Neurology Volume 72(5) February 3, 2009

This week in Neurology® Highlights of the February 3 issue Immunologic, clinical, and radiologic status 14 months after...

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This week in Neurology® Highlights of the February 3 issue

Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis. This is the first long-term follow-up of patients with multiple sclerosis who discontinued natalizumab that demonstrates clinical, radiographic, and immunological stability after discontinuation of this agent.

Automatic detection of preclinical neurodegeneration: Presymptomatic Huntington disease Treatment of neurodegenerative diseases (e.g. presymptomatic Huntington disease) is likely to be most beneficial in the earliest, possibly preclinical stages of degeneration. The authors explored the usefulness of fully automatic structural MRI classification methods for detecting subtle degenerative change. See p. 426

See p. 396; Editorial, p. 392

Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function Progressive multifocal leukoencephalopathy (PML) is an unusual and serious complication of the multiple sclerosis therapy natalizumab. PML is best treated by restoring immune function, which includes reversing the effect of immunomodulating drugs. This study demonstrates that

Incidence and remaining lifetime risk of Parkinson disease in advanced age Accurate estimates of the incidence of Parkinson disease (PD) in people 80 and older are needed to assess individual and population risk. This study provides evidence that PD incidence continues to increase at least to age 90, and that the lifetime risk of PD is dependent on age, life expectancy, and smoking history. See p. 432

plasmapheresis accelerates natalizumab clearance and recovery of immune function, thereby providing a potential treatment option for PML.

Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS

This study expands the categories of human lissencephalies

In this 12-week, multicenter, randomized, double-blind, placebo-controlled trial, the authors found that once daily XP13512 (gabapentin enacarbil) significantly improved restless legs syndrome (RLS) symptoms and was generally well tolerated in adults with moderate-to-severe primary RLS.

and adds to the knowledge of associated mid-hindbrain

See p. 439

See p. 402

Midbrain-hindbrain involvement in lissencephalies

malformations. It ultimately gives a better understanding of the mechanisms by which the brain is formed. See p. 410; Editorial, p. 394

Assessment of potential drug interaction in patients with epilepsy: Impact of age and gender It is recognized that polypharmacy is common in older patients but less commonly appreciated that important drug interactions frequently occur in younger patients as well. This

Educational attainment and cognitive decline in old age Level of education is a well-established risk factor for Alzheimer disease. This study suggests that education is associated with level of cognitive function but not with rate of cognitive decline and that the former association primarily accounts for education’s correlation with risk of dementia in old age. See p. 460

study describes the frequency and pattern of both antiepileptic drug use and potential interactions in a large population of patients with epilepsy. See p. 419

Podcasts can be accessed at www.neurology.org

Copyright © 2009 by AAN Enterprises, Inc.

391

EDITORIAL

Natalizumab Bound to rebound?

Nicoline Schiess, MD Peter A. Calabresi, MD

Address correspondence and reprint requests to Dr. Peter A. Calabresi, Department of Neurology, Johns Hopkins University, 600 N. Wolfe Street, Baltimore, MD 21287 [email protected]

Neurology® 2009;72:392–393

Since it first came to trial, natalizumab (Tysabri) has kept the multiple sclerosis (MS) world in a constant state of flux. Shortly after its initial launch, the appearance of three cases of progressive multifocal leukoencephalopathy (PML), a devastating infection of the CNS caused by the JC virus, resulted in the drug’s withdrawal from the market. Reintroduced in 2006, it is currently in use as monotherapy in thousands of patients worldwide, but four additional cases of PML were recently reported in patients on natalizumab monotherapy for less than 18 months. While these cases strongly support a mechanistic association between the drug and JC virus reactivation/infection,1 the short-term risk of PML still appears to be quite low (4 confirmed cases out of ⬃10,000 patients treated for 18 months). Nonetheless, these new cases are concerning and some patients and physicians will choose to discontinue therapy. Several groups have raised the possibility of a rebound effect in cohorts of patients discontinuing natalizumab.2,3 This has led to the concern that stopping natalizumab might lead to a sudden worsening of MS disease. However, rebound was not seen during a 6-month washout period following a phase II placebo-controlled trial with natalizumab.4 Natalizumab is a monoclonal antibody that binds the ␣4 integrin chain of the very late activation antigen (VLA)-4 adhesion molecule and blocks mononuclear cell migration and perhaps costimulatory activating signals. The question has been raised as to whether immune cells that are blocked from trafficking build up in the blood persistently during natalizumab therapy, or whether these cells eventually die by attrition and thereby avert the potential for a catastrophic flood of immune cells into the CNS. In this issue of Neurology®, Stu¨ve et al.5 explore the idea of a rebound phenomenon by investigating clinical activity, MRI changes, and immunologic peripheral blood/CSF markers in 23 patients with MS who received natalizumab as part of the AFFIRM and SENTINEL trials. Samples were taken at the

time of drug cessation and 14 months later. Reassuringly, most of the patients in this cohort remained clinically and radiographically stable. Immune cell counts in the periphery and CSF still showed natalizumab-mediated effects at 6 months, but returned to normal levels, without any rebound, after 14 months, and no infectious complications occurred. This is encouraging to clinicians treating patients with natalizumab who are concerned about the possibility of a rebound phenomenon upon cessation of the drug. The limitations, however, include a small sample size in which only 21 patients had relapse rates evaluated, 17 had Expanded Disability Status Scale scores, 16 had MRIs, and an even smaller subset had immunologic measurements. Nonetheless, this was a reasonable sample size for such extensive immunologic studies. How can these data be reconciled with the reports of clinical or MRI rebound by Tubridy and Vellinga? The most likely explanation is that short-term treatment with natalizumab, as was characteristic of these two studies, does indeed result in trapping and accumulation of viable activated lymphocytes in the periphery that retain their capacity to cause CNS disease. The Tubridy study only used two doses of natalizumab and in the Vellinga study the effect was driven by patients with short exposures to natalizumab (median of two infusions). In contrast, more prolonged treatment with natalizumab, as was done in the study by Miller et al.4 (6 months) and the phase III trials (120 weeks), probably results in death of the peripheral activated T cells. Thereby, not only is there no rebound, but there may be disease quiescence even upon discontinuing the drug, while new pathogenic immune cells are generated and expanded in the peripheral blood. The persistent leukocytosis seen in the periphery may occur not only through blockade of cell migration, but also due to enhanced egress from the bone marrow. These lymphocytes may not only be less activated through blockade of the costimulatory properties of VLA-4 signaling, but

See page 396 From the Department of Neurology, Johns Hopkins University, Baltimore, MD. Disclosure: Peter A. Calabresi, MD, has received support from the NMSS, NIH, and has received research grants and honoraria from Biogen-IDEC. Dr. Schiess was a National Multiple Sclerosis Society fellow while this manuscript was drafted. 392

Copyright © 2009 by AAN Enterprises, Inc.

perhaps could even have enhanced regulatory properties. Further immunologic studies examining the presence of Foxp3 T regulatory cells and cytokine profiles will be informative in understanding the mechanisms of this drug’s persistent effects. Ideally, we will be able to develop immunologic biomarkers that would allow clinicians to finesse a balance between the potent immune effects of the drugs and the possibility of rendering patients susceptible to infections. Overall, these findings are encouraging to the clinician treating patients with natalizumab and suggest that in patients who have been treated for a prolonged period, it is unlikely that there will be a sudden rebound. Whether a drug holiday can be justified based on these data—that it takes more than 6 months for the immune parameters to even normalize— deserves further study. Short-term usage of the drug (e.g., two doses) may be followed by disease

rebound and some caution is still advisable in patients who must be discontinued due to early hypersensitivity type reactions or choose to discontinue over concern regarding the risk of PML early on in the course of their treatment. REFERENCES 1. Ransohoff RM. Natalizumab and PML. Nat Neurosci 2005;8:1275. 2. Vellinga MM, Castelijns JA, Barkhoff F, Uitdehaag BMJ, Polman CH. Postwithdrawal rebound increase in T2 lesional activity in natalizumab-treated patients. Neurology 2008;70:1150–1151. 3. Tubridy N, Behan PO, Capildeo R, et al. The effect of anti-␣4 integrin antibody on brain lesion activity in MS. Neurology 1999;53:466–472. 4. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15–23. 5. Stu¨ve O, Cravens PD, Frohman EM, et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology 2009;72:404–409.

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EDITORIAL

Cortical malformations Looking behind the cortex

Harvey B. Sarnat, MS, MD, FRCPC

Address correspondence and reprint requests to Dr. Harvey B. Sarnat, University of Calgary Faculty of Medicine and Alberta Children’s Hospital, Division of Paediatric Neurology, 2888 Shaganappi Trail NW, Calgary, Alberta, Canada T3B 6A8 [email protected]

Neurology® 2009;72:394–395

The article by Jissendi-Tchofo et al.1 in the current issue of Neurology® is important not only because of the new data and documentation they present, but because it puts into perspective the global concept of genetic mutations expressed as abnormal morphogenesis of the CNS. In recent years there has been a trend by some authors to describe and classify cerebral cortical malformations in a manner highly focused on the cerebral cortex, as if the rest of the brain were normal or only of secondary importance. Whereas these narrowly designed schemes may be applicable to certain special disorders, such as epilepsy, they are at best misleading and at worst become an old cliche´ of not seeing the forest because of the trees. The importance of thalamic, basal ganglionic, brainstem, and cerebellar malformations in association with cerebral cortical dysgeneses of genetic origin, including lissencephaly and holoprosencephaly, was a message by me and by many other authors who published even just preceding the era of proliferation of novel data on genetic programming of neural tube development2,3 and later emphasized in classification schemes of cerebral malformations.4 The importance of mesencephalic and rhombencephalic involvement in another genetic malformation of the brain, holoprosencephaly, has already been demonstrated and also correlated with facial dysmorphism (hypotelorism, absence of the premaxilla and vomer).5 The dysmorphic facies in this condition results from dorsal mesencephalic defects that include the mesencephalic neural crest; patients with normal facies but holoprosencephalic brains nearly always show sparing of the midbrain. Neural tube induction of craniofacial development, mediated through the prosencephalic and mesencephalic neural crest, is now well established6 and can explain the facial dysmorphism in many neurocutaneous syndromes.7 In the Miller-Dieker syndrome in type 1 lissencephaly the facies also are dysmorphic and characteristic, though different from the facies of holo-

prosencephaly, and thus midbrain dysgenesis is important to consider. Some of these upper brainstem malformations can be detected by MRI, as shown in the article by Jissendi-Tchofo et al.1; other defects are microscopic or require special immunocytochemical techniques of tissue examination, hence are only feasible by postmortem neuropathologic examination, one reason to perform autopsy in patients who do not survive, even though the basic diagnosis has been established by neuroimaging and genetic markers. Other brainstem abnormalities that are below the limits of resolution of present-day imaging techniques might include the nucleus/fasciculus solitarius of the medulla oblongata (the central respiratory center) and the nucleus ambiguus of the vagal nerve for muscles of deglutition. Infants who have unexplained apnea or failure of central respiratory drive, or dysphagia, associated with the lissencephalies should undergo particularly careful examination at autopsy. Some genetic defects of segmentation of the rhombencephalon result in deletion of particular neuromeres, such as absence of the midbrain and upper pons (mesencephalon and metencephalon), as shown in experimental knockout deletions in mice8 and also in humans.9,10 These malformations are generally due to defective genetic expression of Engrailed (EN ) or Wingless (WNT ), genes of embryonic hindbrain segmentation, but these genes are not known to be expressed in the telencephalon at any stage of normal development. What might this condition of aplasia or hypoplasia of the midbrain neuromere have to do, therefore, with lissencephalies due to LIS1, ARX, POMT1, or other mutations of genes not known to be expressed in the hindbrain or cerebellum? The interactions of developmental genes are complex; downregulation of a particular mutated gene may secondarily downregulate other genes in a sequential cascade or, at times, not even related functionally to the primary mutated gene as a component

See page 410 From Paediatric Neurology and Neuropathology, University of Calgary Faculty of Medicine and Alberta Children’s Hospital, Calgary, Alberta, Canada. Disclosure: The author reports no disclosures. 394

Copyright © 2009 by AAN Enterprises, Inc.

of a cascade. Such potential mechanisms should be explored because they may well explain the reason for anatomic brainstem defects in primary disorders of neuroblast migration in the forebrain. A genetic mechanism is needed to explain the association of forebrain and hindbrain malformations in the lissencephalies and certain other cerebral dysgeneses as well. The article by Jissendi-Tchofo and colleagues1 is an excellent beginning to approach such fundamental issues in programming of the neural tube. Future genetic studies will be even more meaningful if accompanied by equally meticulous neuropathologic examinations, not only to better explain the macroscopic anomalies seen by MRI, but to examine microscopic aspects including immunocytochemical markers of differentiation and maturation of various types of neurons, synaptogenesis, and distributions of neurotransmitters. REFERENCES 1. Jissendi-Tchofo P, Kara S, Barkovich AJ. Midbrain– hindbrain involvement in lissencephalies. Neurology 2009;72: 418–426. 2. Sarnat HB. Cerebral Dysgenesis: Embryology and Clinical Expression. New York: Oxford University Press; 1992. 3. Norman MG, McGillivray GC, Kalousek DK, et al. Congenital Malformations of the Brain: Pathological, Embryological, Clinical, Radiological and Genetic Aspects. New York: Oxford University Press; 1995.

4. Sarnat HB, Flores-Sarnat L. Integrative classification of morphology and molecular genetics in central nervous system malformations. Am J Med Genet 2004;126A: 386–392. 5. Sarnat HB, Flores-Sarnat L. Neuropathological research strategies in holoprosencephaly. J Child Neurol 2001;16: 918–931. 6. Carstens MH. Neural tube programming and the pathogenesis of craniofacial clefts. Part 2: Mesenchyme, pharyngeal arches, developmental fields and the assembly of the human face. In: Sarnat HB, Curatolo P, eds. Malformations of the Nervous System. Handbook of Clinical Neurology, Vol 87, 3rd Series. Edinburgh: Elsevier; 2008:277–339. 7. Sarnat HB, Flores-Sarnat L. Embryology of the neural crest: its inductive role in the neurocutaneous syndromes. J Child Neurol 2005;20:637–643. 8. McMahon AP, Joyner AL, Bradley A, McMahon JA. The midbrain– hindbrain phenotype of Wnt-1–/Wnt-1–mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum. Cell 1992;69:581–595. 9. Sarnat HB, Benjamin DR, Siebert JR, Kletter GB, Cheyette SR. Agenesis of the mesencephalon and metencephalon with cerebellar hypoplasia: putative mutation in the EN2 gene: report of 2 cases in early infancy. Pediatr Dev Pathol 2002;5:54–68. 10. Sarnat HB. Disorders of segmentation of the neural tube: agenesis of selective neuromeres. In: Sarnat HB, Curatolo P, eds. Malformations of the Nervous System. Handbook of Clinical Neurology, Vol. 87, 3rd Series. Edinburgh: Elsevier; 2008:105–113.

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ARTICLES

Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy O. Stu¨ve, MD, PhD P.D. Cravens, PhD E.M. Frohman, MD, PhD J.T. Phillips, MD, PhD G.M. Remington, RN G. von Geldern, MD S. Cepok, PhD M.P. Singh, PhD J.W. Cohen Tervaert, MD, PhD M. De Baets, MD, PhD D. MacManus, MD D.H. Miller, MD, PhD E.W. Radu¨, MD E.M. Cameron, BSc N.L. Monson, PhD S. Zhang, PhD R. Kim, MD B. Hemmer, MD*

ABSTRACT

Objective: Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis (MS). A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on MRI 3 months after discontinuation of therapy. The objective of this study was to assess clinical MS disease activity, surrogate disease markers on MRI, immunologic parameters in peripheral blood and CSF, as well as safety in patients with MS after discontinuation of natalizumab therapy.

Methods: This study is a longitudinal and serial cross-sectional assessment, in which 23 patients who were treated with natalizumab in the context of two phase III clinical trials were originally enrolled. A subgroup of patients was followed over 14 months. The annual relapse rate, neurologic disease progression assessed by the Expanded Disability Status Scale, disease surrogate markers on MRI, cellular and humoral immune markers in peripheral blood and CSF, and adverse events of the drug were monitored.

Results: With regard to clinical disease activity, neuroimaging, and immune responses, the majority of patients in our cohort were stable. Decreased lymphocyte cell numbers and altered cell ratios returned to normal 14 months after cessation of natalizumab. No infectious complications were observed.

Conclusion: This is the first long-term follow-up of patients who discontinued natalizumab. We did not observe a clinical, radiographic, or immunologic rebound phenomenon after discontinuation of natalizumab therapy. Neurology® 2009;72:396–401 GLOSSARY

Address correspondence and reprint requests to Dr. Olaf Stu¨ve, Neurology Section, VA North Texas Health Care System, Medical Service, 4500 South Lancaster Rd., Dallas, TX 75216 [email protected]

M.K. Racke, MD*

Supplemental data at www.neurology.org

EDSS ⫽ Expanded Disability Status Scale; FDA ⫽ Food and Drug Administration; MS ⫽ multiple sclerosis; OCB ⫽ oligoclonal band; PML ⫽ progressive multifocal leukoencephalopathy; VLA-4 ⫽ very late activation antigen 4; WBC ⫽ white blood cell.

Natalizumab is a humanized monoclonal antibody that binds to the ␣4 chain of the ␣4␤1 (very late activation antigen 4 [VLA-4]) and ␣4␤7 integrins.1 Based on the results of two phase III clinical trials,2,3 natalizumab was originally approved by the Food and Drug Administration (FDA) for the treatment of relapsing forms of multiple sclerosis (MS) on November 24, 2004. Subsequently, two patients with MS who had been enrolled in the SENTINEL phase III trial were diagnosed with progressive multifocal leukoencephalopathy (PML).4,5 Another patient with Crohn disease who had been treated with natalizumab in the context of clinical trials was later also diagnosed with PML.6 The purpose of this study was to assess MS disease activity with regard to relapse rate and accumulation of neurologic disability after discontinuation of natalizumab. Also, we quantified surrogate markers of MS disease activity by MRI, as well as immunologic parameters in peripheral blood and CSF.

Editorial, page 392 e-Pub ahead of print on November 5, 2008, at www.neurology.org. *These authors contributed equally to this work. Authors’ affiliations are listed at the end of the article. Dr. Stu¨ve was supported by a start-up grant from the Dallas VA Research Corporation, a New Investigator Award grant from VISN 17, Department of Veterans Affairs, a merit award from the Department of Veterans Affairs, research grants from National Multiple Sclerosis Society (NMSS; RG3427A8/T and RG2969B7/T), and a grant from the Viragh Foundation. Supported by grants (NS 37513 and NS 44250) from the NIH and NMSS grant RG 2969-B-7 to Dr. Racke. Drs. Hemmer and Cepok were supported by grants from the Deutsche Forschungsgemeinschaft (He 2386/ 4-2). Supported in part by the Adult AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases (AI 38858 and AI 27664). Dr. Monson was supported by a grant from the NIH (NS 40993). Disclosure: The authors report no disclosures. While the AFFIRM monotherapy trial and the SENTINEL add-on trial with interferon beta-1a (Avonex) were sponsored by Biogen-Idec Inc. and Elan Corp., the manufacturers of natalizumab, the work presented in this study was not. 396

Copyright © 2009 by AAN Enterprises, Inc.

