178t leflunomide as, 189-190 methotrexate as, 178t, 179t, 185-187, 185f mycophenolate mofetil as, 190-191 Antimicrobial activity of dapsone, 202 Antimicrobial therapy for toxoplasmosis, 401, 402-404, 403t Antimuscarinic drugs, 159, 160-162, 160t Antineut:rophil cytoplasmic antibodies (ANCAs) in tubulointerstitial nephritis and uveitis syndrome, 727 in uveitis testing, 95t, 96 in Wegener's granulomatosis, 111-112,662 in ocular inflammation, 669-670 role of, 666 testing of, 668-669, 668f, 669t Antinuclear antibodies (ANAs) in scleroderma, 614 in systemic lupus erythematosus, 60~, in uveitis testing, 95t, 96 "if Antiphospholipid antibodies in Adamantiades-Belwet's disease, 640 in uveitis testing, 95t, 96 Antiphospholipid syndrome (APS), 683-692 clinical characteristics of, 684-687, 684t, 685f, 685t, 686f definition of, 683 diagnosis of, 688-689 epidemiology of, 683-684 history of, 683 immunology of, 687-688, 687t immunopathogenesis of, 688 prognosis for, 690 treatment of, 689-690 AIltiretinal antibodies in vasculitis, 837 An.tiretroviral agents, for human immunodeficiency virus, 493, 494t Antiviral agents, for herpes simplex virus, 321 Aorta, in giant cell arteritis, 620 Aphakic eyes, in retinal detachment, 539 Aphthous ulcers, in Adamantiades-Behr;:et's disease, 632, 634, 634f. See also Adamantiades-Behr;:et's disease. APMPPE. See Acute posterior multifocal placoid pigment epitheliopathy (APMPPE). APOD. See Acute papular onchodermatitis (APOD). Apolipoprotein H (a2-GPI cofactor) in antiphospholipid syndrome, 687-688 Apoptosis, in multiple sclerosis, 704 Appendicular ascariasis clinical characteristics of, 438 treatment of, 441-442, 441t APS. See An.tiphospholipid syndrome (APS). Aqueous cells, 91, 91t Aqueous flare, 91, 9lt Aqueous humor, 10 soluble immunomodulatory constituents of, 18-19, 19t

Arabian peninsula, onchocerciasis in, 443, 444f,445t Arava. See Leflunomide (Arava). Argasidae, 297 Argon laser photocoagulation for diffuse unilateral subacute neuroretinitis, 478 for ophthalmia nodosa, 490 for ophthalmomyiasis, 486 for serpiginous choroiditis, 793 Argyll-Robinson (AR) pupil, 90 Aristocort, 29t ARPE. See Acute retinal pigment epitheliitis (ARPE). Arterial occlusion in Adamantiades-Behr;:et's disease, 635 in systemic lupus erythematosus, 604-605 Arterial wall inflammation in polyarteritis nodosa, 656 Arteries ciliary, 3 of ciliary processes, 10 of iris, 6 Arteriography for Takayasu's arteritis, 112 Arteriolitis in systemic lUpus erythematosus, 603, 604f Arteritis giant cell. See Giant cell arteritis (GCA). in systemic lupus erythematosus, 603, 604f in Wegener's granulomatosis, 667 Arthralgia in extr<.tocubr examination, 94 in Wegener's granulomatosis, 663 in Whipple's disease, 291, 291t Arthritis enteropathic, 589-592 idiopathic inflammatory bowel disease-associated, 589-591, 593 in Adamantiades-Beh~et'sdisease, 636 in ankylosing spondylitis, 582, 583 in extraocular examination, 94 in Lyme borreliosis, 250 prognosis for, 254 treatment of, 253 in Reiter's syndrome, 584 in systemic lupus erythematosus, 602 in Whipple's disease, 291, 291t juvenile, 592-596, 593t, 594f, 596f monoarticular, 587 psoriatic, 587-589, 588f juvenile, 592-593 rheumatoid. See Rheumatoid arthritis (RA). juvenile. See Juvenile rheumatoid arthritis (JRA). symmetric oligoarticular, 587 Arthrography, 106 Arthropathy, in extraocular examination, 94 Arthus' reaction, 62 Articular manifestations in extraocular examination, 94 of juvenile rheumatoid arthritis, 593 Artifacts, in computed tomography, 104 AS. See Ankylosing spondylitis (AS). Asbestosis, 719, 719t A-scan ultrasound, 107 for intraocular foreign bodies, 548, 548f Ascariasis, 437-442 clinical characteristics of, 437-438 complications of, 442 definition of, 437 diagnosis of,· 440-441 epidemiology of, 437 history of, 437 immunology of, 440 life cycle of, 439-440, 439f pathology of, 440

Ascariasis (Continued) treatment of, 441-442, 441t Asexual cycle, of Toxoplasma gondii, 386-387 Asians, uveitis in, 88 Aspiration, vitreous, 367 Aspirin, 29t, 167t Astemizole, 207 Asteroid bodies, in sarcoidosis 716 Asymmetric monoarticular artllritis, 587 Asymmetric oligoarticular arthritis, 587 Atherosclerosis, in ocular ischemic syndromes, 555 ATIN (acute tubulointerstitial nephritis), 726. See also Tubulointerstitial nephritis and uveitis (TINU) syndrome. Atopy, 60, 60t in hypersensitivity reactions, 58-59 Atovaquone, for toxoplasmosis, 402-403, 403t Atrophic scarring, in presumed ocular histoplasmosis syndrome, 351, 352f Atrophy in differential diagnosis, 103 in Fuchs' heterochromic iridocyclitis, 693694,694f in herpes simplex virus, 320 in multifocal choroiditis and panuveitis, 758,758f in multiple sclerosis, 703 in onchocerciasis, 446, 447f, 450, 450f Atropine chemistry of, 159 clinical pharmacology of, 160-162, 160t for loiasis, 465 for traumatic uveitis, 576-577 history and source of, 159 pharmacokinetics and metabolism of, 162 potency of, 160t side effects and toxicity of, 163 structural formula of, 16lf therapeutic use of, 162-163 Auditory manifestations, of Vogt-KoyanagiHarada syndrome, 750 Auricular chondritis, in relapsing polychondritis, 676, 677f Autoantibodies in onchocerciasis, 453 in relapsing polychondritis, 678-679 in retinal vasculitis, 837 in systemic lupus erythematosus, 606-607 Autoimmune disease conjunctiva and lacrimal gland in, 68 in intermediate uveitis, 846-847 in syphilis, 240 multiple sclerosis in, 703 retinal vasculitis in, 828-829, 828f T-lymphocytes in, 56 Autoimmune T cells, immune-mediated injury due to, 63-64 Autoimmune-immune complex diseases, 62 Autoimmunity in birdshot retinochoroidopathy, 733, 734 in cancer-associated retinopathy, 521 in giant cell arteritis, 623 in retinal vasculitis, 834 Azathioprine (huuran) adverse reactions of, 178, 178t dosage and route of administration of, 30t, 178t for Adamantiades-Behr;:et's disease, 643644, 645 for ankylosing spondylitis, 583 for birdshot retinochoroidopathy, 738 for giant cell arteritis, 626 for immunosuppressive chemotherapy, 177f, 178t, 179t, 180-183, 180f for intermediate uveitis, 852

Azathioprine (Imuran) (Continued) for multiple sclerosis, 706 for Reiter's syndrome, 587 for sarcoidosis, 723 for serpiginous choroiditis, 793 for sympathetic ophthalmia, 746 for tubulointerstitial nephritis and uveitis syndrome, 729 for Vogt-Koyanagi-Harada syndrome, 752 for Wegener's granulomatosis, 670 indications for, 179, 179t Azithromycin, for toxoplasmosis, 403, 403t Azolid. See Phenylbutazone (Azolid, Butazolidin) . AZOOR. See Acute zonal occlilt outer retinopathy (AZOOR). Azoospermia, from cyclophosphamide, 182 Azurophil granules, 37, 37t

B B cell(s) in toxoplasmosis, 387 lymphoma of, 503, 504 Babesia species, 297 Babesiosis, 254 Bacillary angiomatosis, 261 Bacillus Calmette-Guerin (BCG) vaccination for leprosy, 306 for tuberculosis, 266, 267 uveitis induced by, 859; 860t Back pain, low in ankylosing spondylitis, 582 uveitis and, 114 Bacteria in endophthalmitis, 533 in multiple sclerosis, 704 in retinal vasculitis, 830-831 Bacterial culture, for vitrectomy, 217 Bacterial endocarditis, 532 Bacterial endophthalmitis, 321 BAL (bronchoalveolar lavage), in sarcoidosis, 719-720 Balanitis, in Reiter's syndrome, 585, 585f Band keratopathy cornea with, 222, 222f, 223, 223f in differential diagnosis, 103 in juvenile rheumatoid arthritis, 594, 594f Barium enema (BE), 107 Bartonella, 260-263, 261£ Bartonellosis, 260-263 Basement membrane, 9 Basophilic membranes, 144 Basophils, 38 Baylisascaris, in neuroretinitis, 477 BCG vaccination. See Bacillus Calmette-Guhin (BCG) vaccination. BCL2 gene, in intraocular-central nervous system lymphoma, 505 BE (barium enema), 107 Beam radiation, for malignant melanoma, 512-513 Bear tick, in Lyme borreliosis, 249, 250f. See also Lyme borreliosis. Bechterew's disease, 581. See also Ankylosing spondylitis (AS). Beef, in toxoplasmosis transmission, 387 Behc;:et's disease. See Adamantiades-Behc;:et's disease (ABD). Belladonna alkaloids, 159, 160t, 161£ Bell's palsy, in Lyme borreliosis, 247-248 Benzathine penicillin G, for syphilis, 241-242, 242t Benznidazole, for trypanosomiasis, 422-423 Berylliosis, 719, 719t Betamethasone chemistry of, 142, 143t

Betamethasone (Continued) pharmaceutics of, 146-147, 146t regional preparation of, 29t systemic preparation of, 28t Beta-2-microglobulin, in sympathetic ophthalmia, 574-575 Biguanides, for ameba infection, 414 Bilateral iridocyclitis with retinal capillaritis (EIRC), 826-827 Bilateral symmetrical hilar lymphadenopathy (BSHL), 717-718, 717f, 718t Bilharziasis. See Schistosomiasis. Biomicroscopy for birdshot retinochoroidopathy, 732 slit-lamp. See Slit-lamp examination. ultrasound. See Ultrasound biomicroscopy (UBM). Biopsy chorioretinal, 218-221, 219f, 220f for tuberculosis, 268 conjunctival for relapsing polychondritis, 678 for sarcoidosis, 720-721 for endophthalmitis, 533 for polyarteritis nodosa, 657 for sarcoidosis, 720-721 in uveitis testing, 95t, 96 jejunal, 591 kidney, 728 retinal, 217-218, 218f for endophthalmitis, 533 temporal artery, 625-626 transbronchial lung, 720 vitreous for candidiasis, 367 for endophthalmitis, 533 for intraocular-central nervous system lympholna, 503, 505 Biphosphonates, uveitis induced by, 860t, 861-862 BIRC (bilateral iridocyclitis with retinal capillaritis), 826-827 Birdshot retinochoroidopathy (BSRC), 731-741 angiography in, 129-132, 131£, .132f clinical features of, 731-732, 732f complications of, 732-733 definition of, 731, 806 diagnosis of, 79, 734-736, 734t, 735f differential, 736-738, 736t epidemiology of, 731 etiology of, 733 history of, 731 multifocal choroiditis and panuveitis versus, 762 natural history and prognosis for, 738-739 pathogenesis and pathology of, 733-734 subretinal fibrosis and uveitis syndrome versus, 802, 802t summary of, 809, 809t treatment of, 738 Black pigmentation in malignant melanoma, 510 Blackfly in onchocerciasis, 443 Black-footed tick in Lyme borreliosis, 249, 250f. See also Lyme borreliosis. Bladder in extraocular examination, 94 in multiple sclerosis, 702 Bladder worm, in cysticercosis, 468. See also Cysticercosis. Blindness in leprosy, 306 in onchocerciasis, 443 in presumed ocular histoplasmosis syndrome, 349

Blindness (Continued) in uveitis, 25, 26 post-measles, 338 Blood tests for leptospirosis, 275 for retinoblastoma, 515 for syphilis, 237 Blood vessels in polyarteritis nodosa, 656 in scleroderma, 614 Blood-aqueous barrier, 91 Blood-retina barrier, 18 Blunt trauma in retinal detachment, 539 Blurred vision from atropine, 163 B-Iymphocyte (s), 34-36 ocular surface immunity and, 68 B-Iymphocyte responses, 45-52 antibody diversity in, 45-50, 46f determination of, 48-50, 49f regulation of, 48, 48f sources of, 47-48 structure and organization of, 46-47, 46f-48f complement in, 50-51, 51£ to antigen, 51-52, 52f Body fluid analysis for leptospirosis, 275 Bone(s) densitometry of, III in sarcoidosis, 711 in sporotrichosis, 381 ultrasonography of, 107, 107t Bone marrow azathioprine and, 189 cyclophosphamide and, 182 Borrelia burgdOlferi in birdshot retinochoroidopathy, 734 in Lyme borreliosis, 245. See also Lyme borreliosis. in tick-borne diseases, 297 Borrelia recurrentis, in relapsing fever, 255 Borreliosis, 245-259 in retinal vasculitis, 830-831 Lyme, 245-255. See also Lyme borreliosis. relapsing fever in, 255-256 Botfly maggots, in ophthalmomyiasis, 485-487, 486f Boutonneuse fever, 298, 298t Bowel disease, inflammatory, 589-591 Bowel dysfunction, in multiple sclerosis, 702 Bradyzoite, in toxoplasmosis, 385, 386, 386f, 387 Brain, in schistosomiasis, 481 Brain radiation, for intraocular-central nervous system lymphoma, 506 Branch retinal artery occlusion, in giant cell arteritis, 622 Breast metastasis, 517, 519 Breast-fed infants, and methotrexate, 187 Brill-Zinsser disease, 299, 301 Brolene. See Propamidine (Brolene). Bromocriptine (Parlodel) adverse reactions of, 178, 178t as adjuvant to immunosuppressive therapy, 178t, 179t, 204-205, 204f dosage and route of administration of, 30t, 178t indications for, 179, 179t Bronchoalveolar lavage (BAL) in sarcoidosis, 719-720 Brucellosis, 278-285 clinical features of, 279-281, 28lt definition of, 278 diagnosis of, 281-282, 282t epidemiology of, 278 etiology of, 278 history of, 278

Brucellosis (Continued) in retinal vasculitis, 831 molecular genetics, pathology, and immunology of, 278-279 prevention of, 283 prognosis for, 283 treatment for, 282-283 Bruch's membrane, in malignant melanoma, 510,511f Brugia malayi in loiasis, 463 in onchocerciasis, 450-451 B-scan ultrasonography, 107 for intraocular foreign bodies, 548, 548f for sympathetic ophthalmia, 743, 743f BSHL (bilateral symmetrical hilar lymphadenopathy), in sarcoidosis, 717-718, 717f, 718t BSRC. See Birdshot retinochoroidopathy (BSRC). Buerger's disease in Adamantiades-Behyet's disease, 637 retinal vasculitis in, 829 Busacca nodules, in Fuchs' heterochromic iridocyclitis, 694 . Butazolidin. See Phenylbutazone (Azolid, Butazolidin) . Butterfly rash, in systemic lupus erythematosus, 601, 602f

C Calabar swelling, in loiasis, 463-464 Calcaneal periostitis, in Reiter's syndrome, 584, 585f Calcification, in congenital toxoplasmosis, 389, 390f Calcitonin gene-related peptide (CGRP)~, 18-19, 19t Calcitriol (1 ,25-dihydroxy-vitamin D:J ), in sarcoidosis, 720 Calcium metabolism, corticosteroids and, 143 Calcofluor white stain, for ameba infection, 413 Calliphora, in ophthalmomyiasis, 485-487, 486f Calreticulin, antibodies to, 453 CALT. See Conjunctival and lacrimal gland-associated lymphoid tissue (CALT). Cancer-associated retinopathy (CAR), 520-522 acute zonal occult outer retinopathy versus, 815 in retinal vasculitis, 832-833 Candida, in endophthalmitis, 531-532 Candidiasis, 364-372 clinical characteristics of, 365-366, 365f complications of, 366 definition of, 364 diagnosis of, 367-368 differential, 368, 368t epidemiology of, 364-365 history of, 364 in human immunodeficiency virus, 499 pathogenesis/histopathology/immunology of,366-367 Pneumocystic carinii choroidopathy versus, 426 prognosis for, 370 treatment for, 368-370 Canine ehrlichiosis, 299 Capillary dropout, in systemic lUpus erythematosus, 605, 605f Capillary permeability, corticosteroids and, 144 Capsulotomy, uveitis after, 575 CAR. See Cancer-associated retinopathy (CAR). 'j

Carbohydrate metabolism, corticosteroids and, 143 Carboxyl terminus, 49 Card agglutination test, for trypanosomiasis (CATT) , 422 Cardiac output, corticosteroids and, 144 Cardiac system in Adamantiades-Behyet's disease, 634-635 in antiphospholipid syndrome, 684, 684t in Lyme borreliosis, 247 in sarcoidosis, 711 in scleroderma, 612 in systernic lUpus erythematosus, 602 in Wegener's granulomatosis, 663 Cardiolipin, in syphilis diagnosis, 240 Cardiomyopathy, in loiasis, 464 Cardiopulmonary schistosomiasis, 481 Cardiovascular disease from ocular ischemic syndromes, 556 in relapsing polychondritis, 677 Cardiovascular syphilis, 238, 238t Cardiovascular system corticosteroids and, 144 in giant cell arteritis, 620 in Lyme borreliosis, 251, 251t in polyarteritis nodosa, 653 Carotid endarterectomy, for ocular ischemic syndromes, 556 Carri6n's disease, 260-263 Cartilage in extraocular examination, 94 in relapsing polychondritis, 676, 677f, 678 CAT (computeri.ed axial tomography), for cysticercosis, 470-471 Cataracts, 92 after radiotherapy, 517 ameba infection and, 413 endophthalmitis and, 534 from ocular toxoplasmosis, 397 from syphilis, 242 from Vogt-Koyanagi-Harada syl.1.drome, 753 in Adamantiades-Behyet's disease, 646 in ciliary body melanoma, 510, 511£ in congenital rubella, 343, 343t in Fuchs' heterochromic iridocyclitis, 693, 695, 698 in intermediate uveitis, 846 in juvenile rheumatoid arthritis, 594 in leprosy, 308 surgery for, 224-226, 225f, 226f candidiasis and, 366 endophthalmitis after, 528-529, 530f for intermediate uveitis, 853-854 for sarcoidosis, 723 nonsteroidal anti-inflammatory drugs for, 170, 171 varicella zoster infection and, 318 Caterpillar hairs, in ophthalmia nodosa, 488-491, 489f Cats in toxoplasmosis transmission, 387 uveitis and, 88 Cat-scratch disease (CSD), 260-263, 831 intermediate uveitis versus, 850 CATT. See Card agglutination test, for trypanosomiasis (CATT). CD. See Clusters of differentiation (CD); Crohn's disease (CD). CD46, 18, 19t CD59,18 CD4 cells, 36 CD4+ cells, 750-751 CD8 cells, 36 CD8+ cells, 750-751 CD4+ effector cells, 63 CD4+ lymphocytes in hl.lman immunodeficiency virus, 493, 494f

CD4+ lymphocytes (Continued) CMV retinitis and, 495 herpes zoster ophthahnicus and, 499 ocular toxoplasmosis and, 497 pneumocystosis and, 498 syphilis and, 499 VZV retinitis and, 497-498 in retinal vasculitis, 834 in sarcoidosis, 717 CD8+ T cells, in toxoplasmosis, 388 CD4+ Th cells in ascariasis, 440 in toxoplasmosis, 387-388 CDRs. See Complementarity-determining regions (CDRs). Ceftriaxone for Lyme borreliosis, 253 for Whipple's disease, 294 Cefuroxime for Lyme borreliosis, 253 Celecoxib (Celebrex) for cataract surgery, 224-225 systemic preparation of, 29t, 167t Cell(s) immune-mediated tissue injury by, 62-64, 63f of pigmented epithelium, 9 Cell surface antigens in toxoplasmosis, 388, 388t CellCept. See Mycophenolate mofetil (CellCept) . Cell~mediated immunity, 55 in Adamantiades-Behyet's disease, 641 in giant cell arteritis, 623 in Lyme borreliosis, 251 in retinal vasculitis, 834 in toxoplasmosis, 387-388 Cellular response to ameba infection, 412 Cellulitis, orbital, 534 Central lymphoid organs, 40, 41£, 42f, 42t Central nervous system (CNS) corticosteroids and, 143 cyclopentolate and, 164 in Lyme borreliosis, 247 in multiple sclerosis, 701. See also Multiple sclerosis (MS). in sarcoidosis, 714-715, 714f in schistosomiasis, 481 in Whipple's disease, 291, 29lt lymphoma of, 503-506, 504f mydriatic-cycloplegic agents and, 163-164 Central retinal artery occlusion (CRAO), 621 Central retinal vein obstruction, 555-556 Central serous chorioretinopathy (CSCR), 783, 783t, 784t Cephalexin, for bartonella, 262 Cerebral cysticercosis, 469 Cerebral involvement, in systemic lupus erythematosus, 606 Cerebrospinal fluid (CSF) analysis for cryptococcosis, 378 for cysticercosis, 470-471 for intraocular-central nervous system lymphoma, 505 for leptospirosis, 275 for syphilis, 241 Cerebrovascular disease, in giant cell arteritis, 619 Cervical spine films, for rheumatoid arthritis,

III Cervical spondylitis, 592 CF (complement fixation) for cysticercosis, 471 for toxoplasmosis, 398 CGRP. See Calcitonin gene-related peptide (CGRP). Chagas' disease, 420

Chancre, in syphilis, 238, 238t Chapel Hill classification, of polyarteritis nodosa, 653, 658t Chelation, in corneal surgery, 222, 223f Chemical injuries, from intraocular foreign bodies; 547 Chemical mediators, of inflammation, 17, 17t Chemokines, in acute inflammation, 17 Chemoprophylaxis, for loiasis, 466 Chemotaxis, in acute inflammation, 17 Chemotherapy for intraocular-central nervous system lymphoma, 506 immunosuppressive, 177-214. See also Immunosuppressive chemotherapy. Cherry-red spot, in VZV retinitis, 497, 497f Chest computed tomography, for intermediate uveitis, 848 Chest x-ray (CXR), 106 for intermediate uveitis, 848 for presumed ocular histoplasmosis syndrome, 354 for sarcoid suspect, 109-110, 109f for sarcoidosis, 717-718, 717f, 718t for uveitis, 95t, 96 Child Adamantiades-Behyet's disease in, 638 atropine for, 163 Candida endophthalmitis in, 369 sarcoidosis in, 715 uveitis in, 88 epidemiology of, 24-25 Chlorambucil (Leukeran) adverse reactions of, 178, 178t dosage and route of administration of, 30t, 178t for Adamantiades-Behyet's disease, 644 for immunosuppressive chemotherapy, 178t, 179t, 183-185, 183f for intermediate uveitis, 852 for sympathetic ophthalmia, 746 for Vogt-Koyanagi-Harada syndrome, 752 indications for, 179, 179t side effects of, 31 Chloramphenicol cyclophosphamide and, 183 for rickettsial diseases, 303 for Whipple's disease, 294 Chlorhexidine, for ameba infection, 414 Chloroma, in leukemia, 509 Cholestyramine, 191 Choriocapillaris, 13-14, 13f, 14f in serpiginous choroiditis, 787 in sympathetic ophthalmia, 743, 744f Chorioretina biopsy of, 218-221, 219f, 220f for tuberculosis, 268 in human immunodeficiency virus, 494-499 candidiasis and, 499 CMV retinitis and, 495-497, 495f, 496f, 496t cryptococcosis and, 498, 499f eye and, 494-495, 495f lymphoma and, 499 ocular toxoplasmosis and, 497, 497f pneumocystosis and, 498, 498f syphilis and, 499 tuberculosis and, 498, 498f VZV retinitis and, 497-498, 497f, 498f in onchocerciasis, 450, 450f in presumed ocular histoplasmosis syndrome, 351, 352f in sarcoidosis, 714, 714f in toxocariasis, 430, 430f scarring of in Adamantiades-Behyet's disease, 638, 638f

Chorioretina (Continued) in Fuchs' heterochromic iridocyclitis, 695, 696 in varicella zoster infection, 318 in Vogt-Koyanagi-Harada syndrome, 749, 749f Chorioretinitis cysticercosis versus, 471 definition of, 364 endogenous Candida, 365, 365f in diffuse unilateral subacute neuroretinitis, 476 in onchocerciasis, 449-450, 450f in presumed ocular histoplasmosis syndrome, 353 in syphilis, 239, 239t, 242 vitiliginous. See Birdshot retinochoroidopathy (BSRC). Chorioretinopathy central serous, 783, 783t, 784t sarcoid, 132-133 Choroid, 11-15, Ilf, 12f definition of, 17 hemangioma of, 107 in clinical examination, 92-93 in giant cell arteritis, 622 in leprosy, 308 in leukemia, 507-508 in loiasis, 464, 464t in sarcoidosis, 713, 713f in scleroderma, 613-614 in serpiginous choroip.itis, 787 in subretinal fibrosis and uveitis syndrome, 799 in sympathetic ophthalmia, 743, 743f in Vogt-Koyanagi-Harada syndrome, 749, 749f innervation of, 3 melanoma of, 509-513 ultra~ound characteristics of,107 metastasis to, 517 Choroidal granuloma, in differential diagnosis, 103 Choroidal lesions in endophthalmitis, 533 in punctate inner choroidopathy, 807, 807f, 808f in tuberculosis, 498 in Whipple's disease, 289, 290f Choroidal melanocytes, in Vogt-KoyanagiHarada syndrome, 750-751 Choroidal neovascular membranes (CNVlVls) history of, 806 in multifocal choroiditis and panuveitis, 757, 759-760, 763-764 in punctate inner choroidopathy, 806, 807f, 808, 808f, 811 Choroidal neovascularization (CNV), 93 angiography of, 135-137, 136f, 137f in birdshot retinochoroidopathy, 732-733 in multifocal choroiditis and panuveitis, 760, 760f in penetrating ocular trauma, 574 in presumed ocular histoplasmosis syndrome, 351 in serpiginous choroiditis, 793-794 in toxoplasmosis retinochoroiditis, 133, 133f Choroidal vasculitis, in polyarteritis nodosa, 655, 655f Choroiditis brucellosis and, 281 focal in differential diagnosis, 103 in tuberculosis, 265 in Lyme borreliosis, 248

Choroiditis (Continued) in presumed ocular histoplasmosis syndroIne, 349-350, 351, 352f in schistosomiasis, 482, 483f in subretinal fibrosis and uveitis syndrome, 797 serpiginous, 787-796. See also Serpiginous choroiditis (SC). tuberculous Pneurnocystic carinii choroidopathy versus, 426 serpiginous choroiditis versus, 792 Choroiditis geographica. See Serpiginous choroiditis (SC). Choroidopathy in systemic lUpus erythematosus, 605-606 Pnewnocystic carinii, 425-427

Chronic cyclitis. See Intermediate uveitis (IU). Chronic inflammation, 17-18 Chronic lymphocytic leukemia (CLL), 506-509 Chronic myelocytic (myelogenous) leukemia (CliL), 506-509, 507f Chronic papular onchodermatitis (CPOD), 446,447f Chronic posterior cyclitis. See Intermediate uveitis (IU). Chronic postoperative endophthalmitis, 528-531, 528t, 530t. See also Endophthalmitis. Chronic uveitis, 87, 87t Churg-Strauss syndrome, 112 CIC (circulating immune complexes), 639...:.640 Cicatricial pemphigoid, 188 Cidofovir for cytomegalovirus, 326-327 retinitis and, 496, 496t uveitis induced by, 860t, 862 Ciliary arteries, 3, 6, 14, 15 Ciliary body, 3, 7-11, 8f-llf definition of, 17 in leprosy, 307-308, 307f, 308f malignant melanoma of, 509-513, 51lf posterior pigment epithelium and, 6 vascular supply and innervation of, 10 Ciliary muscle, 3, 17 Ciliary nerves, 3 Ciliary striae, of Schultze, 8 Cilioretinal artery occlusion, 620, 62lf Ciprofloxacin for bartonella, 262 for rickettsial diseases, 303 Circinate balanitis, in Reiter's syndrome, 585, 585f Circulating immune complexes (CIC) , 639-640 Circulus iridis major, 10 Cirrhosis, angiotensin-converting enzyme in, 719, 719t Cisticercus cellulosae, 468. See also Cysticercosis. Cladribine, for multiple sclerosis, 706 Clarithromycin for leprosy, 310, 311 for toxoplasmosis, 403, 403t rifabutin-related uveitis and, 500 Clear vitreous, in presumed ocular histoplasmosis syndrome, 351 Clindamycin, for toxoplasmosis, 402, 403t Clinical examination, 90-96 differential diagnosis in, 96 for intermediate uveitis, 848 laboratory evaluation in, 95t, 96 of extraocular structures, 93-96, 94t of ocular structures, 90-93, 91t, 92t, 93t Clinoril. See Sulindac (Clinoril).