Table Patient

Patient characteristics

Assessment of patient safety and clinical disease activity. The annual relapse rate was assessed in 21 patients for the 12-month period prior to enrollment into the AFFIRM and SENTINEL trials, for the trial period of the trials, and for the 14-month period after cessation of natalizumab (Tysabri). Neurologic disability assessed by the Expanded Disability Status Scale (EDSS)10 was recorded in 17 patients prior to enrollment into the AFFIRM and SENTINEL trial, at the time of cessation of natalizumab therapy, and 14 months after cessation of natalizumab. At these time points, study patients were seen and assessed for the occurrence of clinical relapses, infections, and any unexpected medical complications. In addition, at months 3, 9, and 12 after cessation of natalizumab therapy, patients were contacted by telephone.

Gender

Diagnosis

EDSS*

Clinical trial

Relapse†

Medication‡

1

Male

1998

1.5

N/A§

None

Glatiramer acetate, mycophenolate mofetil

2

Female

1990

4.5

AFFIRM

None

None

3

Female

2001

0

AFFIRM

2

None

4

Female

1995

4.5

AFFIRM

None

Interferon ␤-1a (Rebif)

5

Female

1992

0

AFFIRM

None

Glatiramer acetate

6

Female

2002

4.0

AFFIRM

None

None

7

Female

1995

3.5

AFFIRM

None

None

8

Female

1999

1.5

SENTINEL¶

None

Interferon ␤-1a (Avonex)

9

Female

1999

3.5

SENTINEL

None

Interferon ␤-1a (Avonex) (for 8 mo)

10

Female

1997

2.5

SENTINEL

None

Interferon ␤-1a (Avonex)

11

Female

1994

6.0

SENTINEL

None

Not known

12

Female

1989

2.5

SENTINEL

None

Interferon ␤-1a (Avonex)

13

Female

1992

1.5

SENTINEL

None

Interferon ␤-1a (Avonex)

14

Female

1999

1.5

SENTINEL

None

Interferon ␤-1a (Avonex)

15

Male

1996

4.0

SENTINEL

None

Interferon ␤-1a (Avonex)

16

Female

2000

1.5

SENTINEL

None

Interferon ␤-1a (Avonex)

17

Female

2001

3.0

SENTINEL

None

Interferon ␤-1a (Avonex)

RESULTS Participants.

18

Female

1996

3.5

SENTINEL

None

Interferon ␤-1a (Avonex)

patient characteristics.

19

Female

1999

2.5

SENTINEL

None

Interferon ␤-1a (Avonex)

Peripheral blood leukocyte and lymphocyte counts. Total

20

Female

1999

2.0

SENTINEL

None

Interferon ␤-1a (Avonex)

21

Female

2001

2.0

SENTINEL

1

Interferon ␤-1a (Avonex)

22

Male

2001

1.5

SENTINEL

None

Interferon ␤-1a (Avonex)

23

Female

2001

3.5

SENTINEL

None

Interferon ␤-1a (Avonex), mycophenolate mofetil

white blood cell (WBC) numbers in peripheral blood of natalizumab-treated patients with MS at study entry were within normal limits (figure 1A). A serial cross-sectional analysis of all study participants showed a nonsignificant decrease in leukocyte numbers at month 6, and at month 14 after cessation of natalizumab. There was also a significant increase in the number of CD4⫹ T cells, CD8⫹ T cells, and CD19⫹ B cells in peripheral blood 14 months after discontinuation of natalizumab therapy (figure 1, B–D), whereas the number of CD138⫹ plasma cells did not change (figure 1E). CD4:CD8 T cell ratios in peripheral blood remained within normal limits (figure 1F). A longitudinal analysis showed a significant decrease of WBC between study entry and month 14 (figure 1G). It also confirmed the increase of CD4⫹ T cells in peripheral blood 14 months after study entry, following an initial decrease at 6 months after cessation of natalizumab (figure 1H). The number of CD8⫹ T cells did not change over the 14-month study period, but there was an initial significant decrease 6 months after cessation of natalizumab (figure 1I). There was no correlation between the numbers of natalizumab doses received and cell numbers within peripheral blood and CSF (data not shown). There was also no difference in the number of cells between patients previously enrolled in the AFFIRM or SENTINEL trial (data not shown).

*Expanded Disability Status Scale (EDSS) assessed at time of enrollment in this study. †The number of clinical relapses during the 14-month follow-up period is shown. ‡Shown are the pharmacotherapies patients were receiving after the discontinuation of natalizumab. §N/A ⫽ Not applicable. Patient started natalizumab after initial approval by the Food and Drug Administration. AFFIRM ⫽ Natalizumab safety and efficacy in relapsing remitting multiple sclerosis. ¶ SENTINEL ⫽ The safety and efficacy of natalizumab in combination with interferon ␤-1a in patients with relapsing-remitting multiple sclerosis.

METHODS Patients. Details on our patient cohort and control cohorts were previously reported.7,8 Written informed consent was obtained, and all study procedures were approved by the IRB.

Lymphocyte counts. Absolute cell numbers in peripheral blood were determined by a commercial clinical laboratory. CSF cells were counted as previously reported.7,8

Flow cytometry. PBMC were stained for flow cytometry and analyzed using standard methods.7,8

Biomarkers of humoral immunity. CSF and serum were examined for protein, albumin, and immunoglobulin G, A, and M levels by nephelometry (BN II; Behring, Marburg, Germany). The specific intrathecal production of IgG, IgA, and IgM was calculated according to the Reiber formula.9 CSF and serum were analyzed for oligoclonal bands (OCBs) by isoelectric focusing and IgG immunoblot (Titan Gel; Rolf Greiner Biochemica, Flacht, Germany).

Evaluation of MR images. Images from 16 patients were analyzed using a dual echo fast/turbo spin echo sequence giving scans with proton density, T1, and T2-weighted contrast while the patients were on natalizumab, and 14 months after cessation of therapy. All scans were performed at 1.5 Tesla.

Statistical analysis. Mann-Whitney U paired test and Wilcoxon matched pair test were utilized to compare samples not independent of each other. GEE analysis was utilized to analyze recurrent event data. Prisms 4 (San Diego, CA) and SAS 9.1.3 (Cary, NC) software were used for data analyses. p Values ⬍0.05 were considered significant.

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397

Figure 1

Analysis of leukocyte and lymphocyte cell numbers in peripheral blood (PB)

Serial cross-sectional analysis showed that the total numbers of white blood cells (WBC) in the PB of natalizumab-treated patients with multiple sclerosis (MS) at study entry (MS Nat) were within normal limits (A). There was a nonsignificant (ns) decrease in WBC numbers between the entry time point, 6 months (MS Nat 6 months), and 14 months (MS Nat 14 months) after cessation of natalizumab therapy (A). The number of CD4⫹ T cells (B), CD8⫹ T cells (C), and CD19⫹ B cells (D) significantly increased 14 months after discontinuation of natalizumab therapy, whereas the number of CD138⫹ plasma cells did not change (E). CD4:CD8 T cell ratios in the PB were normal at all three time points (F). Longitudinal analysis of leukocyte and lymphocyte cell numbers showed a significant decrease of WBC between study entry and month 14 (G). After an initial decrease at 6 months after cessation of natalizumab, there was an increase of CD4⫹ T cells in the PB 14 months after study entry (H). The number of CD8⫹ T cells did not change over the 14-month study period, but there was an initial significant decrease 6 months after cessation of natalizumab (I).

CSF lymphocyte counts and phenotypes. A serial cross-sectional analysis of all study participants showed significantly fewer WBC, CD4⫹ T cells, CD8⫹ T cells, CD19⫹ B cells, and CD138⫹ 398

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February 3, 2009

plasma cells in CSF from natalizumab-treated patients with MS compared to patients with MS who had never received natalizumab therapy (figure e-1 on the Neurology® Web site at www.neurology.org),

Figure 2

Humoral immune parameters in CSF

e-1). A longitudinal analysis of those patients showed very similar results (figure e-1). Humoral immune parameters in the CSF. Two examples of OCBs are shown in figure 2A. The number of OCBs, the amount of intrathecally synthesized IgG, and the CSF/serum albumin quotient did not differ between patients on natalizumab, 6 months, or 14 months after cessation of the drug (figure 2, B, D, and E). The total amount of intrathecal IgG increased significantly 6 months after cessation of natalizumab, and remained stable over the next 8 months (figure 2C). Patient safety. No serious adverse events were re-

corded during the 14-month time period after the cessation of natalizumab therapy. Clinical disease activity. There was a significant de-

crease in the annual relapse rate in patients with MS on natalizumab during the AFFIRM and SENTINEL trials and during the 14-month period compared to the pretrial period (figure 3A). There was no significant difference with regard to neurologic disability as assessed by the EDSS scale among the three time points in this patient cohort (figure 3B). Disease activity on MRI. There was no significant difference with regard to gadolinium-enhancing (Gd⫹) lesions on T1-weighted images, and the total lesion volume on T2-weighted and FLAIR weighted images between patients on natalizumab and 14 months after cessation of treatment (figure 3, C–E). DISCUSSION The pharmacodynamic duration of na-

Oligoclonal bands (OCBs) were assessed in all patient samples. Two examples of the OCBs detection assay are shown (A). The number of OCBs (B), the amount of IgG synthesis (D), and the CSF/serum albumin quotient (E) did not differ between patients on natalizumab [MS (Nat)] and 6 months (MS Nat 6 months) or 14 months (MS Nat 14 months) after cessation of the drug. The total amount of intrathecal IgG increased significantly 6 months after cessation of natalizumab, and remained stable over the next 8 months (C).

as well as 6 months after cessation of natalizumab treatment (figure e-1). In contrast, 14 months after discontinuation of natalizumab, there was no significant difference in cell numbers between these cohorts (figure e-1). This was still true if the two patient outliers with the highest cell numbers at the 14-month time point were excluded from the analysis (data not shown). The CD4:CD8 T cell ratio in CSF, which was reversed in patients with MS who were treated with natalizumab, normalized 6 months after discontinuation of therapy, and remained normal after 14 months (figure

talizumab is important for several reasons. In the context of a phase II clinical trial, it was shown that as early as 3 months after discontinuation of natalizumab there was no difference between the treatment group and the placebo groups with regard to Gd⫹ lesions.11 Another group of investigators recently showed an increase in T2-weighted lesion activity on cerebral MR images in a cohort of 21 patients 15 months after cessation of natalizumab therapy.12 Thus, there is at least a theoretical concern that the discontinuation of natalizumab therapy may rapidly lead to a loss of its beneficial clinical effects, or even to a rebound phenomenon. Our own data do not support these concerns. Specifically, we did not observe a worsening of radiographic or immunologic disease activity after cessation of natalizumab therapy. In the majority of our patients, we also did not observe deterioration in their clinical status. It is important to point out that in contrast to the phase II trial mentioned above,11 the vast majority of patients in our cohort received other pharmacotherapies while involved in the SENTINEL combination trial,2 as well as after discontinuing natalizumab (table). The article by VelNeurology 72

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Figure 3

Measurement of disease activity

Longitudinal analysis of the annual relapse rate was assessed in 21 patients with multiple sclerosis (MS) for the 12-month period prior to enrollment into the AFFIRM and SENTINEL trials (MS pre Nat), for the trial period of the AFFIRM and SENTINEL trials (MS Nat), and for the 14-month period after cessation of natalizumab (MS Nat 14 months) (A). In addition, neurologic disability assessed by the Expanded Disability Status Scale (EDSS) was recorded in 17 patients prior to enrollment into the AFFIRM and SENTINEL trial (MS pre Nat), at the time of cessation of natalizumab therapy (MS Nat), and 14 months after cessation of natalizumab (MS Nat 14 months) (B). There was a significant decrease in the annual relapse rate in patients with MS on natalizumab during the AFFIRM and SENTINEL trials compared to the pretrial period (A). There was also a significant decrease in the annual relapse rate in the 14-month period after cessation of therapy compared to the pretrial period (A). In contrast, there was no significant difference in the annual relapse rate between patients on natalizumab during the AFFIRM and SENTINEL trials and during the 14-month period after cessation of natalizumab therapy (A). There was no significant difference with regard to neurologic disability as assessed by the EDSS scale among the three time points in this patient cohort (B). The number of new gadolinium-enhancing (Gd⫹) lesions on T1-weighted MRI (C), the total lesion volume on T2-weighted (D) and FLAIR-weighted images (E) was assessed while patients received natalizumab, and 14 months after discontinuation of therapy. There was no significant difference with regard to Gd⫹ lesions on T1weighted images (C) and the total lesion volume on T2-weighted (D) and FLAIR weighted images (E).

linga et al. does not comment on the use of other disease-modifying therapies in their patients.12 We had shown earlier that patients with MS who are on natalizumab therapy as well as patients 6 months after discontinuation of natalizumab treatment have significantly decreased numbers of B cells and plasma cells in their CSF. It is intriguing that natalizumab therapy appears to have minimal effects on the total production of IgG in the CNS, and that there is no impact on the number of OCBs in the CSF. These observations may suggest that there are inflammatory lymphocytes in the CNS, including cells of the B cell lineage, that are present in the brain and spinal cord for long periods of time and independent of effects on further lymphocyte migration into the CNS. 400

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The medical community is concerned with the risk of developing PML while on natalizumab therapy.13 Our 14-month data demonstrate that immune surveillance in the peripheral blood and CSF may be restored, even in patients who receive other immunomodulatory therapy. Our patients did not experience any symptoms associated with PML, other opportunistic infections, or any serious treatment-related complications. AUTHORS’ AFFILIATIONS From the Neurology Section (O.S.), VA North Texas Health Care System, Medical Service, Dallas; Departments of Neurology (O.S., P.D.C., E.M.F., G.M.R., M.P.S., E.M.C., N.L.M.), Immunology (O.S., E.M.C., N.L.M.), Ophthalmology (E.M.F.), and Clinical Sciences (S.Z.), University of Texas Southwestern Medical Center at Dallas; Department of Neurology (O.S., G.v.G., S.C.), Heinrich Heine University Du¨sseldorf,

Germany; Multiple Sclerosis Center at Texas Neurology (J.T.P.), Dallas; Departments of Clinical and Experimental Immunology (J.W.C.T.) and Neurology (M.D.B.), University Hospital Maastricht, The Netherlands; Department of Neuroinflammation (D.M., D.H.M.), Institute of Neurology, Queen Square, London, UK; Institute of Neuroradiology (E.W.R.), Department of Medical Radiology, University Hospital Basel, Switzerland; BiogenIdec (R.K.), Cambridge, MA; Department of Neurology (B.H.), Klinikum Rechts der Isar, Technische Universita¨t Mu¨nchen, Germany; and Department of Neurology (M.K.R.), The Ohio State University Medical Center, Columbus.

AUTHOR CONTRIBUTIONS Olaf Stu¨ve: Designed research, performed research, analyzed data, wrote the manuscript. Petra D. Cravens: Performed research, analyzed data, wrote the manuscript. Elliot M. Frohman: Designed research, performed research, wrote the manuscript. J. Theodore Phillips: Designed research, wrote the manuscript. Gina Remington: Performed research, analyzed data, wrote the manuscript. Gloria von Geldern: Performed research, analyzed data, wrote the manuscript. Sabine Cepok: Performed research, analyzed data, wrote the manuscript. Mahendra P. Singh: Performed research, analyzed data. J.W. Cohen Tervaert: Designed research, wrote the manuscript. Marc De Baets: Designed research, wrote the manuscript. David Mac Manus: Designed research, analyzed data. David H. Miller: Designed research, analyzed data. Ernst W. Radu¨: Designed research, analyzed data. Elizabeth M Cameron: Performed research, analyzed data. Nancy L. Monson: Designed research, performed research, analyzed data. Song Zhang: Performed research, analyzed data. Richard Kim: Analyzed data, wrote the manuscript. Bernhard Hemmer: Designed research, performed research, analyzed data, wrote the manuscript. Michael K. Racke: Designed research, performed research, analyzed data, wrote the manuscript.

2.

3.

4.

5.

6.

7.

8.

9.

10.

ACKNOWLEDGMENT The authors thank their patients for participation in this study; Jane Lee, Janey Phillips, Jill Fowler, Nancy Perna, and Subir Sinha for assistance in data acquisition; Lauren Tantalo and April Colina for technical assistance; and Dr. Steven Vernino for help with data analyses.

Received October 31, 2007. Accepted in final form June 9, 2008. REFERENCES 1. Stuve O, Bennett JL. Pharmacological properties, toxicology and scientific rationale for the use of natalizumab (Tysabri) in inflammatory diseases. CNS Drug Rev 2007; 13:79–95.

11.

12.

13.

Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911–923. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899– 910. Kleinschmidt-Demasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353:369–374. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353: 375–381. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005;353:362–368. Stuve O, Marra CM, Jerome KR, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 2006;59:743–747. Stuve O, Marra CM, Bar-Or A, et al. Altered CD4⫹/ CD8⫹ T cells ratios in cerebrospinal fluid of natalizumabtreated patients with multiple sclerosis. Arch Neurol 2006; 63:1383–1387. Reiber H. External quality assessment in clinical neurochemistry: survey of analysis for cerebrospinal fluid (CSF) proteins based on CSF/serum quotients. Clin Chem 1995; 41:256–263. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444–1452. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15–23. Vellinga MM, Castelijns JA, Barkhof F, Uitdehaag BM, Polman CH Postwithdrawal rebound increase in T2 lesional activity in natalizumab-treated MS patients. Neurology 2008;70:1150–1151. Stuve O, Marra CM, Cravens PD, et al. Potential risk of progressive multifocal leukoencephalopathy with natalizumab therapy: possible interventions. Arch Neurol 2007; 64:169–176.

Learn. Earn. Network. 2009 AAN Annual Meeting: An Excellent Value • Learn about the latest scientific advances in neurology • Earn valuable CME credit and fulfill Maintenance of Certification requirements • Network with your peers at exciting social events all week long • Enjoy the convenience and value of all this and more—in just one meeting Early registration and hotel deadline is March 20, 2009. Register today at www.am.com/AM2009.

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Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function B.O. Khatri, MD* S. Man, MD, PhD* G. Giovannoni, MBBCh, PhD A.P. Koo, MD J.-C. Lee, MS B. Tucky, BSc F. Lynn, MS S. Jurgensen, MPH J. Woodworth, PhD S. Goelz, PhD P.W. Duda, MD, PhD M.A. Panzara, MD, MPH R.M. Ransohoff, MD R.J. Fox, MD, MS

ABSTRACT

Background: Accelerating the clearance of therapeutic monoclonal antibodies (mAbs) from the body may be useful to address uncommon but serious complications from treatment, such as progressive multifocal leukoencephalopathy (PML). Treatment of PML requires immune reconstitution. Plasma exchange (PLEX) may accelerate mAb clearance, restoring the function of inhibited proteins and increasing the number or function of leukocytes entering the CNS. We evaluated the efficacy of PLEX in accelerating natalizumab (a therapy for multiple sclerosis [MS] and Crohn disease) clearance and ␣4-integrin desaturation. Restoration of leukocyte transmigratory capacity was evaluated using an in vitro blood– brain barrier (ivBBB).

Methods: Twelve patients with MS receiving natalizumab underwent three 1.5-volume PLEX sessions over 5 or 8 days. Natalizumab concentrations and ␣4-integrin saturation were assessed daily throughout PLEX and three times over the subsequent 2 weeks, comparing results with the same patients the previous month. Peripheral blood mononuclear cell (PBMC) migration (induced by the chemokine CCL2) across an ivBBB was assessed in a subset of six patients with and without PLEX. Results: Serum natalizumab concentrations were reduced by a mean of 92% from baseline to 1

Address correspondence and reprint requests to Dr. Robert J. Fox, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, 9500 Euclid Ave., U-10, Cleveland, OH 44195 [email protected]

week after three PLEX sessions (p ⬍ 0.001). Although average ␣4-integrin saturation was not reduced after PLEX, it was reduced to less than 50% when natalizumab concentrations were below 1 ␮g/mL. PBMC transmigratory capacity increased 2.2-fold after PLEX (p ⬍ 0.006).

Conclusions: Plasma exchange (PLEX) accelerated clearance of natalizumab, and at natalizumab concentrations below 1 ␮g/mL, desaturation of ␣4-integrin was observed. Also, CCL2-induced leukocyte transmigration across an in vitro blood– brain barrier was increased after PLEX. Therefore, PLEX may be effective in restoring immune effector function in natalizumab-treated patients. Neurology® 2009;72:402–409 GLOSSARY AE ⫽ adverse event; BBB ⫽ blood– brain barrier; BW ⫽ body weight; EDSS ⫽ Expanded Disability Status Scale; hIgG4-PE ⫽ human IgG4 monoclonal antibody conjugated with phycoerythrin; Ig ⫽ immunoglobulin; ivBBB ⫽ in vitro blood– brain barrier; mAb ⫽ monoclonal antibody; MFI ⫽ mean fluorescence intensity; MS ⫽ multiple sclerosis; PBMC ⫽ peripheral blood mononuclear cell; PLEX ⫽ plasma exchange; PML ⫽ progressive multifocal leukoencephalopathy; TDL ⫽ total drug load; V1 ⫽ volume of distribution of the central compartment; Vd ⫽ volume of distribution.

Several monoclonal antibodies (mAbs), including natalizumab, rituximab, daclizumab, and alemtuzumab, target proteins expressed on circulating blood cells.1-3 Rare but serious complications have been associated with a number of these therapies.4-10 The pharmacokinetic half-life of mAbs is typically only 10 to 30 days, but the pharmacodynamic half-life can be significantly longer. For example, the pharmacokinetic half-life of natalizumab in patients with multiple Supplemental data at www.neurology.org *These authors contributed equally to this work. From the Regional Multiple Sclerosis Center and Center for Neurological Disorders (B.O.P.), Aurora St. Luke’s Medical Center, Milwaukee, WI; Neuroinflammation Research Center, Lerner Research Institute (S.M., B.T., R.M.R.), Mellen Center for Multiple Sclerosis Treatment and Research (R.M.R., R.J.F.), Department of Hematology (A.P.K.), and Department of Quantitative Health Sciences (J.-C.L.), Cleveland Clinic, Cleveland, OH; Institute of Cell and Molecular Science (G.G.), Barts and London Queen Mary’s School of Medicine and Dentistry, London, UK; Biogen Idec, Inc. (F.L., P.W.D., S.J., J.W., S.G., M.A.P.), Cambridge, MA; and Cleveland Clinic Lerner College of Medicine (R.M.R., R.J.F.), Case Western Reserve University, Cleveland, OH. Supported by Biogen Idec, Inc., Elan Pharmaceuticals, Inc., NIH P50NS38667 (R.M.R.), and K23 47211-01 (R.J.F.). Disclosure: Author disclosures are provided at the end of the article. 402

Copyright © 2009 by AAN Enterprises, Inc.

sclerosis (MS) is approximately 11 ⫾ 4 days; however, mean ␣4-integrin saturation levels remain greater than 70% at 4 weeks after infusion. In addition, natalizumab is detectable in the circulation for up to 12 weeks,11,12 and CSF cell counts are significantly reduced for up to 6 months.13 Accelerated removal of these mAbs, along with increased availability of their ligands, may improve clinical outcomes of some therapy-associated complications. Natalizumab is an effective therapy for the treatment of relapsing forms of MS and Crohn disease.14-16 However, natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML, which is caused by JC virus), with an estimated incidence of 1:1,000 after a median of 18 months of treatment.17 The original natalizumab PML reports were of patients also receiving other immunomodulating therapies, but PML has now been reported with natalizumab monotherapy.18 The ␣4-integrin is an adhesion molecule involved in the entry of leukocytes into tissues, including the CNS.1 The mechanism by which PML develops in the setting of natalizumab therapy is not well understood.19 However, it is clear that immune effector responses to CNS JC viral infection require lymphocyte migration across the blood– brain barrier (BBB), a function suppressed by natalizumab. Accelerated removal of natalizumab from the body may lead to reduced ␣4-integrin saturation, thereby allowing lymphocytes to adhere to vascular endothelium and traffic into the CNS. This could restore immune function, potentially improving the clinical outcome from PML.20,21 Immune reconstitution is the only intervention with demonstrated efficacy for PML, including patients with HIV infection taking highly active antiretroviral therapy22,23 and in transplant patients after reduction in immunosuppressant medications.24,25 Little is known about how to remove therapeutic proteins from the body and whether their removal will restore the native function of the endogenous targets. We evaluated the efficacy of plasma exchange (PLEX) in accelerating the clearance of natalizumab and the subsequent decrease in saturation of ␣4-

integrin by comparing these measures after natalizumab infusion both with and without PLEX. Restoration of the transmigratory capacity of circulating leukocytes was ascertained using an in vitro BBB model. METHODS Patients. Patients with MS were recruited to receive three courses of PLEX. All patients gave written informed consent. Eligible patients were aged 18 –50 years, had a diagnosis of relapsing MS, were treated with natalizumab consistent with product labeling, and were free of signs and symptoms suggestive of immune compromise or serious opportunistic infection, based on medical history, physical examination, or laboratory testing. Patients were excluded from the study if they tested positive for anti-natalizumab antibodies. At the time of PLEX, all patients must have received three or more doses of natalizumab so that natalizumab concentrations would be at stable levels before PLEX.

Study design. This was an open-label, single-arm, time-series longitudinal study conducted at two sites. Only the patients from site 2 were enrolled in the in vitro BBB substudy. Pharmacokinetic and pharmacodynamic data were compared before and after PLEX as well as with data from a historic natalizumabtreated control group26,27 (Biogen Idec and Elan Pharmaceuticals, unpublished data). PLEX was started 10–14 days after natalizumab infusion. Patients underwent three separate exchanges of 1.5 plasma volumes.28,29 Two PLEX schedules were followed: a Monday–Thursday–Monday schedule at site 1 and a Monday–Wednesday–Friday schedule at site 2. Each PLEX occurred over approximately 2.5 to 3 hours, using continuous-flow systems. Vascular access was achieved by a radial artery catheter placed daily or a large-bore, doublelumen catheter placed via the internal jugular vein.30 Figure e-1 on the Neurology® Web site at www.neurology.org depicts the study flow. Two methods were used to calculate plasma volume: a weight-only– based formula (site 1, and three patients from site 2): volume exchanged ⫽ 1.5 ⫻ 0.05 ⫻ weight (kg); and a weight-, height-, sex-, and hematocrit-based formula (three patients from site 2): volume exchanged ⫽ 1.5 ⫻ blood volume (L) ⫻ (1 ⫺ hematocrit). Blood volume (mL) was estimated as follows: men, (367 ⫻ height [m]3) ⫹ (32.2 ⫻ weight [kg]) ⫹ 604; women, (356 ⫻ height [m]3) ⫹ (33.1 ⫻ weight [kg]) ⫹ 183. Because both methods yielded similar pharmacokinetic results, combined data are reported here. Serum natalizumab concentration and ␣ 4-integrin saturation. Natalizumab concentrations (Charles River Laboratories, Sennevile, Quebec, Canada) and ␣4-integrin saturation (Esoterix Clinical Trial Services, Brentwood, TN) were determined by independent laboratories. Serum natalizumab concentration was measured using a sandwich ELISA. Briefly, serum samples were incubated at room temperature for 90 ⫾ 15 minutes in microtiter plates coated with anti-natalizumab antibody. After washing, mouse anti– human immunoglobulin (Ig) G4 alkaline phosphatase conjugate was added to detect bound natalizumab. Para-nitrophenyl phosphate was added to detect the antibody, and absorbance was measured at 405 nm. The concentration of natalizumab was determined by interpolation from a standard curve. Saturation of ␣4-integrin was measured by a flow cytometry assay designed to directly measure natalizumab bound to the surface of peripheral blood mononuclear cells (PBMCs). Neurology 72

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Briefly, 100 ␮L whole-blood aliquots were incubated with or without saturating natalizumab (10 ␮g/mL) for 20 minutes at room temperature. After incubation, red blood cells were lysed, and the remaining leukocytes resuspended with phosphatebuffered saline–normal calf serum. Bound natalizumab was subsequently detected by a fluorescently labeled anti– human IgG4 monoclonal antibody conjugated with phycoerythrin (hIgG4PE). Leukocytes were measured by flow cytometer, collecting 100,000 total nucleated events. Percent natalizumab saturation was calculated from the mean fluorescence intensity (MFI) in each sample by the following formula: MFI – hIgG4-PE signal (without natalizumab)/MFI – hIgG4-PE signal (with natalizumab) ⫻ 100. The performance of the serum natalizumab and ␣4-integrin saturation assays is shown in table e-1.

Calculation of total drug load. Total drug load (TDL) was estimated for each patient based on a mean volume of distribution (Vd) value of 84.1 mL/kg derived from previous studies (Biogen Idec and Elan Pharmaceuticals, unpublished data). The volume of distribution of the central compartment (V1) was estimated based on body weight (BW) in kilograms: V1 ⫽ 3.97 ⫻ (BW/70)0.539 (Biogen Idec and Elan Pharmaceuticals, unpublished data). The amount of drug removed was calculated by multiplying the difference in plasma natalizumab concentration immediately before and after each PLEX procedure by V1. The total amount of natalizumab removed was estimated using pharmacokinetic volumes of distribution (V1 and Vd) and the measured natalizumab concentrations just before initiating PLEX, as well as at the beginning and end of each PLEX session to correct for possible underestimates arising from variations in sample collection. Modeling of a PLEX protocol. Population pharmacokinetic modeling was performed using serum natalizumab concentration data from this study and data from 245 patients who participated in a natalizumab phase 3 clinical trial (AFFIRM)14 to develop a model PLEX schedule that would maximize the speed of immune reconstitution. A two-compartment model with adjustments for body weight and volume of distribution terms was considered the best model for natalizumab. An additive factor was included with the clearance term that represented the impact of PLEX based on the volume of plasma exchanged and the rate of plasma exchange. The ␣4-integrin binding was then modeled based on a direct Emax response relationship determined from previous measurements (Biogen Idec and Elan Pharmaceuticals, unpublished data). Leukocyte transmigration. An in vitro BBB model was used to assay leukocyte transmigratory capacity.31,32 The in vitro BBB model consisted of SV40 T-antigen–immortalized human brain microvascular endothelial cells cultured to confluence in transwell inserts and stimulated with tumor necrosis factor ␣ (10 U/mL) and interferon ␥ (20 U/mL) for 24 hours.32 PBMCs were isolated using Ficoll cushions and labeled with AM calcein. Immediately ex vivo, 106 PBMCs/well were introduced into the upper compartment, with or without the chemokine CCL2 in the lower compartment, which induces ␣4-integrin– dependent transmigration.33 Differences in PBMC transmigration between basal and CCL2-stimulated conditions were assessed using fluorometry to quantify the transmigrated PBMCs.31 Patients were evaluated approximately 2 and 4 weeks after natalizumab infusion without PLEX and 2.5 and 4.5 weeks after natalizumab infusion with PLEX. Controls were patients with MS not receiving any long-term immunomodulating MS therapy (n ⫽ 8) and healthy patients (n ⫽ 7). Appropriate positive controls (natalizumab, which blocks CCL2-induced migration) and negative 404

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Table

Patient demographics and baseline plasma exchange characteristics (n ⴝ 12)

Age, mean ⴞ SD, y

40.8 ⫾ 8.1

Weight, mean ⴞ SD, kg

82.83 ⫾ 18.65

Height, mean ⴞ SD, cm

168.8 ⫾ 12.07

Sex, % female

58

Race, % white

92

Time from previous natalizumab infusion to PLEX, median (min, max), days

13.0 (10, 14)

Volume of PLEX per session, mean ⴞ SD, L

5.65 ⫾ 1.40

PLEX ⫽ plasma exchange.

controls (IgG) were performed with each sample. The difference in cell migration between basal and CCL2-stimulated conditions reflects the functional capacity of ␣4-integrins to mediate leukocyte transmigration in this assay.32

Safety. Safety assessments included clinical examination with Expanded Disability Status Scale (EDSS),34 routine laboratory tests, and adverse event (AE) and concomitant therapy monitoring. All patients resumed natalizumab 2 to 2.5 weeks after completion of PLEX. A safety follow-up telephone call was made 12 weeks after the last PLEX. The study protocol was approved by local ethics committees and was overseen by an independent safety monitor, in accordance with NIH guidelines.35

Statistical analysis. The preplanned, protocol-defined primary outcome was serum concentration of natalizumab after plasma exchange. Changes in natalizumab concentration and ␣4-integrin saturation were assessed using summary statistics, and changes after PLEX were evaluated using a paired t test. Comparisons with historic controls were made using the Satterthwaite t test. Changes in leukocyte transmigration were analyzed using analysis of variance.

Trial registration. This trial is registered at the ClinicalTrials. gov Web site with the following identifier: NCT00424788. RESULTS Patients. Thirteen patients with relapsing MS were enrolled. One patient developed antinatalizumab antibodies and was excluded before initiation of PLEX. All remaining 12 patients completed the three planned PLEX sessions and subsequent follow-up. The table shows the demographic and baseline characteristics of the patients who received PLEX.

Serum natalizumab concentration. Each PLEX session reduced serum natalizumab concentrations (figure 1A). After a single session of PLEX, natalizumab concentrations for all patients decreased by a mean of 82 ⫾ 8.1%. Natalizumab concentrations re-equilibrated within 24 hours of the first PLEX to a mean reduction of 65 ⫾ 8.3%. One week after the final PLEX, the mean serum natalizumab concentration was 3.2 ⫾ 2.4 ␮g/ mL, representing a mean reduction of 92% (range 84%–100%) compared with before PLEX. Compar-

Figure 1

Effects of plasma exchange on serum concentration of natalizumab and ␣4-integrin saturation

integrin saturation was not decreased by PLEX. However, in the three patients in whom natalizumab concentration was sustained below 1 ␮g/mL, receptor saturation declined immediately after PLEX and continued to decline over the following 2 weeks to less than 50%. In the patients who had natalizumab levels greater than 1 ␮g/mL, receptor saturation showed no consistent change. Figure 2 illustrates the dependence of ␣4-integrin saturation on natalizumab concentration. At concentrations less than 1 ␮g/mL, receptor saturation was generally below 50%. Leukocyte transmigration. Patients with MS receiving natalizumab displayed significant reductions in CCL2-induced transmigration (figure 3). Mean CCL2-induced leukocyte transmigration in patients at 2 and 4 weeks after natalizumab infusion (without PLEX) was 29.3% of that observed in eight MS controls not receiving MS therapy (p ⫽ 0.03) and 37.6% of that observed in seven healthy controls (p ⬍ 0.01). At 18 days after PLEX (corresponding to 4.5 weeks after natalizumab), CCL2-induced transmigration was increased an average of 2.2-fold, with all patients demonstrating increased CCL2-induced transmigration (p ⬍ 0.006). At that time, mean CCL2-induced leukocyte transmigration was 64.1% of that observed in MS controls (p ⫽ 0.27) and 82.4% of that observed in healthy controls (p ⬎ 0.4).

Effects of plasma exchange (PLEX) on serum concentration of natalizumab (A) and ␣4integrin saturation (B). Historic data were obtained from a separate group of patients with multiple sclerosis after six monthly doses of natalizumab, with no PLEX.28,29 For ␣4-integrin saturation (B), PLEX patients were divided into two groups: those with sustained natalizumab concentration of less than 1 ␮g/mL after PLEX and those with natalizumab concentration of 1 ␮g/mL or greater after PLEX.

ing natalizumab concentrations in the same patients with and without PLEX, PLEX led to a 75 ⫾ 28% reduction in natalizumab concentrations (p ⫽ 0.002) 4 weeks after natalizumab infusion. Comparison with historic controls also showed a similar result (p ⫽ 0.003). TDL and amount of natalizumab removed. The mean

(⫾standard deviation) TDL before PLEX was 256 ⫾ 127 mg. The three PLEX sessions removed a mean total of 191 ⫾ 82 mg of natalizumab, which was 75% of the initial TDL. ␣4-Integrin saturation. PLEX had a variable effect on

␣4-integrin saturation (figure 1B). Average ␣4-

Modeling of a PLEX protocol. Assuming that PLEX would be initiated approximately 1 week after administration of the last natalizumab dose (i.e., a higher initial TDL than in the present study), the model predicts that five PLEX sessions of 1.5 plasma volumes each (calculated by the weight-only formula above) would be required for more than 95% of patients to reach a serum natalizumab concentration less than 1 ␮g/mL (figure 4). Extrapolation of the historic pharmacokinetic data suggests that it would take approximately 97 days to achieve a serum natalizumab concentration less than 1 ␮g/mL without PLEX. Safety. PLEX was generally well tolerated, with no relapses or other disease activity and no evidence of a rebound in disease activity. AEs were generally mild or moderate with no resultant discontinuations. The most common AE was hypotension (n ⫽ 4), one case of which was serious, because the patient required overnight hospitalization for observation. Other AEs considered by the investigator to be possibly related to PLEX included fatigue, catheter pain, knee pain, diaphoresis, dry mouth, anxiety, and emesis (all n ⫽ 1). One patient developed auditory hallucinations after the unanticipated removal of his antipsychotic medication by PLEX. No AEs were considered related to natalizumab. All patients returned to natalizumab treatment at the conclusion of the study Neurology 72

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Figure 2

Relationship between serum natalizumab concentration and ␣4integrin saturation

The steady-state correlation between serum natalizumab concentration (log scale) and ␣4integrin saturation in plasma exchange (PLEX) patients is shown. At serum natalizumab concentrations below 1.0 ␮g/mL, there is reliable ␣4-integrin desaturation. To allow for re-equilibration, only data points ⱖ24 hours after each PLEX session are shown.

without incident. All patients had stable or improving EDSS. Telephone follow-up 12 weeks after PLEX revealed no new AEs. Clinically effective mAbs may cause rare complications for which expedited removal of the therapeutic entity from the body would be desirable.

DISCUSSION

Figure 3

Given the efficacy of plasmapheresis in removing serum proteins, it is not surprising that PLEX accelerated the clearance of natalizumab in this study, reducing mean serum natalizumab concentrations by an average of 92% from baseline to 1 week after the final PLEX session. Using the same patients as their own controls, PLEX reduced natalizumab concentration 75% compared with the same time after natalizumab without PLEX (figure 1A). Comparison with historic pharmacokinetic data shows similar results. The clinical efficacy of natalizumab in MS is thought to be mediated via the blockade of the ␣4integrin, thereby decreasing leukocyte transmigration across the BBB or blood–CSF barrier into the CNS.26,36 Accordingly, decreased ␣4-integrin saturation is a desired target to restore trafficking of immune cells into the CNS, which would be desired in the case of a CNS-based infection such as PML. Clinical data from phase 3 clinical trials suggest that saturation levels greater than 70% are associated with continued therapeutic efficacy (Biogen Idec, data on file). Although average ␣4-integrin saturation was not decreased after PLEX, we observed a reduction of ␣4-integrin saturation to less than 50% when natalizumab concentration was below 1 ␮g/mL (figure 2). Factors that likely influence the efficacy of natalizumab removal by PLEX are initial TDL and total plasma volume exchanged. After three PLEX sessions, only 25% of the initial TDL remained.