CLL (chronic lymphocytic leukemia), 506-509 Clodronate, uveitis induced by, 860t, 861-862 Clofazimine, for leprosy, 310, 311 Clonal anergy, 66 Clonal deletion, 66 Clump cells, in stroma, 5 Clusters of differentiation (CD), 34, 35t CIvIE. See Cystoid macular edema (CIvIE). CIvIL. See Chronic myelocytic (myelogenous) leukemia (CIvIL). CMV. See Cytomegalovirus (CMV). CNS. See Central nervous system (CNS). CNV. See Choroidal neovascularization (CNV). CNVMs. See Choroidal neovascular membranes (CNVMs). Coagulation abnormalities in polyarteritis nodosa, 656 Coats' disease retinoblastoma versus, 105-106 toxocariasis versus, 433 Cocaine with epinephrine and atropine, 163 Coccidioidomycosis, 373-376 angiotensin-converting enzyme in, 719, 719t Coefficient of Witmer-Desmonts, 400, 400t Cogan's syndrome, peripheral ulcerative, 655 Cognitive dysfunction in multiple sclerosis, 702 Colchicine adverse reactions of, 178, 178t as adjuvant to immunosuppressive therapy, 208-209, 208f , dosage and route of administration of, 30t, 178t for Adamantiades-Beh\=et's disease, 645 indications for, 179, 179t Colitis, ulcerative, 589-591 Collagen in Adamantiades-Beh\=et's disease, 641 in sarcoidosis, 717 in stroma, 5 in supraciliary layer, 10 Collagen vascular disease, in relapsing polychondritis, 677 Collar-button configuration, in malignant melanoma, 510, 511£ Collarette of iris, 3, 4 Color Doppler ultrasonography, 107 for giant cell arteritis, 625 Color matching testing, for multiple evanescent white dot syndrome, 770 Coltivirus species, 297 Complement, 50-51, 51£ in uveitis testing, 95t, 96 Complement fixation (CF) for cysticercosis, 471 for toxoplasmosis, 398 Complementarity-determining regions (CDRs),46 Complex fluid, 107, 107t Computed tomography (CT), 104 for bone disease, 114-115 for Graves' disease, 115, 116 for intermediate uveitis, 848 for in traocular foreign bodies, 548 for intraocular-central nervous system lymphoma, 505 for masquerade syndromes, 116-118 for retinoblastoma, 514-515 for sarcoid suspect, 108f, 109, 109f for scleritis, 110, 11Of for Takayasu's arteritis, 112 for uveitis testing, 95t, 96 for Wegener's granulomatosis, 112 magnetic resonance imaging versus, 105

Computerized axial tomography (CAT) for cysticercosis, 470-471 Concentration-effect relationship of corticosteroids, 147-150, 148t, 149t Conductive hearing loss, in i:elapsing polychondritis, 679 Confocal microscopy, for free-living amebas, 413 Congeners, 142, 143t Congenital measles, 336 Congenital rubella, 343-345, 343t, 344f Congenital toxoplasmosis, 385, 388-389, 389f, 389t, 390f diagnosis of, 398-400, 399t differential diagnosis of, 397 Conjunctiva immunity of, 68-69 in clinical examination, 90 in leprosy, 306-307 in loiasis, 464, 464t in onchocerciasis, 448-449 in relapsing polychondritis, 678 in sarcoidosis, 712, 712f in schistosomiasis, 481 in sporotrichosis, 382 Conjunctival and lacrimal gland-associated lymphoid tissue (CALT) , 68 Conjunctival biopsy in relapsing polychondritis, 678 in sarcoidosis, 720-721 Conjunctival fornix foreshortening, in scleroderma, 613, 613f Conjunctival infarction, in polyarteritis nodosa, 654 Conjunctivitis from atropine, 163 in Lyme borreliosis, 247, 253 in measles, 337 in psoriatic arthritis, 588 in Reiter's syn.drome, 584, 586 in rickettsial diseases, 301 in Wegener's granulomatosis, 663, 664t Connective tissue diseases, 112-113, 113f Connective tissue mast cell (CTIvIC), 38-39, 38t, 58 Contact dermatitis, from atropine, 163 Contact hypersensitivity, 64, 64t Contact lens, ameba infection of, 411, 412 Coombs hypersensitivity reaction, 56, 56t Copper foreign bodies, 547 Cor pulmonale in sarcoidosis, 711 Cornea immunity of, 68-69 in clinical examination, 90-91 in diffuse unilateral subacute neuroretinitis, 476 in leprosy, 306-307 in onchocerciasis, 449, 449f in relapsing polychondritis, 678 in uveitis diagnosis, 89, 89t therapeutic surgery of, 222-223, 222f, 223f Corneal band keratopathy, 713 Corneal edema in endophthalmitis, 533 Corneal toxicity, with latanoprost, 863 Corneal transplantation immunology, 71-73 Corona ciliaris, 8-9 Corticosteroid-resistant ocular inflammatory disease, 188 Corticosteroids, 142-157 adverse effects and toxicity of, 153-155, 153t, 154t clinical trials with, 155-156 cyclophosphamide and, 183 drug interactions with, 155 for Adamantiades-Beh\=et's disease, 643, 645 for ankylosing spondylitis, 583-584

Corticosteroids (Continued) for birdshot retinochoroidopathy, 738 for candidiasis, 369 for free-living amebas, 414 for giant cell artelitis , 625, 626, 627 for inflammatory bowel disease-associated arthritis, 590 for intermediate uveitis, 851-852 for iridocyclitis and trabeculitis, 321 for juvenile rheumatoid arthritis, 595 for loiasis, 466 for polyarteritis nodosa, 657 for presumed ocular histoplasmosis syndrome, 358-359 for psoriatic arthritis, 588 for retinal vasculitis, 837-838 for serpiginous choroiditis, 792-793 for sympathetic ophthalmia, 746 for toxoplasmosis, 401, 404 for traumatic uveitis, 577 for tubulointerstitial nephritis and uveitis syndronle, 728-729 for type I hypersensitivity reactions, 59-60 for Vogt-Koyanagi-Harada syndrome, 752 for Wegener's granulomatosis, 661-662, 670, 671 introduction and history of, 142 official name and chemistry of, 142, 143t pharmaceutics of, 144-147, 145t pharmacokinetics, concentration-effect relationship, and metabolism of, 147-150, 148t, 149t pharmacology of, 142-144, 143t regional preparations of, 27, 29t systemic preparations of, 27, 28t therapeutic use of, 150-153 topical preparations of, 27, 28t tropicamide combined with, 163 uveitis induced by, 860t, 862-865 Cortisol, 142, 143t Cortisone, 142, 143t Costs of uveitic blindness, 27 Cotton-wool spots in differential diagnosis, 103 in HIV retinopathy, 495 in systemic lUpus erythematosus, 602t-604t, 603-604, 604f in Whipple's disease, 289, 290f Cox-2 inhibitors, 29t, 167t CPOD. See Chronic papular onchodermatitis (CPOD). C1q binding assay, in uveitis testing, 95t, 96 Cracked mud appearance, in VZV retinitis, 497, 498f Cranial arteritis. See Giant cell arteritis (GCA).

Cranial nerves, in extraocular examination, 94 Cranial neuropathy, in Lyme borreliosis, 247-248 Cranial radiation, for intraocular-central nervous system lymphoma, 506 CRAO (central retinal artery occlusion), 621 C-reactive protein in giant cell arteritis, 625 in uveitis testing, 95t, 96 Cream-colored spots, in birdshot retinochoroidopathy, 732, 732f CREST syndrome, 610 Crohn's disease (CD), 589-591 retinal vasculitis in, 829 Cryotherapy for amebiasis, 414 for intermediate uveitis, 852-853 for retinoblastoma, 516 Cryptococcosis, 377-379 in human immunodeficiency virus, 498, 499f

INDEX Crystal disease, 113, 113f CSA. See Cyclosporine A (CSA). CSCR. See Central serous chorioretinopathy (CSCR). . CSD (cat-scratch disease), 260-263, 26lf, 831 intermediate uveitis versus, 850 CSF. See Cerebrospinal fluid (CSF) analysis. CT. See Computed tomography (CT). CTMC. See Connective tissue mast cell (CTMC). Culture for candidiasis, 367 for endophthalmitis, 530 for free-living amebas, 413 for Lyme borreliosis, 251 for relapsing fever, 256 for sporotrichosis, 383 Cutaneous anergy in sarcoidosis, 716-717 Cutaneous involvement in polyarteritis nodosa, 653-654, 654f Cuterebra in ophthalmomyiasis, 485-487, 486f CXR. See Chest x-ray (CXR). Cyclitic membrane, in juvenile rheumatoid arthritis, 594 Cyclitis chronic. See Intermediate uveitis (IV). steroid-resistant, 186 Cyclochorioretinitis. See Intermediate uveitis (IV). Cyc;lopentolate chemistry of, 159 clinical pharmacology of, 161-162 history and source of, 159 pharmacokinetics and metabolism of, 162 potency of, 160t side effects and toxicity of, 164 structural formula of, 16lf therapeutic use of, 162 Cyclophosphamide (Cytoxan, Neosar) adverse reactions of, 178, 178t dosage and route of administration of, 30t, 178t for Adamantiades-Beh~et'sdisease, 644-645 for giant cell arteritis, 626 for immunosuppressive chemotherapy, 177f, 179t, 180-183, 180f for intermediate uveitis, 852 for multiple sclerosis, 706 for polyarteritis nodosa, 657, 658 for scleroderma, 616 for Vogt-Koyanagi-Harada syndrome, 752 for Wegener's granulomatosis, 661-662, 667-668, 670 complications of, 671 indications for, 179, 179t side effects of, 31 Cycloplegics, 159-166. See also Mydriaticcycloplegic agents. Cyclosporine A (CSA) adverse reactions of, 178, 178t bromocriptine and, 205 dosage and route of administration of, 30t, 178t for acute posterior multifocal placoid pigment epitheliopathy, 777 for Adamantiades-Beh~et'sdisease, 645 for birdshot retinochoroidopathy, 738-739 for giant cell arteritis, 626 for immunosuppressive chemotherapy, 191196 clinical trials with, 196 contraindications for, 196 dosage and route of administration for, 194-195 drug interactions with, 196 high-risk groups and, 196

Cyclosporine A (CSA) (Continued) history and source of, 191 official name and chemistry of, 191, 19lf overdose of, 196 pharmaceutics of, 192 pharmacokinetics and metabolism of, 192-194 pharmacology of, 191-192, 192f, 193f side effects and toxicity of, 195-196 therapeutic use of, 194 for intermediate uveitis, 852 for psoriatic arthritis, 588 for retinal vasculitis, 838 for sarcoidosis, 723 for serpiginous choroiditis, 793 for sympathetic ophthalmia, 746 for tubulointerstitial nephritis and uveitis syndrome, 729 for type I hypersensitivity reactions, 60 for Vogt-Koyanagi-Harada syndrome, 753 indications for, 179, 179t ketoconazole and, 206 Cystic retinal tufts, 539 Cysticercosis, 468-473 clinical features of, 468-469, 469f complications of, 472 definition of, 468, 469f diagnosis of, 470-471, 470t differential diagnosis of, 471 epidemiology of, 468 history of, 468 pathogenesis and pathplogy of, 469-470 prognosis for, 472':':'473 treatment of, 471-472 Cystoid macular edema (CME) after ocular surgery, 573 angiography in, 134, 135f from latanoprost, 863-864 in Adamantiades-Beh~et'sdisease, 646-647 in birdshot retinochoroidopathy, 732, 735, 735f in sarcoidosis, 713 in serpiginous choroiditis, 794 nonsteroidal anti-inflammatory drugs for, 171 vitreous surgery and, 228, 228f, 229 Cytochrome P-450, 196 Cytokines in ascariasis, 440 in giant cell arteritis, 623-624 in intraocular-central nervous system lymphoma, 504-505 target cells and, 44, 45t Cytology, 95t, 96 Cytomegalovirus (CrvIV), 323-328 clinical characteristics of, 324-325, 324f complications of, 327 definition of, 323 diagnosis of, 325 epidemiology of, 323-324 history of, 323 in human immunodeficiency virus, 493497, 495f, 496f, 496t in retinal vasculitis, 831-832 in Wegener's granulomatosis, 666 pathophysiology, immunology, pathology, and pathogenesis of, 325 prognosis for, 327-328 treatment of, 325-327, 327f Cytoplasmic steroid receptor complex, 142 Cytotoxic agents for Adamantiades-Beh~et'sdisease, 643-645 for sympathetic ophthalmia, 746 for Vogt-Koyanagi-Harada syndrome, 752753 for Wegener's granulomatosis, 671

Cytotoxic immunosuppressive drugs, 179-191, 179t alkylating agents as, 180-185 antimetabolites as, 185-191. See also An.timetabolites. Cytotoxic T cells, 36 Cytoxan. See Cyclophosphamide (Cytoxan, Neosar).

D Dacliximab (Zenapax) for immunosuppressive chemotherapy, 201-202 Dactylitis in psoriatic arthritis, 587, 588f in Reiter's syndrome, 584, 585f DAF. See Decaying accelerating factor (DAF). Dalen-Fuchs nodules in sympathetic ophthalmia, 742, 743, 743f in Vogt-Koyanagi-Harada syndrome, 749, 749f Dapsone adverse reactions of, 178, 178t dosage and route of administration of, 30t, . 178t for immunosuppressive chemotherapy, 202204,202f for leprosy, 310 indications for, 179, 179t Darkfield microscopy, for syphilis, 240, 240t Deafness, from congenital rubella, 343 DEC. See Diethylcarbamazine (DEC). Decadron regional preparation of, 29t topical preparation of, 28t Decaying accelerating factor (DAF), 18 Deer tick, in Lyme borreliosis, 249, 250f. See also Lyme borreliosis. Degenerative retinoschisis, 539 Delayed-onset endophthalmitis, 528, 528t. See also Endophthalmitis. Delayed-type hypersensitivity (DTH) in acute posterior multifocal placoid pigment epitheliopathy, 776-777 in sarcoidosis, 717 Deletion, clonal, 66 Deltasone, 28t Dendritic cells, 53 ocular surface immunity and, 68 Dendritic epithelial keratitis, 91 Dendritic epitheliopathy, 412 Densitometry, foveal, 770 Depigmentation in acute retinal pigment epitheliitis, 780, 780f in Fuchs' heterochrom-ic iridocyclitis, 693694, 694f in onchocerciasis, 446, 448f in Vogt-Koyanagi-Harada syndrome, 749, 749f Depo-Medrol; 29t Dermatitis from atropine, 163 from methotrexate, 187 lupus, 601 onchocercal, 446 Dermatographia in Adamantiades-Beh~et's disease, 634 Dermatologic system in antiphospholipid syndrome, 684t, 685 in Wegener's granulomatosis, 663 Dernouchani.ps antibody coefficient test, 215, 216f Desensitization immunotherapy, 60 Desmosomes of pigmented epithelium, 9 DEX. See Dual-energy x-ray (DEX) absorptiometry.

Dexamethasone chemistry of, H2, 143t for vitrectomy, 229 pharmaceutics of, 144, 145-146, 145t, H6t regional preparation of, 29t systemic preparation of, 28t topical preparation of, 28t uveitis induced by, 862-863 DHPG, for cytomegalovirus, 326, 327 Diabetes mellitus, 719, 719t Diabetic retinopathy, 555 Diacetate, 28t Diagnostic imaging, 104-139 angiography in, 119-137, 120f acute posterior multifocal placoid pigment epitheliopathy and, 121, 122f Adamantiades-Beh\;:et's retinal vasculitis and, 127, 128f birdshot retinochoroidopathy and, 129132, 131£, 132f choroid neovascularization and, 135-137, 136f, 137f cystoid macular edema and, 134, 135f epiretinal membrane and, 135; 136f Harada's disease and sympathetic uveitis and, 125-126, 125f-127f macular ischemia and, 134-135, 135f multiple evanescent white-dot syndrome and, 121-125, 124f posterior scleritis and, 126-127 presumed ocular histoplasmosis and pseudo-presumed ocular histoplasmosis and, 127-129, 129f, 130f sarcoid chorioretinopathy and, 132:-133 serpiginous choroiditis and, 121, 123f toxoplasmosis retinochoroiditis and, 133134, 133f, 134f '1{ viral retinitis and, 133 computed tomography in, 104 for immunologic diseases, 109-119 masquerade syndromes and, 116-119, 116f-118f, 119t pseudotumor versus Graves' disease and, 115-116, 115f, 116f sarcoid suspect and, 108f, 109-110, 109f scleritis and, 110-113, 110f-113f seronegative spondyloarthropathies and, 114-115, 114f, 114t magnetic resonance imaging in, 104-106, 105t nuclear medicine in, 106-107 plain films in, 106 retinal angiography in, 137 salivary gland radiology in, 107 ultrasound in, 107-109, 107t upper gastrointestinal series in, 107 Diagnostic surgery, 215-221 chorioretinal biopsy in, 218-221, 219f, 220f paracentesis in, 215-216, 216f retinal biopsy in, 217-218, 218f vit:rectomy in, 216-217, 216f, 217f Diagnostic vitrectomy, for intermediate uveitis, 849 Diamines, for ameba infection, 414 Diazepam, for anticholinergic overdose, 164 Diclofenac (Voltaren), 29t, 167t, 168t Dicloxacillin, for bartonella, 262 Diethylcarbamazine (DEC) for loiasis, 464, 466 for onchocerciasis, 454-455 Diffuse subretinal fibrosis (DSF) syndrome, 797 Diffuse unilateral subacute neuroretinitis (DUSN),475-479 acute zonal occult outer retinopathy versus, 815

Diffuse unilateral subacute neuroretinitis (DUSN) (Continued) birdshot retinochoroidopathy versus, 736, 736t clinical characteristics of, 475-476, 476f complications of, 478 cysticercosis versus, 471 definition of, 475 diagnosis of, 477 epidemiology of, 475 history of, 475 pathophysiology of, 476-477 prognosis for, 478 subretinal fibrosis and uveitis syndrome versus, 802, 802t treatment of, 477-478 Diflucan (fluconazole), for coccidioidomycosis, 374 Diflunisal (Dolobid) for intermediate uveitis, 852 systemic, 29t, 167t Digitalis, 196 Digits, sausage in psoriatic arthritis, 587, 588f in Reiter's syndrome, 584, 585f 1,25-Dihydroxy-vitamin D g (calcitriol), in sarcoidosis, 720 Dilated indirect ophthalmoscopy, 540 Dilator muscles, 4, 7 Diloxanide, for ameba infection, 414 Diphosphonate complexes, 106-107 Diplopia in giant cell arteritis, 622 in multiple sclerosis, 702 in sarcoidosis, 715 Diptera, in ophthalmomyiasis, 485-487, 486f Direct observed therapy (DOT), for tuberculosis, 269 Disappearing lesions, in presumed ocular histoplasmosis syndrome, 353 Disciform macular degeneration, 797 Discoid lesions, in extraocular examination, 94 Discoid lUpus erythematosus, 601, 602-603, 602f Disseminated choroiditis, in presumed ocular histoplasmosis syndrome, 349-350 Disseminated disease, in Lyme borreliosis, 246-247 ocular findings of, 247-249, 248f, 249f Disseminated tuberculous choroiditis, 792 Distomum haematobium, in schistosomiasis, 480 DNA probes, for onchocerciasis; 454 Dog owners, uveitis in, 88 Dolobid. See Diflunisal (Dolobid). Doppler ultrasound, 107 for giant cell arteritis, 625 Doxorubicin, 183 Doxycycline for bartonella, 262 for brucellosis, 283 for Lyme borreliosis, 253 for rickettsial diseases, 303 for syphilis, 242, 242t DPA. See D-Penicillamine (DPA). Dracetate, 28t Drasone, 28t Drug abuse, intravenous, 365 Drug hypersensitivity, in tubulointerstitial nephritis and uveitis syndrome, 728 Drug-induced uveitis, 859-868 clinical characteristics of, 860t, 861-865 definition of, 859, 860t diagnosis of, 866 epidemiology of, 859 etiology of, 859-861, 860t

Drug-induced uveitis (Continued) history of, 859 in human immUnodeficiency virus, 499500, 499f, 500f pathogenesis of, 861 prognosis for, 866 treatment of, 866 Dry eyes, from cyclophosphamide, 182 DSF (diffuse subretinal fibrosis) syndrome, 797 DTH. See Delayed-type hypersensitivity (DTH). Dual-energy x-ray (DEX) absorptiometry, for rheumatoid arthritis, 111 Duodenal ulcer, 144 DUSN. See Diffuse unilateral subacute neuroretinitis (DUSN). Dyes, photoactive, 516

E Eales' disease, 826, 826f EAPU. See Experimental autoimmune pigment epithelial membrane protein-induced uveitis (EAPU). Ear(s) in extraocular examination, 94 in relapsing polychondritis, 679 Early disease, in Lyme borreliosis, 246, 246f, 247 Early receptor potential (ERP) amplitudes, 770 EAU (experimental autoimmune uveitis), 733, 734 Ebola virus, 335 EBRT (external beam radiation therapy), for retinoblastoma, 515-516 EBV (Epstein-Barr virus), 322-323 intermediate uveitis versus, 850 multifocal choroiditis and panuveitis and, 762 Echography for intermediate uveitis, 848 for toxocariasis, 433 Ecology in Lyme borreliosis, 249, 250f in onchocerciasis, 445-446, 445f Ectopic schistosomiasis, 481 Edema corneal, 533 cystoid macular. See Cystoid macular edema (CME). in acute inflammation, 17 in Adamantiades-Beh\;:et's disease, 637 optic disc in giant cell arteritis, 620 in sarcoidosis, 714, 714f periorbital, 613 EDTA. See Ethylenediaminetetraacetic acid (EDTA). Effector T cells, immune-mediated injury due to, 62-64, 63f Ehrlichia chaffeensis, 297

Ehrlichiosis canine, 299 human granulocytic, 254-255 pathophysiology of, 300 treatment of, 303 EIA (enzyme immunoassay) for bartonella, 262 Electrodiagnostic testing for diffuse unilateral subacute neuroretinitis, 477 Electroencephalography, for Vogt-KoyanagiHarada syndrome, 752 Electrolyte and fluid balance, 143-144, 143t Electromagnets, for intraocular foreign bodies, 549

INDEX Electron microscopy (EM) for subretinal fibrosis and uveitis syndrome, 799 for Whipple's disease, 287, 292, 292t Electro-oculogi"am (EOG) for acute posterior multifocal placoid pigment epitheliopathy, 774 for multiple evanescent white dot syndrome, 770 for serpiginous choroiditis, 788t, 791 for subretinal fibrosis and uveitis syndrome, 801 for Vogt-Koyanagi-Harada syndrome, 752 Electrophysiology for acute posterior multifocal placoid pigment epitheliopathy, 774 for acute zonal occult outer retinopathy, 815 for Adamantiades-Beh~et'sdisease, 641 for birdshot retinochoroidopathy, 736 for multiple evanescent white dot syndrome, 770 for multiple sclerosis, 705 for serpiginous choroiditis, 791 for subretinal fibrosis and uveitis syndrome, 801 for Vogt-Koyanagi-Harada syndrome, 752 Electroretinogram (ERG) for acute posterior multifocal placoid pigment epitheliopathy, 774 for birdshot retinochoroidopathy, 736 for intermediate uveitis, 849 for multifocal choroiditis and panuveitis, 759 for multiple evanescent white dot syndrome, 770 for serpiginous choroiditis, 788t, 791 for subretinal fibrosis and uveitis syndrome, 801 for uveitis, 95t, 96 for Vogt-Koyanagi-Harada syndrome, 752 ELISA. See Enzyme-linked immunosorbent assay (ELISA). ELK classification, of Wegener's granulomatosis, 668 Elschnig's spots, in systemic lupus erythematosus, 605 EM. See Electron microscopy (EM). Enbrel. See Etanercept (Enbrel). Encephalitis, in loiasis, 466 Encephalomalacia, in congenital toxoplasmosis, 389, 390f Encephalopathy in loiasis, 464 in retinal vasculitis, 828 of late Lyme borreliosis, 254 Endarterectomy, carotid, 556 Endemic typhus, 298, 298t Endemicity, in onchocerciasis, 445 Endocarditis bacterial, 532 bartonella, 260-263, 261£ Libman-Sacks, 602 Endocrine system, in antiphospholipid syndrome, 684t, 685 Endogenous Candida chorioretinitis/ endophthalmitis, 365, 365f Endogenous endophthalmitis, 531-535, 533t Endogenous infection, 364 Endophthalmitis, 528-536 acute retinal necrosis versus, 321 Candida, 365-366, 365f chronic postoperative, 528-531, 528t, 530t endogenous, 531-535, 533t in lens-induced uveitis, 819-821 in rickettsial diseases, 302