Absolute peripheral blood mononuclear cell transmigration to chemokine CCL2 in natalizumab-treated patients

Induced transmigration (i.e., difference in transmigrating peripheral blood mononuclear cells across an in vitro blood– brain barrier in the presence and absence of CCL2) is shown at two time points before plasma exchange (PLEX; no shading) and after PLEX (lighter shading). Black bars represent the mean. For comparison, values for eight patients with multiple sclerosis (MS) not receiving any MS treatment or PLEX and values for seven healthy patients also are shown (darker shading). 406

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Figure 4

Population pharmacokinetic and pharmacodynamic modeling of plasma exchange

Through population modeling of five alternating-day plasma exchange (PLEX) sessions (blue arrows) starting 7 days after natalizumab dosing, PLEX reduces natalizumab concentration to less than 1 ␮g/mL by day 15. Without PLEX, the same concentration would be expected by day 97.

In a model based on results from this study and pharmacokinetic data from a phase 3 clinical trial, five PLEX sessions, each of 1.5 plasma volumes 2 days apart, would reduce serum natalizumab concentrations to less than 1 ␮g/mL and ␣4-integrin saturation levels to less than 50% in more than 95% of patients. Fewer PLEX sessions may be needed in patients with lower initial TDL (e.g., in those who have a greater time interval between the last dose of natalizumab and the start of PLEX), whereas an additional session may be required in patients with a higher initial TDL, such as those who start PLEX less than 1 week after natalizumab infusion. Similar protocols have been shown to be safe in other neurologic disorders, including MS, Guillain–Barre´ syndrome, chronic inflammatory demyelinating polyneuropathy, and myasthenia gravis.35,37-40 Thus, using the protocol suggested by the model, the 1-␮g/mL threshold can be reached approximately 15 days after natalizumab dosing. In the absence of PLEX, historic pharmacokinetic data indicate that the same threshold would take approximately 82 days longer. PLEX significantly increased the ability of PBMCs from natalizumab recipients to transmigrate across an in vitro BBB in response to CCL2. We previously reported that addition of exogenous natalizumab to the in vitro BBB assay consistently abolished induction of leukocyte transmigration by chemokines, including CCL2, confirming that this assay is a valid tool to assess the efficiency of ␣4integrin inhibition of cell trafficking.32 Somewhat

surprisingly, even in patients with greater than 70% receptor saturation, we consistently observed increased CCL2-induced transmigration after PLEX. Even though gross changes in receptor saturation were not observed, increased receptor-mediated transmigratory capacity was demonstrated in many patients. We speculate that restored transmigratory capacity despite persistently high ␣4-integrin saturation may be attributable to sensitivity of the functional transmigration assay to small changes in receptor saturation. In the present study, three sessions of PLEX accelerated the clearance of natalizumab, restored CCL2induced leukocyte transmigration across the in vitro BBB, and led to decreased ␣4-integrin saturation when the serum natalizumab concentration reached levels below approximately 1 ␮g/mL. The validity of our results is supported by comparison both with the same patients without PLEX and with an external historic control group. The results of this study suggest that PLEX may be effective in rapidly restoring CNS immune effector responses in natalizumabtreated patients, which may benefit patients with serious opportunistic infections such as PML. However, none of the patients who underwent PLEX had PML, and the utility of this procedure in such cases is unknown. Similarly, the long-term effect of PLEX on clinical relapses and disability in the present setting are unknown. To our knowledge, this is the only study to date to demonstrate the efficacy of PLEX in reducing serum concentrations and receptor saturation of any mAb. Because mAbs differ in their pharmacokinetic and pharmacodynamic profiles, the efficacy of PLEX in accelerating the clearance of other protein-based therapeutic agents is unknown. AUTHOR CONTRIBUTIONS The main study protocol was written by G.G. and B.O.K.; the in vitro BBB substudy protocol was written by R.J.F., S.M., and R.M.R.; the manuscript was written by R.J.F. and B.O.K. The other authors provided input to each of these documents. Pharmacokinetic and pharmacodynamic data were held and analyzed by the study sponsor; in vitro BBB data were held and analyzed by the Cleveland Clinic. The authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. Statistical analyses were performed by F.L., J.W., and J.-C.L.

ROLE OF MEDICAL WRITER OR EDITOR Paul Benfield and Matthew Hasson, Scientific Connections, are acknowledged for proofreading the manuscript and editing the figures. This assistance was funded by Biogen Idec.

ACKNOWLEDGMENT The authors thank Dean Wingerchuk, independent safety monitor, for his contribution and Neil Ashman, consultant nephrologist at Barts and The London NHS Trust, for his help in developing the study protocol. The authors also thank the following for assistance with this study: Vinette Zinkand, Maria Eisen, Charlene Belsole, Michaela Lerner, Debra Neurology 72

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Goodwin, John Kramer, the plasmapheresis nurses, and the patients with MS who volunteered for this study.

13.

DISCLOSURE

14.

B.O.K. has served as a consultant for and received honoraria from Bayer Healthcare, Biogen Idec, Inc., GlaxoSmithKline, Medtronic, Pfizer, Serono, and Teva Pharmaceuticals. G.G. has received consulting fees from Bayer-Schering Healthcare, Biogen Idec, Inc., GlaxoSmithKline, MerckSerono, Novartis, Protein Discovery Laboratories, Teva-Aventis, and UCB Pharma; lecture fees from Bayer-Schering Healthcare, Biogen Idec, Inc., Merck-Serono, and Teva-Aventis; and grant support from BayerSchering Healthcare, Biogen Idec, Inc., Merck-Serono, Merz Pharma, Novartis, Teva-Aventis, and UCB Pharma. S.M., A.K., J.-C.L., and B.T. have no conflicts of interest to disclose. F.L., S.J., J.W., S.G., P.W.D., and M.A.P. are employees of Biogen Idec, Inc., and own stock in the company. R.M.R. has served as a consultant for Bayer, Biogen Idec, Inc., and Merck-Serono. R.J.F. has received speaking fees, received consulting honoraria, received research support, and/or served on clinical trial steering committees for Biogen Idec, Inc., Genentech, and Teva Neurosciences.

Received August 18, 2008. Accepted in final form October 16, 2008. REFERENCES 1. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992;356:63–66. 2. Monson NL, Cravens PD, Frohman EM, Hawker K, Racke MK. Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol 2005;62:258–264. 3. Bielekova B, Catalfamo M, Reichert-Scrivner S, et al. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci USA 2006;103:5941–5946. 4. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353:369–374. 5. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375–381. 6. Van Assche G, Van Ranst M, Sciot RB, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005;353:362–358. 7. Kranick SM, Mowry EM, Rosenfeld MR. Progressive multifocal leukoencephalopathy after rituximab in a case of non-Hodgkin lymphoma. Neurology 2007;69:704–706. 8. Steurer M, Clausen J, Gotwald T, et al. Progressive multifocal leukoencephalopathy after allogeneic stem cell transplantation and posttransplantation rituximab. Transplantation 2003;76:435–436. 9. Mullen JC, Oreopoulos A, Lien DC, et al. A randomized, controlled trial of daclizumab vs anti-thymocyte globulin induction for lung transplantation. J Heart Lung Transplant 2007;26:504–510. 10. Coles AJ, Cox A, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 2006;253:98–108. 11. TYSABRI [package insert]. Cambridge, MA: Biogen Idec, Inc.; 2007. 12. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15–23. 408

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Stuve O, Marra CM, Jerome KR, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 2006;59:743–747. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899–910. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911–923. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005;353:1912–1925. Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354:924–933. Wenning W, Haghikia A, Laubenberger J, et al. Treatment of PML unfolding during monotherapy with natalizumab. World Congress on Treatment and Research in Multiple Sclerosis; September 18 –20, 2008; Montreal, Canada. Ransohoff RM. Natalizumab and PML. Nat Neurosci 2005;8:1275. Kappos L, Bates D, Hartung HP, et al. Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. Lancet Neurol 2007;6:431– 441. Stuve O, Marra CM, Cravens PD, et al. Potential risk of progressive multifocal leukoencephalopathy with natalizumab therapy: possible interventions. Arch Neurol 2007; 64:169–176. Clifford DB, Yiannoutsos C, Glicksman M, et al. HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology 1999; 52:623–625. Wyen C, Lehmann C, Fatkenheuer G, Hoffmann C. AIDS-related progressive multifocal leukoencephalopathy in the era of HAART: report of two cases and review of the literature. AIDS Patient Care STDS 2005;19: 486–494. Crowder CD, Gyure KA, Drachenberg CB, et al. Successful outcome of progressive multifocal leukoencephalopathy in a renal transplant patient. Am J Transplant 2005;5:1151– 1158. Shitrit D, Lev N, Bar-Gil-Shitrit A, Kramer MR. Progressive multifocal leukoencephalopathy in transplant recipients. Transplant Int 2005;17:658–665. Rudick RA, Sandrock A. Natalizumab: alpha 4-integrin antagonist selective adhesion molecule inhibitors for MS. Expert Rev Neurother 2004;4:571–580. Biologics License Application 125104. Clinical pharmacology and biopharmaceutics review(s). Washington, DC: US Food and Drug Administration, Center for Drug Evaluation and Research; 2004. Available at: http://www. fda.gov/cder/foi/nda/2004/125104s000_Natalizumab_ Biopharmr.pdf. Accessed August 12, 2008. Pinching AJ. Recent advances in immunological therapy: plasma-exchange and immunosuppression. Br J Anaesth 1979;51:21–28. Khatri B, McQuillen M, Harrington G, Schmoll D, Hoffmann R. Chronic progressive multiple sclerosis: double-blind controlled study of plasmapheresis in patients taking immunosuppressive drugs. Neurology 1985;35:312–319.

30. Khatri BO. Vascular access via temporary radial artery catheterization for therapeutic plasma exchange. J Clin Apheresis 2003;18:134. 31. Callahan MK, Williams KA, Kivisakk P, Pearce D, Stins MF, Ransohoff RM. CXCR3 marks CD4⫹ memory T lymphocytes that are competent to migrate across a human brain microvascular endothelial cell layer. J Neuroimmunol 2004;153:150–157. 32. Ubogu EE, Callahan MK, Tucky BH, Ransohoff RM. Determinants of CCL5-driven mononuclear cell migration across the blood-brain barrier: implications for therapeutically modulating neuroinflammation. J Neuroimmunol 2006;179:132–144. 33. Man S, Ubogu EE, Ransohoff RM. Inflammatory cell migration into the central nervous system: a few new twists on an old tale. Brain Pathol 2007;17:243–250. 34. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444–1452.

35.

36. 37.

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Weinshenker BG, O’Brien PC, Petterson TM, et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 1999;46:878–886. Ransohoff RM. Natalizumab for multiple sclerosis. N Engl J Med 2007;356:2622–2629. Hahn AF, Bolton CF, Pillay N, et al. Plasma-exchange therapy in chronic inflammatory demyelinating polyneuropathy: a double-blind, sham-controlled, cross-over study. Brain 1996;119:1055–1066. Greenwood RJ, Newsom-Davis J, Hughes RA, et al. Controlled trial of plasma exchange in acute inflammatory polyradiculoneuropathy. Lancet 1984;1:877–879. Group TG-BsS. Plasmapheresis and acute Guillain-Barre syndrome. Neurology 1985;35:1096–1104. Yeh JH, Chiu HC. Plasmapheresis in myasthenia gravis: a comparative study of daily versus alternately daily schedule. Acta Neurol Scand 1999;99:147–151.

Editor’s Note to Authors and Readers: Levels of Evidence coming to Neurology® Effective January 15, 2009, authors submitting Articles or Clinical/Scientific Notes to Neurology® that report on clinical therapeutic studies must state the study type, the primary research question(s), and the classification of level of evidence assigned to each question based on the classification scheme requirements shown below (left). While the authors will initially assign a level of evidence, the final level will be adjudicated by an independent team prior to publication. Ultimately, these levels can be translated into classes of recommendations for clinical care, as shown below (right). For more information, please access the articles and the editorial on the use of classification of levels of evidence published in Neurology.1-3 REFERENCES 1. French J, Gronseth G. Lost in a jungle of evidence: we need a compass. Neurology 2008;71:1634 –1638. 2. Gronseth G, French J. Practice parameters and technology assessments: what they are, what they are not, and why you should care. Neurology 2008;71:1639 –1643. 3. Gross RA, Johnston KC. Levels of evidence: taking Neurology® to the next level. Neurology 2008;72:8 –10.

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Midbrain– hindbrain involvement in lissencephalies

Patrice Jissendi-Tchofo, MD Simay Kara, MD A. James Barkovich, MD

Address correspondence and reprint requests to Dr. Patrice Jissendi-Tchofo, Radiology Department, Erasme Hospital, Route de Lennik 808, B-1070 Brussels, Belgium [email protected]

ABSTRACT

Objectives: To determine the involvement of the midbrain and hindbrain (MHB) in the groups of classic (cLIS), variant (vLIS), and cobblestone complex (CBSC) lissencephalies and to determine whether a correlation exists between the cerebral malformation and the MHB abnormalities.

Methods: MRI scans of 111 patients (aged 1 day to 32 years; mean 5 years 4 months) were retrospectively reviewed. After reviewing the brain involvement on MRI, the cases were reclassified according to known mutation (LIS1, DCX, ARX, VLDLR, RELN, MEB, WWS) or mutation phenotype (LIS1-P, DCX-P, RELN-P, ARX-P, VLDLR-P) determined on the basis of characteristic MRI features. Abnormalities in the MHB were then recorded. For each structure, a score was assigned, ranging from 0 (normal) to 3 (severely abnormal). The differences between defined groups and the correlation between the extent of brain agyria/pachygyria and MHB involvement were assessed using Kruskal–Wallis and ␹2 McNemar tests.

Results: There was a significant difference in MHB appearance among the three major groups of cLIS, vLIS, and CBSC. The overall score showed a severity gradient of MHB involvement: cLIS (0 or 1), vLIS (7), and CBSC (11 or 12). The extent of cerebral lissencephaly was significantly correlated with the severity of MHB abnormalities (p ⫽ 0.0029). Conclusion: Our study focused on posterior fossa anomalies, which are an integral part of cobblestone complex lissencephalies but previously have not been well categorized for other lissencephalies. According to our results and the review of the literature, we propose a new classification of human lissencephalies. Neurology® 2009;72:410–418 GLOSSARY A ⫽ autosomal; ACC ⫽ agenesis of corpus callosum; AD ⫽ autosomal dominant; AP ⫽ anteroposterior; AR ⫽ autosomal recessive; CBL ⫽ cerebellar; CBSC ⫽ cobblestone complex; cLIS ⫽ classic lissencephaly; CMD ⫽ congenital muscular dystrophy; CSZ ⫽ cell-sparse zone; DV ⫽ dorsal–ventral; FCMD ⫽ Fukuyama congenital muscular dystrophy; IVH ⫽ inferior vermis hypoplasia; LV ⫽ lateral ventricle; m ⫽ medulla; M ⫽ midbrain; MDS ⫽ Miller–Dieker syndrome; MEB ⫽ muscle– eye– brain; MHB ⫽ midbrain and hindbrain; MR ⫽ magnetic resonance; ND ⫽ not determined; P ⫽ pons; RC ⫽ rostrocaudal; SCBH ⫽ subcortical band heterotopia; SELH ⫽ subependymal linear heterotopia; V ⫽ vermis; vLIS ⫽ variant lissencephaly; WI ⫽ weighted image; WWS ⫽ Walker–Warburg syndrome; XLD ⫽ X-linked dominant; XLR ⫽ X-linked recessive.

The term lissencephaly (smooth outer brain surface) refers to a paucity of gyral and sulcal development.1 It encompasses a spectrum of gyral malformations ranging from complete agyria to regional pachygyria and includes subcortical band heterotopia. Lissencephaly has been traditionally classified in two distinct groups: classic (cLIS, formerly called lissencephaly type 1) and cobblestone complex (CBSC, formerly called lissencephaly type 2) based on both brain imaging and pathology. To date, five genes have been identified as causing or contributing to human cLIS: LIS1, 14-3-3␧ in Miller–Dieker syndrome (MDS), DCX, RELN, and ARX.1-6 A new classification has recently been proposed defining four groups of cLIS differing from each other by genetics and neuropathologic features of the cerebral cortex, cerebellum, and brainstem.3 1) Supplemental data at www.neurology.org Editorial, page 394 e-Pub ahead of print on November 19, 2008, at www.neurology.org. From the Neuroradiology section (P.J.-T., S.K., A.J.B.), Department of Radiology, University of California, San Francisco, CA; Service de Neuroradiologie (P.J.-T.), Hoˆpital R. Salengro, Centre Hospitalier Re´gional de Lille, France; Neuroradiology section (P.J.-T.), Department of Radiology, Erasme Hospital, Brussels, Belgium; and Department of Radiology (S.K.), Faculty of Medicine, Kirikkale University, Turkey. Supported by R37 NS035129 from the National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD. Disclosure: The authors report no disclosures. 410

Copyright © 2009 by AAN Enterprises, Inc.

LIS1 mutations and MDS show a fourlayered cortex predominantly posterior with white matter heterotopia in the cerebellum, a normal three-layered cerebellar cortex, and normal to small pons. 2) DCX mutations show a four-layered cortex similar to LIS1 but predominantly anterior; cerebellar and pontine abnormalities are similar to those in LIS1 mutations. 3) ARX mutations have a threelayered cortex; the cerebellum is normal, but the pons is small due to hypoplastic corticospinal tracts. 4) Lissencephaly with a twolayered cortex, diffuse involvement of the brain surface with no gradient; the cerebellum is extremely hypoplastic with pontine and medullary disorganization. No RELN-like mutations were studied. The authors divided these lissencephalies into two groups: LIS1 and DCX were classified as cLIS, whereas ARX and two-layered lissencephalies were classified as variant lissencephaly (vLIS).3 Numerous genes have been identified in association with the CBSC (also called dystroglycanopathies).7-12 Most affected patients have symptoms of congenital muscular dystrophies (CMDs) with CNS involvement. Among these disorders, three phenotypes are well defined: Fukuyama congenital muscular dystrophy (FCMD), Walker–Warburg syndrome (WWS), and muscle– eye– brain disease (MEB).1,7-11 These phenotypes have been associated with mutations of multiple genes involved in O-glycosylation of ␣-dystroglycan, including FCMD, FKRP, POMT1, POMT2, LARGE, and POMGnT1.12 The aim of our study was to determine the involvement of the midbrain and hindbrain (MHB) in these disorders, and to determine whether a correlation exists between the cerebral malformation and the MHB characteristics as determined by MRI. METHODS MRI scans or portions of MRI scans of 120 patients were retrospectively reviewed. The scans were acquired from the private teaching collection of the senior author (acquired over 22 years), from the teaching file of the radiology department at our institution (searching using lissencephaly, agyria, pachygyria, band heterotopia, cobblestone malformation, and congenital muscular dystrophy as key words), and from MRIs reviewed for a study of the genetics of epilepsy. MRIs were only included if good quality images of the cerebrum (to assess the type and severity of the cortical malformation) and posterior fossa were available as determined by a consensus of the authors.

Most studies included T1-weighted and T2-weighted images with scans performed in at least two planes. Four cases were excluded because only CT images were available and, therefore, assessment of the posterior fossa content was suboptimal. Five others were excluded because the posterior fossa structures were not assessed on magnetic resonance (MR) images available. The remaining 111 MRI studies were analyzed. Patients were aged 1 day to 32 years (mean 5 years 4 months; median 2 years) at the time of MRI, including 54 men, 41 women, and 16 with unavailable sex information. The MRIs included sagittal and axial T1-weighted, axial, and coronal T2-weighted images with slices of 3- to 5-mm thickness. Cases were classified as “lissencephalies” in the database according to the diagnosis based on brain MRI features or known genetics. Clinical information was not often available; when available, it was usually brief, reporting mental retardation and seizures and, sometimes, family history. After reviewing the brain involvement, the cases were reclassified according to known mutation (LIS1, DCX, ARX, VLDLR, RELN, MEB, WWS) or mutation phenotype (LIS1-P, DCX-P, RELN-P, ARX-P, VLDLR-P) according to characteristic MR features1; many of the patients were imaged before testing for specific mutations was available and were not able to be found; therefore, the number with a confirmed genetic diagnosis is low. Phenotypes were determined as follows: • LIS1-P: agyria (absence of gyri) or pachygyria (few broad and flat gyri) more severe posteriorly (parietal and occipital lobes) than anteriorly with a thick cortex (10 –15 mm), smooth brain surface, reduced white matter, and cellsparse zone between a thin outer layer cortex and a thick inner layer of gray matter (figure 1A). • DCX-P: the same features as in LIS1-P but more severe in anterior brain (frontal or frontocentral regions). Band heterotopia that was more severe in the frontal and frontoparietal regions was included in this group (figure 1C). • RELN-P: thickened cortex (8 –10 mm) with too few sulci, decreased hippocampal rotation, no cell-sparse zone. • ARX-P: moderately thick cortex (5–7 mm) with undersulcation most severe in temporal and occipital lobes, absence of corpus callosum, and small, dysplastic basal ganglia. No ARX-P were identified in our database. • Not determined (ND): no definite genetic diagnosis and features too non specific to propose a “probable” genetic diagnosis. The VLDLR mutation was proposed (VDLR-P) for patients having the so-called dysequilibrium syndrome.13,14 Patients with cLIS (LIS1, LIS1-P, DCX, DCX-P) were designated as cLIS, and those with ARX, RELN, RELN-P, and ND were designated as vLIS. All cases with defined mutations of O-glycosylation genes (FKRP, POMGnT1) and those without defined mutation (CMD-P) but features of CBSC on brain MRI were classified as CBSC. Cases not fitting the previously defined groups were considered to be a new group. We did not include CMD with Merosin deficiency in this study, because it does not manifest brain features of CBSC and is not of the group of disorders previously called type 2 lissencephaly.15 After this initial classification, the posterior fossa in each case was carefully reviewed with separate attention to the midbrain, the pons, the medulla, the cerebellar vermis, and the cerebellar hemispheres. Morphologic features were then recorded according to a systematic visual analysis as follows: • Midbrain: dorsal–ventral (DV) and rostrocaudal (RC) size, tectal size, and collicular morphology. Neurology 72

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Figure 1

Classic and variant lissencephalies

• Cerebellar hemispheres: overall size and fissures. Hypoplasia, dysplasia, and cysts were defined with same criteria as for the vermis. The degree of involvement was further characterized as mild or severe, based on consensus by the authors. For statistics, a score was assigned for each main feature: normal ⫽ 0; mildly hypoplastic (including inferior vermis hypoplasia) ⫽ 1; severely hypoplastic (including vermian hypoplasia) ⫽ 2; dysplastic (including cerebellar and vermian cysts as well as pontomedullary “kink”) ⫽ 3. To assess the differences between defined groups of patients based on MHB features and to evaluate the correlation between the brain agyria/pachygyria and MHB involvement, nonparametric statistical tests were used, Kruskal–Wallis test for multiple group comparison and ␹2 McNemar test (Statistica version 7.1, StatSoft France, 2005, www.statsoft.fr). A p value less than 0.05 was considered significant.

Table e-1 (on the Neurology® Web site at www.neurology.org) shows all patients included in the study listed by number, sex, and age, and classified according to lissencephaly groups and genotype/ phenotype. For each patient, corresponding forebrain, midbrain, and hindbrain involvement are reported. Table 1 summarizes the results of the statistical tests. Only significant p values are reported to show group differences. The discriminating MR feature makes the difference between groups for each MHB structure. Significant differences were found between cLIS and vLIS, and between cLIS and CBSC. Moreover, according to the predefined score assignment, we found a severity gradient of MHB involvement. Normal mid-hindbrain was found in 85% of cLIS patients, including all LIS1, 60% of LIS1-P, 50% of DCX, and 58% of DCX-P (figure 1, A and B). Moderate mid-hindbrain involvement corresponded to isolated inferior vermis hypoplasia (IVH), small or hypoplastic vermis, cerebellar hemispheres, midbrain, pons, or medulla. Among the cLIS patients with IVH, 75% were either DCX or DCX-P (in equal proportions) (figure 1, C and D). Severe midhindbrain involvement included severe hypoplasia or dysplasia of the vermis and cerebellar hemispheres, cysts within the vermis and cerebellar hemispheres, midbrain hypoplasia or dysplasia, severe hypoplasia of the pons and medulla, pontomedullary kink, and pontine midline cleft. These features were remarkably predominant among the vLIS (figure 1, E–G) and CBSC groups, differentiating them significantly from cLIS groups (table 1). Interestingly, all patients with WWS phenotype had a ventral midline pontine cleft associated with severe hindbrain hypoplasia (figure 2). We found an association between agyria/ pachygyria of the entire brain (with or without gradient) and severe MHB involvement (p ⫽ 0.0029). RESULTS

(A and B) Patient 2 with LIS1 mosaicism. Axial T2-weighted image (WI) (A) shows a pachygyria with a gradient that is worse posteriorly. The inner cortex is thick and separated from the outer thin layer (black arrowheads) by a cell-sparse zone (white arrowheads) that has signal intensity of myelinated white matter with some areas of hyperintensity. Sagittal T1WI (B) shows the smooth surface of the brain involving the posterior frontal, parietal, and occipital cortices (white arrowheads). In the posterior fossa, midbrain and hindbrain appear normal. The vermis is normal with visible primary fissure (short arrow) and prepyramidal fissure (long arrow) defining three parts in equal proportions. (C and D) Patient 34 with DCX mutation. Axial T1WI (C) shows a thick cortex with few broad gyri (white arrowheads) that are worse anteriorly. On the sagittal T1WI (D), the inferior vermis (arrowheads) appears small compared with the anterior vermis (limited posteriorly by the primary fissure [arrow]). The other posterior fossa structures are normal. (E) Patient 61 with presumed RELN mutation having the same brain magnetic resonance features as his female sibling (patient 59) in whom RELN mutation was found. On sagittal T1WI, pachygyria is worse anteriorly, the midbrain (M) is small, and the pons (P) is hypoplastic, resulting in the flattening of its ventral aspect (double arrows). The medulla (m) is mildly hypoplastic, whereas the vermis is severely hypoplastic. (F) Patient 54 with ARX mutation. Sagittal T1WI shows agenesis of the corpus callosum with prominent anterior commissure (arrowheads), small basal ganglia (arrow), hypoplastic midbrain (M), pons (P) and medulla (m), and hypoplastic and dysplastic vermis (V). (G) Patient 89, from a Hutterite family, having dysequilibrium syndrome and VLDLR mutation. Sagittal TIWI shows same features of midbrain and hindbrain involvement as in RELN mutation (A), including a severe hypoplasia of the vermis (V) and cerebellar hemispheres.

• Pons and medulla: DV and RC size. Hypoplasia refers to loss of pontine anterior curvature and small ventral pons. • Cerebellar vermis: Anteroposterior (AP) and RC size. Hypoplasia refers to a small vermis showing a few or no fissures and no identifiable prepyramidal fissure; dysplasia refers to abnormal foliation or disorientation of fissures. The presence or absence of cysts was noted. 412

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0.006137 0.022306 0.000176 0.000039

WWS ⫽兾 ND VLDLR-P ⫽兾 DCX-P WWS ⫽兾 LIS1-P WWS ⫽兾 DCX-P

Severe hypoplasia

Severe hypoplasia

Pontomedullary “kink”

Mild hypoplasia

0.000006 0.000001

WWS ⫽兾 LIS1-P WWS ⫽兾 DCX-P

Severe hypoplasia–dysplasia

0.030652

CMD-P ⫽兾 DCX-P

Severe hypoplasia–dysplasia

0.005544

WWS ⫽兾 ND

Dysplasia–large tectum

Mild hypoplasia

0.000008 0.000112

WWS ⫽兾 LIS1-P WWS ⫽兾 DCX-P

Dysplasia–large tectum

Dysplasia–large tectum

0.003119 0.013815

CMD-P ⫽兾 LIS1-P CMD-P ⫽兾 DCX-P

Dysplasia–large tectum

0.021621

VLDLR-P ⫽兾 LIS1-P

Dysplasia–large tectum

0.002345

WWS ⫽兾 DCX-P

Mild hypoplasia

Severe hypoplasia

0

0

0

0

0

0

LIS1-P

cLIS DCX-P

1

0

0

0

0

0 or 1

7

1

1

1

1

3

ARX

vLIS

Group score for MHB involvement

RELN-P

7

1

1

1

2

2

VLDLR-P

7

1

1

1

2

2

11

1

1

3

3

3

CMD-P

CBSC

11

1

1

1 or 3

3

3

MEB

12

2

3

3

2

2

WWS

ND

3

1

0

0

0

2

Significant p values for group differences and for each midbrain and hindbrain (MHB) structure. Discriminating MRI feature refers to the predominant feature within the first group cited in the “Group differences” column. Group score is the score corresponding to the predominant MRI feature (the most frequent in each group according to statistic histograms). cLIS ⫽ classic lissencephaly; vLIS ⫽ variant lissencephaly; CBSC ⫽ cobblestone complex; ND ⫽ not determined; CBL ⫽ cerebellar.

Total score

Medulla

Pons

Midbrain

0.041018 0.000452

CMD-P ⫽兾 LIS1-P CMD-P ⫽兾 DCX-P

Dysplasia–cysts

0.018496

VLDLR-P ⫽兾 DCX-P

Dysplasia–cysts

0.012228

CMD-P ⫽兾 DCX-P

Severe hypoplasia

Hypoplasia and dysplasia

CBL hemispheres

0.036295

Group differences ARX ⫽兾 DCX-P

Discriminating MRI feature

Hypoplasia and dysplasia

p Value (<0.05)

Structure

Statistical analyses

CBL vermis

Table 1

Figure 2

Cobblestone complex in patient 107 with WWS phenotype

(A) Coronal T2-weighted image (WI) showing typical magnetic resonance appearance of cobblestone complex with irregular inner layer of ectopic neurons (black arrowheads) and overmigrated neurons at the surface of the cortex (white arrowheads) and between both fibroglial bundles crossing the white matter radially, hydrocephalus, and profound hypomyelination. Midbrain and hindbrain (white stars on cerebellar hemispheres) are severely hypoplastic with near total absence of the vermis and pontine midline cleft (black arrow). (B) Sagittal T1WI showing the characteristic dysplastic large tectum (arrowheads), deformity of the mid-hindbrain junction (pontomedullary “kink,” white line), and near total absence of the vermis with very hypoplastic cerebellar hemisphere (white star).

Agenesis of corpus callosum (ACC) (1.27% of all lissencephalies) was always associated with severe involvement of the vermis; it was found in vLIS with no defined genotype, as expected in all ARX mutations, and in two patients with complete agyria and undulating band heterotopia (figure 3, A and B). In addition, periventricular nodular heterotopia was seen in patients with normal to mild MHB involvement and subependymal linear heterotopia (SELH) in two patients with near total absence of the vermis and hypoplastic pons (figure 3, C and D). This study used a database including many patients with lissencephalies to perform a systematic review of MHB structures in a large series including many types of lissencephalies. More than a simple, exploratory approach to the distribution of cerebellar and brainstem abnormalities in lissencephalies, this study tested whether a relationship existed between the type and extent of supratentorial involvement and the involvement of the mid-hindbrain, and whether, as hypothesized, the distribution among different defined groups could help to predict the mutation by associating the pattern of cerebral involvement with mid-hindbrain involvement. The patterns of cerebral involvement have been well documented in human lissencephalies and have helped to classify them and to correlate them with histology and genetics.1-10 Consistent differences were found in the gyral patterns among cLISs, with the malformation more severe posteriorly in individuals with LIS1 mutations and more severe anteriorly DISCUSSION

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in individuals with DCX mutations.4 These observations were later correlated with neuropathologic findings as mentioned in the introduction.3 The pattern of cortical brain involvement in cLIS is typically different from what is seen in “cobblestone malformations” associated with defects in O-glycosylation of ␣-dystroglycan.7-11,16 The agyria/pachygyria complex seen in cLIS and vLIS is mainly the result of incomplete migration of neurons,2-6 whereas CBSC is primarily a result of overmigration of neurons, many of which pass through gaps in the glial limiting membrane.7-11 Involvement of the cerebellum and the pons has been described in cLISs that were classified according to mutation analysis. Some authors found hypoplasia of the cerebellar vermis to be more common in patients with DCX mutations, whereas both DCX and LIS1 sometimes had normal cerebellum and brainstem.4 The new pathologic classification recently proposed included cerebellum and brainstem abnormalities associated with cLIS (LIS1 and DCX) and vLIS (ARX and two-layered cortex).3 They found the most severe involvement of the hindbrain (hypoplasia) in vLIS group and, most notably, in two-layered cortex. In our series, the midhindbrain in cLIS ranged from normal to small (more frequently among DCX and DCX-P patients) in agreement with previous studies. Our observations were similar, revealing an association between the extent of brain involvement and severity of MHB abnormalities (p ⫽ 0.0029). Marked to severe MHB hypoplasia was most often found in patients with pachygyria involving the entire cerebrum, relatively thin cortex (5 mm or less), and no cell-sparse zone (vLIS-ND, likely Forman’s two-layered cortex lissencephaly). As discussed by previously cited authors,3 this association could be related to extensive impairment of cortical fibers projecting to the pons as well as hypoplasia of mid-hindbrain nuclei. Of interest, we found a high rate of isolated inferior vermis hypoplasia associated with DCX. This sign is probably to be considered as the smallest degree of MHB involvement and would give an interesting clue for differential diagnosis if the finding is substantiated on subsequent studies. MHB was severely hypoplastic in ARX patients (with dysmorphic features of the vermis) and in patients with RELN mutations. Different phenotypes of lissencephaly with cerebellar hypoplasia (LCH) are associated with LIS1, DCX, and RELN genes.6,17 All patients initially classified as VLDLR and VLDLR-P had MHB features similar to patients with RELN mutation. Consequently, the two groups had the same overall score for MHB involvement (table 2). Severe hypoplasia of the vermis was found in all RELN (two cases) and in five of eight VLDLR and

Figure 3

Not-determined lissencephalies

(A and B) Patient 67 classified as not determined (ND). Axial T2-weighted image (WI) (A) shows entire brain agyria with very thin outer cortex layer (black arrows) and undulating gray matter heterotopia (white arrows) surrounding the enlarged lateral ventricles (LVs). Sagittal T1WI (B) displays callosal hypogenesis with small posterior genu (white arrows) but absent body (arrowheads), with small midbrain (M), pons (P), and medulla (m), and enlarged dysplastic vermis. (C and D) Patient 78 classified as ND. Axial T2WI (C) shows agyria of the entire brain with subependymal linear gray matter heterotopia bilaterally (white arrowheads) and marked ventriculomegaly in this microcephalic patient. Sagittal T1WI (D) displays callosal agenesis and extremely hypoplastic midbrain (M), pons (P), and medulla (m). The entire cerebellum is nearly absent.

VLDLR-P patients. These were grouped together as vLIS. The VLDLR mutation has been described as responsible for the so-called dysequilibrium syndrome and can therefore be presumed in any patient with characteristic clinical and brain MRI features.18 CBSC was formerly called type 2 lissencephaly.12 It is the main CNS feature of CMDs with O-glycosylation defects of ␣-dystroglycan, even though it is difficult to differentiate the genetic causes on the basis of brain MRI because of overlapping phenotypes.19-23 Cerebral, cerebellar, and brainstem abnormalities have been well documented in the major phenotypes: FCMD, WWS, and MEB. WWS displays severe cerebral cortical dysplasia, hypomyelination, dysplastic tectum, pontomedullary kink, severe hypoplasia of the vermis, and dysplastic cerebellar hemispheres.1,10 A ventral midline cleft of the ventral pons is often associated with MEB and WWS and could also be considered among their typical MR features. The midline cleft is probably due to reduced number of crossing pontine axons, possibly resulting from impaired tangential migration of pon-

tine nuclei, as demonstrated in mice with mutation of Large.24,25 We found that callosal agenesis is not uncommon among patients with lissencephaly. ACC is among the characteristic features of ARX-associated lissencephaly.26,27 The frequent association of ACC with vLIS-ND patients in our series suggests considering this feature as a supplementary criteria to differentiate cLIS from vLIS. It is important to note, however, that ACC may also be found in other types of lissencephalies.28 Interestingly, the cerebellar vermis was dysplastic or severely hypoplastic in 13 of 14 patients with ACC; it will be interesting to see whether this association holds up in other series. A recent study of callosal agenesis associated with DCX found that the doublecortin protein might be involved in the early stages of corpus callosum formation29; however, none of the DCX or DCX-P patients in this study had ACC. This study is limited by the small number of cases with established genetic diagnoses. An attempt was made to increase this number by assigning a presumed genetic classification based on established cerebral MRI features in different lissencephaly groups and correlation of imaging features with known pathologic features such as cell-sparse zones, associated callosal anomalies, and cortical thickness. This is obviously not scientifically rigorous and may be considered an artificial classification. However, we observed relative homogeneity of MHB involvement both within groups with presumed classification (LIS1-P) and between groups with known and presumed mutations of the same gene (DCX, RELN, and VLDLR). This homogeneity and our statistical results emboldened us to group together those with presumed and proved mutations for purposes of correlation. Results of these groupings are shown in the two first columns of table 2. For each structure analyzed, a gradient of involvement was found to be associated with each presumed genotype (mutation phenotype) (table e-2). We suggest that these presumed groupings might be useful to determine which tests for specific gene mutations should be performed in such patients. Based on the data in this project and that in the literature, we propose a classification similar to that recently proposed,3 separating cLIS (LIS1 and DCX) from vLIS (RELN and ARX) (table 2). We included VLDLR and some ND cases with markedly atypical MR features, namely ND1, ND2, and ND3, within the vLIS group. ND3 refers to a case with microcephaly, paracentral pachygyria, and ACC resembling Baraitser–Winter syndrome, but other phenotypes may be associated with this syndrome.30 ND2 refers to two cases with undulating band heterotopia (a configuration that must be extremely rare, Neurology 72

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Variant LIS

Classic LIS

Classification LIS group

Table 2

7q22

9p24

ND

ND

inv p12q14 (PAX8)

ND

RELN (similar to Norman– Roberts type)

VLDLR (including HDS)

ND1

ND2

ND3 (similar to Baraitser– Winter syndrome)

TL-LIS (twolayered LIS)

Xq22.3-q23

DCX (XLIS)

Xp22.13

Somatic mosaicism (R241P-R8X)

LIS1 mosaicism

ARX (XLAG)