Endophthalmitis (Continued) infectious definition of, 364 toxocariasis versus, 433 mycotic, 365 sporotrichosis and, 382 traumatic, 574 Endothelial cells in polyarteritis nodosa, 656 of choriocapillaries, 14 Endothelial injury, 39 Enema, barium, 107 Enteropathic arthritis, 589-592 Enthesitis, in seronegative spondyloarthropathies, 114, 115 Enthesopathy, in ankylosing spondylitis, 583 Enucleation after perforating eye injury, 574 for retinoblastoma, 516 in sympathetic ophthalmia, 746 Enzyme immunoassay (EIA) for bartonella, 262 Enzyme-linked immunosorbent assay (ELISA) for brucellosis, 282 for cysticercosis, 471 for leptospirosis, 275 for Lyme borreliosis, 251-252 for onchocerciasis, 282 for relapsing fever, 256 for toxocaliasis, 430, 432 for toxoplasmosis, 398, 39'9 for trypanosomiasis, 4 t 2 . for Wegener's granulomatosis, 668-669 EOG. See Electro-oculogram (EOG). Eosinophils, 37, 37t corticosteroids and, 144 in cysticercosis, 471 in loiasis, 465 in toxocariasis, 429, 431 in Wegener's granulomatosis, 667 Epidemic typhus, 298, 298t clinical characteristics of, 301, 301 t epidemiology of, 299 pathophysiology of, 300 Epidermal changes, in uveitis, 93-94 Epididymal pain, in polyarteritis nodosa, 654 Epididymitis in Adamantiades-Beh~et'sdisease, 636 in extraocular examination, 94 Epileptiform seizures, in cerebral cysticercosis, 469 Epinephrine, with cocaine and atropine, 163 Epiretinal membrane, 135, 136f Episclera, in clinical examination, 90 Episclelitis in inflammatory bowel disease-associated arthritis, 589-590 in leprosy, 307 in Lyme borreliosis, 247 in polyarteritis nodosa, 654, 655 in psoriatic arthritis, 588 in Reiter's syndrome, 586 in systemic lUpus erythematosus, 603 in Wegener's granulomatosis, 663, 664t Epithelial keratitis, in measles, 337 Epitheliitis, acute retinal pigment, 780-786. See also Acute retinal pigment epitheliitis (ARPE). Epithelioid cells in intermediate uveitis, 847 in sarcoidosis, 716, 716f Epitheliopathy, dendritic, 412 Epithelium of ciliary body, 7, 9 of iris, 5, 5f, 6, 6f Epstein-Barr virus (EBV), 322-323 intermediate uveitis versus, 850

Epstein-Barr virus (EBV) (Continued) multifocal choroiditis and panuveitis and, 762 ERG. See Electroretinogram (ERG). ERP (early receptor potential) amplitudes, 770 Erythema migrans, in Lyme borreliosis clinical characteristics of, 246, 246f diagnosis of, 251-253, 25lt history of, 245 prognosis for, 253 treatment of, 253 Erythema nodosum, in AdamantiadesBeh~et's disease, 632. See also Adamantiades-Beh~et's disease. Erythematosus, systemic lupus. See Systemic lUpus erythematosus (SLE). Erythrocyte sedimentation rate (ESR) in giant cell arteritis, 624-625 in uveitis testing, 95t, 96 in Wegener's granulomatosis, 668 Erythromycin bromocriptine and, 205 for bartonella, 262 for rickettsial diseases, 303 Esophageal sphincter, in scleroderma, 611-612 ESR. See Erythrocyte sedimentation rate (ESR). Etanercept (Enbrel), for immunosuppressive chemotherapy, 200-201 Ethylenediaminetetraacetic acid (EDTA), in corneal surgery, 222, 223f Etidronate, uveitis induced by, 860t, 861-862 Evans blue stain, for ameba infection, 413 Evisceration, sympathetic ophthalmia after, 746 Exciting eye, in sympathetic ophthalmia, 742. See also Sympathetic ophthalmia. Exogenous Candida endophthalmitis, 365-366 Exogenous infection, 364 Experimental autoimmune pigment epithelial membrane protein-induced uveitis (EAPU),781 Experimental autoimmune uveitis (EAU) , 733, 734 Expert Committee on Onchocerciasis, 443 External beam radiation therapy (EBRT), for retinoblastoma, 515-516 Extrafoveal laser photocoagulation, 355-356 Extrafoveal membranes, in photocoagulation, 355 Extraocular motility, in clinical examination, 90 Extraocular muscle in sarcoidosis, 715 Extrapulmonary Pneurnoeystic carinii infection, 425 Extremity films, 106 Exudate, in acute inflammation, 17 Exudative retinal detachment, 540 Eye in human immunodeficiency virus, 494495, 495f in onchocerciasis, 446, 446t in sympathetic ophthalmia, 744-745 regional immunity and, 67-71 Eye-derived antigens, 70 Eyelids in cysticercosis, 468 in leprosy, 306~307, 311 in leukemia, 509 in sarcoidosis, 715, 715f, 715t in scleroderma, 613 in systemic lupus erythematosus, 602-603 loiasis and, 464, 464t sporotrichosis of, 382

INDEX F FA. See Fluorescein angiography (FA). Face, sporotrichosis of, 382 Familial exudative vitreoretinopathy (FEVR) , 433 Family history, 98 Farnsworth 100 hue test, 607 Fas ligand, 18 Fatigue, in multiple sclerosis, 701-702 Fat-suppression sequences, in magnetic resonance imaging, 106 FAZ (foveal avascular zone), 355, 356f Feces," in toxoplasmosis transmission, 387 Feet, in sarcoidosis, 711 Feldene. See Piroxicam (Feldene). Fenamates, 29t, 167t Fenoprofen (Nalfon), 29t, 167t Fetal losses, in antiphospholipid syndrome, 688 Fever in borreliosis, 255-256 Rift Valley, 333-335 in retinal vasculitis, 832 trench, 260-263 FEVR (familial exudative vitreoretinopathy), 433 FHI. See Fuchs' heterochromic iridocyclitis (FHI). Fibrin formation, after retinal surgery, 231, 232f Fibroblasts, 5 Fibrocartilage, 107, 107t Fibromyalgia, 254 Fibroplasia, corticosteroids and, 144 Fibrosis pulmonary interstitial, 612, 612f subretinal. See Subretinal fibrosis ana uveitis (SFU)" syn.drome. Filarial meningoencephalitis, 465 Filarial worms, in loiasis, 463 Filgrastim, for cyclophosphamide overdose, 182 Filiform hemorrhage, in Fuchs' heterochromic" iridocyclitis, 694 Fite-Faraco acid-fast stain, for leprosy, 309 FK 506 (tacrolimus) adverse reactions of, 178, 178t dosage and route of administration of, 30t, 178t for Adamantiades-Beh<;:et's disease, 645 for immunosuppressive chemotherapy, 196200 for Vogt-Koyanagi-Harada syndrome, 753 indications for, 179, 179t Flat worms, in diffuse unilateral subacute neuroretinitis, 476 Flexner-Wintersteiner rosettes, 514, 515f Floaters in intraocular-central nervous system lymphoma, 503 in Lyme borreliosis, 248, 248f in rhegmatogenous retinal detachment, 538 Fluconazole (Diflucan) for Candida endophthalmitis, 369 for coccidioidomycosis, 374 rifabutin-related uveitis and, 500 Flucytosine for candidiasis, 368-369 for sporotrichosis, 383 Fluff balls, in endophthalmitis, 533 Fluid balance, corticosteroids and, 143-144, 143t Fluorescein angiography (FA), 119-137, 120f for acute posterior multifocal placoid pigment epitheliopathy, 121, 122f, 774, 775f, 776f

Fluorescein angiography (FA) (Continued) for acute retinal necrosis, 320 for acute retinal pigment epitheliitis, 781, 782f for acute zonal occult outer retinopathy, 814-815 for Adamantiades-Beh<;:et's disease, 641, 641£,642f for Adamantiades-Beh<;:et's retinal vasculitis, 127, 128f for birdshot retinochoroidopathy, 129-132, 131£ 132£ 735, 735f for congenital rubella, 344-345 for cysticercosis, 470 for cystoid macular edema, 134, 135f for diffuse unilateral suba.cute neuroretinitis, 477 for giant cell arteritis, 625 for Harada's disease, 125-126, 125f-127f for intermediate uveitis, 848 for leukemia, 508 for macular ischemia, 134-135, 135f for malignant melanoma, 512 for masquerade syndromes, 118 for multifocal choroiditis and panuveitis, 760, 760f for multiple evanescent white dot syndronle, 121-125, 124f, 768-769, 768£ 768t, 769f for multiple sclerosis, 705 for ocular ischemic syndromes, 555 for penetrat.ing ocular trauma, 574 for polyarteritis nodosa, 655, 655f, 656f for posterior scleritis, 126-127 for presumed ocular histoplasmosis and pseudo-presumed ocular histoplasmosis, 127-129, 129f, 130f for punctate inner choroidopathy, 810, 810f for retinal vasculitis, 824-825, 825f for Rift Valley fever, 334 for sarcoid chorioretinopathy, 132-133 for sarcoidosis, 714 for serpiginous choroiditis, 121, 123f, 788t, 790, 790f for subacute sclerosing panencephalitis, 339 for subretinal fibrosis and uveitis syndrome, 801 for synlpathetic ophthalmia, 743, 743f for systemic lUpus erythematosus, 603-606, 604f,605f for toxoplasmosis, 400-401, 401£ for toxoplasmosis retinochoroiditis, 133134, 133f, 134f for tuberculosis, 266 for uveitis testing, 95t, 96 for viral retinitis, 133 for Vogt-Koyanagi-Harada syndrome, 751, 751£ of choroid neovascularization, 135-137, 136f, 137f of epiretinal membrane, 135, 136f Fluorescent treponema! antibody absorption (FTA-ABS) test for syphilis, 240, 240t, 241 intermediate uveitis and, 850 for uveitis, 95t, 96 Fluorinated topical steroids, 142, 143t 9-a-Fluorohydrocortisone, 142, 143t Fluorometholone (FML) pharmaceutics of, 145, 145t topical preparation of, 28t Flurbiprofen (Ansaid) for ameba infection, 414 systemic preparation of, 29t, 167t topical preparation of, 168t

Fly in 10iasis,463 in onchocerciasis, 443 FML. See Fluorometholone (FML). Focal choroiditis ~n differential diagnosis, 103 III tuberCUlosis, 265 Focal necrotizing glomerulonephritis, 667 Folex. See Methotrexate (Folex, Mexate, Rheumatrex) . Folic acid antagonists, 204 Folinic acid (Leucovorin), for toxoplasmosis, 402,403t Follicular conjunctivitis, from atropine, 163 Folliculitis, in Adamantiades-Behcet's disease " 634 Fomivirsen for cytomegalovirus, 327 for cytomegalovirus retinitis, 496, 496t Food, in toxoplasmosis transmission, 387 Foreign body from penetrating ocular injury, 574 intraocular, 546-550, 548f Foscarnet for cytomegalovirus, 326, 327 for cytomegalovirus retinitis, 496, 496t Foster-Fuchs spots, in presumeo ocular histoplasmosis syndrome, 354 Foveal avascular zone (FAZ), 355, 356f Foveal densitometry, for multiple evanescent white dot syndrome, 770 Fi-acture, stress, 115 Franceschetti's syndrome, 392, 393f Francisella tularensis, 297

Free cortisol, 19, 19t Free-living amebas, 411-416 clinical features of, 412-413 definition of, 411 diagnosis of, 413-414 epidemiology of, 411-412 histopathology of, 412 history of, 411 microbiology of, 411 pathogenesis of, 412 prevention of, 414-415 prognosis for, 415 treatment for, 414 Frosted branch angiitis, 827 FTA-ABS (fluorescent t:reponemal antibody absorption) test for syphilis, 240, 240t, 241 intermediate uveitis and, 850 for uveitis, 95t, 96 Fuchs' crypts, 4 Fuchs' heterochromic iridocyclitis (FHI) , 693-700 clinical manifestations and complications of, 693-695, 694f, 695f corticosteroids for, 151 definition of, 693 diagnosis of, 697, 697t epidemiology of, 693 etiology and pathogenesis of, 696-697 history of, 693 pathology of, 695-696 toxoplasmosis and, 396 treatment and prognosis for, 697-698 Full-scatter panretinal laser photocoagulation, 556 Fundus in punctate inner choroidopathy, 807, 807f, 808f in Vogt-Koyanagi-Harada syndrome, 749, 749f Fundus flavimaculatus, 801 Funduscopic examination for birdshot retinochoroidopathy, 732

INDEX Funduscopic examination (Continued) for serpiginous choroiditis, 787-788, 788t for subretinal fibrosis and uveitis syndrome, 798 Fungal endophthalmitis, 531-532 Fungus haematodes, 513

G Ga scan. See Gallium (Ga) scan. Gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA), 105 Gadolinium dimeglumine, in magnetic resonance imaging, 105 Gallium (Ga) scan for intermediate uveitis, 848 for rheumatoid arthritis, III for sarcoidosis, 108f, 1l0, 718, 718f for uveitis, 95t, 96 Gamma camera technology, 106 Gamma globulin injections, for hypersensitivity reactions, 60 Ganciclovir for acute retinal necrosis, 321 for cytomegalovirus, 327 for cytomegalovirus retinitis, 496, 496t mycophenolate mofetil and, 190 Gap junction, 6, 9 Gastritis, corticosteroids and, 144 Gastrointestinal (GI) system azathioprine and, 189 colchicine and, 208 corticosteroids and, 144 cyclopentolate and, 164 in Adamantiades-Behyet's disease, 636 in antiphospholipid syndrome, 684t, 685 in brucellosis, 280 in giant cell arteritis, 620 in inflammatory bowel disease-associated arthritis, 589 in polyarteritis nodosa, 654, 654f in scleroderma, 611-612 in vVhipple's disease, 291, 291t methotrexate and, 187 Gaucher's disease, 719, 719t GCA. See Giant cell arteritis (GCA). Gd-DTPA (gadolinium diethylenetriaminepentaacetic acid), 105 Gell hypersensitivity reaction, 56, 56t Gene diversity, immunoglobulin, 47-48 Gene expression, immunoglobulin, 48, 48f General hyperresponsiveness, 58 Genetics in Adamantiades-Behyet's disease, 633, 640 in brucellosis, 278-279 in multiple sclerosis, 704 in retinoblastoma, 514, 515 in sympathetic ophthalmia, 745 in systemic lUpus erythematosus, 606 in type I hypersensitivity reactions, 58-59 in uveitis, 88 in vitrectomy, 217 in Vogt-Koyanagi-Harada syndrome, 751 Genital lesions in Adamantiades-Behyet's disease, 632, 634, 634f, 635f. See also Adamantiades-Behyet's disease. in extraocular examination, 94 Genitourinary system in Adamantiades-Behyet's disease, 636 in brucellosis, 280 in polyarteritis nodosa, 654 in Reiter's syndrome, 585 Genospecies, in Lyme borreliosis, 249-250 Gentamicin, for bartonella, 262 Geographic choroiditis. See Serpiginous choroiditis.

GI. See Gastrointestinal (GI) system. Giant cell(s), in sarcoidosis, 716, 716f Giant cell arteritis (GCA), 619-631 clinical manifestations of, 619-622, 621£ definition of, 619 diagnosis of, 624-626, 624t epidemiology of, 619 history of, 619 immunology and pathogenesis of, 622-624 pathology of, 622 prognosis for, 626-627 treatment of, 626 Giardia lamblia, 417-419

Giemsa's stain, for endophthalmitis, 530 Gilbert-Koeppe nodules, in leprosy, 310 Gingival hyperplasia, from cyclosporine A, 196 Glaucoma, 92 corticosteroids and, 153-154 in Adamantiades-Behyet's disease, 637, 646, 647 in differential diagnosis, 103 in endophthalmitis, 534 in Fuchs' heterochromic iridocyclitis, 693, 695, 697, 698 in juvenile rheumatoid arthritis, 594 in leprosy, 308 in leukemia, 508 in malignant melanoma, 512 in ocular toxoplasmosis, 396-397 in retinoblastoma, 514 in sarcoidosis, 7!-3, 723 in syphilis, 242 in systemic lupus erythematosus, 603 in Vogt-Koyanagi-Harada syn.drome, 749, 749f,753 mydriatic-cycloplegic agents and, 163-164 therapeutic surgery for, 226-227, 227f Glaucomenflecken, 92 Glioma, retinal, 513 Glomerulonephritis in Adamantiades-Behyet's disease, 636 in Wegener's granulomatosis, 662-663 Glossina, in trypanosomiasis transmission, 420 Glucocorticoid response elements (GREs) , 142 Glucocorticoids central nervous system and, 143 chemistry of, 142, 143t for multiple sclerosis, 706 Glutaraldehyde, for retinal biopsy, 218 Glycosylation-enhancing factor, 58, 58f Glycosylation-inhibition factor, 58, 58f Goldmann field, in multifocal choroiditis and panuveitis, 758, 759f Goldmann-Witmer coefficient test, 215, 216f for toxocariasis, 431 Gomori's stain, for endophthalmitis, 530 Gonadal dysfunction from chlorambucil, 184 from cyclophosphamide, 182 Gonioscopy for intraocular foreign bodies, 548 for pigmentary dispersion syndrome, 552 Goodpasture's syndrome, 61 Gout, 113, 113f a2-GPI cofactor in antiphospholipid ~~ldrome, 687-688 Gram's stain for endophthalmitis, 530 Granules eosinophilic, 37, 38t· neutrophil, 37, 37t platelet, 39, 39t Granulocytic ehrlichiosis, 298, 298t clinical characteristics of, 301 t epidemiology of, 300

Granulocytic ehrlichiosis (Continued) history of, 299 Lyme borreliosis and, 254-255 Granulocytic sarcoma, 509 Granuloma in differential diagnosis, 103 in diffuse unilateral subacute neuroretinitis, 475, 476 in ophthalmia nodosa, 488 iil sarcoidosis, 714, 714f, 716, 716f in schistosomiasis, 482, 483f in toxocariasis, 430, 430f, 431, 431£, 432f in Wegener's gran'ulomatosis, 667, 667f Granulomatosis, Wegener's, 661-675. See also Wegener's granulomatosis. Granulomatous anterior uveitis, 93, 94t Granulomatous arteritis. See Giant cell arteritis (GCA). Granulomatous fundus lesions, 355 Granulomatous hypersensitivity, 64, 64t Granulomatous inflammation clinicopathologic characteristics of, 87-88, 88t definition of, 18 in subretinal fibrosis and uveitis syndrome, 799 in syphilis, 238, 238t Granulomatous iridocyclitis, 396 Granulomatous iritis, 310 Granulomatous uveitis. See also Sympathetic ophthalmia. in sarcoidosis, 109, 109f in sympathetic ophthalmia, 574, 742 pathologic classification of, 20 Graves' disease, 115-116, 115f, 116f Gray-white lesions, in punctate outer retinal toxoplasmosis, 393-394, 394f GREs. See Glucocorticoid response elements (GREs). Gumma, in syphilis, 238

H HI antihistamines, 59 HAART (highly active antiretroviral therapy) for cytomegalovirus, 326 for human immunodeficiency virus, 493, 494t for Pneumocystic cminii choroidopathy, 425 Hair in uveitis, 93-94 in Vogt-Koyanagi-Harada syndrome, 749750, 749f, 750f Hairy spiders, in ophthalmia nodosa, 488-491, 489f Halo, in acute retinal pigment epitheliitis, 780, 780f Halothane, cyclophosphamide and, 183 Hands, in sarcoidosis, 711 Hanging groin, in onchocerciasis, 448 Hansen's disease. See Leprosy. Hantavirus, 335 Harada's disease acute posterior multifocal placoid pigment epitheliopathy versus, 777 angiography in, 125-126, 125f-127f Hard ticks, 297 Hassall's corpuscles, 41£ Headache in giant cell arteritis, 619 in Vogt-Koyanagi-Harada syndrome, 750 Hearing loss in relapsing polychondritis, 679 in retinal vasculitis, 828 in Vogt-Koyanagi-Harada syndrome, 750 Heavy-chain genes, 46-47, 47f, 48f Heerfordt's syndrome, 715

Helicoid peripapillary chorioretinal degeneration. See Serpiginous choroiditis. Helminth in ascariasis, 437. See also Ascariasis. in diffuse unilateral subacute neuroretinitis, 476 Helper (CD4) T cells, 36 Hemagglutination test for cysticercosis, 471 for toxoplasmosis, 398 Hemangioma, choroidal, 107 Hematologic system in antiphospholipid syndrome, 684t, 685 in Rift Valley fever, 333, 334 in systemic lUpus erythematosus, 602 Hematologic tests, for giant cell arteritis, 624-625 Hematologic toxicity, from chlorambucil therapy, 184 Hemolysis, from dapsone, 203 Hemorrhage in Adamantiades-Beh\=et's disease, 637, 646, 647 in differential diagnosis, 103 in giant cell arteritis, 620, 621£ in leukemia, 507, 507f in malignant melanoma, 510 in ocular toxoplasmosis, 397 in presumed ocular histoplasmosis syndrome, 351, 352f in Toxoplasma neuroretinitis, 394, 395f in Wegener's granulomatosis, 662, 666 Hemorrhagic fever virus, 335 Hepatitis B vaccine, uveitis induced by, 859, 860t Hepatitis C virus, in Adamantiades-Beh\=et's disease, 639 ''I Hepatitis serology, in uveitis testing, 95t, 96 Hepatobiliary and pancreatic ascariasis (HPA) clinical characteristics of, 438 diagnosis of, 440-441 treatment of, 441-442, 441t Hepatobiliary complications, of brucellosis, 280 Hepatosplenic schistosomiasis, 482 Hepatotoxicity from ketoconazole, 207 from methotrexate, 186-187 Heredity. See Genetics. Hermes glycoprotein, 42 Herpes simplex keratitis (HSK), 64 Herpes simplex virus (HSV), 315-322 clinical characteristics of, 317-319, 318f complications of, 322 diagnosis of, 320-321, 320f epidemiology of, 317 history of, 317 in Adamantiades-Belwet's disease, 639 paracentesis in, 215 pathogenesis of, 319-320 prognosis for, 322 treatment of, 321-322 virology of, 315-317, 315f, 316f, 316t Herpes zoster ophthalmicus, 499, 499f Herpesviruses, 315-332 cornea and sclera in, 89, 89t cytomegalovirus in, 323-328. See also Cytomegalovirus (CMV). Epstein-Barr virus in, 322-323 herpes simplex virus and varicella zoster virus in, 315-322. See also Herpes simplex virus (HSV); Varicella zoster virus (VZV). in retinal vasculitis, 832 multiple sclerosis and, 706 Heterochromia, 4 in differential diagnosis, 103

Heterochromic iridocyclitis, Fuchs'. See Fuchs' heterochromic iridocyclitis (FHI). Heterogeneity, T-lymphocyte, 55 Highly active antiretroviral therapy (HAART) for cytomegalovirus, 326 for human immunodeficiency virus, 493, 494t for Pneumocystic carinii choroidopathy, 425 High-resolution computed tomography (HRCT), 110 Hilar adenopathy, in sarcoidosis, 109 Hilar lymphadenopathy, in sarcoidosis, 71'7-718, 717f, 718t Hirschberg's spots, in measles, 337 Hirsutism, from cyclosporine A, 196 Histiocytes in intraocular-central nervous system lymphoma, 504 in sarcoidosis, 716, 716f Histo spots, 349, 350, 353 Histochemical staining, for intraocular-central nervous system lymphoma, 505 Histocompatibility antigens in Adamantiades-Beh\=et's disease, 640 in intermediate uveitis, 847 in presumed ocular histoplasmosis syndrome, 349, 354 in relapsing polychondritis, 679 Histoplasma capsulatum

in human immunodeficiency virus, 498 in presumed ocular histoplasmosis syndrome. 348. See also Presumed ocular histoplasmosis syndrome (POHS). Histoplasmosis angiotensin-converting enzyme in, 719, 719t presumed and pseudo-presumed ocular, 127-129, 129£ 130f Whipple's disease versus, 293 History taking, 89-200 HIV. See Human immunodeficiency virus (HIV). HLA. See Human leukocyte antigens (HLA). HLA-A29, 24 HLA-B27,24 in seronegative spondyloarthropathies, 114, 114f HLA-B51, 24 HLA-B27-associated uveitis, 829 HMS. See Medrysone (HMS). Hodgkin's· disease angiotensin-converting enzyme in, 719, 719t systemic, 503-506, 504f Homatropine chemistry of, 159 clinical pharmacology of, 161-162 history and source of, 159 pharmacokinetics and metabolism of, 162 potency of, 160t side effects and toxicity of, 164 structural formula of, 161£ therapeutic use of, 163 Hormones recurrent uveitis and, 32 thymic, 40, 40t Horner's syndrome, 696 Host factors in onchocerciasis,. 451 Host response in ameba infection, 412 in syphilis, .240 Host sensitivity, in Lyme borreliosis, 250 Hottentot apron, in onchocerciasis, 448 HPA (hepatobiliary and pancreatic ascariasis) clinical characteristics of, 438 diagnosis of, 440-441

HPA (hepatobiliary and pancreatic ascariasis) (Continued) treatment of, 441-442, 44lt HRCT (high-resolution computed tomography),110 HSK (herpes simplex keratitis), 64 HSV. See Herpes simplex virus (HSV). HTLV (human T-cell leukemia/lymphoma virus)-l in retinal vasculitis, 832 intermediate uveitis versus, 850 multiple sclerosis and, 706 Human granulocytic ehrlichiosis, 298, 298t clinical characteristics of, 30lt epidemiology of, 300 history of, 299 Lyme borreliosis and, 254-255 Human immunodeficiency virus (HIV) , 493-502. See also Acquired immunodeficiency syndrome (AIDS). changing patterns of uveitis in, 493-494, 494£,494t chorioretinal involvement in, 494-499 candidiasis and, 499 CMV retinitis and, 495-497, 495f, 496f, 496t cryptococcosis and, 498, 499f eye and, 494-495, 495f lymphoma and, 499 ocular toxoplasmosis and, 497, 497f pneumocystosis and, 498, 498f syphilis and, 499 tuberculosis and, 498, 498f VZV retinitis and, 497-498, 497f, 498f drug-related uveitis in, 499-500, 499f, 500f herpes zoster ophthalmicus in, 499, 499f in retinal vasculitis, 832 Pneumocystic caTinii choroidopathy in, 425 syphilis in, 242 tuberculosis and, 269-270, 270t Human leukocyte antigens (HLA) corneal tissue and, 71-72 in acute posterior multifocal placoid pigment epitheliopathy, 775-776 in ankylosing spondylitis, 582, 582f, 583 in anterior uveitis, 581, 581t in birdshot retinochoroidopathy, 733, 734, 737 in giant cell arteritis, 623 in multiple sclerosis, 704 in presumed ocular histoplasmosis syndrome, 349 in Reiter's syndrome, 584 in sarcoidosis, 711 in tubulointerstitial nephritis and uveitis syndrome, 727 Human lymphocyte antigen, 95t, 96 Human monocytic ehrlichiosis, 298, 298t clinical characteristics of, 30lt . epidemiology of, 300 history of, 299 Human T-cell leukemia/lymphoma virus (HTLV)-l in retinal vasculitis, 832 intermediate uveitis versus, 850 multiple sclerosis and, 706 Humoral autoimmunity in giant cell arteritis, 623 Humoral immunity, 55 in retinal vasculitis, 837 Humoral response in Lyme borreliosis, 250 in toxoplasmosis, 387 Hyaline cartilage, 107, 107t Hydrocortisone pharmaceutics of, 145, 146t

Hydrocortisone (Continued) regional preparation of, 29t systemic preparation of, 28t Hydroxycortisone chemistry of, 142, 143t introduction and history of, 142 Hyoscine, 159 Hypercalcemia in sarcoidosis, 720 Hypercalciuria in sarcoidosis, 720 Hyperfluorescence in acute retinal pigment epitheliitis, 781, 782f in multifocal choroiditis and panuveitis, 760-761, 761£ in serpiginous choroiditis, 790, 790f in sympathetic ophthalmia, 743, 743f of white dots, 768-769, 768f Hyperplasia of gingiva, 196 of uvea, 504 Hyperplastic primary vitreous, 471 Hyperresponsiveness, general, 58 Hypersensitivity, 56-57, 56t drug, 728 in sarcoidosis, 717 in toxoplasmosis, 398 in Wegener's granulomatosis, 666 type I, 57-60, 57f, 58f, 58t, 60t type II, 60-61, 61£ type III, 61-62, 62f Hypertension corticosteroids and, 144 from cyclosporine A, 195 in intermediate uveitis, 845 in scleroderma, 612 in systemic lUpus erythematosus, 604t, 605, 605f,606t Hyperthyroidism, 719, 719t Hypertrophic discoid lesions, 601, 602f Hyphema in differential diagnosis, 103 in Fuchs' heterochromic iridocyclitis, 694 Hypoderma bovis, 485-487, 486f Hypofluorescence in birdshot retinochoroidopathy, 735-736, 735f in serpiginous choroiditis, 790, 791 of white dots, 769, 769f Hypopigmentation, in extraocular examination, 94 Hypopyon clinicopathologic characteristics of, 88 in Adamantiades-Behc;:et's disease, 636, 637, 637f in ameba infection, 412-413 in ankylosing spondylitis, 582, 582f in differential diagnosis, 103 in endophthalmitis, 533 in ophthalmia nodosa, 488, 489f Hypothalamic-pituitary-adrenal. axis, corticosteroids and, 143 Hypotony from cidofovir, 862 in juvenile rheumatoid arthritis, 594 in leprosy, 308

I lAU (idiopathic anterior uveitis), 697 IB (immunoblotting), for toxoplasmosis, 399, 399t IBD (inflammatory bowel disease)-associated arthritis, 589-591, 593 Ibuprofen (Advil, Mou-in, Nuprin, Rufen), 29t, 167t ICG angiography. See Indocyanine green (ICG) angiography.