17p13.3 (PAFAH1B1) 14-3-3␧ (Miller–Dieker syndrome)

Gene defect

LIS1

Classification (genotype)

New classification

ND

PAX 8 maps to chrom 2 and controls the differentiation of primordial cells and is involved in organogenesis

ND

ND

RELN binds directly and specifically to the extracellular domains of VLDLR and ApoER2Reelin acts via VLDLR and ApoER2 to guide neuroblast migration in the cerebral cortex and cerebellum

Gene encoding reelin (RELN), leading disengagement of migrating neurons from radial glial cells

Probably encoding for a protein involved in migration and differentiation of interneurons containing ␥-aminobutyric acid (GABAergic interneurons)

Gene encoding doublecortin (DCX), leading edge of the cells during neuronal migration

Same mutation as LIS1 but two cell populations have distinct genotypes

Gene encoding platelet activating factor acetylhydrolase 1 subunit B1 (PAFAH1B1) assembling microtubules and leading neuronal migration (cell nucleus migration, generation of neuroblast and cell survival)

Role

Pathology

Similar to RELN or thick cortex with simplified gyral pattern

AR

ND

Sporadic

ND

ND

Entire brain pachygyria with no gradient; disorganized neurons

Microcephaly; paracentral pachygyria; CSZ; ACC

Entire brain pachygyria; undulating band heterotopia; ACC

Entire brain agyria; subependymal linear heterotopia; ACC; severe mid-hindbrain involvement

*

Smooth brain; thickened cortex (10 mm) A ⬎ P; hippocampal abnormalities; severe midhindbrain involvement

A

Two-layered cortex

ND

ND

Four-layered cortex

ND

Three-layered cortex

XLR

Smooth brain; pachygyria A ⬎ P (6–7 mm ⬍ thickness ⬍ 10 mm); posterior agyria; basal ganglia and white matter anomalies; ACC

Four-layered cortex

Four-layered cortex

Four-layered cortex

Less severe involvement than LIS1

Smooth brain; agyria; pachygyria (15- to 20-mm thickness); SCBH; worse posteriorly (P ⬎ A)

Smooth brain; agyria; pachygyria (15- to 20-mm thickness); SCBH; worse anteriorly (A ⬎ P) in hemizygous males; milder involvement or only SCBH in heterozygous females

XLD

A

A

Pattern of inheritance Brain MRI

OMIM resource

—Continued

Forman et al. J Neuropathol Exp Neurol 2005;64: 847–857†

243310

None

Miyata et al. Acta Neuropathol 2004; 107:69–81†

192977 224050

257320

300215

300067

607432

607432

Proposal adapted from Forman et al.,3 including all lissencephaly (LIS) types and details from Online Mendelian Inheritance in Man (OMIM) resources. *No pathology described. †No OMIM resource. A ⫽ autosomal; XLD ⫽ X-linked dominant; XLR ⫽ X-linked recessive; AR ⫽ autosomal recessive; ND ⫽ not determined; AD ⫽ autosomal dominant; SCBH ⫽ subcortical band heterotopia; ACC ⫽ agenesis of corpus callosum; CSZ ⫽ cell-sparse zone; FCMD ⫽ Fukuyama congenital muscular dystrophy; WWS ⫽ Walker–Warburg syndrome.

607855 6q22-q23 CMD Merosin deficiency Related muscular dystrophy syndromes

19q13.3, 1p34-p33 (POMGnT1) MEB

Occipital agyria (no cobblestone cortex); striking leukodystrophy involving U fibers; pontocerebellar hypoplasia; cerebellar cysts AD Mutation in the laminin ␣2 gene (LAMA2), which is a permissive substrate for migration of oligodendrocyte precursors

Same as LIS1 in affected occipital cortex?

253280 Cobblestone cortex

19q13.3, 14q24.3 (POMT2), 9q34.1 (POMT1), 9q31 (FKRP) WWS

Same features but intermediate severity between FCMD and WWS AR Mutations in O-mannose ␤-1,2-Nacetylglucosaminyltransferase (POMGnT1), which participates in O-mannosyl glycan synthesis, results in disorder of radial migration and disruption of the pial barrier

236670 Cobblestone cortex Cobblestone cortex; hydrocephalus; retinal dysplasia; leukodystrophy; severe brainstem and cerebellum hypoplasia; mid-hindbrain junction dorsal kink AR Gene encoding protein O-mannosyltransferase1 (POMT1) involved in O-mannose–linked glycosylation of proteins important for the formation of glial limiting membrane

OMIM resource

253800

Pathology

Unlayered frontal polymicrogyria; bundles of neurons separated by fibroglial vascular tissue extending radially through the cortex into subarachnoid spaces (cobblestone cortex); irregular gray–white matter junction; dysplasia; leptomeningeal cysts Thick cortex with frontal polymicrogyria; temporo-occipital cobblestone cortex; irregular inner surface with bundles of neurons crossing radially to subpial spaces; smooth outer surface; subcortical cysts; leukodystrophy AR Mutation in the gene encoding fukutin-related protein (FKRP), which probably participates in the pathway of biosynthesis of dystroglycan involved in binding activity for the ligand laminin 9q31-q33 (FKRP)

Gene defect

FCMD (Fukuyama type and similars) Cobblestone complex

Role

Pattern of inheritance Brain MRI Classification (genotype) Classification LIS group

Continued Table 2

because we found no previous reports) and ACC. ND1 refers to two cases with complete agyria, SELH, ACC, and severe MHB involvement. Further investigations or more cases are needed to determine whether the ND groups should be classified with vLIS or in still another category. As noted in the previous paragraph, it was difficult to determine which entities to include in the vLIS category and how to classify them. More than 80% of vLIS patients did not have characteristic imaging findings (ND). The protein products of VLDLR and RELN act in the same pathway but are coded by different genes that have different patterns of inheritance, so they were included as separate malformations. Based on a previously cited work, we included two-layered lissencephaly as part of the vLIS category.3 Another weakness of this study is a lack of clinical data that could help clinicians to better identify patients with these malformations. It would also have helped to better classify those patients who were ultimately assigned to the ND category. Despite this obvious deficiency, important information has emerged from this study for both radiologists and other physicians interested in brain development. This study expands the categories of lissencephalies and adds to the knowledge of associated malformations. This information will, hopefully, lead to further studies of the molecular disorders involved in the many brain anomalies associated with agyria and pachygyria and, ultimately, a better understanding of the mechanisms by which the brain is formed. AUTHOR CONTRIBUTIONS P.J.-T. conducted the statistical analysis.

ACKNOWLEDGMENT The authors thank Drs. Chistopher Walsh, William Dobyns, Daniela Pilz, Sean Bryant, and Naci Koc¸er for the MRI scans that they kindly contributed to this work.

Received March 7, 2008. Accepted in final form July 16, 2008. REFERENCES 1. Barkovich AJ. Congenital malformations of the brain and skull. In: Pediatric Neuroimaging, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. 2. Kato M, Dobyns WB. Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet 2003;12: R89–R96. 3. Forman MS, Squier W, Dobyns WB, et al. Genotypically defined lissencephalies show distinct pathologies. J Neuropathol Exp Neurol 2005;64:847–857. 4. Dobyns WB, Truwit CL, Ross ME, et al. Differences in the gyral pattern distinguish chromosome 17-linked and X-linked lissencephaly. Neurology 1999;53:270–277. 5. Dobyns WB, Reiner O, Carrozzo R, et al. Lissencephaly: a human brain malformation associated with deletion of the Neurology 72

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LIS1 gene located at chromosome 17p13. JAMA 1993; 270:2838–2842. Ross ME, Swanson K, Dobyns WB. Lissencephaly with cerebellar hypoplasia (LCH): a heterogeneous group of cortical malformations. Neuropediatrics 2001;32:256–263. van der Knaap MS, Smit LM, Barth PG, et al. Magnetic resonance imaging in classification of congenital muscular dystrophies with brain abnormalities. Ann Neurol 1997; 42:50–59. Aida N, Tamagawa K, Takada K, et al. Brain MR in Fukuyama congenital muscular dystrophy. AJNR Am J Neuroradiol 1996;17:605–613. Valanne L, Pihko H, Katevuo K, et al. MRI of the brain in muscle-eye-brain (MEB) disease. Neuroradiology 1994; 36:473–476. Mercuri E, Topaloglu H, Brockington M, et al. Spectrum of brain changes in patients with congenital muscular dystrophy and FKRP gene mutations. Arch Neurol 2006;63: 251–257. Vajsar J, Schachter H. Walker-Warburg syndrome. Orphanet J Rare Dis 2006;29:1–5. Barkovich AJ, Kuzniecky RI, Jackson GD, et al. A developmental and genetic classification for malformations of cortical development. Neurology 2005;65:1873–1887. Schurig V, Orman AV, Bowen P. Nonprogressive cerebellar disorder with mental retardation and autosomal recessive inheritance in Hutterites. Am J Med Genet 1981;9: 43–53. Boycott KM, Flavelle S, Bureau A, et al. Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification. Am J Hum Genet 2005;77:477–483. Leite CC, Lucato LT, Martin MGM. Merosin-deficient congenital muscular dystrophy (CMD): a study of 25 Brazilian patients using MRI. Pediatr Radiol 2005;35:572–579. Philpot J, Pennock J, Cowan F, et al. Brain magnetic resonance imaging abnormalities in merosin-positive congenital muscular dystrophy. Eur J Paediatr Neurol 2000;4:109–114. Hong SE, Shugart YY, Huang DT, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 2000;26:93–96. Glass HC, Boycott KM, Adams C, et al. Autosomal recessive cerebellar hypoplasia in the Hutterite population. Dev Med Child Neurol 2005;47:691–695.

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26.

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28. 29.

30.

Longman C, Brockington M, Torelli S, et al. Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. Hum Mol Genet 2003;12:2853–2861. Beltran-Valero de Bernabe´ D, Voit T, Longman C, et al. Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. J Med Genet 2004;41:e61. van Reeuwijk J, Janssen M, van den Elzen C, et al. POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome. J Med Genet 2005;42:907–912. van Reeuwijk J, Maugenre S, van den Elzen C, et al. The expanding phenotype of POMT1 mutations: from Walker-Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation. Hum Mutat 2006;27:453–459. van Reeuwijk J, Grewal PK, Salih MA, et al. Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome. Hum Genet 2007;121:685–690. Qu Q, Crandall JE, Luo T, et al. Defects in tangential neuronal migration of pontine nuclei neurons in the Largemyd mouse are associated with stalled migration in the ventrolateral hindbrain. Eur J Neurosci 2006; 23:2877–2886. Barkovich AJ, Millen KJ, Dobyns WB. A developmental classification of malformations of the brainstem. Ann Neurol 2007;62:625–639. Dobyns WB, Berry-Kravis E, Havernick NJ, et al. X-linked lissencephaly with absent corpus callosum and ambiguous genitalia. Am J Med Genet 1999;86:331–337. Paul LK, Brown WS, Adolphs R, et al. Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity. Nat Rev Neurosci 2007;8:287–299. Dobyns WB. Absence makes the search grow longer. Am J Hum Genet 1996;58:7–16. Kappeler C, Dhenain M, Tuy FPD, et al. Magnetic resonance imaging and histological studies of corpus callosal and hippocampal abnormalities linked to doublecortin deficiency. J Comp Neurol 2007;500:239–254. Ganesh A, Al-Kindi A, Jain R, Raeburn S. The phenotypic spectrum of Baraitser-Winter Syndrome: a new case and review of literature. J AAPOS 2005;9:604–606.

Calling All New and International Members! Don’t miss these FREE AAN Annual Meeting events designed just for you: • New Member Information Session Sunday, April 26 / 5:00 p.m. to 6:00 p.m. Learn about the AAN, its resources and benefits, and network with Academy leaders. • International Attendee Summit Monday, April 27 / 7:00 a.m. to 9:00 a.m. Meet Academy leaders and make your voice heard on matters most important to you. Learn more at www.aan.com/specialevents.

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Assessment of potential drug interactions in patients with epilepsy Impact of age and sex

Barry E. Gidal, PharmD Jacqueline A. French, MD Patricia Grossman, PharmD Gwe´nae¨l Le Teuff

Address correspondence and reprint requests to Dr. Barry E. Gidal, School of Pharmacy and Department of Neurology, University of Wisconsin, 777 Highland Ave., Madison, WI 53705 [email protected]

ABSTRACT

Objectives: To understand and quantify the exposure to concomitant medications other than antiepileptic drugs (AEDs) within an age-diverse group of men and women with epilepsy and explore the likelihood of relevant drug interactions as a result.

Methods: The PharMetrics medical and pharmaceutical claims database was used to extract data for commercially insured adult patients with a diagnosis of epilepsy and treated with any AED during the period from July 1, 2001, to December 31, 2004. Data were analyzed for concomitant non-AEDs used after initiating AEDs in six age groups, spanning the ages 18 to 85⫹ years, in both men and women. Results: Use of concomitant medications occurred in every age group and increased with age for both men and women (mean number of non-AEDs ranging from 2.41 to 7.67 in males aged 18 –34 and 85⫹ years and from 4.04 to 7.05 in females aged 18 –34 and 85⫹ years; p ⬍ 0.001 for age trend). ␤-Hydroxy-␤-methylglutaryl– coenzyme A reductase inhibitors (statins), calcium channel blockers (CCBs), and selective serotonin reuptake inhibitors (SSRIs) were the most commonly used non-AED medications with the potential for adverse drug interactions. SSRIs use was substantial in all age groups and greater than for statins or CCBs in patients aged 18 –54 years. Use of antipsychotics, tricyclic antidepressants, and warfarin was also noted in more than 10% of patients across different age groups.

Conclusions: Polypharmacy with non–antiepileptic drug (AED) medications is common in both men and women, and is not a situation unique to only elderly patients with epilepsy. In particular, use of potentially interacting, enzyme inducing AEDs was common. These findings suggest that clinicians must be mindful of potential AED–non-AED drug interactions, in patients of all age groups. Neurology® 2009;72:419–425 GLOSSARY ADR ⫽ adverse drug reaction; AED ⫽ antiepileptic drug; CCB ⫽ calcium channel blocker; EIAED ⫽ enzyme-inducing antiepileptic drug; HMG-CoA ⫽ ␤-hydroxy-␤-methylglutaryl– coenzyme A; ICD ⫽ International Classification of Diseases; NEIAED ⫽ non– enzyme-inducing antiepileptic drug; SSRI ⫽ selective serotonin reuptake inhibitor; TCA ⫽ tricyclic antidepressant.

Epilepsy is a common disorder, affecting between 1% and 2% of the US population,1-6 and is seen across all age ranges. Seizures can be controlled in the majority of patients with currently available medications, used either singly or in combination.7-11 Some antiepileptic drugs (AEDs), such as carbamazepine, phenytoin, and phenobarbital, can induce drug-metabolizing enzymes in both the gut and the liver and therefore have the potential to modify the kinetics of other concomitantly administered drugs a patient may be receiving. This is important because pharmacokinetic interactions may result in clinically meaningful adverse drug reactions (ADRs).11-15 Indeed, it has been estimated that more than 2 million serious ADRs occur annually in the United States, leading to 100,000 deaths.14 Although pharmacokinetic interactions have long been recognized as potential confounders in optimizing epilepsy treatment, most clinical studies have focused on interactions between

From the School of Pharmacy and Department of Neurology (B.E.G.), University of Wisconsin, Madison, WI; New York University School of Medicine Comprehensive Epilepsy Center (J.A.F.), New York, NY; UCB (P.G.), Global Outcomes Research, Atlanta, GA; and Keyrus Biopharma (G.L.T.), Levallois Perret, France. Disclosure: Author disclosures are provided at the end of the article. Copyright © 2009 by AAN Enterprises, Inc.

419

various AEDs. Although clearly this is important, an issue that has received relatively less attention is the potential impact of AEDs on commonly used non-AEDs. It has also long been recognized that older patients typically receive more medications than do younger individuals.16,17 Less information is available on the medication habits of younger individuals. This poses an important question, namely, what are the potential drug interaction risks in the younger segments of the epilepsy population? Data describing the likelihood of interactions in younger or middle-aged patients are lacking. In addition, with the exception of oral contraceptive use, there are few if any data regarding the impact of patient sex on the patterns of AED–non-AED interactions. The objectives of this study were to assess the potential clinically important AED–non-AED interactions in an age-diverse group of patients with epilepsy. In particular, we sought to determine whether the pattern or risk of AED-mediated drug interactions varied by either patient age or sex. In addition, we also compared the exposure of patients with epilepsy to potentially meaningful drug interactions with that of the general US population. METHODS PharMetrics, a comprehensive patient-centric database comprising fully adjudicated medical and pharmaceutical claims for more than 45 million unique patients enrolled in 80 health plans across the United States and representative of the national managed care population, was used to extract relevant data for the commercially insured epilepsy population.

Patient selection and classification. Patients were included if they met the following criteria: 1) diagnosis of epilepsy, based

Table

Demographic and clinical characteristics of patients with epilepsy

Characteristic

EIAED, n ⴝ 7,142

NEIAED, n ⴝ 4,046

Sex, no. (%) male

3,053 (42.8)

1,306 (32.1)

Age, mean ⴞ SD, y

42.3 ⫾ 14.0

39.5 ⫾ 14.0

Partial seizures

2,380 (33.3)

1,496 (36.8)

Generalized seizures

4,762 (66.7)

2,568 (63.2)

Monotherapy

1,172 (16.4)

508 (12.5)

Adjunctive

5,970 (83.6)

3,556 (87.5)

Seizure type, no. (%)

AED therapy, no. (%)

EIAED ⫽ enzyme-inducing antiepileptic drug; NEIAED ⫽ non– enzyme-inducing antiepileptic drug; AED ⫽ antiepileptic drug. 420

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on International Classification of Diseases (ICD)-9 codes 345.0/ 1/4/5 in their claims history and treated with any AED during the period from July 1, 2001, to December 31, 2004; 2) 6-month AED claim-free period for the index therapy before AED therapy; 3) minimum 3-month follow-up period; and 4) continuous enrollment for the duration of the study. We chose to use ICD-9 codes where either generalized or partial epilepsy was specified. In this way, we would identify only those patients who had received a formal diagnosis where medication is most likely indicated. Patients were classified into two mutually exclusive groups based on treatment with specified enzyme-inducing AEDs (EIAEDs; phenytoin, carbamazepine, phenobarbital, and primidone) or non– enzyme-inducing AEDs (NEIAEDs; valproate, tiagabine, levetiracetam, lamotrigine, gabapentin, topiramate, oxcarbazepine, and zonisamide). Topiramate and oxcarbazepine may possess modest, dose-dependent enzyme induction; however, we decided to categorize these medications as NEIAEDs. Patients were categorized by age into four groups: 1) young adults (18 –34 years), 2) adults (35–54 years), 3) older adults (55– 64 years), and 4) seniors (65⫹ years). The seniors were further categorized into three age groups of 65–74, 75– 84, and 85⫹ years for more detailed analyses.

PharMetrics database assessments. Concomitant medications. Concomitant medications were defined as non-AED medications that are metabolized or a known inhibitor of the cytochrome P-450 isozyme system. Evaluation of Drug Interactions was used in combination with clinical experience to determine the impact of these medications considered to have a high potential for drug interaction with AEDs.18 National Drug Codes reported on each patient’s pharmaceutical claim were used to determine AEDs and concomitant medications. The Generic Product Identifier codes were used to assist in further medication classification. A major implication to this type of medication identification was that patients taking more that one drug within a specific drug class were identified as being exposed to only one medication with a high potential for drug interactions with AEDs, particularly EIAEDs. Time frame for data analyses. Patients were examined for 6 months after initiation of AED therapy to understand concomitant medication exposures. General exposure to concomitant medications, defined as the number of days for this medication overlapping with either an NEIAED or an EIAED, was taken into consideration for subsequent analyses for each patient.