Icteric leptospirosis, 273-274 Idiopathic acute tubulointerstitial nephritis and uveitis, 726. See also Tubulointerstitial nephritis and uveitis (TINU) syndrome. Idiopathic anterior uveitis (lAU), 697 Idiopathic inflammatory bowel disease-associated arthritis, 589-591, 593 Idiopathic recurrent branch retinal arteriolar occlusion, 827 Idiopathic retinal vasculitis, 825, 825f Idiopathic retinal vasculitis aneurysms and neuroretinitis (IRVAN) , 826 Idiopathic stellate neuroretinitis, 260 Idiopathic uveitis, 22 IFAT (indirect fluorescent antibody test) for bartonella, 262 for toxoplasmosis, 398, 399 for Wegener's granulomatosis, 668, 670 IFN. See Interferon (IFN). Ig. See Immunoglobulins (Ig). IIF (indirect immunofluorescence), for Wegener's granulomatosis, 668, 670 Imidazole derivatives, for candidiasis, 369 Immune complex, in retinal vasculitis, 837 Immune complex-scavenging system, 62 Immune deviation, 57 anterior chamber-associated, 18, 19, 70 in sympathetic ophthalmia, 745 Immune expression, 70 Immune phase, of leptospirosis, 273 Immune privilege definition of, 18-19, 1St in corneal transplantation, 72-73 in intraocular inflammatory diseases, 71 in sympathetic ophthalmia, 744-745 ocular, 69 tissue and sites of, 69-70, 69t, 70t Immune response, 42-43, 43f, 44f in Adamantiades-Behc;:et's disease, 639-640 in Candida infections, 367 in multiple sclerosis, 703 in syphilis, 240 regulation of, 65-73 by antigen, 65 by suppressor T cells, 66 by Th1 and Th2 cells, 65-66 corneal u-ansplantation and, 71-73 regional, 67-71 tolerance as expression of, 66-67 Immune response (IR) gene, 24 Immune suppression, 56-57 in intraocular-central nervous system lymphoma, 503 Immune-mediated tissue injury, 56-65, 56t by antibody, 57-62 type I reactions and, 57-60, 57f, 58f, 58t, 60t type II reactions and, 60-61, 61£ type III reactions and, 61-62, 62f by cells, 62-64, 63f herpes simplex keratitis and, 64 Immunity expression of, 43-44 in giant cell arteritis, 623 in retinal vasculitis, 834 induction of, to eye-derived· antigens, 70 Immunoblotting (IB), for toxoplasmosis, 399, 399t Immunocompromised patient brucellosis in, 281 endophthalmitis in, 532 toxoplasmosis in, 390-391 Immunocytology, in Vogt-Koyanagi-Harada syndrome, 750-751 Immunofluorescence for bartonella, 262

Immunofluorescence (Continued) for toxoplasmosis, 398, 399 for Wegener's granulomatosis, 668, 670 Immunoglobulins (Ig), 50 in B-Iymphocyte responses, 45-50, 46f determination of, 48-50, 49f regulation of, 48, 48f sources of, 47-48 su'ucture and organization of, 46-47, 46f-48f in congenital rubella, 344, 345 in Fuchs' heterochromic iridocyclitis, 697 in Lyme borreliosis; 250, 251, 25lt in ocular surface immunity, 68 in paracentesis, 215 in retinal vasculitis, 838 in sarcoidosis, 716 in toxocariasis, 431 in toxoplasmosis, 387 in type I hypersensitivity reactions, 58, 58f polypeptide chains of, 49 Immunologic diseases diagnostic imaging for, 109-119 masquerade syndromes and, 116-119, 116f-118f, 119t pseudotumor versus Graves' disease and, 115-116, 115f, 116f sarcoid suspect and, 108f, 109-110, 109f scleritis and, 110-113, 110f-113f seronegative spondyloarthropathies and, 114-115, 114f, 114t in tubulointerstitial nephritis and uveitis syndrome, 727-728 Immunologic memory, 44 Immunologic skin test. See Skin test. Immunology, 34-77 B-iymphocyte responses in, 45-52. See also B-Iymphocyte responses. cells in, 34-45, 35t, 45t expression of immunity and, 43-44 immune response and, 42-43, 43f, 44f Langerhans', 36-37 lymphocyte, 34-36 macrophage, 36 mast, 38-39, 38t, 39t ontogeny of, 39-42, 40t, 41£, 42f, 42t platelet, 39, 39t polymorphonuclear leukocyte, 37-38, 37t, 38t immune response in, 65-73. See also Immune response. immune-mediated tissue injury in, 56-65, 56t. See also Immune-mediated tissue injury. in bartonella, 261-262 in corneal transplantation, 71-73 in Fuchs' heterochromic iridocyclitis, 696 in ocular Whipple's disease, 289 T-Iymphocyte responses in, 52-56 Immunology and Uveitis Service of Massachusetts Eye and Ear Infirmary, 19, 20t Immunomodulatory properties, of anterior chamber, 18 Immunomodulatory therapy for multifocal choroiditis and paJ.Tuveitis, 763 therapeutic principles of, 29-32, 30t Immunopathogenesis, in Lyme borreliosis, 250-251 Immunopathogenic disease, 56 Immunopathogenic T cells, 63 Immunoperoxidase staining, for ameba infection, 413 Immunoregulation, for retinal vasculitis, 838-839

INDEX Immunosorbent agglutination assay (ISAGA) for toxoplasmosis, 398, 399 Immunosuppressive agents for Adamantiades-Beh\=et's disease, 643-645 for retinal vasculitis, 838 for Vogt-Koyanagi-Harada syndrome, 752753 Immunosuppressive chemotherapy, 177-214 class, dosage, and route of administration of, 178, 178t cytotoxic drugs for, 179-191. See also Cytotoxic immunosuppressive drugs. general considerations for, 177-179, 177f, 178t, 179t indications for, 178, 178t mechanism of action of, 177, 177f noncytotoxic drugs for, 191-209. See also N oncytotoxic immunosuppressive drugs. philosophy for, 32 Immunosuppressive effects, of corticosteroids, 144 Immunotherapy for leprosy, 310, 311 for type I hypersensitivity reactions, 60 Indirect fluorescent antibody test (IFAT) for bartonella, 262 for toxoplasmosis, 398, 399 for Wegener's granulomatosis, 668, 670 Indirect hemagglutination, for cysticercosis, 471 Indirect ophthalmoscopy for intraocular foreign bodies, 548. for malignant melanoma, 510 for retinal detachment, 540 Indocin. See Indomethacin (Indocin). Indocyanine green (ICG) angiography! 119-137, 120f for acute posterior multifocal placoid pigment epitheliopathy, 121, 122f, 774 for Adamantiades-Beh\=et's disease, 641, 641£,642f for Adamantiades-Beh\=et's retinal vasculitis, 127, 128f for birdshot retinochoroidopathy, 129-132, 131£, 132f, 735-736, 735f for choroid neovascularization, 135-137, 136f, 137f for cystoid macular edema, 134, 135f for epiretinal membrane, 135, 136f for Harada's disease and sympathetic uveitis, 125-126, 125f-127f for macular ischemia, 134-135, 135f for malignant melanoma, 512 for multifocal choroiditis and panuveitis, 760-761, 761£ for multiple evanescent white dot syndrolne, 121-125, 124£ 768-769, 768£ 768t, 769f for posterior scleritis, 126-127 for presumed ocular histoplasmosis and pseudo-presumed ocular histoplasmosis, 127-129, 129f, 130f for punctate inner choroidopathy, 810, 810f for sarcoid chorioretinopathy, 132-133 for serpiginous choroiditis, 121, 123f, 790791, 790f, 791£ for subretinal fibrosis and uveitis sYndrome, 801 for sympathetic ophthalmia, 575 for toxoplasmosis, 400-401, 401£ for toxoplasmosis retinochoroiditis, 133134, 133f, 134f for uveitis testing, 95t, 96 for viral retinitis, 133 for Vogt-Koyanagi-Harada syndrome, 751

Indoles,29t, 167t Indomethacin (Indocin) systemic, 29t, 167t topical, 168t INF. See Interferon (IFN). Infants methotrexate and, 187 with congenital rubella, 343 Infarcts, in polyarteritis nodosa, 654 Infections in Adamantiades-Beh\=et's disease, 639 in brucellosis, 280 in human immunodeficiency virus, 495498, 495f-499£ 496t in retinal vasculitis, 830-832 intermediate uveitis versus, 849-850 T-Iymphocytes in, 56 Infectious chorioretinitis, 364 Infectious endophthalmitis after ocular surgery, 573 definition of, 364 toxocariasis versus, 433 Inferior crescent, in presumed ocular histoplasmosis syndrome, 354 Inflammation choroidal, 93 clinicopathologic characteristics of, 87-88, 88t corticosteroids for, 150-151 course and onset of, 87, 87t in amebiasis, 414 in cat-scratch disease, 261 in lens:induced uveitis, 818 in Lyme borreliosis, 248, 248f, 249f in retinal detachment, 540 in retinoblastoma, 514 in schistosomiasis, 483 in toxoplasmosis, 388, 398 optic disc, 93 orbital, 248-249 postsurgical, 170-171 source of, 89 T cell-dependent, 55-56 Inflammatory bowel disease (IBD)-associated arthritis, 589-591, 593 Inflammatory cells, in retinal detachment, 538 Inflammatory diseases corticosteroid-resistant, 188 diagnostic imaging of, 104-139. See also Diagnostic imaging. Inflammatory pseudotumor, 186 Influenza vaccines, uveitis induced by, 859, 860r Injury. See also Trauma. endothelial, 39 blood vessel, 656 immune-mediated tissue, 56-65, 56t. See also Immune-mediated tissue injury. penetrating ocular, 574 INO (internuclear ophthalmoplegia), 702 Insects in onchocerciasis, 443 in ophthalmomyiasis, 485-487, 486f Integumentary system, in Vogt-KoyanagiHarada syndrome, 749-750, 749f, 750f. See also Skin. Intensive care, in antiphospholipid syndrome, 684t, 685 Intercellular adhesion molecule-1 (ICAM-1) in retinal vasculitis, 835-836, 835f-836f Interference fringe instruments, 90 Interferon (IFN) in multiple sclerosis, 704 in scleroderma, 615 in subacute sclerosing panencephalitis, 339

Interferon (IFN) (Continued) in toxoplasmosis, 387 Interleukins (ILs) in Adamantiades-Behcet's disease, 639 in ascariasis, 440 ' in intermediate uveitis 847 in intraocular-central I~ervous system lymphoma, 504-505 in multiple sclerosis, 704 in sarcoidosis, 719-720 in scleroderma, 614 in toxoplasmosis, 387-388 in uveitis testing, 95t, 96 Intermediate uveitis (IU), 844-857. See also Vitritis. anatomic classification of, 19, 19t, 20t classification of, 86-87, 86f clinical features of, 844-845, 844f, 845f complications of, 845-846, 846f definition of, 844 diagnosis of, 848-849 differential diagnosis of, 79, 80t, 849-851 epidemiology of, 21, 22t, 23, 23f, 844 etiology of, 846-847 history of, 844 initial work-up for, 93, 94t natural history and prognosis for, 854 pathogenesis and pathology of, 847-848 treatment of, 851-854 International Uveitis Study Group (IUSG), 19, 19t, 30, 31 classification system of, 81-82, 82t Internuclear ophthalmoplegia (INO), 702 Interphotoreceptor retinoid binding protein (IRBP),733 Interstitial fibrosis, pulmonary, 612, 612f Interstitial keratitis, 89, 89t Intestinal ascariasis clinical characteristics of, 438 diagnosis of, 440 treatment of, 441-442, 441t Intracranial calcification, in congenital toxoplasmosis, 389, 390f Intraocular cysticercosis, 468-469 Intraocular foreign body (IOFB), 546-550, 548f Intraocular immunology, 69 Intraocular inflammation in Lyn1e borreliosis, 248, 248f, 249f in retinal detachment, 540 in retinoblastoma, 514 Intraocular lens (IOL) implantation in cataract surgery, 225 nonsteroidal anti-inflammatory drugs for, 170 Intraocular lymphoma acute retinal necrosis versus, 321 in birdshot retinochoroidopathy, 737-738 intermediate uveitis versus, 850 multifocal choroiditis and panuveitis versus, 762 Intraocular pressure (lOP) in clinical examination, 92 in retinal detachment, 540 increased from corticosteroids, 153-154 in pigmentary dispersion syndrome, 553 Intraocular schistosomiasis, 482 Intraocular worm, 482 Intraocular-central nervous system lyn1phoma, 503-506, 504f Intraoperative miosis, 170 Intraretinal hemorrhage, 495 Intrauterine toxoplasmosis, 385, 388-389, 389f, 389t, 390f Intravenous drug abuse, 365, 533

Intravenous immunoglobulins, for retinal vasculitis, 838 Iodoquinol, for ameba infection, 414 IOFB. See Intraocular foreign body (IOFB). IOL implantation. See Intraocular lens (IOL) implantation. lOP. See Intraocular pressure (lOP). IR gene. See Immune response (IR) gene. IRBP (interphotoreceptor retinoid binding protein), 733 Iridectomy, surgical, 223-224 Iridocyclitis complications of, 322 Fuchs' heterochromic. See Fuchs' heterochromic iridocyclitis (FHI). in Adamantiades-Beh<;:et's disease, 636 in herpes simplex virus clinical characteristics of, 317 diagnosis of, 320, 320f pathogenesis of, 319 treatment of, 321 in juvenile rheumatoid arthritis, 111, 594, 594f,595 azathioprine for, 188 chlorambucil for, 184 in leprosy, 307, 307f, 308, 310, 311 in relapsing polychondritis, 678 in toxoplasmosis, 396 mydriatic-cycloplegic agents for, 163 Iridolenticular adhesions, mydriaticcycloplegic agents for, 163 Iridotomy, laser, 223 Iris, 3-7 arteries of, 6 development of, 3-4 function of, 7 gross appearance of, 4, 4f histology of, 5-6, 5f in clinical examination, 91 in Fuchs' heterochromic iridocyclitis, 693694,694f in leprosy, 307-308, 307f, 308f in leukemia, 508 innervation of, 3 macroscopic appearance of, 4, 4f malignant melanoma of, 509-513 melanoma of, 512 pigmentation of, 161 therapeutic surgery of, 223-224, 224f vascular supply and innervation of, 6-7, 7f Iris atrophy in differential diagnosis, 103 in herpes simplex virus, 320 Iris nodules in differential diagnosis, 103 in sarcoidosis, 712-713, 713f in syphilis, 238, 238t in Vogt-Koyanagi-Harada syndrome, 748, 749f Iris pearls in leprosy, 307-308, 308f, 310 Iritis from cidofovir, 862 in ophthalmia nodosa, 488, 489f Iron foreigil bodies, 547 Irradiation, for juvenile xanthogranuloma, 558 Irritable bowel syndrome in toxocariasis, 429 IRVAN (idiopathic retinal vasculitis aneurysms and neuroretinitis), 826 ISAGA (immunosorbent agglutination assay), for toxoplasmosis, 398, 399 Ischemia after retinal surgery, 231, 232f angiography of, 134-135, 135f in giant cell arteritis, 622 i~l systemic lupus erythematosus, 605

Ischemic optic neuropathy, 620-621, 62lf Ischemic. syndrome, ocular, 553-556 Isolated central nervous system angiitis, 828 Isoniazid toxicity, 269 Itraconazole (Sporanox) for coccidioidomycosis, 374 for sporotrichosis, 383 IU. See Intermediate uveitis (IU). IUSG. See International Uveitis Study Group (IUSG). Ivermectin for loiasis, 466 for onchocerciasis, 455 Ixodidae, 297 in Lyme borreliosis, 245, 249, 250f

J

Jarisch-Herxheimer reaction, from syphilis, 242-243 Jejunal biopsy, for Whipple's disease, 591 Joints in Adamantiades-Beh<;:et's disease, 636 in inflammatory bowel disease-associated arthritis, 589 in Lyme borreliosis, 246-247 prognosis for, 254 in psoriatic arthritis, 587, 588f in sporotrichosis, 381 Jones-Mote hypersensitivity, 64, 64t JRA. See Juvenile rheumatoid arthritis (JRA). Juvenile ankylosing spondylitis, 592-593 Juvenile arthritis, 592-596, 593t, 594f, 596f ;. Juvenile rheumatoid arthritis (JRA), 593-596, 593t, 594f, 596f cataract surgery and, 226 cyclophosphamide and, 182-183 ~ diagnostic imaging for, 111, I1lf etanercept for, 201 iridocyclitis associated with, 184, 188 sarcoidosis versus, 715 Juvenile xanthogranuloma (JXG), 556-558 Juvenile-onset spondyloarthropathies, 592-593 Juxtafoveallaser photocoagulation, 355, 356-357 Juxtapapillary region, toxoplasmosis in, 394, 395f, 396f JXG. See Juvenile xanthogranuloma (JXG).

K Katayama fever, 480-481 KCS (keratoconjunctivitis), 613 Kenalog, 29t Keratectomy, superficial, 222-223 Keratic precipitates (KP), 88, 90 in Fuchs' heterochromic iridocyclitis, 694695, 695f in sympathetic ophthalmia,742 Keratitis in differential diagnosis, 103 in inflammatory bowel disease-associated arthritis, 590 in Lyme borreliosis, 249, 253 in measles, 337 in onchocerciasis, 449, 449f in ophthalmia nodosa, 488, 489f in Reiter's syndrome, 586 in rickettsial diseases, 301 interstitial, 89, 89t ulcerative cyclophosphamide for, 181 in polyarteritis nodosa, 654-655, 655f in Wegener's granulomatosis, 663-664, 664t, 665f Keratoconjunctivitis in ophthalmia nodosa, 488, 489f in scleroderma, 613

Keratoconjunctivitis (Continued) in systemic lupus etythematosus, 603 Keratoderma blennorrhagicum, 585, 585f Keratoneuritis, in ameba infection, 412 Keratopathy, band cornea with, 222, 222f, 223, 223f in differential diagnosis, 103 in juvenile rheumatoid arthritis, 594, 594f Keratoplasty iIi amebiasis, 414 perforating, 366 Keratouveitis anatomic classification of, 20, 20t cornea and sclera in, 89, 89t Ketoconazole (Nizoral) adverse reactions of, 178, 178t as adjuvant to immunosuppressive therapy, 205-207, 206f dosage and route of administration of, 30t, 178t for Candida endophthalmitis, 369 indications for, 179, 179t Ketoprofen (Oridus), 29t, 167t Ketorolac (Toradol) systemic, 29t, 167t topical, 168t Kidneys. See also Renal entries. in tubulointerstitial nephritis and uveitis syndrome, 728 in Wegener's granulomatosis, 661, 661t, 662 Killer cells, 34 Klebsiella pneumoniae, in ankylosing spondylitis, 583 Knott's technique, in loiasis, 465 Koeppe nodules in Fuchs' heterochromic iridocyclitis, 694 in Vogt-Koyanagi-Harada syndrome, 748, 749f Koplik's spots, in measles, 337 KP. See Keratic precipitates (KP). Krill's disease, 780. See also Acute retinal pigment epitheliitis (ARPE). Kveim-Siltzbach (KS) test, in sarcoidosis, 716, 717 Kyrieleis arterialitis, 393, 393f

L LAC (lupus anticoagulant), in antiphospholipid syndrome, 687 Lackmann hypersensitivity reaction, 56, 56t Lacrimal gland immunity of, 68-69 in sarcoidosis, 715, 715f, 721 a-Lac tam antibiotics, for Lyme borreliosis, 253 Lactate dehydrogenase (LDH), in retinoblastoma, 515 Lactoferrin, 68 Lagophthalmos, 306-307 management of, 311 Lamb, in toxoplasmosis transmission, 387 Lambda image, in sarcoidosis, 718 Lamina fusca, 12, 12f Langerhans' cells, 36-37 in corneal autograft, 72, 73 Large granular lymphocytes, 34 Large-cell lymphoma, intraocular in birdshot retinochoroidopathy, 737-738 multifocal choroiditis and panuveitis versus, 762 Larva in ascariasis, 437. See also Ascariasis. in cysticercosis, 468, 472. See also Cysticercosis. in ophthalmomyiasis, 485-487, 486f in toxocariasis, 428. See also Toxocariasis.

Laryngotrachea, in relapsing polychondritis, 676 Laser flare-cell photometry, 736 Laser iridotomy, 223 Laser ophthalmoscopy, 815 Laser photocoagulation for diffuse unilateral subacute neuroretinitis, 478 for intermediate uveitis, 852-853, 853-854 for multifocal choroiditis and panuveitis, 763-764 for ophthalmia nodosa, 490 for ophthalmomyiasis, 486 for presumed ocular histoplasmosis syndrome, 355-358, 356f, 357f for punctate inner choroidopathy, 811 for retinal detachment, 322 for serpiginous choroiditis, 793 for systemic lupus erythematosus, 608 for toxocariasis, 434 for toxoplasmosis, 404, 405f of subretinal neovascular membrane, 233234, 233f, 234£ Laser treatment, for retinal vasculitis, 839 Laser-induced uveitis, 575 . Latanoprost, uveitis induced by, 860t, 863-864 Lattice degeneration, in retinal detachment, 539 LDH (lactate dehydrogenase), in retinoblastoma, 515 Leber's idiopathic stellate neuroretinitis (LISN) , 260 Leflunomide (Arava), for immunosuppressive chemotherapy, 189-190·' Legal blindness, 26 Lens implantation of in cataract surgery, 225 nonsteroidal anti-inflammatory drugs for, 170 in clinical examination, 92 in cysticercosis, 472 in loiasis, 464, 464t Lensectomy, pars plana, 852, 853 Lens-induced uveitis (LID), 575, 817-821 clinical features of, 818-819, 819f complications of, 821 definition of, 817 diagnosis of, 819 differential diagnosis of, 819-821, 819f, 819t, 820t epidemiology of, 817 etiology and pathogenesis of, 817-818 following cataract surgery, 229, 229f history of, 817 pathology of, 818, 818f treatment of, 821 Leopard skin, in onchocerciasis, 453-454 Lepidoptera, in ophthalmia nodosa, 488-491, 489f Leprosy, 305-314 angiotensin-converting enzyme in, 719, 719t clinical characteristics of, 306-308, 307f, 308f definition of, 305 diagnosis of, 310, 310f differential diagnosis of, 310 epidemiology of, 305-306 histopathology of, 309 history of, 305 iris in, 307-308, 308f pathogenesis and immunology of, 309-310 treatment of, 310-311 Leptospirosis, 273-277 clinical characteristics of, 273-274

Leptospirosis (Continued) definition and history of, 273 differential diagnosis of, 275-276 epidemiology of, 273 laboratory diagnosis of, 275 pathogenesis of, 274-275 prognosis for, 276 treatment of, 276 Letter optotypes, 90 Leucovorin (folinic acid), for toxoplasmosis, 402, 403t Leukemia, 506-509, 507f from chlorambucil therapy, 184 in retinal vasculitis, 833 optic disc and, 93 Leukeran. See Chlorambucil (Leukeran). Leukocytes in Adamantiades-Beh~et'sdisease, 641 in retinal vasculitis, 834-837, 834f-836f in toxocariasis, 429 Leukocytosis, neutrophilic, 144 Leukokoria, 471, 514 Leukopenia, from azathioprine, 189 Levamisole, for ascariasis, 44lt, 442 LFA-1 (lymphocyte function-associated adhesion molecule-I), 835-836, 835f-836f Lhermitte's sign, in multiple sclerosis, 702 Libman-Sacks endocarditis, 602 Lichenified onchodermatitis (LOD), 446, 447f Lids. See Eyelids. Light microsc~py (LM), for Whipple's disease, 287, 292, 292t Light-chain genes, 46, 47f Lightning flashes, in retinal detachment, 538 Limbal inflammation, in amebiasis, 414 Linear scars, in ophthalmomyiasis, 485-486, 486f Linear streaks, in presumed ocular histoplasmosis syndrome, 350, 351£ Linomide, for multiple sclerosis, 707 Lipid metabolism, corticosteroids and, 143 Lipopolysaccharide (LPS) , in brucellosis, 279 LISN (Leber's idiopathic stellate neuroretinitis), .260 LID. See Lens-induced uveitis (LID). Liver in sarcoidosis, 711 methotrexate and, 186-187 nonsteroidal anti-inflammatory drugs and, 170 Liver function tests in giant cell arteritis, 625 in Rift Valley fever, 334 LL (lepromatous leprosy) definition of, 305 epidemiology of, 306 iris, 307-308, 308f LM. See Light microscopy (LM). Loa wa, 450-451, 463 LOD. See Lichenified onchodermatitis (LOD). Laffler's pneumonia, in ascariasis, 440 Lofgren's syndrome, in sarcoidosis, 715-716 Loiasis, 463-467 clinical features of, 463-465, 464t definition of, 463 diagnosis of, 465-466 epidemiology of, 463 history of, 463 morphology of, 463 prevention of, 466 treatment of, 466 Loteprednol (Lotemax), 28t, 149 Louse-borne disease relapsing fever in, 255-256

Louse-borne disease (Continued) typhus in; See Epidemic typhus. Lovastatin, cyclosporine A and, 196 Low back pain ~n ankylosing spondylitis, 582 111 uveitis, 114 Lucio leprosy, 306 Luetic chorioretinitis, 815-816 Lumbar puncture for intraocular-central nervous system lymphoma, 505 for Vogt-Koyanagi-Harada syn.drome, 752 Lumbosacral spine films, 95t, 96 Lungs. See also Pulmonary entries. high-resolution computed tomography of, 110 in sarcoidosis, 711 transbronchial biopsy of, 720 metastasis to, 517,519 Lupus anticoagulant (LAC), in antiphospholipid syndrome, 687 Lupus erythematosus. See Systemic lUpus erythematosus (SLE). Lyme borreliosis, 245-255 clinical characteristics of ocular, 247-249, 247t, 248f, 249f systemic, 246-247, 246f coinfection with, 254-255 definition of, 245 diagnosis of, 251-253, 25lt epidemiology of, 245, 245t, 246t history of, 245 pathogenesis of, 249-251, 250f prevention of, 253 prognosis for, 253-254 treatment of, 253 Lyme disease epidemiology of, 299 intermediate uveitis versus, 850 Lyme neuroborreliosis, 706 Lyme titers, 95t, 96 Lymph nodes characteristics of, 40, 41£ in extraocular examination, 94 in sarcoidosis, 711 Lymphadenopathy in acquired toxoplasmosis, 390 in sarcoidosis, 717-718, 717f, 718t in syphilis, 238, 238t Lymphatic system, in onchocerciasis, 448 Lymphocutaneous infection, of sporotrichosis, 380 Lymphocyte function-associated adhesion molecule-l (LFA-l), 835-836, 835f-836f Lymphocytes, 34-36. See also B cell (s); T cell(s). in Adamantiades-Beh~et'sdisease, 641 in scleroderma, 614 Lymphocytoma, in Lyme borreliosis, 246 Lymphocytopenia, corticosteroids and, 144 Lymphoid hyperplasia, of uvea, 504 Lymphoid organs, 40, 41£, 42f, 42t Lymphoid traffic, 40-42, 42t Lymphokines, in sarcoidosis, 716-717 Lymphoma diagnostic imaging for, 116, 116f, 117f in birdshot retinochoroidopathy, 737-738 in human immunodeficiency virus, 499 in retinal vasculitis, 833 intermediate uveitis versus, 850 intraocular-central nervous system, 503506,504f multifocal choroiditis and panuveitis versus, 762 toxoplasmosis in, 390 Lysozomal membranes, corticosteroids and, 144

-INDEX Lysozyme in ocular surface immunity, 68 in sarcoidosis, 720

M Macrophage migration inhibition factor, 18-19, 19t Macrophages, 36 corticosteroids and, 144 in giant cell arteritis, 623, 624 in intermediate uveitis, 847 in intraocular-central nervous system lymphoma, 504 in toxoplasmosis, 387 Macroscopic polyarteritis nodosa (MaPAN), 653. See also Polyarteritis nodosa (PAN). Macular cotton-wool spot, in Whipple's disease, 289, 290f Macular edema cystoid. See Cystoid macular edema (CME). in Adamantiades-Belwet's disease, 646647 in birdshot retinochoroidopathy, 732, 735, 735f in sarcoidosis, 713 in intermediate uveitis, 846, 846f Macular geographic helicoid choroidopathy. See Serpiginous choroiditis. Macular ischemia, 134-135, 135f Macular pseudohypopyon, in syphilis, 239 Macular skin lesions, in leprosy, 310 Macular star, in cat-scratch disease, 260-261, 261£ Macular subretinal cysticercosis, 469 Maculopathy in intermediate uveitis, 846, 846f in presumed ocular histoplasmosis syndrolne, 350£ 351-352, 352f in subacute sclerosing panencephalitis, 338, 339f Maggots, in ophthalmomyiasis, 485-487, 486f Magnet techniques, for intraocular foreign bodies, 549 Magnetic resonance angiography (MRA), 106 for Takayasu's arteritis, 112 Magnetic resonance imaging (MRI), 104-106, 105t for Graves' disease, 115, 116 for intraocular foreign bodies, 548 for intraocular-central nervous system lymphoma, 505 for masquerade syndromes, 116-118 for multiple sclerosis, 705, 705f for sarcoid suspect, 108f, 109, 109f for uveitis testing, 95t, 96 for Vogt-Koyanagi-Harada syndrome, 752 for Wegener's granulomatosis, 112 Major histocompatibility (MHC) molecules in acute posterior multifocal placoid pigment epitheliopathy, 775-776 in birdshot retinochoroidopathy, 733 Malar rash, in systemic lupus erythematosus, 601, 602f Malignancy (ies) , 503-527 from chlorambucil therapy, 184 from cyclophosphamide, 182 intraocular-central nervous system lympholnain, 503-506, 504f leukemias in, 506-509, 507f malignant melanoma in, 509-513, 511£ medications and, 31-32 metastatic disease in, 517-519, 518f paraneoplastic syndromes in, 520-522 retinoblastoma in, 513-517, 515f, 515t Malignant melanoma, 509-513, 511f Mansonella ozzardi, 450-451

Mansonella perstans, 450-451 Mansonella streptocerca, 450-451

MaPAN (niacroscopic polyarteritis nodosa), 653. See also Polyarteritis nodosa (PAN). MAR syndrome. See Melanoma-associated retinopathy CMAR) syndrome. Marburg virus, 335 Marie-Striimpell disease, 581. See also Ankylosing spondylitis (AS). Masquerade syndromes diagnostic imaging studies for, 116-119, 116f-118f, 119t endophthalmitis in, 528-536. See also Endophthalmitis. malignancies in, 503-527. See also Malignancy(ies) . nonmalignant, noninfectious, 537-571. See also Nonmalignant, noninfectious masquerade syndromes. Massachusetts Eye and Ear Infirmary (MEEI), 19, 20t Mast cell-stabilizing agents, 59 Mast cells, 38-39, 38t, 39t corticosteroids and, 144 in scleroderma, 614-615 in stroma, 5 in type I hypersensitivity reactions, 58 ocular surface immunity and, 68 Mast cells-tryptase and chymase (MC-TC), 38-39, 38t Mast cells-tryptase (MC-T), 38, 38t, 39 MAT (microscopic agglutination test), for leptospirosis, 275. ' ;Maternal rubella, 343 Maxidex (Alcon), 28t Maxillary sinus, in Wegener's granulomatosis, 662,662f Mazzotti test, for onchocerciasis, 454 MCP. See Membrane cofactor protein (MCP); Multifocal choroiditis and panuveitis (MCP). MC-T. See Mast cells-tryptase (MC-T). MC-TC. See Mast cells-tryptase and chymase (MC-TC). MDT regimens, for leprosy, 310, 311 Measles, 336-341 acquired, 336-338 congenital, 336 definition of, 336 history of, 336 subacute sclerosing panencephalitis and, 338-340 Meat, in toxoplasmosis transmission, 387 Mebendazole for ascariasis, 441, 441t for loiasis, 466 for toxocariasis, 434 Meclofenamate (Meclomen), 167t Medication-induced uveitis. See Drug-induced uveitis. Mediterranean spotted fever, 298, 298t, 301 t Medrol,28t Medroxyprogesterone (Provera) pharmaceutics of, 145, 145t topical preparation of, 28t Medrysone (HMS) pharmaceutics of, 145, 145t topical preparation of, 28t -Medulla, 40, 41£ MEEI. See Massachusetts Eye and Ear Infirmary (MEEI). Mefenamate (Pronstel), 2Qt, 167t Melanocytes in anterior border layer, 5 in stroma, 5 in Vogt-Koyanagi-Harada syndrome, 750751

Melanoma, 509-513, 511£ ultrasound characteristics of, 107 Melanoma-associated retinopathy (MAR) ~~ldrome, 520-522 acute zonal occult outer retinopathy versus, 815 Membrane cofactor protein (MCP) definition of, 18 diagnosis of, 79 Membrane inhibitor, of reactive lysis, 18 Membrane peeling, after Candida endophthalmitis, 366 Meningitis, 377, 378 Meningoencephalitis in loiasis, 465 in Rift Valley fever, 334 Meningovascular syphilis, 238, 238t Mental status examination, 93 6-Mercaptopurine for intermediate uveitis, 852 Mesench)~al cells, 3-4 Mesenteric arteriography, for Takayasu's arteritis, 112 Mesenteric thrombosis, in polyarteritis nodosa, 654 Metallic foreign bodies, 547 Metastasis, in masquerade syndromes, 116, 117f, 118 Metastatic disease, 517-519, 518f Methemoglobinemia, from dapsone, 203 Methotrexate (Folex, Mexate, Rheumatrex) adverse reactions of, 178, 178t dapsone and, 203 dosage and route of administration of, 30t, 178t for ankylosing spondylitis, 583 for giant cell arteritis, 626 for immunosuppressive chemotherapy, 178t, 179t, 185-187, 185f for inflammatory bowel disease-associated arthritis, 590 for intermediate uveitis, 852 for juvenile rheumatoid arthritis, 595 for multiple sclerosis, 706, 707 for psoriatic arthritis, 588 for Reiter's syndrome, 587 for scleroderma, 616 for tubulointerstitial nephritis and uveitis syndrome, 729 for Wegener's granulomatosis, 670 indications for, 179, 179t Methylprednisolone chemistry of, 142, 143t cyclosporine A and, 196 for multiple sclerosis, 706 for Vogt-Koyanagi-Harada syndrome, 752 pharmaceutics of, 145, 146t regional preparation of, 29t systemic preparation of, 28t Meticorten, 28t Metipranolol, uveitis induced by, 860t, 864 Metreton, 28t Metronidazole for ameba infection, 414 for giardiasis, 417 MEWDS. See Multiple evanescent wh.ite dot syndrome (MEWDS). Mexate. See Methotrexate (Folex, Mexate, Rheumatrex) . MHA-TP. See Microhemagglutination assay antibodies, to Treponema pallidwn (MHATP). MHC (major histocompatibility) molecules in acute posterior multifocal placoid pigment epitheliopathy, 775-776 in birdshot retinochoroidopathy, 733

Microaneurysms in leukemia, 507 in systemic lupus erythematosus, 605, 605f Microangiopathy HIV, 494-495, 495f in retinal vasculitis, 828 in systemic lupus erythematosus, 606 Microfilariae, in onchocerciasis, 453, 453f Microgliomatosis, 503-506, 504f Microhemagglutination assay antibodies, to Treponerna pallidmn (MHA-TP), 95t, 96 Microscopic agglutination test (MAT), for leptospirosis, 275 Microscopic polyarteritis nodosa (MiPAN), 653, 658, 658t. See also Polyarteritis nodosa (PAN). Microscopy for free-living amebas, 413 for loiasis, 465 for subretinal fibrosis and uveitis syndrome, 799 for syphilis diagnosis, 240, 240t for Whipple's disease, 287, 292, 292t Microvascular occlusion, in systemic lupus erythematosus, 603-604, 603t, 604f, 604t Migration inhibition factor (MIF), 18-19, 19t Mikulicz's syndrome, in sarcoidosis, 716 Miliary iris lepromas, 307-308, 308f Mineralocorticoids chemistry of, 142, 143t electrolyte and fluid balance and, 143-144 Minocycline, for leprosy, 310, 311 Miosis, intraoperative, prevention of, ; nonsteroidal anti-inflammatory drugs for, 170 Miotic pupil, examination of, 90 MiPAN (microscopic polyarteritis noddSa), 653, 658, 658t. See also Polyarteritis nodosa (PAN). MMC. See Mucosal mast cell (MMC). Mobility, in multiple sclerosis, 702 Molecular biology, of free-living amebas, 413 Molecular diagnosis, of loiasis, 465 Molecular genetics, of brucellosis, 278-279 Monkeys, in loiasis, 463 Monoarticular arthritis, asymmetric, 587 Monocytes corticosteroids and, 144 in Adamantiades-Behyet's disease, 641 in sarcoidosis, 717 in scleroderma, 614 Monocytic ehrlichiosis, human, 298, 298t clinical characteristics of, 301 t epidemiology of, 300 history of, 299 Monokines, in toxoplasmosis, 387 Mononuclear cell infiltrate, in choroid, 743, 744f Mononuclear inflammatory response, 398 Mooren's ulcer, 181 Moorfields Eye Hospital protocol for ameba infection, 413 Mosquitoes, in Rift Valley fever, 333, 334f Motility, extraocular, 90 Motrin. See Ibuprofen (Advil, Motrin, Nuprin, Rufen). Mouse, white-footed, 249 MPO (myeloperoxidase), for Wegener's granulomatosis, 669, 669t MRI. See Magnetic resonance imaging (MRI). MS. See Multiple sclerosis (MS). a-MSH. See Alpha melanocyte stimulating hormone (a-MSH). Mucocutaneous lesions, in Reiter's syndrome, 585, 585f Mucosal immunity, to ameba infection, 412

Mucosal mast cell (MMC), 38, 38t, 39, 58 Mucosal surface ulceration, 94 MillIeI' cells, in subretinal fibrosis and uveitis syndrolne, 799-800 Multifocal choroiditis and panuveitis (MCP), 757-765 acute zonal occult outer retinopathy and, 813-816 angiography for, 127-129, 129f, 130f birdshot retinochoroidopathy versus, 736t, 737 clinical characteristics of, 757-759, 758f, 759f course and complications of, 759-760 definition of, 757, 806 diagnosis of, 760-761, 760f, 76lf differential diagnosis of, 761-762, 76lt in presumed ocular histoplasmosis syndrome, 355 epidemiology of, 757 etiopathogenesis of, 762-763 FA and ICGA of, 129, 130f history of, 757 in subretinal fibrosis and uveitis syndrome, 797 prognosis for, 764 punctate inner choroidopathy and, 806 serpiginous choroiditis versus, 792 subretinal fibrosis and uveitis syndrome versus, 802, 802t, 803t summary of, 809, 809t treatment ot, 763-764 Multifocal choroiditis of unknown etiology, 806 Multifocal choroiditis with progressive subretinal fibrosis, 797 Multifocal retinitis, 103 Multinucleated giant cells, in intermediate uveitis, 847 Multiplanar imaging, in magnetic resonance imaging, 105 Multiple evanescent white dot syndrome (MEvrDS), 767-771 acute zonal occult outer retinopathy and, 813-816 birdshot retinochoroidopathy versus, 736t, 737 clinical characteristics of, 767, 768f definition of, 767 diagnosis of, 768-770, 768f, 768t, 769f differential diagnosis of, 770 in presumed ocular histoplasmosis syndrome, 355 fluorescein and indocyanine green angiography in, 121-125, 124f history and epidemiology of, 767 multifocal choroiditis and panuveitis and, 757, 761, 762-763 pathogenesis of, 767-768 subretinal fibrosis and uveitis syndrome versus, 802, 802t summary of, 809, 809t treatment of, 770 Multiple pseudoretinitis, 396, 397f Multiple sclerosis (MS), 701-709 clinical features of, 701-703 complications of, 703 definition of, 701 diagnosis of, 705, 705f differential diagnosis of, 705-706, 706t epidemiology of, 701 etiology of, 703-704 history of, 701 intermediate uveitis versus, 849 natural course of, 706 pathogenesis and pathology of, 704-705

Multiple sclerosis (MS) (Continued) prognosis for, 706 retinal vasculitis and, 827-828 subacute sclerosing panencephalitis versus, 339 therapy for, 706-707 Murine typhus, 298, 298t clinical characteristics of, 301, 301 t epidemiology of, 299 pathophysiology of, 300 Muscles ciliary, 7-8, 9-10, 10f of iris, 4· ultrasonography of, 107, 107t Musculoskeletal system in antiphospholipid syndrome, 684t, 685 in Lyme borreliosis, 251, 25lt in polyarteritis nodosa, 654 Mutton-fat keratic precipitates, in sympathetic ophthalmia, 742 Myalgia, in Wegener's granulomatosis, 663 Mycobacteria, in tuberculosis, 267-268 Mycobacteriurn avillrn-intmcelllllare

in human immunodeficiency virus, 498 in Whipple's disease, 293 Nlycobacteriurn avillrn-intmcelllllare choroidal lesions, 427 Mycobacteriurn lepme, 305, 309. See also Leprosy. Mycology in presumed ocular histoplasmosis syndrome,348 in sporotrichosis, 380, 380f, 38lf Mycophenolate mofetil (CellCept) for Adamantiades-Behyet's disease, 645 for immunosuppressive chemotherapy, 190191 for intermediate uveitis, 852 for retinal vasculitis, 838 Mycotic endophthalmitis, 365 acute retinal necrosis versus, 321 after trauma, 365 Mydriatic-cycloplegic agents, 159-166 drug interactions with, 165 for high-risk groups, 164-165 for iridocyclitis and trabeculitis, 321 for Vogt-Koyanagi-Harada syndrome, 752 history and source of, 159 major clinical trials with, 165 official drug names and chemistry of, 159, 160t, 16lf pharmaceutics of, 160t, 162 pharmacokinetics and metabolism of, 162 pharmacology of, 159 clinical, 160-162, 160t side effects and toxicity of, 163-164 therapeutic use of, 162-163, 162t Myeloperoxidase (MPO), for Wegener's granulomatosis, 669, 669t Myelosuppression from azathioprine, 189 from methotrexate, 186 Myocysticercosis, 471 Myopia in retinal detachment, 539 subretinal fibrosis and uveitis syndrome versus, 803 . Myopic crescent, in presumed ocular histoplasmosis syndrome, 354 Myorrhythmia, oculomasticatory, 287, 291-292 Myositis, orbital, 186

N Nails in extraocular examination, 94

INDEX Nails (Continued) in psoriatic arthritis, 587, 588f Nalfon.· See Fenoprofen (Nalfon). Naproxen (Anaprox, Naprosyn), 29t, 167t Nasal cartilage, in relapsing polychondritis, 676,677f Nasal chondritis, in relapsing polychondritis, 676 Nasociliary nerve, 3 Nasolacrimal drainage system (NLDS), in sarcoidosis, 715 Nasolacrimal duct, 170 Nasopharyngeal manifestations, in extraocular examination, 94 Native Americans, uveitis in, 88 Natural killer (NK) cells, 34 in Adamantiades-Behc;:et's disease, 639 in toxoplasmosis, 387 Necrosis in herpes simplex virus clinical characteristics of, 317-318, 318f diagnosis of, 320-321 pathogenesis of, 319-320 treatment of, 321-322 in VZV retinitis, 497 in Wegener's granulomatosis, 667, 667f Necrotizing chorioretinitis, 471 Necrotizing retinitis in syphilis, 239, 239t toxoplasmosis versus, 397 Necrotizing vasculitis, in Wegener's granulomatosis, 661. See also Wegener's granulomatosis. Negative selection, 53 Nemathelminthes, in diffuse unilateral subacute neuroretinitis, 476 Nematodes in ascariasis, 437. See also Ascariasis. in diffuse unilateral subacute neuroretinitis, 475, 476 in toxocariasis, 428. See also Toxocariasis. Neonate Adamantiades-Behc;:et's disease in, 638 with congenital rubella, 343-344 Neoplasia, from azathioprine, 189 Neosar. See Cyclophosphamide (Cytoxan, Neosar). Neovascular glaucoma endophthalmitis and, 534 in Adamantiades-Behc;:et's disease, 637 in Fuchs' heterochromic iridocyclitis, 697 Neovascular membrane, 121, 123f, 129, 129f. See also Choroidal neovascularization. Neovascularization choroidal. See Choroidal neovascularization (CNV).

in Adamantiades-Behc;:et's disease, 646, 647 in leukemia, 507 in retinal vasculitis, 833 optic disc, 93 in sarcoidosis, 714, 714f retinal. See Retinal neovascularization. submacular in presumed ocular histoplasmosis syndrome, 351 subretinal in congenital rubella, 343 in serpiginous choroiditis, 794 in Vogt-Koyanagi-Harada syndrome, 753 Nephritis in extraocular examination, 94 in systemic lUpus erythematosus, 602 tubulointerstitial, 726-730 Nephropathy, in loiasis, 464 Nephrotoxicity, from cyclosporine A, 195 Nerves, ciliary, 3

Nervous system in Fuchs' heterochromic iridocyclitis, 696 in Lyme borreliosis clinical characteristics of, 247 diagnosis of, 251, 251 t in systemic lupus erythematosus, 606 in Wegener's granulomatosis, 663 Neural crest cells, in choroidal development, 11 Neural retina, 6, 6f Neuritis optic, 701, 702, 706 Toxoplasma, 394-396, 396f Neuroborreliosis multiple sclerosis and, 706 treatment of, 253 Neurocysticercosis, 471 Neuroectodermal optic cup, 3 Neurologic disease in giant cell arteritis, 619 retinal vasculitis as manifestation of, 827828 Neurologic system in Adamantiades-Behc;:et's disease, 635-636 in antiphospholipid syndrome, 684, 684t in Lyme borreliosis, 247 prognosis for, 254 in polyarteritis nodosa, 654 in Rift Valley fever, 333 in Vogt-Koyanagi-Harada syndrome, 750 Neuro-ophthalmic system in antiphospholipid s)'l1drome, 686-687 in giant cell arteritis, 622 in Lyme borreliosis, 247 in polyarteritis nodosa, 655-656 in systemic lupus erythematosus, 606 ,~europathy

in endophthalmitis, 534 in extraocular examination, 94 in giant cell arteritis, 620-621, 621£ in L)'lne borreliosis, 247-248 Neurophthalmology, in Whipple's disease, 288t, 291-292 Neuropsychiatric manifestations, of systemic lUpus erythematosus, 602 Neuroretina, 8 Neuroretinitis diffuse unilateral subacute. See Diffuse unilateral subacute neuroretinitis (DUSN). in cat-scratch disease, 260-262 in syphilis, 239, 239t Leber's idiopathic stellate, 260 Toxoplasma, 394, 395f, 396f Neurosarcoidosis, 714-715, 714f Neurosensory detachment, of retina, 239, 239t Neurosyphilis, 238, 238t multiple sclerosis and, 706 pupil assessment in, 90 treatment of, 241-242, 242t Neutrophilic leukocytosis, 144 Neutrophils, 37, 37t in Adamantiades-Behc;:et's disease, 639, 641 ocular surface immunity and, 68 Newborn Adamantiades-Behc;:et's disease in, 638 with congenital rubella, 343-344 Nitrous oxide, cyclophosphamide and, 183 Nizoral. See Ketoconazole (Nizoral). NK cells. See Natural killer (NK) cells. NLDS (nasolacrimal drainage system), in sarcoidosis, 715 Nodular episcleritis, in leprosy, 307 Nodular granuloma, in sporotrichosis and, 380

Nodular skin lesions, in leprosy, 310 Nodulectomy, for onchocerciasis, 456 Nodules in Fuchs' heterochromic iridocyclitis, 694 in onchocerciasis, 448, 448f, 453-454 in polyarteritis nodosa, 654 in schistosomiasis, 482, 483f iris, 91, 103 Noncaseating granulomas, in sarcoidosis, 716, 716f Noncytotoxic immunosuppressive drugs, 191-209 adjuvant(s) to, 204-209 bromocriptine as, 204-205, 204f colchicine as, 208-209, 208f ketoconazole as, 205-207, 206f antibiotics as, 191-204. See also Antibiotics. Nongranulomatous anterior uveitis, 93, 94t Nongranulomatous inflammation, 87-88, 88t Nongranulomatous uveitis, 20 Non-Hodgkin's l)'lnphoma, 503-506, 504f Nonmalignant, noninfectious masquerade s)'lldromes, 537-571 intraocular foreign body in, 546-550, 548f juvenile xanthogranuloma in, 556-558 ocular ischemic syndrome in, 553-556 pigment dispersion syndrome in, 550-553, 551£ retinitis pigmentosa in, 541-546. See also Retinitis pigmentosa (RP). rhegmatogenous retinal detachment in, 537-541. See also Rhegmatogenous retinal detachment. Non-necrotizing granulomas, in sarcoidosis, 716,716f Nonocular disease, in sporotrichosis, 380-382 Nonpenetrating ocular trauma, 575 Nonsteroidal anti-inflammatory drugs (NSAIDs),167-176 clinical trials with, 174 cyclosporine A and, 196 drug interactions with, 174 for ameba infection, 414 for ankylosing spondylitis, 583 for cataract surgery, 224-225 for inflammatory bowel disease-associated arthritis, 590 for intermediate uveitis, 852 for juvenile rheumatoid arthritis, 595 for psoriatic arthritis, 588 for Reiter's s)'lldrome, 587 for sarcoidosis, 723 high-risk groups and, 173-174 introduction, history, and source of, 167, 167t, 168t official name and chemistry of, 167-168, 167t, 168f, 168t pharmaceutics of, 170 pharmacokinetics of, 170 pharmacology of, 168-169, 169f clinical, 169-170, 170t side effects and toxicity of, 172-173 therapeutic principles of, 28-29, 29t therapeutic use of, 170-172 Nuclear medicine, 106-107 Nucleic acid amplification, for tuberculosis, 267-268 Null cells, 34 Nuprin. See Ibuprofen (Advil, Motrin, Nuprin, Rufen). Nursing mothers azathioprine and, 189 methotrexate and, 187 Nystagmus, in multiple sclerosis, 702

o Obliterative endarteritis, in syphilis, 238, 238t Obstetrics, in antiphospholipid syndrome, 684t, 685 Occlusion, microvascular, 603-604, 603t, 604f, 604t OCP. See Onchocerciasis Control Program (OCP). Ocular ascariasis clinical characteristics of, 438 treatment of, 441-442, 44lt Ocular coccidioidomycosis, 373 Ocular disease in Lyme borreliosis, 247-249, 247t, 248f, 249f in onchocerciasis, 451-452 in sporotrichosis, 382 retinal vasculitis in, 825-827, 825f, 826f Ocular histoplasmosis syndrome (OHS) acute zonal occult outer retinopathy versus, 815 angiography in, 127-129, 129f, 130f birdshot retinochoroidopathy versus, 736, 736t Ocular hypertension, in intermediate uveitis, 845 Ocular hypotony, in leprosy, 308 Ocular immune privilege, 69 definition of, 18-19, 18t Ocular immunologists, 27, 30 Ocular inflammation corticosteroid-resistant, 188 corticosteroids for, 150-151 in cat-scratch disease, 261 Ocular ischemic syndrome (OIS), 553-556 Ocular lesions in leprosy, 306-308 in onchocerciasis, 448 Ocular lymphoma, in retinal vasculitis, 833 Ocular surface immunity, 68-69 Ocular syndrome, in Rift Valley fever, 333 Ocular toxoplasmosis, in human immunodeficiency virus, 497, 497f Ocular trauma, uveitis after, 573-575 Ocular Whipple's disease (OWD), 287-296 clinical characteristics of, 288t, 289-292, 289t, 290f, 291t definition of, 287 diagnosis of, 289t, 29lt, 292-293, 292t epidemiology of, 287, 288t, 289t etiology of, 287 history of, 287 immunology of, 289 pathology of, 287-289 treatment of, 293-294 Oculomasticatory myorrhythmia (OMM), 287 in Whipple's disease, 291-292 Oculoplethysmography, in ocular ischemic syndromes, 555 Oestrus ovis, in ophthalmomyiasis, 485-487 Ofloxacin for brucellosis, 283 for leprosy, 310, 311 for rickettsial diseases, 303 OHS. See Ocular histoplasmosis syndrome (OHS). OIS. See Ocular ischemic syndrome (OIS). Oligoarticular arthritis, asymmetric, 587 Oligoarticular onset juvenile rheumatoid arthritis, 593-594, 593t, 595 Oligospermia, from methotrexate, 187 OMM. See Oculomasticatory myorrhythmia (OMM). Onchocerca caecutiens, 443 Onchocerca volvulus, 443 in loiasis, 463