Specific analyses. Several analyses were performed for concomitant medications in both EIAED and NEIAED groups by age group and by sex, including 1) the mean number of concomitant medications after initiating the EIAEDs or NEIAEDs; 2) the number and percentage of patients with at least 1 and at least 5 concomitant medications after initiating the EIAEDs or NEIAEDs; and 3) the number and percentage of patients with specific concomitant medications (including selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs], antipsychotics, calcium channel blockers [CCBs], oral contraceptives, warfarin, ␤-hydroxy-␤-methylglutaryl– coenzyme A [HMG-CoA] reductase inhibitors [statins], antineoplastics, and stimulants). Specifically, we focused on the potential for an AED to interfere with a non-AED concomitant medication after initiating the AED. A secondary analysis was performed to address the question of whether medication use rates differed in the study population as compared with the general US population as a whole. Previously published Centers for Disease Control and Prevention data of the general US population were compared with this study’s specific AED

use data to understand the medication exposure of people in the general US population compared with that of our epilepsy population.

Statistical analyses. Differences in concomitant medications noted in patients treated with EIAEDs or NEIAEDs were assessed by means of ␹2 tests for categorical variables and Wilcoxon ranksum (i.e., Kruskal–Wallis) tests for continuous variables. Age trend was assessed using the Cochran–Armitage statistic. All analyses were performed using SAS software, version 8.2 (SAS Institute Inc., Cary, NC), with significance assigned at the p ⬍ 0.05 level. RESULTS Demographic and clinical characteristics.

A total of 11,206 patients with epilepsy were identified, of whom 7,142 patients were treated with an EIAED and 4,064 were treated with an NEIAED (table), administered as monotherapy or adjunctive therapy. Both treatment groups were similar with respect to mean age, the percentage of patients experiFigure 1

Antiepileptic drugs used by patients with epilepsy, by age

encing partial or generalized seizures, and the percentage of patients receiving either monotherapy or adjunctive therapy. The NEIAED-treated group comprised a slightly greater proportion of women as compared with those treated with an EIAED. AED use. Overall carbamazepine, phenytoin, gabapentin, and valproate were the most commonly used AEDs, taken by between 19% and 61% of all patients across the different age groups (figure 1). In particular, the use of EIAEDs was common in all patient groups. Phenytoin was the most frequently used AED and seemed to be used by patients of both sexes and across all age groups (n ⫽ 2,464 women [49.27%] and n ⫽ 2,234 men [60.17%]). Carbamazepine was found to be the second most frequently used drug, with greatest use by patients aged 18–74 years. Primidone and zonisamide were the least used AEDs (⬍3.5%). Phenobarbital was used slightly more commonly in women (8.6%) as compared with men (6.1%). Valproate was used in 13.6% of women aged 18–34 years and in 9% of women aged 35–54 years. Concomitant medications. Polytherapy with prescription concomitant medications occurred in every age group and generally increased with age in both men and women, until age 64 years (figure 2). The increase in the mean number of prescription concomitant medications ranged from 2.41 for men aged 18 –34 years to 7.67 for men aged 85⫹ years and from 4.04 for women aged 18 –34 years to 7.05 for women aged 85⫹ years, with significant age trends noted for all age groups between 18 and 64 years (p ⬍ 0.001). Overall, women aged 18 –74 years took more prescription concomitant medications compared with men within the same age groups (p ⬍ 0.001 for all groups), with significant differences noted in age groups 18 –34, 35–54, and 55– 64 years, but not in age group 65–74 years (p ⬎ 0.098). However, regardless of sex and whether the patients were given EIAEDs or NEIAEDs, there were no differences in the overall use of these prescription concomitant medications within the entire study population. Assessment based on prescription of EIAEDs or NEIAEDs showed that the percentages of patients with at least one and at least five concomitant prescription medications were generally higher in the NEIAED group than in the EIAED group for all age groups, with the differences being significantly greater for patients with at least one concomitant prescription medication in age groups 18 –34 years (p ⬍ 0.001), 35–54 years (p ⬍ 0.001), and 55– 64 years (p ⬍ 0.05); and with at least five concomitant prescription medications in age groups 35–54 years (p ⬍ 0.001) and 55– 64 years (p ⬍ 0.001). Patterns of concomitant medication use. Statins, CCBs, and SSRI antidepressants were generally the Neurology 72

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421

Figure 2

Mean number of concomitant medications, by age and sex

were taking five or more medications, compared with 2% of men and 3% of women in the general population. Similarly, in the group aged 45– 64 years, the percentages of men and women with epilepsy receiving five or more medications were increased to 47% and 60%, respectively, compared with 10% and 15% in the general population. Our data confirm that polypharmacy with multiple prescription medications is common in both younger and elderly patients with epilepsy. Therefore, the potential for unanticipated pharmacokinetic interactions is not limited to elderly nursing home patients, but is possible for young, middleaged men and women as well.11,20-23 Although our data confirm previous observations 20 that the older-generation AEDs such as phenytoin and carbamazepine were the most frequently prescribed AEDs in elderly patients, our data additionally show that this use pattern is true across the spectrum of age groups studied, including younger patients of both sexes. It is notable that the number of patients taking EIAEDS vs NEIAEDs was similar among the patients, regardless of concomitant medications. These observations clearly suggest that although attention toward potential drug interactions is certainly warranted in elderly patients, younger men and women with epilepsy seem to be at risk in that they also receive many prescription medications, perhaps more frequently than the general population. Thus, in treating the patients with epilepsy, it is important for the clinician to recognize that treatment with AEDs, particularly the older EIAEDs, and the medications used for other conditions may have real and substantial implications in treatment because they may complicate the management of comorbid disorders; particularly cardiovascular disease, psychiatric disorders, and cancer. For example, coronary heart disease is among the single largest causes of death in the United States.24 Epidemiologic data have suggested that the risk of ischemic cardiac disease is substantially increased (approximately 30%) in patients with epilepsy and that the standardized mortality ratios for death due to ischemic heart disease or stroke were 2.5 and 5.3, respectively.25,26 Clearly, pharmacokinetic interactions that impact commonly used drugs such as antihypertensive or lipid-lowering agents may have serious, long-term medical implications. Hypertension, which has a 30% prevalence rate in the US population,27 may require treatment with multiple drugs of differing pharmacologic classes. Several commonly used antihypertensive medications evaluated in this study, such as the dihydropyrDISCUSSION

three most commonly used drugs, particularly in patients aged older than 55 years, of which statin use was highest among patients aged 65–74 years (approximately 41% of the age group), CCB use was highest among patients aged 85⫹ years (approximately 35% of the age group), and SSRI use was highest among the patients aged 55– 64 years (approximately 30% of the age group) (figure 3). Use of statins and CCBs was similar in men and women, whereas use of SSRIs seemed to be significantly greater in women (p ⬍ 0.001). Overall analysis of these medications indicated that SSRI antidepressant use seemed to be marked in all age groups and more common than statin and CCB use in the patients aged 18 –54 years. The use of antipsychotics was also appreciable (i.e., ⬎10% of patients) in all age groups, whereas the use of TCAs and warfarin was noted in ⬎10% patients aged 35– 64 years and 65⫹ years. In contrast, the contraceptives were mostly restricted to the group aged 18 –34 years. The use of antineoplastic drugs, including cyclophosphamide, ifosfamide, busulfan, teniposide, etoposide, paclitaxel, methotrexate, and vincristine, were found to be used by a relatively small number of patients across the different age groups (figure 3). The use of antineoplastics seemed to be most marked in patients aged between 55 and 74 years; with between 1.13% and 1.70% of patients taking these drugs, compared with between 0% and 0.62% of patients in other age groups. Comparison of medication use between patients with epilepsy and the general population in the United States. Patients in every age and sex group were more

likely to have received more concomitant medications compared with data documented for the general population19 (figure 4). To compare these population data with our specific epilepsy population, we undertook a similar analysis. Overall, we found that 23% of male and 39% of female patients aged 18 – 44 years with epilepsy in our study cohort 422

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Figure 3

Percentage of patients with most frequent use of specified medications, by age group

SSRI ⫽ selective serotonin reuptake inhibitors; TCA ⫽ tricyclic antidepressants.

idine CCBs, have been shown to interact with EIAEDs, with comedication resulting in substantial reductions in the oral bioavailability of these agents.28 Given our observed frequency of concomitant administration, increased monitoring of blood pressure management seems prudent in these patients. Increased serum cholesterol levels are a risk factor for stroke as well as heart disease in both women and men. EIAEDs, such as carbamazepine and phenytoin, have been associated with increases in lipoproteins and homocysteine in both children and adults,29-32 whereas NEIAEDs are not.33 Our data suggest that extensively metabolized HMG-CoA reductase inhibitors are commonly prescribed in the epilepsy population, especially in middle-aged pa-

Figure 4

Medication use in patients with epilepsy and the general population in the United States

tients. These agents are susceptible to enzyme induction, and in one study a reduction of nearly 80% in simvastatin oral bioavailability was seen in subjects receiving carbamazepine compared with placebo.34 An obvious clinical question, therefore, is: If systemic availability of a cholesterol-lowering medication were reduced, would it impact cardiovascular morbidity or mortality in later years? Another class of frequently prescribed medications in our population was the psychotropics. Depressive disorders are commonly seen in patients with epilepsy. Our data confirm the notion that patients of both sexes frequently receive both antidepressant and antipsychotic drugs and that this trend increases with patient age. Because most antidepressant and antipsychotic medications are substrates for one or more of the cytochrome P-450 isozymes, comedication with an inducing drug would be expected to increase the systemic clearance of these medications, resulting in lower serum concentrations.35 Indeed, it is not unreasonable to expect that in patients receiving inducers, the serum concentrations of many commonly used tricyclic antidepressants as well as SSRIs, could be decreased perhaps by as much as 25% to 50%. In contrast, the inhibitor valproate may cause significant increases (50%– 60%) in serum concentrations of antidepressants such as amitriptyline and nortriptyline,36 suggesting the possibility of increased adverse effects in patients receiving this combination. With regard to antipsychotic medications, both carbamazepine and phenytoin have been reported to markedly decrease the serum concentration of a number of both typical and atypical antipsychotic medications. It is not known whether concomitant therapy with antipsychotic or antidepressant medications and EIAEDs results in suboptimal treatment of affective disorders. It would therefore seem reasonable to speculate that given the Neurology 72

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423

magnitude of the increase in systemic clearance of many of these drugs by enzyme inducers, individual patients may require larger-than-anticipated doses of various psychotropic drugs to achieve optimal response. Finally, between 3% and 5% of incident cases of newly diagnosed epilepsy can be related to brain tumors.37 Although the use of concomitant antineoplastic drugs was low in our population, the clinical consequences of drug interactions with AEDs may be enormous. Numerous commonly used antineoplastic drugs, such as the vinca alkaloids, taxanes, camptothecins, and etoposide, are metabolized via the cytochrome P-450 system, and substantial reductions in area under the curve (40%–50%) have been noted when used in combination with EIAEDs. These interactions may have devastating clinical consequences, including increased relapse rate and decreased survival.38-40 Whether due to fear of seizure destabilization as a consequence of AED switching or due to lack of awareness of certain pharmacokinetic interactions, our observations clearly suggest that that physicians are not selecting AEDs based on the likelihood of drug– drug interactions. Because a large number of patients are taking enzyme-inducing drugs, our data indicate that the potential for interactions is significant. Clearly, there is an urgent need for clinical studies that would explore the likelihood of adverse outcomes resulting from AED– concomitant medication interactions. Because our study used the PharMetrics database, we are limited to the information captured within this health care claims database and information on those patients who sought medical treatment for epilepsy during this time frame. As with all health care claims analyses, medication is not linked with diagnosis; therefore, we could not verify the actual intent of each prescription. The linking of medical claims and pharmaceutical claims by date is commonly used in these types of analyses to suggest prescription intent as we did in our study. Use of polytherapy AED treatment after a 6-month AED-free interval was prevalent in our study (84%– 88%), suggesting that patients were not necessarily new epileptic patients. Two suggestions are that these are patients restarting AED therapy after a 6-month or more non-AED period or that these are patients activating different insurance carriers to fill their prescriptions. However, we believe that this limitation due to the data source does not impact our findings. Finally, it is important to recognize that these analyses were exploratory in nature, and therefore tests for multiplicity were not considered. Although we did not correct for multiplicity, many of our findings are well below the 0.05 significance level, and we therefore believe that our 424

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findings are robust and would not likely change if tests for multiplicity were conducted. AUTHOR CONTRIBUTIONS Statistical analyses were performed by G.L.T.

ACKNOWLEDGMENT The authors thank Dr. Jagdish Devalia and Ms. Celine Bugli, LACO, for their input, editorial assistance, and critique of the manuscript.

DISCLOSURE B.E.G. reports he has received research and consulting honoraria from GlaxoSmithKline, UCB, and Abbott Labs. J.A.F. reports consulting activities with Spherics, Johnson & Johnson, Pfizer, and AstraZeneca; lecture fees from Kyowa; grant support from Eisai, UCB, Jazz, SK Pharmaceuticals, and Intranasal Therapeutics; and consulting, lecture, and research fees from Bial, Cyberonics, Eisai, Endo Pharmaceuticals, GlaxoSmithKline, Icagen, Intranasal Therapeutics (Q45), Jazz, Johnson & Johnson, NeuroTherapeutics, NeuroMolecular Pharmaceuticals, NeuroVista (Q48), Ortho-McNeil, Ovation, Pfizer, Schwarz Pharma, SK Pharmaceuticals, Supernus Pharmaceuticals, Taro Pharmaceuticals, Teva Pharmaceuticals, UCB, and Valeant Pharmaceuticals. P.G. is employed by UCB.

Received July 9, 2008. Accepted in final form October 21, 2008. REFERENCES 1. Hauser WA. The prevalence and incidence of convulsive disorders in children. Epilepsia 1994;35 (suppl 2):S1–S6. 2. Hauser WA, Annegers JF, Rocca WA. Descriptive epidemiology of epilepsy: contributions of population-based studies from Rochester, Minnesota. Mayo Clin Proc 1996; 71:576–586. 3. Brodie M, Kwan P. Epilepsy in elderly people. BMJ 2005; 331:1317–1322. 4. Cloyd J, Hauser W, Towne A, et al. Epidemiological and medical aspects of epilepsy in the elderly. Epilepsy Res 2006;68 (suppl 1):S39–S48. 5. Collins NS, Shapiro RA, Ramsay RE. Elders with epilepsy. Med Clin North Am 2006;90:945–966. 6. Ramsay RE, Macias FM, Rowan AJ. Diagnosing epilepsy in the elderly. Int Rev Neurobiol 2007;81:129–151. 7. Czapinski P, Blaszczyk B, Czuczwar SJ. Mechanisms of action of antiepileptic drugs. Curr Top Med Chem 2005; 5:3–14. 8. Landmark CJ. Targets for antiepileptic drugs in the synapse. Med Sci Monit 2007;13:RA1–RA7. 9. Ochoa JG, Riche W. Antiepileptic drugs: an overview. Available at: http://www.emedicine.com/neuro/. Accessed April 2, 2007. 10. Kwan P, Brodie MJ. Combination therapy in epilepsy: when and what to use. Drugs 2006;66:1817–1829. 11. Patsalos PN, Froscher W, Pisani F, van Rijn CM. The importance of drug interactions in epilepsy therapy. Epilepsia 2002;43:365–385. 12. Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2003;2:347–356. 13. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2006;61:246–255. 14. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279:1200–1205. 15. French JA, Gidal BE. Antiepileptic drug interactions. Epilepsia 2000;41 (suppl 8):S30–S36.

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Automatic detection of preclinical neurodegeneration Presymptomatic Huntington disease

S. Klo¨ppel, MD C. Chu, MSc G.C. Tan, BSc B. Draganski, MD H. Johnson, PhD J.S. Paulsen, PhD W. Kienzle, PhD S.J. Tabrizi, MD J. Ashburner, PhD R.S.J. Frackowiak, MD PREDICT-HD Investigators of the Huntington Study Group*

Address correspondence and reprint requests to Dr. Stefan Klo¨ppel, Department of Psychiatry, University Clinic Freiburg, Hauptstr. 5, Freiburg, Germany [email protected]

ABSTRACT

Background: Treatment of neurodegenerative diseases is likely to be most beneficial in the very early, possibly preclinical stages of degeneration. We explored the usefulness of fully automatic structural MRI classification methods for detecting subtle degenerative change. The availability of a definitive genetic test for Huntington disease (HD) provides an excellent metric for judging the performance of such methods in gene mutation carriers who are free of symptoms.

Methods: Using the gray matter segment of MRI scans, this study explored the usefulness of a multivariate support vector machine to automatically identify presymptomatic HD gene mutation carriers (PSCs) in the absence of any a priori information. A multicenter data set of 96 PSCs and 95 age- and sex-matched controls was studied. The PSC group was subclassified into three groups based on time from predicted clinical onset, an estimate that is a function of DNA mutation size and age.

Results: Subjects with at least a 33% chance of developing unequivocal signs of HD in 5 years were correctly assigned to the PSC group 69% of the time. Accuracy improved to 83% when regions affected by the disease were selected a priori for analysis. Performance was at chance when the probability of developing symptoms in 5 years was less than 10%. Conclusions: Presymptomatic Huntington disease gene mutation carriers close to estimated diagnostic onset were successfully separated from controls on the basis of single anatomic scans, without additional a priori information. Prior information is required to allow separation when degenerative changes are either subtle or variable. Neurology® 2009;72:426–431 GLOSSARY AD ⫽ Alzheimer disease; CI ⫽ confidence interval; DWI ⫽ diffusion-weighted imaging; FWE ⫽ family-wise error; HD ⫽ Huntington disease; PSC ⫽ presymptomatic Huntington disease gene mutation carrier; ROI ⫽ region of interest; SVM ⫽ support vector machine; VBM ⫽ voxel-based morphometry.

Group studies in familial Alzheimer disease (AD)1 or Huntington disease (HD)2 have shown substantial neurodegeneration before the onset of typical clinical symptoms. Preclinical degeneration, detectable by standard MRI scans, implies a substantial functional reserve, which indicates that therapeutic attempts to limit degenerative damage are disadvantaged when delayed until a disease is manifest clinically. Consequently, there is a principled need for accurate, early, preclinical diagnosis. Time-efficient methods, applicable with little or no expert knowledge, would be advantageous for screening large numbers of subjects. Machine-learning techniques meet these requirements. They are fully automatic and have been used to successfully separate magnetic resonance (MR) images on the basis of group characteristics such as sex, or presence/absence of disease.3-11 Methods such as support vector Supplemental data at www.neurology.org

426

*See appendix e-1 on the Neurology威 Web site for a list of the participating centers and researchers collecting scans. From the Department of Psychiatry and Psychotherapy (S.K.), Freiburg Brain Imaging, University Clinic Freiburg, Germany; Wellcome Trust Centre for Neuroimaging (S.K., C.C., G.C.T., B.D., J.A., R.S.J.F.) and Department of Clinical Neurology (S.J.T.), Institute of Neurology, University College London, UK; Department of Psychiatry (H.J., J.S.P.), The University of Iowa, Iowa City, IA; Max Planck Institute for Biological Cybernetics (W.K.), Tu¨bingen, Germany; De´partement d’e´tudes cognitives (R.S.J.F.), Ecole Normale Supe´rieure, Paris, France; and Laboratory of Neuroimaging (R.S.J.F.), IRCCS Santa Lucia, Rome, Italy. This work was supported by the Wellcome Trust (grant 075696 2/04/2 to R.S.J.F., J.A., and S.J.T.). The PREDICT-HD study is supported by grants from the NIH (NS 40068) and the High Q Foundation to the principal investigator, J.S.P. Disclosure: The authors report no disclosures. Copyright © 2009 by AAN Enterprises, Inc.