Onchocerciasis, 443-462 clinical features of, 446-450, 446t, 447f450f complications of, 450 control of, 456-457 definition of, 443 diagnosis of, 453-454, 453f epidemiology of, 25-26, 443-446, 444f, 445t etiology of, 450-451, 450f history of, 443 natural history and prognosis for, 457 pathogenesis and pathology of, 451-453 treatment of, 454-456 Onchocerciasis Control Program (OCP), 443, 456-457 Onchocercomata, 448, 448f Ontogeny, of immune system, 39-42, 40t, 41£, 42f,42t Onycholysis in psoriatic arthritis, 587, 588f in Reiter's syndrome, 585, 586f Oocysts, in toxoplasmosis, 386, 387 Open-angle glaucoma from corticosteroids, 153-154 mydriatic-cycloplegic agents and, 163-164 Open-sky vitrectomy, for cysticercus, 472 Operating room, 529-530 Ophthalmia nodosa, 488-491, 489f Ophthalmicus, herpes zoster, 499, 499f Ophthalmodynamometry, in ocular ischemic syndromes, 555 Ophthalmologists, 27, 30 Ophthalmomyiasis, 485-487, 486f Ophthalmoplegia in multiple sclerosis, 702 in sarcoidosis, 715 in Whipple's disease, 291 Ophthalmoscopy for acute zonal occult outer retinopathy, 815 for intraocular foreign bodies, 548 for malignant melanoma, 510 for onchocerciasis, 453 for retinal detachment, 540 Opportunistic chorioretinal infections, 495-498, 495f-499£ 496t Optic atrophy, in onchocerciasis, 450, 450f Optic disc in clinical examination, 93 in cysticercosis, 472 in giant cell arteritis, 620 in sarcoidosis, 714, 714f in Vogt-Koyanagi-Harada syndrome, 748, 748f, 749, 749f Optic nerve atrophy of, 397 in Adamantiades-Behc;:et's disease, 637-638 in brucellosis, 281, 28lt in cysticercosis, 469 in diffuse unilateral subacute neuroretinitis, 476 in intermediate uveitis, 846 in leukemia, 508 in Lyme borreliosis, 248 in multiple sclerosis, 703 in onchocerciasis, 450, 450f in polyarteritis nodosa, 655 in sarcoidosis, 713, 713f, 714, 714f in schistosomiasis, 483-484 Optic nerve drusen, 355 Optic neuritis, 701, 702, 706 Optic neuropathy in endophthalmitis, 534 in giant cell arteritis, 620-621, 621£ Optic pallor,in multiple sclerosis, 702 Ora serrata, 8

Oral lesions, 94 in Reiter's syndrome, 585 Oral ulcers in Adamantiades-Behcet's disease, 632, 634, 634£. See also Ada;nantiades-Behc;:et's disease. in systemic lUpus erythematosus, 602 Orbit in cysticercosis, 468 in leukemia, 509 in polyarteritis nodosa, 655 in sarcoidosis, 715, 715f, 715t in schistosomiasis, 481, 482f in Wegener's granulomatosis, 663, 664t, 665f loiasis and, 464, 464t Orbit coils, in magnetic resonance imaging, 105 Orbital cellulitis, 534 Orbital inflammation, in Lyme borreliosis, 248-249 Orbital myositis, 186 Orbital pseudotumor, 116, 116f, 118 Oridus. See Ketoprofen (Oridus). Oriental spotted fever, 298, 298t Osalid. See Oxyphenylbutazone (Osalid, Tendearil) . Osteoarticular involvement, in brucellosis, 280 Outer retinal toxoplasmosis, 393-396, 394£, 395f Overdose of azathioprine, 189 of bromocriptine, 205 of chlorambucil, 184 of colchicine, 209 of cyclophosphamide, 182 of cyclosporine, 196 of dapsone, 203-204 of ketoconazole, 207 of methotrexate, 187 of nonsteroidal anti-inflammatory drugs, 173 of sirolimus, 199-200 OWD. See Ocular Whipple's disease (OWD). Oxyphenylbutazone (Osalid, Tendearil), 29t, 167t

P PA (psoriatic arthritis), 587-589, 588f juvenile, 592-593 Pain in amebiasis, 414 in ankylosing spondylitis, 582 in multiple sclerosis, 702 in polyarteritis nodosa, 654 in uveitis, 114 Palpable nodules, in onchocerciasis, 453-454 Palsy, seventh cranial nerve, 247-248 Pamidronate, uveitis induced by, 860t, 861-862 PAN. See Polyarteritis nodosa (PAN). Panda image, in sarcoidosis, 718, 718f Panda sign, in sarcoidosis, 110 Panencephalitis, subacute sclerosing, 338-340 Panretinal photocoagulation (PRP), for intermediate uveitis, 853 Panuveitis, 19, 19t, 20t classification of, 87, 87f epidemiology of, 21, 22t, 23, 24f in sympathetic ophthalmia, 742 in syphilis, 239, 239t initial work-up for, 93, 94t sarcoid-associated, 186 Papanicolaou's staining, for intraocularcentral nervous system lymphoma, 505

Papillary conjunctivitis, from atropine, 163 Papilledema in cryptococcosis, 498, 499f in Lyitle borreliosis, 248 in polyarteritis nodosa, 655 Papillitis, 93 in Adamantiades-Beht;:et's disease, 637-638 in birdshot retinochoroidopathy, 737 in Lyitle borreliosis, 248, 248f in polyarteritis nodosa, 655 in Toxoplasma neuroretinitis, 394, 395f Paracentesis, diagnostic, 215-216, 216f Paramethasone, chemistry of, 142, 143t Paraneoplastic retinopathy, 815 Paraneoplastic syndromes, 520-522 Parasitemia, in human immunodeficiency virus, 497 Parasites in onchocerciasis, 443, 450-451, 450f diagnostic methods for, 453, 453f in toxocariasis, 428. See also Toxocariasis. Parasitic endophthalmitis, 321 Parasympathetic fibers, 10 Parenchymatous neurosyphilis, 238, 238t Paresthesia, in multiple sclerosis, 702 Parinaud's oculoglandular syitdrome, 260, 262 Parlodel. See Bromocriptine (Parlodel). Paromomycin, for ameba infection, 414 Pars plana, 8, 8f, 9, 9f in cysticercus, 472 in intermediate uveitis, 845, 845f, 847 in uveitis, 93 Pars plana lensectomy (PPL) , 852, 853 Pars plana vitrectomy (PPV), 216 after Candida endophthalmitis, 366 for candidiasis, 367-368 for cataract surgery, 225, 226f for intermediate uveitis, 852, 853 for intraocular-central nervous system lymphoma, 505 for multifocal choroiditis and panuveitis, 764 for toxocariasis, 434 for toxoplasmosis, 404--405 Pars planitis azathioprine for, 188 in birdshot retinochoroidopathy, 737 in intermediate uveitis, 844 in retinal vasculitis, 827 Pars plicata, of ciliary body, 8-9, 9f PAS (periodic acid-Schiff) staining for Whipple's disease, 292, 292t Pathergy in Adamantiades-Beht;:et's disease, 634 PAU (phacoantigenic uveitis) in sympathetic ophthalmia, 744 paracentesis in, 215 PCR. See Polymerase chain reaction (PCR). PDS. See Pigment dispersion syndrome (PDS). Pefloxacin, for leprosy, 310, 311 Pemphigoid, cicatricial, 188 Penetrating ocular trauma, 573-575 Penetrating wound in sympathetic ophthalmia, 742, 744. See also Sympathetic ophthalmia. D-Penicillamine (DPA) , for scleroderma, 615 Penicillin for syphilis, 237, 241-242, 242t for Whipple's disease, 294, 591 )entamidine, for PneU1nocystic cminii choroidopathy, 427 )erfluoropropane, for retinal biopsy, 218 >erforating keratoplasty, 366 >eriarteritis. See also Polyartetitis nodosa (PAN).

Pericarditis in systemic lupus erythematosus, 602 in Wegener's granulomatosis, 663 Perimetry, in multifocal choroiditis and panuveitis, 758-759, 759f Periodic acid-Schiff (PAS) staining for Whipple's disease, 292, 292t Periorbital edema, in scleroderma, 613 Periostitis, in Reiter's syndrome, 584, 585f Peripapillary atrophy, in multifocal choroiditis and panuveitis, 758, 758f Peripapillary chorioretinal degeneration, 351, 352f Peripapillary choroidal coloboma, 354--355 Peripapillary laser photocoagulation, 357 Peripheral arthritis, in ankylosing spondylitis, 582 Peripheral lesions, Toxoplasma, 396 Peripheral nervous system (PNS) in extraocular examination, 94--95 in leprosy, 310 in Lyme borreliosis, 247 Peripheral ulcerative keratitis (PUK) in polyarteritis nodosa, 654--655, 655f in Wegener's granulomatosis, 663-664, 664t, 665f Peripheral uveitis. See Intermediate uveitis (IU). Peripheral uveoretinitis. See Intermediate uveitis (IU). Periphlebitis in Adamantiades-Beht;:et's disease, 637 in multiple sclerosis,703 ' Peritoneal ascariasis clinical characteristics of, 438 treatment of, 441-442, 44It Perornyscus leucopus, in Lyme borreliosis, 249 Pe'Dsistence of hyperplastic primary vitreous (PHPV),433 Persistent disease, in Lyme borreliosis, 247, 249 Personal medical history, 99-102 Phacoanaphylactic endophthalmitis. See Lensinduced uveitis (LIU). Phacoantigenic uveitis (PAU) in sympathetic ophthalmia, 744 paracentesis in, 215 Phacogenic uveitis, 817-821. See also Lensinduced uveitis (LIU). Phenobarbital, 183 Phenylacetic acids, 29t, 167t Phenylalkanoic acids, 29t, 167t Phenylbutazone (Azolid, Butazolidin), 29t, 167t Phenylephrine chemistry of, 159 clinical pharmacology of, 160-162, 160t history and source of, 159 pharmaceutics of, 162 pharmacokinetics and metabolism of, 162 pharmacology of, 159 potency of, 160t side effects and toxicity of, 164 structural formula of, 16lf therapeutic use of, 162-163 Philosophy, 27-33 immunomodulatory therapy and, 29-32, 30t nonsteroidal anti-inflammatory drugs and, 28-29 steroid therapy and, 27-28, 28t, 29t PHMB (polyhexamethyl biguanide), for ameba infection, 414 Photoactive dyes, for retinoblastoma, 516 Photocoagulation for diffuse unilateral subacute neuroretinitis, 478

Photocoagulation (Continued) for intermediate uveitis, 852-854 for multifocal choroiditis and panuveitis, 763-764 for ophthalmia nodosa, 490 for ophthalmomyiasis, 486 for presumed ocular histoplasmosis syitdrome, 355-358, 356f, 357f for punctate inner choroidopathy, 811 for retinal detachment, 322 for retinoblastoma, 516 for serpiginous cho,roiditis, 793 for toxocariasis, 434 for toxoplasmosis, 404, 405f of subretinal neovascular membrane, 233234, 233f, 234f Photometry, for birdshot retinochoroidopathy, 736 Photophobia, from atropine, 163 Phototherapeutic keratectomy, 222-223 PHPV (persistence of hyperplastic primary vitreous),433 PHTN. See Pulmonary hypertension (PHTN). Physostigmine salicylate, for anticholinergic overdose, 164 PIC. See Punctate inner choroidopathy (PIC). Picture optotypes, 90 Pigment atropine administration and, 161 in malignant melanoma, 510-511 in presumed ocular histoplasmosis syndrome, 351, 352f Pigment .cells in retinal detachment, 538 of iris, 3-4 Pigment dispersion syndrome (PDS), 550-553, 55lf Pigment epithelium of iris, 5, 5f, 6, 6f Pigmentary retinopathy in congenital rubella, 343, 343t, 344--345, 344f toxoplasmosis and, 396 Pigmented melanocytes, in anterior border layer, 5 Pigmented paravenous retinochoroidal atrophy, 337 Pilocarpine, for loiasis, 465 Pineal gland, in birdshot retinochoroidopathy, 734 Pinealoblastoma, 514 Pink-orange color, in malignant melanoma, 510 PION (posterior ischemic optic neuropathy), 621 Piperazine, for ascariasis, 441, 441 t Piroxicam (Feldene), 29t, 167t PIs (protease inhibitors), for human immunodeficiency virus, 493, 494f, 494t Plain radiography, 106 for intraocular foreign bodies, 548 for seronegative spondyloarthropathies, 114, 114t Plasma cells in Adamantiades-Beht;:et's disease, 641 in toxocariasis, 430 ocular surface immunity and, 68 Plasma exchange, for retinal vasculitis, 838 Plasma viscosity, in giant cell arteritis, 625 Plasmapheresis for hypersensitivity reactions, 60 for intermediate uveitis, 854 Platelets, 39, 39t Plumbers, uveitis in, 88 Pluripotential primordial stem cell, 39-40 PMB. See Post-measles blindness (PMB). PMNs. See Polymorphonuclear leukocytes (PMNs).

PMR (polymyalgia rheumatica), 620 Pneumocystic carinii choroidopathy, 425-427 Pneumocystis carinii pneumonia, 498, 498f Pneumocystosis, 425-427 .in human immunodeficiency virus, 498, 498f Pneumonia, Ascaris, 437, 440 Pneumonitis, from methotrexate, 187 PNS. See Peripheral nervous system (PNS). POHS. See Presumed ocular histoplasmosis syndrome (POHS). Poliosis, in Vogt-Koyanagi-Harada syndrome, 749,749f Polyangiitis. See Polyarteritis nodosa (PAN). Polyarteritis nodosa (PAN), 653-660 clinical characteristics of, 653-656, 654f definition of, 653 diagnosis of, 657 differential diagnosis of, 657 epidemiology of, 653 history and classification of, 653 pathogenesis and etiology of, 656 pathology of, 656-657, 657f prognosis for, 657-658, 658t retinal vasculitis in, 830 treatment of, 657 Polyarthralgia, in Whipple's disease, 291, 291t Polyarthritis, symmetric, 587 Polyarticular onset juvenile rheumatoid arthritis, 593, 593t, 595 Polychondritis, relapsing. See Relapsing polychondritis (RP). Polyhexamethyl biguanide (PHMB k for ameba infection, 414 Polymerase chain reaction (PCR) for bartonella,. 262 for diagnostic surgery, 215-216 for free-living amebas, 413 for intraocular-central nervous system lymphoma, 505-506 for leptospirosis, 275 for Lyme borreliosis, 252-253 for onchocerciasis, 453 for paracentesis, 215-216 for syphilis, 240t, 241 for toxoplasmosis, 400 for tuberculosis, 267 for uveitis testing, 95t, 96 for Whipple's disease, 287, 292-293, 292t, 591 Polymeric human immunoglobulins, 49, 49f Polymorphonuclear leukocytes (PMNs), 37-38, 37t, 38t in ameba infection, 412 in brucellosis, 279 Polymyalgia rheumatica (PMR), 620 Polypeptide chains, of immunoglobulins, 49 Pork, in toxoplasmosis transmission, 387 PORN. See Progressive outer retinal necrosis (PORN). Posner-Schlossmann syndrome, in Fuchs' heterochromic iridocyclitis, 697 Posterior ischemic optic neuropathy (PION), 621 Posterior pigmented iris epithelium, 4 Posterior scleritis, 126-127 Posterior segment in Adamantiades-Belwet's disease, 637-638, 637f-639f in leprosy, 308 in loiasis, 465 in sarcoidosis, 713-715, 713f, 714f Posterior subscapular cataracts (PSCs), 154 Posterior synechiae in Fuchs' heterochromic iridocyclitis, 694 in sarcoidosis, 713

Posterior uveitis, 19, 19t, 20t classification of, 82-86, 82t, 84f-86f differential diagnosis of, 79, 80t epidemiology of, 21, 22t, 23, 23f in inflammatory bowel disease-associated arthritis, 589, 590 initial work-up for, 93, 94t syphilitic, 239, 239t toxoplasmosis in, 385. See also Toxoplasmosis. Posterior vitreous detachment (PVD), 538, 539 Postganglionic parasympathetic fibers, 3, 10 Post-Lyme syndrome, 254 Post-measles blindness (PMB), 338 Postoperative endophthalmitis, chronic, 528-531, 528t, 530t Postoperative exogenous Candida endophthalmitis, 365-366 Postoperative uveitis, 103 Postsurgical inflammation, 170-171 Postsurgical uveitis, 573, 573t Post-traumatic exogenous Candida endophthalmitis, 365 Potassium iodide, for sporotrichosis, 383 PPL (pars plana lensectomy), 852, 853 PPY. See Pars plana vitrectomy (PPV). Prausnitz-Kiistner reaction, 59 Praziquantel, for schistosomiasis, 484 Pre-B lymphocyte, 45 Precipitin reaction, for cysticercosis, 471 Prednisolone chemistry of, 142, 143t for cataract surgery, 224 for giant cell arteritis, 626 for glaucoma surgery, 227 for intermediate uveitis, 851 for leprosy reactions, 311 for polyarteritis nodosa, 657 for punctate inner choroidopathy, 811 for toxocariasis, 434 for traumatic uveitis, 577 introduction and history of, 142 pharmaceutics of, 144-145, 145, 145t, 146t systemic preparation of, 28t topical preparation of, 28t Prednisone chemistry of, 142, 143t cyclosporine A and, 195 for acute retinal necrosis, 321 for bartonella, 262 for birdshot retinochoroidopathy, 738 for cataract surgery, 224 for diffuse unilateral subacute neuroretinitis, 478 for giardiasis, 418 for glaucoma surgery, 227 for multiple sclerosis, 706 for polyarteritis nodosa, 658 for sarcoidosis, 723 for serpiginous choroiditis, 793 for sympathetic ophthalmia, 746 for traumatic uveitis, 576, 577 for tubulointerstitial nephritis and uveitis syndrolue, 728-729 for Vogt-Koyanagi-Harada syndrome, 752 for Wegener's granulomatosis, 670 ketoconazole and, 206-207 pharmaceutics of, 145, 146t systemic preparation of, 28t Preferential looking test, 90 Pregnancy Adamantiades-Beh\=et's disease in, 638-639 antiphospholipid syndrome in, 690 azathioprine and, 189 chlorambucil and, 184

Pregnancy (Continued) cytomegalovirus and, 323 leptospirosis in, 273 rubella in, 343 toxoplasmosis during, 387, 389 treatment for, 405 Presumed ocular histoplasmosis syndrome (POHS), 348-363 clinical characteristics of, 349-353, 350f352f definition of, 348 diagnosis of, 354 differential diagnosis of, 354-355 epidemiology of, 348-349 fluorescein and indocyanine green angiography in, 127-129, 129f, 130f history of, 348 mycology of, 348 pathogenesis/pathophysiology/ immunology/pathology of, 353-354 subretinal fibrosis and uveitis syndrome versus, 802, 802t subretinal neovascular membrane from, 233-234, 233£ 234f treatment of, 355-360 amphotericin Bin, 360 corticosteroids in, 358-359 laser photocoagulation in, 355-358, 356f, 357f submacular/ subretinal surgery in, 359360 Primary biliary cirrhosis, 719, 719t Primary lymphoid organs, 40, 4lf, 42f, 42t Primordial stem cells, 39-40 Probenecid dapsone and, 204 for Lyme borreliosis, 253 Progressive outer retinal necrosis (PORN) acute retinal necrosis and, 318 in VZV retinitis, 497 Pneumoc)'stic cminii choroidopathy versus, 426-427 Progressive subretinal fibrosis punctate inner choroidopathy and, 806 with fundus flavimaculatus, 801 Progressive systemic sclerosis (PSS), 610 Proliferative vitreoretinopathy (PVR), 574 Pronstel. See Mefenamate (Pronstel). Propamidine (Brolene), for ameba infection, 414 Properdin factor B, in uveitis testing, 95t, 96 Propionibacterium" 217, 217f in endophthalmitis, 366, 528-529 in vitrectomy, 217, 217f Proptosis in retinoblastoma, 514 in Wegener's granulomatosis, 663, 665f Prostaglandins corticosteroids and, 144 nonsteroidal anti-inflammatory drugs and, 169-170, 170t Prostatitis, in extraocular examination, 94 Protease inhibitors (PIs), for human immunodeficiency virus, 493, 494f, 494t Protein corticosteroids and, .143 in paracentesis, 215 Protozoal infection, in retinal vasculitis, 831 Provera. See Medroxyprogesterone (Provera). PRP (panretinal photocoagulation), for intermediate uveitis, 853 Pseudohypopyon . in leukemia, 508 in syphilis, 239 Pseudophakic eyes, in retinal detachment, 539

INDEX Pseudo-presumed ocular histoplasmosis syndrome. See Multifocal choroiditis and panuveitis (Mep). Pseudoretinitis, Toxoplasma multiple, 396, 397f Pseudoretinitis pigmentosa, 545 Pseudotuberculosis, 488 Pseudo tumor diagnostic imaging of, 115-116, 115f, 116f, 118 methotrexate for, 186 Psoriatic arthritis (PA), 587-589, 588f juvenile, 592-593 PSS. See Progressive systemic sclerosis (PSS). Psychiatric care, for hypersensitivity reactions, 60 Psychiatric disturbances in Adamantiades-Behc;:et's disease, 635-636 in multiple sclerosis, 702 PUK (peripheral ulcerative keratitis) in polyarteritis nodosa, 654-655, 655f in Wegener's granulomatosis, 663-664, 664t, 665f Pulfrich phenomenon, in multiple sclerosis, 702 Pulmonary. See also Lungs. Pulmonary ascariasis clinical characteristics of, 437 diagnosis of, 440 treatment of, 441-442, 441t Pulmonary fibrosis angiotensin-converting enzyme in, 719, 719t from methotrexate, 187 in scleroderma, 612, 612f Pulmonary function tests, in sarcoidosis, 719 Pulmonary hemorrhage, in Wegener's granulomatosis, 662 Pulmonary hypertension (PHTN), in scleroderma, 612 Pulmonary infiltrates, in Wegener's granulomatosis, 662, 663f Pulmonary lesions, in systemic lupus erythematosus, 602 Pulmonary system in Adamantiades-Behc;:et's disease, 636 in brucellosis, 280 in giant cell arteritis, 620 Pulmonary toxicity, from methotrexate, 187 Punched-out multifocal lesions, in sarcoidosis, 714, 714f Puncta adherentia of pigmented epithelium, 9 Punctate inner choroidopathy (PIC), 806-812 angiography of, 129, 129f birdshot retinochoroidopathy versus, 736t, 737 clinical characteristics of, 807-808, 807f, 808f,808t complications of, 811 definition of, 806 diagnosis of, 809-810, 809t, 810f differential diagnosis of, 355 epidemiology of, 806-807 history of, 806 in presumed ocular histoplasmosis syndrome, 355 in subretinal fibrosis and uveitis syndrome, 797 multifocal choroiditis and panuveitis and, 757, 761, 762-763 pathophysiology of, 808-809 prognosis for, 811 subretinal fibrosis and uveitis syndrome versus, 802, 802t, 803t treatment of, 810-811 Punctate keratitis, in onchocerciasis, 449

Punctate outer retinal toxoplasmosis, 393-396, 394£ 395f diagnosis of, 401 differential diagnosis of, 397 Pupil(s) function of, 7 gross appearance of, 4 in clinical examination, 90 in Lyme borreliosis, 248 Pupillary expansion, in cataract surgery, 225, 225f Pupillary nodules in Fuchs' heterochromic iridocyclitis, 694 in Vogt-Koyanagi-Harada syndrome, 748, 749f Pupillary ruff, 4 Purified protein derivative (PPD), in uveitis testing, 95t, 96 Purpura, in Wegener's granulomatosis, 663 Puumala virus, 335 PVR (proliferative vitreoretinopathy), 574 Pyrantel pamoate, for ascariasis, 441, 44It Pyrazolones, 29t, 167t Pyrimethamine, for toxoplasmosis, 401, 402, 403t during pregnancy, 405

Q Q fever, 298, 298t clinical characteristics of, 301, 301t epidemiology of, 299-300 history of, 298-299 • pathophysiology of, 300 treatment of, 303 Queensland tick typhus, 298, 298t clinical characteristics of, 301 t Quinacrine hydrochloride, for giardiasis, 417 QUinolones, for rickettsial diseases, 303

R RA. See Rheumatoid arthritis (RA). Radial bands of fibrosis, 798, 799f Radial keratoneuritis, 412 Radiation exposure, in computed tomography, 104 Radiation therapy for intraocular-central nervous system lymphoma, 506 for malignant melanoma, 512-513 for retinoblastoma, 515-516 Radio frequency (RF) energy, in magnetic resonance imaging, 104-105 Radiography, 106 for cysticercosis, 471 for intermediate uveitis, 848 for intraocular foreign bodies, 548 for presumed ocular histoplasmosis syndrome, 354 for sarcoid suspect, 109-110, 109f for Takayasu's arteritis, 112 for uveitis, 95t, 96 Radioimmunoassay (RIA) in onchocerciasis, 454 Radiology for sarcoidosis, 717-718, 717f, 718t for toxocariasis, 433 salivary gland, 107 .Radionuclide scintigraphy, 106 Raised skin lesions, in leprosy, 310 Raji cell assay, 95t, 96 Rapamycin. See Sirolimus (rapamycin). Rapid plasma reagin (RPR) test, for syphilis, 240, 240t, 241 Rash in extraocular"examination, 94 in syphilis, 238, 238t

Rash (Continued) in systemic lupus erythematosus, 601, 602f Raynaud's phenomenon in scleroderma, 611, 61lf in systemic lupus erythematosus, 602 Recurrent aphthous ulcers, in AdamantiadesBehc;:et's disease, 632. See also Adamantiades-Behc;:et's disease. Recurrent uveitis, 87, 87t Red pulp of spleen, 40, 42f Red-dot card screening test, in onchocerciasis, 453 Reese-Ellsworth criteria, for retinoblastoma, 515, 515t, 516 Regional corticosteroids pharmaceutics of, 145-147, 146t pharmacokinetics, concentration-effect relationship, and metabolism of, 147-150, 148t, 149t Regional immunity, 67-71 Regulatory T cells, 36 Reiter's syndrome (RS), 584-587, 585f, 586f, 586t Adamantiades-Behc;:et's disease versus, 634, 642 juvenile, 592 methotrexate for, 186 psoriatic arthritis versus, 588 Relapsing fever, in borreliosis, 255-256 Relapsing infection, in brucellosis, 280 Relapsing polychondritis (RP), 676-682 azathioprine for, 188 clinical characteristics of, 676-677, 677f clinical manifestations of, 677-678 definition of, 676 diagnosis of, 679 imaging for, 113 epidemiology of, 676 history of, 676 pathophysiology/immunology/pathology/ pathogenesis of, 678-679 prognosis for, 680 retinal vasculitis in, 830 scleritis associated with, 203 treatment of, 679-680 Relative afferent pupillary defect (RAPD), 90 Renal. See also Kidneys. Renal crisis, in scleroderma, 612-613 Renal failure, from methotrexate, 187 Renal insufficiency, in sarcoidosis, 711 Renal lesion, in Wegener's granulomatosis, 667 Renal syndrome, hemorrhagic fever with, 335 Renal system in antiphospholipid syndrome, 684-685, 684t in polyarteritis nodosa, 653 in relapsing polychondritis, 677 in systemic lupus erythematosus, 602, 605 Renal-ocular syndrome, 726. See also Tubulointerstitial nephritis and uveitis (TINU) syndrome. Respiratory system in Adamantiades-Behc;:et's disease, 636 in coccidioidomycosis, 373 in Wegener's granulomatosis, 661,.:661t, 662, 666 Reticulum cell sarcoma, 503-506, 504f Retina angiography of, 137 in Adamantiades-Behc;:et's disease, 637, 637f in clinical examination, 92-93 in diffuse unilateral subacute neuroretinitis, 476, 476f in leukemia, 507, 507f in loiasis, 464, 464t

Retina (Continued) in rickettsial diseases, 302, 302f in Wegener's granulomatosis, 666 susceptibility of, to Candida infections, 366 therapeutic surgery of, 229-234, 230f-234£ Retinal arteriolar occlusions, in retinal vasculitis, 828 Retinal arteritis, 603, 604f Retinal artery, in systemic lUpus erythematosus, 605, 605f Retinal artery occlusion in Adamantiades-Behc;:et's disease, 637, 638f in giant cell arteritis, 621, 622 Retinal autoimmunity, in birdshot retinochoroidopathy, 733, 734 Retinal biopsy, 217-218, 218f for endophthalmitis, 533 Retinal capillary microaneurysms, 605, 605f Retinal detachment (RD) in acute retinal necrosis, 322 in GMV retinitis, 497 in endophthalmitis, 534 in intermediate uveitis, 846, 846f in ocular toxoplasmosis, 397 in punctate inner choroidopathy, 807, 807f in sarcoidosis, 713 in serpiginous choroiditis, 794 in syphilis, 239, 239t, 242 in toxocariasis, 430, 430f, 432f in Vogt-Koyanagi-Harada syndrome, 748, 748f rhegmatogenous, 537-541. See also Rhegmatogenous retinal detachment. therapeutic surgery for, 230-231, 230f, 231£ Retinal glioma, 513 Retinal granuloma, in diffuse unilateral subacute neuroretinitis, 475 Retinal hemorrhage in Adamantiades-Behc;:et's disease, 637 in ocular toxoplasmosis, 397 Retinal ischemia, after retinal surgery, 231, 232f Retinal necrosis in herpes simplex virus clinical characteristics of, 317-318, 318f diagnosis of, 320-321 pathogenesis of, 319-320 treatment of, 321-322 in VZV retinitis, 497 Retinal neovascularization after retinal surgery, 231, 232f, 233f in birdshot retinochoroidopathy, 732-733 in clinical examination, 93 in intermediate uveitis, 844, 845f in retinal vasculitis, 833 Retinal nerve fiber atrophy, 703 Retinal pigment epitheliitis, 780-786. See also Acute retinal pigment epitheliitis (ARPE). Retinal pigment epithelium (RPE) appearance of, 8 disturbance of, 93 in acute posterior multifocal placoid pigment epitheliopathy, 774 in acute zonal occult outer retinopathy, 813, 813f, 814 in onchocerciasis, 449-450, 450f in schistosomiasis, 483 in serpiginous choroiditis, 787, 788-789 in subretinal fibrosis and uveitis syndrome, 797. See also Subretinal fibrosis and uveitis (SFU) syndrome. in syphilis, 239, 239t in toxoplasmosis, 400-401 in Vogt-Koyanagi-Harada syndrome, 749, 749f, 751

Retinal toxoplasmosis punctate outer, 393-396, 394£, 395f diagnosis of, 401 differential diagnosis of, 397 serpiginous choroiditis versus, 792 Retinal vasculitis, 822-843 after radiotherapy, 517 anatomic classification of, 19, 20t angiography in, 127, 128f as manifestation of neurologic disease, 827828 clinical characteristics of, 823-825, 824t, 825f complications of, 833 definition of, 822, 822f, 823t drug~nduced, 830-832 epidemiology of, 823 history of, 822-823 humoral immunity and immune complexes in, 837 in birdshot retinochoroidopathy, 737 in intermediate uveitis, 846, 846f in multiple sclerosis, 703 in ocular disease, 825-827, 825f, 826f in polyarteritis nodosa, 655, 655f in syphilis, 239, 239t in systemic autoimmune disease, 828-829, 828f in systemic vasculitis, 829-830 in Wegener's granulomatosis, 666 infections associated with, 830-832 initial work-l,lp for, 93, 94t methotiexate for, 186 pathophysiology of, 833-837, 834f-836f prognosis for, 839-840 secondary to malignancy, 832-833 treatment of, 837-839, 839f Retinal vein occlusion, in AdamantiadesBehc;:et's disease, 637, 638f Retinal vessels, in loiasis, 464, 464t Retinal wipeout, 103 Retinitis, 93 angiography in, 133 in differential diagnosis, 103 in human immunodeficiency virus, 493498, 495f-498L 496t in measles, 337, 338 in subacute sclerosing panencephalitis, 338, 339, 339f in syphilis, 239, 239t in toxocariasis, 431, 431£, 432f in Wegener's granulomatosis, 666 Rift Valley fever versus, 335 toxocariasis versus, 433 varicella zoster infection and, 318 Retinitis pigmentosa (RP), 541-546 clinical features of, 543, 543f complications of, 546 definition of, 541-542 diagnosis of, 544-545 differential diagnosis of, 545 epidemiology of, 542-543 history of, 542 pathogenesis and etiology of, 543-544 prognosis for, 546 treatment of, 545 Retinoblastoma, 513-517, 515f, 515t Coats' disease versus, 105-106 cysticercosis versus, 471 diagnostic imaging of, 116, 117f toxocariasis versus, 433 Retinochoroiditis cysticercosis versus, 471 in ocular toxoplasmosis, 391-392, 391£-393f in toxoplasmosis, 385 acute retinal necrosis versus, 321

Retinochoroiditis (Continued) angiography in, 133-134, 133f, 134f congenital, 389, 389f diagnosis of, 400, 401£ in AIDS patients, 390-391 Retinochoroidopathy, birdshot. See Birdshot retinochoroidopathy (BSRC). Retinopathy acute zonal occult outer, 813-816 cancer-associated, 832-833 diabetic, 555 human immunodeficiency virus, 494-495, 495f in congenital rubella, 343, 343t, 344f diagnosis of, 344-345 in herpes simplex virus clinical characteristics of, 318-319 diagnosis of, 320 in measles, 337, 338 in retinal vasculitis, 832-833 in systemic lupus erythematosus, 603, 603t, 604£ of prematurity, 433 paraneoplastic, 815 rubella, 545 unilateral pigmentary, 396 vaso-occlusive, 686 Retinoschisis, age-related degenerative, 539 Retinotomy, for cysticercus, 472 Reverse-transcriptase inhibitors, 493, 494f, 494t Rhegmatogenous retinal detachment, 537-541 clinical features of, 538 complications of, 541 definition of, 537 diagnosis of, 539-540 differential, 540-541, 540f epidemiology of, 538 from ocular toxoplasmosis, 397 history of, 537-538 pathogenesis and etiology of, 538-539 prognosis for, 541 treatment of, 541 Rheumatic diseases, 79 Rheumatoid arthritis (RA) imaging for, 111, 111£ in subretinal fibrosis and uveitis syn.drome, 801 juvenile, 593-596, 593t, 594f, 596f. See also Juvenile rheumatoid arthritis (JRA). leflunomide for, 189-190 malignancy and, 32 methotrexate for, 186 Rheumatoid disease, 829 Rheumatoid factor in uveitis testing, 95t, 96 in Wegener's granulomatosis, 668 Rheumatoid spondylitis, 581. See also Ankylosing spondylitis (AS). Rheumatrex. See Methotrexate (Folex, Mexate, Rheumatrex). RIA. See Radioimmunoassay (RIA). Rickettsia rickettsii, 297

Rickettsial diseases, 297-304 clinical characteristics .of, 300-302, 30lt, 302f complications of, 303 definition of, 297-298, 298t diagnosis of, 302 epidemiology of, 298t, 299-300 history of, 298-299 immunology of, 300 pathogenesis of, 300 pathology of, 300 pathophysiology of, 300

Rickettsial diseases (Continued) prognosis for, 303 treatment of, 302-303 Rickettsialpox, 298, 298t clinical characteristics of, 301, 301 t epidemiology of, 299 Rifabutin for toxoplasmosis, 404 uveitis induced by, 860t, 864-865 Rifabutin-relateduveitis, 499-500, 499f Rifampin dapsone and, 204 for bartonella, 262 for brucellosis, 283 for leprosy, 310, 311 for rickettsial diseases, 303 Rifapentine, for toxoplasmosis, 404 Rift Valley fever (RVF), 333-335 in retinal vasculitis, 832 Rimexolone, 149 topical preparation of, 28t Ring melanoma, 510 Risedronate, uveitis induced by, 860t, 861-862 Rocky Mountain spotted fever (RMSF), 298, 298t clinical characteristics of, 300-301, 301 t epidemiology of, 299 history of, 298 in retinal vasculitis, 831 Rofecoxib (Vioxx), 29t, 167t Root of iris, 4 Roseolae of iris, 238, 238t Roth spots in candidiasis, 365 in endophthalmitis, 533 in leukemia, 507 Round worms, in diffuse unilateral subacute neuroretinitis, 476 Roxithromycin, for toxoplasmosis, 404 RP. See Relapsing polychondritis (RP). RPE. See Retinal pigment epithelium (RPE). RPR (rapid plasma reagin) test for syphilis, 240, 240t, 241 RS. See Reiter's syndrome (RS). Rubella, 343-347 acquired, 345-346 congenital, 343-345, 343t, 344f definition of, 343 history of, 343 Rubella retinopathy, 545 Rubeola. See Measles. Rubeosis, from ocular ischemic syndromes, 556 Rufen. See Ibuprofen (Advil, Motrin, Nuprin, Rufen). Russell bodies, in Fuchs' heterochromic iridocyclitis, 694 RVF (Rift Valley fever), 333-335 in retinal vasculitis, 832

S Sabin-Feldman test, for toxoplasmosis, 385, 398 Sacroiliac joint in ankylosing spondylitis, 582,582f in extraocular examination, 94 x-ray of, 106 Sacroiliitis in Adamantiades-Belwet's disease, 636 in inflammatory bowel disease-associated arthritis, 589 in Reiter's syndrome, 584 in uveitis, 114 Saddle-nose deformity, in relapsing polychondritis, 676, 677f S-AG (S-antigen), in birdshot retinochoroidopathy, 733, 734

Salicylates, 29t, 167t Salivary gland radiology, 107 Salt-and-pepper pigmentary retinopathy, 343, 343t, 344f San Joaquin Valley fever, 373-376 Sanguinopurulent inflammation, 88 S-antigen (S-Ag), in birdshot retinochoroidopathy, 733, 734 Sarcoid chorioretinopathy, 132-133 Sarcoid granulomas, 712, 712f Sarcoid-associated panuveitis, 186 Sarcoid-like disturbances, in Whipple's disease, 291 Sarcoidosis, 710-725 acute retinal necrosis versus, 321 acute zonal occult outer retinopathy versus, 816 Adamantiades-Beh<;:et's disease versus, 642 birdshot retinochoroidopathy versus, 736737, 736t characteristic presentations of, 715-716 complications of, 723 definition and history of, 710 diagnosis of, 79, 721, 721£ diagnostic imaging studies for, 108f, 109110, 109f differential diagnosis of, 721-722, nIt epidemiology of, 710-711 etiology and pathogenesis of, 717-721, 717f, 718f, 718t, 719t histology of, 716-717, 716f in juvenile rheumatoid arthritis, 595 in optic disc, 93 • intermediate uveitis versus, 849 multifocal choroiditis and panuveitis versus, 762 multiple sclerosis and, 706 ocular manifestations of, 712-715, 712f715f, 715t prognosis for, 723 retinal vasculitis in, 828, 828f subretinal fibrosis and uveitis syndrome versus, 803 systemic manifestations of, 711-712,711£, 712f, 712t treatment of, 722-723 Whipple's disease versus, 293 Sarcoma granulocytic, 509 reticulum cell, 503-506, 504f SAT. See Serum agglutination test (SAT) . Sattler's layer, 14 Sausage digits in psoriatic arthritis, 587, 588f in Reiter's syndrome, 584, 585f SC. See Serpiginous choroiditis (SC). Scaling of skin, 94 Scanning laser densitometry studies, 770 Scanning laser ophthalmoscopy, 815 Scars in Fuchs' heterochromic iridocyclitis, 695, 696 in ophthalmomyiasis, 485-486, 486f in presumed ocular histoplasmosis syndrome, 351, 352f in subretinal fibrosis and uveitis syndrome, 798, 799f in Vogt-Koyanagi-Harada syndrome, 749, 749f Scatter laser photocoagulation, 853-854 Schaumann's bodies, in sarcoidosis, 716 Schistosomiasis, 480-484, 482f, 483f Schwalbe's contraction, 4 Sclera immunity of, 68-69 in clinical examination, 90

Sclera (Continued) in leprosy, 307 in relapsing polychondritis, 676 in scleroderma, 613, 613f in uveitis, 89, 89t in Wegener's granulomatosis, 667, 667f Scleritis amebas in, 412 angiography in, 126-127 corticosteroids for, 151 dapsone for, 203 imaging studies for, 110-113, 110f-113f in amebiasis, 414 in ankylosing spondylitis, 583 in differential diagnosis, 103 in inflammatory bowel disease-associated arthritis, 590 in leprosy, 307, 311 in psoriatic arthritis, 588 in Reiter's syndrome, 586 in relapsing polychondritis, 677-678 in systemic lupus erythematosus, 603 in toxocariasis, 432 in Wegener's granulomatosis, 663-664, 664t, 665f methotrexate for, 186 Scleroderma, 610-618 clinical characteristics of, 611-614, 611£614f definition of, 610 diagnosis of, 611 t, 615 epidemiology of, 610-611, 611t history of, 610 pathophysiology, immunology, pathology, and pathogenesis of, 614-615 prognosis for, 616 treatment of, 615-616 Scleroderma renal crisis (SRC), 612-613 Sclerokeratitis, in polyarteritis nodosa, 654, 655 Sclerosing panencephalitis, subacute, 338-340 Sclerosing vitritis, in toxocariasis, 430 Sclerosis keratitis, in onchocerciasis, 449, 449f Sclerotomy, for cysticercus, 472 Sclerouveitis anatomic classification of, 20, 20t cornea and sclera in, 89, 89t Scolex in cysticercosis, 469, 469f, 470 Scopolamine chemistry of, 159 clinical pharmacology of, 161 for traumatic uveitis, 577 history and source of, 159 potency of, 160t side effects and toxicity of, 164 structural formula of, 161£ therapeutic use of, 163 Scotomata in multifocal choroiditis and panuveitis, 758, 759f Scrub typhus, 298, 298t clinical characteristics of, 301 t epidemiology of, 299 pathophysiology of, 300 Secondary malignancies, from cyclophosphamide, 182 Secreted antigens, in toxoplasmosis, 388, 388t Segmented worms, in diffuse unilat~ral subacute neuroretinitis, 476 Seizures, in cerebral cysticercosis, 469 Senile halo, in presumed ocular histoplasmosis syndrome, 354 Sennetsu fever, 298, 298t, 301 t Sensorineural hearing loss, in relapsing polychondritis, 679 Sensory disturbance, in multiple sclerosis, 702 Sentinel vessels, in malignant melanoma, 510, 511£

INDEX Septicemic stage, of leptospirosis, 273 Serologic testing for Adamantiades-Beh~et'sdisease, 642 for coccidioidomycosis, 374 for diffuse unilateral subacute neuroretinitis, 477 for intermediate uveitis, 848 for Lyme borreliosis, 251-252 for relapsing fever, 256 for syphilis, 240-241, 240t for toxoplasmosis, 398-400, 399t for Vogt-Koyanagi-Harada syndrome, 752 Seronegative spondyloarthropathies, 581-600 ankylosing spondylitis in, 581-584, 582f, 583t enteropathic arthritis in, 589-592 imaging studies for, 114-115, 114£, 114t juvenile arthritis in, 592-596, 593t, 594f, 596f psoriatic arthritis in, 587-589, 588f Reiter's syndrome in, 584-587, 585f, 586f, 586t Serous retinal detachment (SRD), 239, 239t Serpiginous choroiditis (SC), 787-,.796 acute posterior multifocal placoid pigment epitheliopathy versus, 777 angiography in, 121, 123f clinical characteristics of, 787-789, 788f, 788t, 789f complications of, 794 definition of, 787 diagnosis of, 790-791, 790f, 791£ differential diagnosis of, 791-792, 79lt diffuse unilateral subacute neuroretinitis versus, 477 epidemiology of, 787 history of, 787 pathogenesis/immunology/pathology of, 789-790 prognosis for, 794 subretinal fibrosis and uveitis syndrome versus, 803 summary of, 809, 809t toxoplasmosis versus, 397 treatment of, 792-794 Serum agglutination test (SAT), for brucellosis, 282 Seventh cranial nerve palsy, in Lyme borreliosis, 247-248 Sewer workers, 88 Sexual dysfunction, in multiple sclerosis, 702 Sexual transmission, in AdamantiadesBeh~et's disease, 633 SFU syndrome. See Subretinal fibrosis and uveitis (SFU) syndrome. Sheep nasal botfly, in ophthalmomyiasis, 485-487, 486f Shigella flexneri, in ankylosing spondylitis, 583 Sialic acid, in sympathetic ophthalmia, 574-575 Sialography, 107 Siberian tick typhus, 298, 298t, 30lt Signal transduction, 43, 44£ Silicosis, 719, 719t Simulium fly, in onchocerciasis, 443 Single photon emission computed tomography (SPECT), 107 Sinus films of, 106 in Wegener's granulomatosis, 662, 662f Sirolimus (rapamycin) adverse reactions of, 178, 178t dosage and route of administration of, 30t, 178t for immunosuppressive chemotherapy, 196200

Sirolimus (rapamycin) (Continued) indications for, 179, 179t Sjogren's syndrome diagnostic imaging for, 113 in systemic lupus erythematosus, 603 Sjogren's syndrome A (SS-A) antigen, 829 Skin in Lyme borreliosis, 246 in onchocerciasis, 446, 446t, 453, 453f in uveitis, 93-94 in Vogt-Koyanagi-Harada syndrome, 749750, 749f, 750f Skin biopsy in polyarteritis nodosa, 657 in sarcoidosis, 721 Skin lesions in Adamantiades-Beh~et'sdisease, 632, 634, 634£. See also Adamantiades-Beh~et's disease. in leprosy, 306, 310 in onchocerciasis, 446-448, 447f, 448f in psoriatic arthritis, 587 in relapsing polychondritis, 677 in sarcoidosis, 711, 711£, 712f Skin test for bartonella, 262 for coccidioidomycosis, 374 for onchocerciasis, 454 for sarcoidosis, 717 for tuberculosis, 266-267 uveitis induced by, 859, 860t SLE. See Systemic lupus erythematosus (SLE). Sleeping sickness, 420. See also Trypanosomiasis. Slit-lamp examination, 90 for intraocular foreign bodies, 548 for intraocular-central nervous system lymphoma, 503 for onchocerciasis, 453 for retinal detachment, 540 nonsteroidal anti-inflammatory drugs for, 170, 171 Smooth muscle cells in giant cell arteritis, 623 of posterior pigment epithelium, 6 Snellen acuity chart, 90 Snowballs in intermediate uveitis, 844, 845f in ophthalmia nodosa, 488, 489f in sarcoidosis, 713, 713f Snowbanks, in intermediate uveitis, 845, 845f Snowman, in ophthalmia nodosa, 488, 489f Social history, 99 Sodium phosphate, 29t Soft ticks, 297 Soluble interleukin-2 receptor, 95t, 96 Solu-Medrol, 28t, 29t for traumatic uveitis, 577 Sowda, 446-448 Sparfloxacin, for leprosy, 310, 311 Specimen collection, for loiasis, 465 SPECT. See Single photon emission computed tomography (SPECT). Spectroscopy, magnetic resonance, 106 Speech disturbance, in multiple sclerosis, 702 Sphincter muscle of iris, 4, 5, 5f Sphincter pupillae, 5, 7 Spiders, in ophthalmia nodosa, 488-491, 489f Spin density images, 105 Spinal cord, in schistosomiasis, 481 Spine, in ankylosing spondylitis, 582, 582f Spiramycin, for toxoplasmosis, 402, 403t, 405 Spirochetemic phase, of leptospirosis, 273 Spirochetes, 297 in syphilis diagnosis, 240-241 Spirocheturic phase, of leptospirosis, 273

Spleen characteristics of, 40, 41£ in sarcoidosis, 711 Splendore-Hoeppli phenomenon, in toxocariasis, 431 Splinter hemorrhage, in giant cell arteritis, 620, 621£ Spondylitis ankylosing, 581-584, 582f, 583t in Adamantiades-Beh~et'sdisease, 636 juvenile, 592 cervical, 592 in Reiter's syndrome, 584 rheumatoid, 581. See also Ankylosing spondylitis (AS). Spondyloarthritis, 587-588 Spondyloarthropathies, seronegative. See Seronegative spondyloarthropathies. Sporanox (itraconazole), for coccidioidomycosis, 374 Sporothrix schenckii endophthalmitis, 498 Sporotrichosis, 380-384 clinical characteristics of, 380-382 definition of, 380 diagnosis of, 383 differential, 383 epidemiology of, 380, 380f, 381£ history of, 380 pathology of, 382 prognosis for, 383 treatment of, 383 Sporozoites, in toxoplasmosis, 385, 386, 387 Sports iruuries, 573 Spotted fever classification of, 298, 298t clinical characteristics of, 300-301, 30lt epidemiology of, 299 history of, 298 pathophysiology of, 300 SRC. See Scleroderma renal crisis (SRC). SRD (serous retinal detachment), 239, 239t SRNV. See Subretinal neovascularization (SRNV). SS recombination, 48, 251£ SS-A (Sjogren's syndrome A) antigen, 829 SSe. See Systemic sclerosis (SSc). Staining for ameba infection, 413 for endophthalmitis, 530 for intraocular-central nervous system lymphoma, 505 for sporotrichosis, 383 Staphylococcus endophthalmitis caused by, 366 in Wegener's granulomatosis, 662 Stellate neuroretinitis, 260 Sterility, 31-32 Steroid-resistant cyclitis, 186 Steroids chemistry of, 142, 143t for acute posterior multifocal placoid pigment epitheliopathy, 777 for acute retinal necrosis, 321 for ankylosing spondylitis, 583-584 for birdshot retinochoroidopathy, 738 for giant cell arteritis, 626 for iridocyclitis and trabeculitis, 321 for multifocal choroiditis and panuveitis, 763 for rickettsial diseases, 303 for sarcoidosis, 722, 723 for traumatic uveitis, 576, 577 for tubulointerstitial nephritis and uveitis syndrome, 728-729 for Vogt-Koyanagi-Harada syn.drome, 752 for Whipple's disease, 293-294

Steroids (Continued) synthesis of, 207 therapy with, 27-28, 28t, 29t uveitis induced by, 860t, 862-865 Stevens-:Johnson syndrome, 634 Stimon's line; in measles, 337 Streptococcus sanguis, 639

Streptomycin for brucellosis, 283 for Whipple's disease, 294, 591 Stress fracture, 115 Stress, in recurrent uveitis, 32 String of pearls in candidiasis, 365, 365f in sarcoidosis, 713 Stroma of choroid, 12-13, 12f, 13f of ciliary body, 9 of iris, 5, 5f Stromal nodules, in Fuchs' heterochromic iridocyclitis, 694 Subacute neuroretinitis, 471 Subacute sclerosing panencephalitis, 338-340, 339f Subconjunctiva, in cysticercosis, 468 Subcutaneous nodules in extraocular examination, 94 in polyarteritis nodosa, 654 Subfoveal laser photocoagulation, 355, 356f, 357-358, 357f Subfoveal surger~ 764 Submacular neovascularization, 351 Submacular space, in cysticercosis, 472 Submacular surgery, 359-360 Subretinal cysticercosis, 469 Subretinal fibrosis and uveitis (SFU) syndrome, 797-805 clinical features of, 798, 798f, 799f definition of, 797 diagnosis of, 800-801, 800t differential diagnosis of, 802-803, 802t, 803t diseases with, 801-802 epidemiology of, 797-798 histopathology of, 798-799 history of, 797, 798f, 806 multifocal choroiditis and panuveitis and, 757, 761, 762-763 pathogenesis of, 799-800 prognosis for, 803-804 punctate inner choroidopathy and, 806808 treatment of, 803 Subretinallesions, 218, 218f Subretinal neovascular membrane, 233-234, 233f,234f Subretinal neovascularization (SRNV) in congenital rubella, 343 in serpiginous choroiditis, 794 in Vogt-Koyanagi-Harada syndrome, 753 Subretinal space, in cysticercosis, 470, 472 Subretinal surger~ 359-360 Succinylcholine, 183 Sugiura's sign, in Vogt-Koyanagi-Harada syndrome, 748-749, 749f Sulfadiazine, for toxoplasmosis, 405 Sulfahexafluoride, for retinal biopsy, 218 Sulfamethoxazole for Pneumocystic carinii choroidopathy, 427 for toxoplasmosis, 403-404, 403t Sulfasalazine for inflammatory bowel disease-associated arthritis, 590 for multiple sclerosis, 707 Sulfonamides for toxoplasmosis, 402

Sulfonamides (Continued) uveitis induced by, 860t, 865 Sulindac. (Clinoril), 29t, 167t Sunset-glow appearance, in Vogt-KoyanagiHarada syndrome, 749, 749f Superficial keratectomy, 222-223 Superficial punctate keratitis, 91 Suppressor T cells, in immune response regulation, 66 Suprachoroid lamina, 12, 12f Supraciliary layer, 10 Suprofen, 168t Suramin, for onchocerciasis, 454-455, 456 Surface antigens, in toxoplasmosis, 388, 388t Surgery diagnostic, 215-221. See also Diagnostic surgery. exogenous Candida endophthalmitis after, 365-366 for intermediate uveitis, 852-853 for sympathetic ophthalmia, 746 sympathetic ophthalmia after, 742 Surgical iridectomy, 223-224 Swallowing disturbance, in multiple sclerosis, 702 Symmetric polyarthritis, 587 Symmetrical hilar lymphadenopathy, 71 7-718, 717f, 718t Sympathetic fibers, 10 Sympathetic nervous system, in Fuchs' heterochromic iridocyclitis, 696 Sympathetic ophthalmia, 742-747 after penetrating ocular trauma, 574-575 birdshot retinochoroidopathy versus, 736t, 737 clinical features of, 742-743, 743f definition of, 742 differential diagnosis of, 745-746, 745t etiology of, 744-745 history of, 742 incidence and epidemiology of, 742 pathology and pathogenesis of, 743-744, 744f prevention and management of, 746 prognosis for, 746 steroid-resistant, methotrexate for, 186 subretinal fibrosis in, 797, 798f Sympathetic uveitis, 125-126, 125f-127f Sympathizing eye, 742. See also Sympathetic ophthalmia. Synechiae in differential diagnosis, 103 prevention of, 163 Syneresis, in retinal detachment, 539 Syphilis, 237-244 birdshot retinochoroidopathy versus, 736, 736t clinical presentation of, 237-239, 238t, 239t complications of, 242-243 definition of, 237 diagnostic tests for, 240-241, 240t epidemiology of, 237 history of, 237 in human immunodeficiency virus, 499 in human immunodeficiency virus infection, 242 in retinal vasculitis, 830 intermediate uveitis versus, 850 pathology and pathogenesis of, 239-240 prognosis for, 243 treatment of, 241-242, 242t Systemic autoimmune disease, 828-829, 828f Systemic Hodgkin's disease, 503-506, 504£ Systemic immune response, in onchocerciasis, 452-453 Systemic lupus erythematosus (SLE), 601-609 definition of, 601

Systemic lupus erythematosus (SLE) (Continued)

diagnosis of, 607 diagnostic imaging for, 112 epidemiology of, 601 FA and ICGA of, 127, 128f history of, 601, 601 t ocular manifestations of, 602-606, 603f, 603t, 604f, 604t pathophysiology of, 606-607 prognosis for, 608 retinal vasculitis in, 829-830 systemic manifestations of, 601-602, 601 t, 602 treatment of, 607-608 Systemic necrotizing vasculitis, 661. See also Wegener's granulomatosis. Systemic non-Hodgkin's lymphoma, 503-506, 504f Systemic sclerosis (SSc), 610. See also Scleroderma.

T T cell(s), 34-36,40,52-56 autoimmune, 63-64 cytotoxic, 36 effector, 62-64, 63f helper, 36 hypersensitivity reactions mediated by, 64, 64t immunopathogenic, 63 in acute retinal necrosis, 318 in Adamantiades-Beh~et'sdisease, 639, 641 in giant cell arteritis, 623, 624 in intermediate uveitis, 847 in multiple sclerosis, 704 in retinal vasculitis, 834 in sarcoidosis, 717 in toxoplasmosis, 387 in tubulointerstitial nephritis and uveitis syndrome, 727 in Vogt-Koyanagi-Harada syndrome, 750751 in Wegener's granulomatosis, 666 lymphoma of, 503, 504 ocular surface immunity and, 68 T cell-dependent inflammation, 55-56 Tabes dorsalis, 238, 238t Taches de bougie, 713-714 Tachyzoites, in toxoplasmosis, 385-388, 386f, 398 Tacrolimus. See FK 506 (tacrolimus). Taenia saginata, 468. See also Cysticercosis. Taenia solium, 468. See also Cysticercosis. Takayasu's arteritis, 112 Tapeworm infection, in cysticercosis, 468, 469f Tapioca melanoma, 510 Tarantulas, in ophthalmia nodosa, 488-491, 489f Target cells and cytokines, 44, 45t TB. See Tuberculosis (TB). TBLB (transbronchiallung biopsy), in sarcoidosis, 720 T-cell proliferation assay, in Lyme borreliosis, 252-253 T-cell receptor (TCR), 52-53 Tear film, 68-69 Technetium bone scan, in seronegative spondyloarthropathies, 114-115 Temporal arteritis. See Giant cell arteritis (GCA). Temporal artery biopsy, for giant cell arteritis, 625-626 Tendearil. See Oxyphenylbutazone (Osalid, Tendearil) .

Tendons, 107, 107t Terfenadine, ketoconazole and, 207 Tessler classification, of uveitis, 81, 82t Testicular biopsy, for polyarteritis nodosa, 657 Tetnicycline for brucellosis, 283 for Lyme borreliosis, 253 for relapsing fever, 256 for rickettsial diseases, 303 for syphilis, 242, 242t for toxoplasmosis, 403, 403t for Whipple's disease, 294 TGF-a. See Transforming growth factor-a (TGF-a). T-helper cells in ascariasis, 440 in immune response regulation, 65-66 in sarcoidosis, 716-717 Thiabendazole for diffuse unilateral subacute neuroretinitis, 478 for toxocariasis, 434 Three-dimensional ultrasound imaging, 107-108 Three-port pars plana vitrectomy, 505 Thromboangiitis obliterans in Adamantiades-Behc;:et's disease, 637 in retinal vasculitis, 829 Thrombocytopenia from azathioprine, 189 in antiphospholipid syndrome, 688, 689 Thrombophlebitis in Adamantiades-Behc;:et's disease, 634, 635 Thrombosis in antiphospholipid syn.drome, 684, 684t immunopathogenesis of, 688 treatment of, 689 in ocular ischemic syndromes, 555 in polyarteritis nodosa, 654 Thymic cortex, 52-53 Thymic hormones, 40, 40t Thymic medulla, 53 Thymus, 40, 41£, 42t Thymus-derived cells. See T cell(s). Tick-borne diseases in relapsing fever, 255-256 in rickettsial diseases, 297 Ticks, in Lyme borreliosis, 245. See also Lyme borreliosis. TINU syndrome. See Tubulointerstitial nephritis and uveitis (TINU) syndrome. Tissue biopsy, in sarcoidosis, 720-721 Tissue eosinophilia, in Wegener's granulomatosis, 667 Tissue injury, immune-mediated, 56-65, 56t. See also Immune-mediated tissue injury. Tissue necrosis factor (TNF)-a in multiple sclerosis, 704 Tissue plasminogen activator (tPA), after retinal surgery, 231, 232f TMA. See Transcription-mediated amplification (TMA). TMP-SMX. See Trimethoprimsulfamethoxazole (TMP-SMX). TNF (tissue necrosis factor), in mUltiple sclerosis, 704 TNFa (tumor necrosis factor alpha), in toxoplasmosis, 387 Tobacco dust, in retinal detachment, 538 Tolectin. See Tolmetrin (Tolectin). Tolerance, in immune regulation, 66-67 Tolerance induction, for intermediate uveitis, 854 Tolmetrin (Tolectin), 29t, 167t Toxocara, in ocular ascariasis, 438 Toxocariasis, 428-436 clinical manifestations of, 428-429

Toxocariasis (Continued) clinical variations of, 431£, 431-432, 432f complications of, 432 definition of, 428 diagnosis of, 432-433 differential diagnosis of, 433 epidemiology of, 430 etiology of, 428 history of, 429-430 immunopathology of, 430f, 430-431 prognosis for, 434 treatment of, 434 Toxoplasma gondii. See Toxoplasmosis. Toxoplasma pyrogenes. See Toxoplasmosis. Toxoplasma titers in uveitis testing, 95t, 96 Toxoplasmic retinochoroiditis, 321 Toxoplasmosis, 385-410 acquired, 389-390 congenital, 388-389, 389f, 389t, 390f diagnosis of, 398-401, 399t, 400t, 401£ differential diagnosis of, 397-398 histopathology of, 398 history of, 385, 385f immunobiology of, 387-388, 388t in Fuchs' heterochromic iridocyclitis, 696 in immunocompromised patients, 390-391 in retinal vasculitis, 831 ocular, 391~397, 391£-393f atypical forms of, 393-396, 394f-397f diagnosis of, 400-401, 400t, 401£ in human immunodeficiency virus, 497, 497f , pathogeilesis of, 385-387, 386f Pneumoeystic carinii choroidopathy versus, 426 prevalence of, 388, 388t prevention of, 406 prognosis for,' 405-406 retinal, 792 therapy for, 401-405, 403t, 405f Toxoplasmosis retinitis, 433 Toxoplasmosis retinochoroiditis, 133-134, 133f, 134£ Trabeculitis in herpes simplex virus clinical characteristics of, 317 diagnosis of, 320 pathogenesis of, 319 treatment of, 321 Tractional retinal detachment, 397 Transbronchial lung biopsy (TBLB), in sarcoidosis, 720 Transcription-mediated amplification (TJ\iIA) , for tuberculosis, 267 Transforming growth factor-a (TGF-a), 18-19, 19t in multiple sclerosis, 704 Transient synechiae, in Fuchs' heterochromic iridocyclitis, 694 Transplacental transmission, of toxoplasmosis, 387, 389 Transplantation immunology, corneal, 71-73 Transudate, in acute inflammation, 17 Trauma. See also Injury. exogenous Candida endophthalmitis after, 365 in sympathetic ophthalmia, 742. See also Sympathetic ophthalmia. Traumatic uveitis, 573-579 after nonpenetrating ocular trauma, 575 after penetrating ocular trauma, 573-575 after surgery, 573, 573t laser-induced, 575 lens-induced, 575 pathogenesis and pathology of, 575-576 treatment of, 576-577 T1-relaxation, in magnetic resonance imaging, 105, 105t

T2-relaxation, in magnetic resonance imaging, 105, 105t Trematode, in diffuse unilateral subacute neuroretinitis, 477 Trench fever, 260-263 Treponema pallidwn, 237. See also Syphilis. Triamcinolone chemistry of, 142, 143t for ankylosing spondylitis, 583 for birdshot retinochoroidopathy, 738 for inflammatory bowel disease-associated arthritis, 590 for juvenile rheumatoid arthritis, 595 for psoriatic arthritis, 588 for Reiter's syndrome, 587 for serpiginous choroiditis, 793 for vitrectomy, 229, 230f pharmaceutics of, 145, 146t regional preparation of, 29t systemic preparation of, 28t Triazoles, for coccidioidomycosis, 374 Trimethoprim dapsone and, 204 for Pneumoeystic carinii choroidopathy, 427 Trimethoprim-sulfamethoxazole (TMP-SMX) for bartonella, 262 for rickettsial diseases, 303 for toxoplasmosis, 403-404, 403t for Wegener's granulomatosis, 671 for Whipple's disease, 294, 591 uveitis induced by, 860t, 865 Tropheryma whippelii, 287, 289, 290f Trophozoite, in toxoplasmosis, 385-386, 386f, 387 Tropicamide chemistry of, 159 clinical pharmacology of, 161-162 for juvenile rheumatoid arthritis, 595 history and source of, 159 pharmacokinetics and metabolism of, 162 potency of, 160t side effects and toxicity of, 164 structural formula of, 161£ therapeutic use of, 162, 163 Trovafloxacin, for toxoplasmosis, 404 Trypanosomiasis, 420-424 clinical characteristics of, 420-421 definition of, 420 diagnosis of, 422 epidemiology of, 420 history of, 420 pathology of, 421-422 treatment of, 422-423 Tsetse fly, in trypanosomiasis transmission, 420 TT (tuberculoid) leprosy, 305, 306 Tuberculin contact hypersensitivity, 64, 64t Tuberculin skin testing for tuberculosis, 266-267 uveitis induced by, 859, 860t Tuberculoid (TT) leprosy, 305, 306 Tuberculosis (TB), 264-271 acute retinal necrosis versus, 321 angiotensin-converting enzyme in, 719, 719t birdshot retinochoroidopathy versus, 736, 736t clinical presentation of, 264-265 complications of, 269 definition of, 264 diagnostic tests for, 266-268 epidemiology of, 264 history of, 264 in human immunodeficiency virus, 269270, 270t, 498, 498f in retinal vasculitis, 830

~

INDEX

Tuberculosis (TB) (Co'ntinued) intermediate uveitis versus, 849-850 pathogenesis of, 266 pathology of, 265-266 prognosis for, 270 treatment of, 268-269 Tuberculous choroiditis Pneumocystic carinii choroidopathy versus, 426 serpiginous choroiditis versus, 792 Tubulointerstitial nephritis and uveitis (TINU) syndrome, 726-730 clinical features of, 726-727, 727t definition of, 726 diagnosis and differential diagnosis of, 728, 728t epidemiology of, 726 history of, 726 pathology, immunology, and pathogenesis of, 727-728 treatment and prognosis for, 728-729 Tumor necrosis factor alpha, in toxoplasmosis, 387 Tunica media, 6 Tunica vasculosa lentis, 3 Type I hypersensitivity reactions, 57-60, 57f, 58f, 58t, 60t Type II hypersensitivity reactions, 60-61, 6lf Type III hypersensitivity reactions, 61-62, 62f Type IV hypersensitivity reactions, 62-64, 63f Typhus classification of, 298, 298t clinical characteristics of, 301, 301 t history of, 298 pathophysiology of, 300

U UBM. See Ultrasound biomicroscopy (UBM). UC (ulcerative colitis), 589-591 UGH (uveitis-glaucoma-hyphema) syndrome, 530 UGI (upper gastrointestinal) series, 107 Uhthoff's phenomenon, in multiple sclerosis, 702 Ulcer(s) cyclophosphamide for, 181 in Adamantiades-Beh~et'sdisease, 632. See also Adamantiades-Beh~et's disease. in systemic lupus erythematosus, 602 mucosal surface, 94 Ulcerative colitis (UC), 589-591 Ulcerative keratitis cyclophosphamide for, 181 in polyarteritis nodosa, 654-655, 655f in Wegener's granulomatosis, 663-664, 664t, 665f Ultrasound, 107-109, 107t for cysticercosis, 470 for giant cell arteritis, 625 for intraocular foreign bodies, 548 for lens-induced uveitis, 819 for malignant melanoma, 512 for masquerade syndromes, 118 for ocular ischemic s)'lidromes, 555 for sympathetic ophthalmia, 743, 743f for uveitis testing, 95t, 96 for Vogt-Koyanagi-Harada syndrome, 751-,. 752 Tltrasound biomicroscopy (UBM), 108-109 for intermediate uveitis, 848 for pigmentary dispersion syndrome, 552 for Vogt-Koyanagi-Harada syndrome, 751752

Unilateral pigmentary retinopathy, 396 Unilateral subacute neuroretinitis, 471 Upper gastrointestinal (UGI) series, 107 Upper respiratory tract infection, 373 Urethritis, in Reiter's s)'lidrome, 584, 585 Urogenital manifestations, of extraocular examination, 94 Uroprostone, uveitis induced by, 863 Uvea definition of, 17 inflammation of. See Uveitis. lymphoid hyperplasia of, 504 Uveal effusion in systemic lUpus erythematosus, 603 rhegmatogenous retinal detachment versus, 541 Uveal melanoma, 118 Uveal tract, 3-16 choroid in, 11-15, llf, 12f ciliary body in, 7-11, 8f, 9f, 10f, Ilf in leukemia, 507-508 iris in, 3-7. See also Iris. Uveitis amebas in, 412-413 anterior. See Anterior uveitis. brucellosis and, 281, 28lt classification of, 81 corticosteroids for, 151 definition of, 17 diagnosis of, 79-103 age of patient in,88 classification in, 81 clinical examination for, 90-96. See also Clinical examination. confusion in, 81 '~ cornea and sclera in, 89, 89t differential, 79, 80t, 103 family history in, 98 focal infection in, 79 frustration in, 81 history taking for, 89-90 inflammation in, 87-,.88, 87t, 88t, 89 location in, 81-87, 82f-87f, 82t personal medical history in, 99-102 problems in, 80-81 social and geographic characteristics in, 88-89 social history in, 99 drug-induceCl. See Drug-induced uveitis. granulomatous. See also Sympathetic ophthalmia. in sarcoidosis, 109, 109f in s)'lnpathetic ophthalmia, 742 in giant cell arteritis, 622 in human immunodeficiency virus, 495 in Lyme borreliosis, 248, 248f in multiple sclerosis, 702-703 in ocular Whipple's disease, 291-292, 291t in ophthalmia nodosa, 488, 489f in toxocariasis, 432 in tuberculosis, 265 in Wegener's granulomatosis, 664t, 665666,665f intermediate. See Intermediate uveitis (IU). location of, 81-87, 82f-87f, 82t nonsteroidal anti-inflammatory drugs for, 171-172 phacoantigenic, in s)'lupathetic ophthalmia, 744 phacogenic. See Lens-induced uveitis. postoperative, in differential diagnosis, 103 steroid-resistant, 186

Uveitis (Continued) subretinal fibrosis and. See Subretinal fibrosis and uveitis (SFU) syndrome. s)'lnpathetic, 125-126, 125f-127f traumatic, 573-579. See also Traumatic uveitis. tubulointerstitial nephritis and, 726-730. See also Tubulointerstitial nephritis and uveitis (TINU) syndrome. Uveitis-glaucoma-hyphema (UGH) s)'lidrome, 530 Uveomeningitic syndroine. See Vogt-KoyanagiHarada (VKH) s)'lidrome. Uveomeningo-encephalitic S)'lidrome. See Vogt-Koyanagi-Harada (VKH) S)'lidrome. Uveoparotid fever, 715

v V regions, of immunoglobulins, 46 Vaccination for Lyme. borreliosis, 253 for rickettsial diseases, 303 for tuberculosis, 266, 267 uveitis induced by, 859, 860t Vaccine-related disease, in brucellosis, 281 Valley fever, 373-376 Varicella zoster virus (VZV), 315-322 clinical characteristics of, 317-319, 318f complications of, 322 diagnosis of, 320-321, 320f epidemiology of, 317 history of, 317 pathogenesis of, 319-320 prognosis for, 322 treatment of, 321-322 virology of, 315-317, 315f, 316f, 316t Varicella zoster virus (VZV) retinitis, 497-498, 497f,498f Varices, in Adamantiades-Beh~et'sdisease, 635 Vascular occlusion, in Adamantiades-Beh~et's disease, 637 Vascular supply and innervation of choroid, 14-15 of ciliary body, 10 of iris, 6-7, 7f Vascular system in Adamantiades-Beh~et'sdisease, 634-635 in birdshot retinochoroidopathy, 731 in systemic lupus erythematosus, 607 Vasculitic disorders, in acute posterior multifocal placoid pigment epitheliopathy, 777 Vasculitis, 93 in acute posterior multifocal placoid pigment epitheliopathy, 777 in intermediate uveitis, 844, 845f in ocular toxoplasmosis, 392-393, 393f in polyarteritis nodosa, 655, 655f in relapsing polychondritis, 678 in scleritis, 111-112, 112f in systemic lupus erythematosus, 603, 604f, 607 in Wegener's granulomatosis, 661, 667, 667f. See also Wegener's granulomato~~

.

retinal. See Retinal vasculitis. Vasoactive intestinal peptides (VIP), 18-19, 19t Vasodilation, corticosteroids and, 144 Vasodisruption, in systemic lupus erythematosus, 605-606, 605f, 606t Vaso-occlusion, in systemic lUpus erythematosus, 603-605, 603t, 604f, 604t Vaso-occlusive retinopathy, in antiphospholipid syndrome, 686

Vectors in Lyme borreliosis, 249 in onchocerciasis, 451 Venae vorticosae, 14-15 Venereal Disease Research Laboratory (VDRL) test for syphilis, 240, 240t false-positive results in, 241 intermediate uveitis and, 850 Venous drainage, of uvea, 3 Venous engorgement, in Toxoplasma neuroretinitis, 394, 395f Venous occlusion in Adamantiades-Beh<;:et's disease, 635 in systemic lupus erythematosus, 605 Ventriculomegaly, in congenital toxoplasmosis, 389, 390f Venulitis, in Wegener's granulomatosis, 667 Vernier acuity cards, 90 Vesicular lesions, in extraocular examination,94 Vexol (Alcon), 28t Vioxx. See Rofecoxib (Vioxx). VIP. See Vasoactive intestinal peptides (VIP). Viral retinitides, 783-784, 784t Viral retinitis, 133 Virology of herpesviruses, 315-317, 315f, 316f, 316t Virus in multiple sclerosis, 703-704 in polyarteritis nodosa, 656 in retinal vasculitis, 831-832 in systemic lupus erythematosus, 606 Visceral larva migrans (VLM), in toxoeariasis, 428. See also Toxocariasis. Vision atropine and, 163 in ameba infection, 415 in birdshot retinochoroidopathy, 731, 739 in cancer-associated retinopathy, 520 in clinical examination, 90 in diffuse unilateral subacute neuroretinitis, 476 in giant cell arteritis, 620, 621£ in leprosy, 306 in multiple sclerosis, 702 in ocular toxoplasmosis, 393 in presumed ocular histoplasmosis syndroIne, 349, 351-353 in punctate inner choroidopathy, 806-808, 807 in Rift Valley fever, 334 in sarcoidosis, 723 in uveitis, 25, 26 Visual field testing for acute zonal occult outer retinopathy, 815 for multiple evanescent white dot syndrome, 769-770 for serpiginous choroiditis, 788t, 791 for subretinal fibrosis and uveitis syndrome, 801 Vitamin B12 , colchicine and, 209 Vitiliginous chorioretinitis. See Birdshot retinochoroidopathy (BSRC). Vitiligo, in Vogt-Koyanagi-Harada syndrome, 748-750, 749L 750f Vitrectomy, 216-217, 216f, 217f, 227-229, 228f, 229f, 230f for candidiasis, 369 for cysticercus, 472 for intermediate uveitis, 849, 853 for intraocular foreign bodies, 549 for intraocular-central nervous system lymphoma, 505 for retinal vasculitis, 839 in traumatic uveitis, 577

Vitrectomy (Continued) pars plana after Candida endophthalmitis, 366 for candidiasis, 367-368 for intermediate uveitis, 852, 853 for toxocariasis, 434 for toxoplasmosis, 404-405 Vitreoretinal involvement in ophthalmia nodosa, 488, 489f Vitreoretinopathy from ocular toxoplasmosis, 397 from penetrating ocular trauma, 574 Vitreous cysticercosis in, 468, 469, 469f in Adamantiades-Beh<;:et's disease, 637 in clinical examination, 92, 92t, 93t in CMV retinitis, 497 in cysticercosis, 470, 472 in Fuchs' heterochromic iridocyclitis, 695 in intermediate uveitis, 844, 844£ in lens-induced uveitis, 819 in Lyme borreliosis, 248, 248f in presumed ocular histoplasmosis syndrome, 351 in Whipple's disease, 289, 290f therapeutic surgery of, 227-229, 228f-230f Vitreous biopsy for candidiasis, 367 for endophthalmitis, 533 for intraocular-central nervous system lymphoma, 503, 505 Vitreous hemor.rhage from onilar toxoplasmosis, 397 in Adamantiades-Beh<;:et's disease, 637, 646, 647 in differential diagnosis, 103 Vitritis. See also Intermediate uveitis (IV). in birdshot retinochoroidopathy, 737 in diffuse unilateral subacute neuroretinitis, 476,476f in human immunodeficiency virus, VZV retinitis and, 498 in Lyme borreliosis, 248, 248f, 249f in ocular toxoplasmosis, 392, 393f in sarcoidosis, 713, 713f, 714, 714f in sympathetic ophthalmia, 742 in Toxoplasma neuroretinitis, 394, 395f sclerosing, in toxocariasis, 430 VKH syndrome. See Vogt-Koyanagi-Harada (VIlli) syndrome. VLM (visceral larva migrans), in toxocariasis, 428. See also Toxocariasis. Vogt-Koyanagi-Harada (VIlli) syndrome, 748-756 birdshot retinochoroidopathy versus, 736t, 737 clinical manifestations of, 748-749, 748f, 749f complications of, 753 definition and history of, 748 diagnosis of, 751 differential diagnosis of, 752 electrophysiologic tests for, 752 epidemiology of, 748 etiology and pathogenesis of, 750 extraocular manifestations of, 749-750, 749f,750f genetic factors of, 751 histopathology of, 750-751 in subretinal fibrosis and uveitis syndrome, 801-802 investigation of, 751-752, 751£ prognosis for, 753 rhegmatogenous retinal detachment versus, 540 synlpathetic ophthalmia compared to, 745746, 745t

Vogt-Koyanagi-Harada (VIlli) syndrom.e (Continued)

treatment of, 752-753 Voltaren. See Diclofenac (Voltaren). von Willebrand factor (VWF), 789 in giant cell arteritis, 625 Vortex veins, 15 VWF (von Willebrand factor), 789 in serpiginous choroiditis, 789 VZV. See Varicella zoster virus (VZV).

W Warthin-Starry silver impregnation stain, for bartonella, 262 Wegener's granulomatosis, 661-675 classification of, 661, 66lt clinical characteristics of, 661 t, 662-666, 662f, 663f, 664t, 665f cyclophosphamide for, 181 diagnosis of, 667-670, 668f, 669t criteria for, 661, 66lt diagnostic imaging for, 111-112, 112f epidemiology of, 662 history of, 661-662 pathogenesis/immunopathology of, 666 pathology of, 667, 667f prognosis for, 671-672 retinal vasculitis in, 830 treatment of, 670-671 Weil's syndrome, 273-274 Wesenberg-Hamazaki bodies, in sarcoidosis, 716 Wessley's ring, in ameba infection, 412 Westergren technique, for giant cell arteritis, 624-625 Western blot, for bartonella, 262 Whipple's disease, 591-592 in retinal vasculitis, 831 ocular, 287-296. See also Ocular Whipple's disease (OWD). White collagen band, in intermediate uveitis, 845, 845f White corneal opacification, in onchocerciasis, 449, 449f White cyst, 469, 469f, 470 White dot syndromes, 806, 809t. See also Multiple evanescent white dot syndrome (MEWDS). acute zonal occult outer retinopathy and, 813-816 birdshot retinochoroidopathy versus, 736, 736t differential diagnosis of, 761, 761t multifocal choroiditis and panuveitis and, 757, 761, 762-763 punctate inner choroidopathy and, 806 summary of, 809, 809t unilateral versus bilateral, 20, 20t White eye, 87, 87t White infiltrate, in Whipple's disease, 289, 290f White pulp, of spleen, 40; 42f White pupillary reflex, in toxocariasis, 429 White spots, in rickettsial diseases, 302, 302f White-footed mouse, in Lyme borreliosis, 249 White-yellow lesions, in sympathetic ophthalmia, 742, 743f Wipe-out syndrome, in diffuse unilateral subacute neuroretinitis, 475 Witmer-Desmonts, coefficient of, 400, 400t Worms, in diffuse unilateral subacute neuroretinitis, 476

INDEX Wound in endophthalmitis, 530 in syinpathetic ophthalmia, 742, 744. See also Sympathetic ophthalmia. Wucheria bancrojti

in loiasis, 463 in onchocerciasis, 450-451

X Xanthogranuloma, juvenile, 556-558 Xenon-arc photocoagulation, for presumed ocular histoplasmosis syi1drome, 355 X-ray, 106 for cysticercosis, 471 for intermediate uveitis, 848

X-ray (Continued) for intraocular foreign bodies, 548 for presumed ocular histoplasmosis syndrome, 354 for sarcoid suspect, 109-110, 109f for Takayasu's arteritis, 112 for uveitis, 95t, 96

y YAG (yttrium-aluminum-garnet) laser capsulotom~ 575 Yellow-white lesions, in Vogt-Koyanagi-Harada syi1drome, 749, 749f Yellow-white spots, 767, 768f Yellow-white subretinallesions, 797, 798, 798f

Yttrium-aluminum-garnet (YAG) laser capsulotom~ 575

Z Zenapax. See Dacliximab (Zenapax). Zidovudine, for human immunodeficiency virus, 495 Zonal granulomas, 87-88, 88t Zonal inflammation, in lens-induced uveitis, 818 Zonula adherens, 6 Zonula occludens, 6 Zonulae occludentae, 9 Zonular tight junctions, 6