Table

Demographic information on whole group and on subgroups separated by estimated probability of developing symptoms in 5 years Full group

n

Near group

Mid group

Far group

HD

Controls

HD

Controls

HD

Controls

HD

Controls

96

95

32

32

32

32

32

32

Sex, F/M

68/28

66/29

21/11

21/11

26/6

24/8

21/11

24/8

Age at MRI scan, mean (range), y

41.8 (25–70)

44.6 (20–63)

46.1 (28–70)

47.2 (30–63)

44.2 (28–70)

44.6 (20–63)

35.1 (25–54)

36.45 (19–52)

CAG, mean (range)

42.9 (39–61)

NA

44.69 (40–61)

NA

42.46 (39–48)

NA

41.47 (39–45)

NA

Probability of symptom onset in next 5 y, %

25.1 (0.7–76.1)

NA

49.29 (35–76)

NA

22.1 (10–33)

NA

3.87 (0.7–9.5)

NA

HD ⫽ Huntington disease; NA ⫽ not applicable.

machines (SVMs)12 require well-defined training images from which they learn to separate diagnostic categories. The application of automatic classification methods is often limited by lack of a diagnostic gold standard for validation. Presymptomatic HD is an important model for study of the earliest stages of neurodegeneration and atrophy because this autosomal dominant disorder has complete penetrance and results from an expanded CAG trinucleotide repeat in the huntingtin gene that is readily detectable in the blood.13 Because machine-learning techniques can potentially be used in large, multicenter treatment trials,14,15 we sought to explore SVM performance on images from several centers. Encouraging SVM performance with HD will support the strategy of using a similar approach to identify a preclinical phase in other neurodegenerative disorders, such as AD. METHODS Subjects. A cohort of 96 PSCs and 95 control subjects enrolled in the PREDICT-HD study15 were included. PREDICT-HD is an international multicenter study to discover biologic and refined clinical predictors of disease progression in PSCs. Inclusion criteria for PSCs included at least 39 CAG repeats in the HD gene, whereas controls had fewer than 30 repeats. Exclusion criteria for both PSCs and controls included evidence of unstable illness, alcohol or drug abuse, a history of special educational needs, and a history of other CNS diseases or events.15 All T1-weighted anatomic brain MRI scans were checked for artifacts using a semiautomatic quality control procedure at the time of acquisition. PSCs were stratified by their estimated time to clinical manifestation based on age and CAG repeat length (algorithm available at http://www.cmmt.ubc.ca/clinical/hayden).16 This is a robust model for age of disease diagnosis based on data from almost 3,000 gene carriers. As in previous work on the PREDICT-HD data,15 we used the algorithm to estimate the probability of developing unequivocal signs of HD in the next 5 years. PSCs were classified into three equally sized subgroups

with 1) less than 10%, 2) 10% to 33%, and 3) more than 33% probability of clinical manifestation in 5 years. Controls were matched to each PSC subgroup to achieve the best possible age match; a control subject could serve in more than one group. See the table for full details. The study was performed according to the Declaration of Helsinki and was approved by the ethics review boards of each participating center. All subjects gave written informed consent.

MRI and processing. T1-weighted MRI scans were acquired using a three-dimensional volumetric spoiled gradient echo series on 1.5-tesla scanners (echo time 3 msec, repetition time 18 msec, flip angle 20°, field of view 240 mm, 124 slices at 1.5 mm thickness, matrix size 256 ⫻ 192). Because data were acquired from several centers, different hardware was used so small deviations from these sequence parameters were allowed. Where available, phased arrays were preferred over quadrature head coils because of increased signal-to-noise ratio. There was no systematic difference in scanning parameters between groups because participating centers acquired data from PSCs and controls using the same setup. Images were first segmented into gray matter, white matter, and CSF using statistical parametric mapping software, SPM5 (Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, UK; http:// www.fil.ion.ucl.ac.uk/spm). Then, gray matter segments were normalized to the population templates generated from all study images using a diffeomorphic registration algorithm.17 A separate “modulation” step18 was used to ensure that the overall amount of each tissue class remained constant after normalization. After these steps, the value of a voxel reflects the local gray matter volume. To evaluate and illustrate the extent of differences in regional gray matter volume between controls and the three PSC subgroups, we performed an analysis using voxel-based morphometry (VBM)18,19 and applied an exploratory threshold at p ⫽ 0.001 (uncorrected for multiple comparisons). After preprocessing as above, we smoothed with an 8-mm gaussian kernel and contrasted PSC groups with controls to identify areas with gray matter atrophy. The T scores at the voxels showing the most significant differences in each contrast are reported. Support vector classification. In what follows, we provide an intuitive understanding of linear SVMs and how they are implemented in the current work. A more technical account of this method can be found in the e-Methods on the Neurology® Web site at www.neurology.org, in textbooks,12,20 or in our previous work.6,7 Neurology 72

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Figure 1

Illustration of the concept used in support vector machines

The algorithm tries to find a (multidimensional) boundary that maximizes the distance between presymptomatic Huntington disease gene mutation carriers (squares) and controls (circles). The figure reduces the problem to two dimensions or voxels for the purpose of illustration only. Cases wrongly classified (with gray connectors) are penalized with a specific weight (see Methods for details).

For the present work, we focused on the gray matter segment, because any neurodegenerative process is likely to manifest in that tissue class. We used an off-the-shelf linear SVM (http:// www.csie.ntu.edu.tw/˜cjlin/libsvm/). In a first step, all but one scan from PSCs and controls is used to train an SVM. During this training process, all image characteristics (i.e., the gray matter volume in a brain region as reflected by the value of a voxel) are used to define a boundary that separates diagnostic groups. Figure 1 illustrates the principles of SVM in two dimensions (i.e., each subject has two image characteristics or voxels). In practice, there would be several thousand voxels (features) in an image, each of which forms a separate dimension. During this training process, those subjects that are most difficult to separate are used to define the boundary between the diagnostic groups. Sometimes there is too much overlap between the groups, in which case higher accuracy can be achieved by allowing some of the training data to fall on the wrong side of the boundary. A

Figure 2

parameter C is used to control how much misclassification of the training data is allowable. The next step is to ensure that this boundary is useful to correctly separate new data. These new data do not contribute to the definition of the classification boundary. In the clinical setting, this new data could come from a patient to be diagnosed. In our implementation, we used a further round of training and testing to optimize the C parameter (called a three-way split validation). We report the average accuracy, i.e., what percentage of scans left out of the training set were assigned to their correct group. This percentage can be converted into a p value by assumption of a binomial distribution with a chance probability of correct classification of 0.5. Another way to check whether the classification boundary relies on meaningful information is to localize the pattern of voxels characterizing differences between groups (figure 2 and e-Methods).

Region of interest approach. Optimally, classification methods should be capable of detecting preclinical degeneration without additional disease-specific information. Such information will often be unavailable because symptoms may be subtle and nonspecific or absent, or the earliest site of pathology is unknown. In an additional analysis, we explored whether an improvement of classification accuracy accrues with addition of prior information about regions known to be affected by the disease. HD, like other neurodegenerative diseases, does not affect all brain areas to a similar extent. We used a group comparison between normal and PSC scans with VBM to generate a weighted map of areas involved by preclinical neurodegeneration. Meaningful classification by SVMs has to generalize to new images. If regions involved in a disease process had been identified from the same data set later used for classification, any differences could be specific only to the scans of that data set, but not to the underlying disease process in general. Therefore, to ensure generalization of results, a separate data set of PSC and control scans was acquired using three-dimensional structural magnetic resonance images from 42 PSCs and control subjects to define the regions of interest (see table e-1 for demographic details). We used a 1.5-tesla Siemens Sonata scanner (T1-weighted MDEFT sequence, 176 slices at 1-mm thickness, sagittal, phase encoding in anterior/posterior, field of view 224 ⫻ 256 mm2, matrix 224 ⫻ 256, repetition time 20.66 msec, echo time 8.42

Brain regions most relevant for group separation

Voxels most relevant for the separation of Huntington disease mutation carriers and controls in the group closest to clinical presentation. A dual color bar is used. Blue to green areas indicate higher gray matter density, increasing the likelihood of classification as normal. Red and yellow show regions where higher gray matter density characterizes asymptomatic Huntington disease mutation carriers. See main text for interpretation. Results are overlaid on the mean gray matter compartment from all subjects. 428

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msec, inversion time 640 msec, flip angle 25 degrees, fat saturation, bandwidth 178 Hz/pixel).21 We used the t value at each voxel to evaluate its involvement in the disease process. To reduce the number of voxels, we restricted this analysis only to those voxels surviving correction for multiple comparisons across whole brain using a FWE correction as implemented in SPM5. To assess the performance of such a region of interest (ROI) definition process, we also generated a weighted image with a more liberal threshold of p ⫽ 0.01 (uncorrected; see figure e-1 for resulting T-maps). Previous imaging studies have shown that the striatum is most affected and that it atrophies early in HD.2 The degree of atrophy is comparable to the early degeneration of the hippocampus in AD. In the extreme case, we selected our region for categorization as that with the coordinates of the single voxel showing the greatest atrophy (indexed by the highest VBM T score) in the VBM comparison of the separate groups of PSCs and control. To include maximum a priori information from this comparison, we applied the same amount of gaussian smoothing to the classifier images as applied to the VBM ROIdefining image set before extracting the voxel value.

Categorization accuracy depended greatly on estimated time to disease presentation. Subjects with at least a 33% chance of developing unequivocal signs of HD in 5 years were correctly assigned, with no a priori information, to the PSC group 69% (p ⫽ 0.002) of the time. Best performance (82.8%; p ⬍ 0.001) was obtained with the weighted VBM voxel procedure. Classification accuracy for the PSC group furthest from clinical onset was at chance. Figure 2 illustrates that the striatum was critical for a separation of controls from preclinical HD subjects. The distribution of blue and green colors also indicates that in regions including the insula and parts of the parietal cortex, reduced gray matter was indicative of PSC status. The effect of different levels of a priori information for each of the groups is demonstrated in figure 3. Table e-2 summarizes all the results and provides specificity and sensitivity values together with confidence intervals (CIs). Even at an exploratory threshold, no significant VBM gray matter differences were found between controls and the PSC group with a less than 10% probability of developing symptoms in 5 years. Subjects closer to estimated onset and subjects from all subgroups combined showed the expected gray matter loss in the striatum compared with controls (figure e-2). In these group comparisons, the maximal difference was located in striatum (combined group T ⫽ 7.67; group closest T ⫽ 7.98; middle group T ⫽ 7.39). RESULTS

DISCUSSION We sought to characterize the ability of a fully automatic image classification method to separate structural MRI brain scans of HD gene carriers in the presymptomatic phase from those of con-

Figure 3

Classifications accuracy for different levels of a priori information

Illustration of accuracy in each subgroup and with all subjects pooled together for different levels of a priori information. Error bars indicate 95% confidence intervals (calculated by the efficient-score method29; http://faculty. vassar.edu/lowry/clin1.html). One-sided error bars are used for illustration purposes. FWE ⫽ family-wise error.

trols. Subjects with a more than 33% probability of clinical diagnosis of HD within 5 years were correctly separated from controls 69% of times without any a priori regional weighting. Although this accuracy is clearly above chance (see CIs in figure 3), it is nowhere near perfect. It is interesting that whole brain classification accuracy—this study—falls substantially below the 82% correct classification achieved in an earlier study using an SVM on diffusion-weighted imaging (DWI) data less readily available in clinical practice than T1-weighted data.6 Subjects in the DWI study were unrelated to those of this one and as a group were estimated to be on average 19 years from clinical presentation. Although CIs will overlap, the suggestion is that diffusion imaging is better at classifying HD images. This conclusion is at odds with results from (univariate) VBM studies that show highly significant differences between PSC and control group T1-weighted images2 that are larger than those obtained using DWI.22,23 The differences in acquisition time (10 minutes for a T1 compared with 22 minutes [12 minutes without cardiac gating] for a DWI sequence) and the fact that the study reported here used a multicenter data set are two likely explanations for this apparent disagreement. As expected, classification accuracy improved for PSC subjects closest to estimated symptom onset. The best performance was achieved when brain areas used for classification were limited to regions identified by VBM as affected in the PSC group. In genNeurology 72

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eral, a multivariate method that includes information from various brain areas should show favorable performance when more voxels (reflecting the volume of more brain regions) yield relatively more signal than noise. Figure 2 illustrates that group separation relies heavily on voxels within the caudate nucleus and particularly its head. Reduced gray matter reflected PSC status in insula and parietal cortex also; findings well in line with previous imaging studies.2,24 The figure also displays cortical voxels scattered throughout the brain, without a regionally specific pattern. These scattered voxels constitute a source of “noise,” which explains the superior performance of classification using the caudate alone, a procedure equivalent to minimizing noise. Figure 3 illustrates the benefit of various levels of a priori information, which becomes most obvious for subjects in the middle group but also when all subjects are combined. In contrast, no meaningful classification accuracy was achieved in subjects far from estimated clinical onset, no matter how much a priori information was used. VBM-derived prior information from an independent set of images served two purposes. We avoided overoptimistic claims and any circular logic about result generalization, which would have arisen had we created VBM-weighted images from the images that were also classified with SVM. VBM analysis also created a specific weighted group image that characterized the preclinical HD phase. The creation of similarly informative images could have been achieved using atlas-based masks of putamen and caudate. The approach we present here is more flexible. It allows the creation of disease-specific weighted images when disease distribution does not respect anatomic boundaries or is more widespread. A further advantage of our approach is that each voxel obtains a specific weighting. In contrast, anatomically based masks are normally binary and hence less specific. As expected, no improvement of classification was achieved when VBM derived T-maps were binarized (data not shown). Relatively labor-intensive manual outlining methods, often used in HD,25 would be less suitable for screening than the one presented here. A study comparing both approaches in early HD26 found that both methods reliably showed expected degeneration, but VBM detected additional changes in brain regions not selected a priori. Performance was at chance level when we attempted to separate the subgroup far from clinical presentation from matched controls. Depending on the individual number of CAG repeats and age, subjects in this group were an estimated 20 years or more from developing signs of disease. It is a matter of debate when striatal degeneration starts. A large-scale study based on striatal 430

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volume change in PSC27 illustrates that decline of striatal volume is very subtle in subjects with more than 20 years to estimated onset but becomes substantially steeper around 15 years beforehand. VBM analysis confirms that structural changes were either absent or too subtle in the group farthest from onset to be detected in a group-level VBM analysis. In contrast, bilateral striatal gray matter loss found in the other subgroups confirms previous work using VBM.2 Classification performance was far from perfect. There is a wide range of techniques for extracting image characteristics to feed into various classification methods.3,9,11,28 The purpose of our study was to test gray matter– based SVM classification successfully applied to patients with mild to moderate AD on preclinical HD.7 The study in AD demonstrated the utility when cases were at a point where clinical signs were significant and disease-related atrophy was significant. Here we use genetic information not only to recruit individuals before the manifestation of any clinical deterioration, but also to estimate years to onset of disease and thus make use of the technique to detect the earliest and most subtle degenerative change in the brain. Both studies used data acquired at multiple imaging centers. Although this has to be shown for each disease, our work suggests that data can be exchanged between centers. If this proves true for other diseases, it would make excessive data acquisitions unnecessary and would facilitate the application to rarer neurodegenerative disorders. Our results show that fully automatic detection of preclinical degeneration is possible so that identified subjects could become candidates for longitudinal follow-up in clinical trials, possibly many years before clinical presentation.27 It will be another topic of future studies to test whether multivariate classification methods such as those presented here can play a part in the detection of longitudinal changes alongside currently used, well-established imaging, cognitive, and behavioral changes.27 AUTHOR CONTRIBUTIONS S.K., C.C., G.C.T., B.D., S.J.T., J.A., and R.S.J.F. planned and designed the study. J.S.P. and H.J. provided quality control data. S.K., C.C., W.K., and J.A. were involved in the analyses. All authors contributed to the manuscript and approved the final version.

ACKNOWLEDGMENT The authors thank Ric Davis from the Functional Imaging Laboratory for providing additional computer processing time.

Received May 9, 2008. Accepted in final form October 23, 2008. REFERENCES 1. Fox NC, Crum WR, Scahill RI, Stevens JM, Janssen JC, Rossor MN. Imaging of onset and progression of Alzheimer’s disease with voxel-compression mapping of serial magnetic resonance images. Lancet 2001;358:201–205.

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Thieben MJ, Duggins AJ, Good CD, et al. The distribution of structural neuropathology in pre-clinical Huntington’s disease. Brain 2002;125:1815–1828. Davatzikos C, Fan Y, Wu X, Shen D, Resnick SM. Detection of prodromal Alzheimer’s disease via pattern classification of MRI. Neurobiol Aging 2008;29:514–523. Fan Y, Shen D, Davatzikos C. Classification of structural images via high-dimensional image warping, robust feature extraction, and SVM. Med Image Comput Comput Assist Interv Int Conf Med Image Comput Comput Assist Interv 2005;8:1–8. Kawasaki Y, Suzuki M, Kherif F, et al. Multivariate voxelbased morphometry successfully differentiates schizophrenia patients from healthy controls. Neuroimage 2007;34: 235–242. Kloppel S, Draganski B, Golding CV, et al. White matter connections reflect changes in voluntary-guided saccades in presymptomatic Huntington’s disease. Brain 2008;131:196–204. Kloppel S, Stonnington CM, Chu C, et al. Automatic classification of MR scans in Alzheimer’s disease. Brain 2008; 131:681–689. Lao Z, Shen D, Xue Z, Karacali B, Resnick SM, Davatzikos C. Morphological classification of brains via highdimensional shape transformations and machine learning methods. Neuroimage 2004;21:46–57. Teipel SJ, Born C, Ewers M, et al. Multivariate deformation-based analysis of brain atrophy to predict Alzheimer’s disease in mild cognitive impairment. Neuroimage 2007;38:13–24. Teipel SJ, Stahl R, Dietrich O, et al. Multivariate network analysis of fiber tract integrity in Alzheimer’s disease. Neuroimage 2007;34:985–995. Vemuri P, Gunter JL, Senjem ML, et al. Alzheimer’s disease diagnosis in individual subjects using structural MR images: validation studies. Neuroimage 2008;39:1186–1197. Vapnik V. Statistical Learning Theory. New York: Wiley Interscience; 1998. Huntington Study Group. Unified Huntington’s Disease Rating Scale: reliability and consistency. Mov Disord 1996;11:136–142. Mueller SG, Weiner MW, Thal LJ, et al. The Alzheimer’s disease neuroimaging initiative. Neuroimaging Clin North Am 2005;15:869–877, xi–xii. Paulsen JS, Hayden M, Stout JC, et al. Preparing for preventive clinical trials: the Predict-HD study. Arch Neurol 2006;63:883–890. Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR. A new model for prediction of the age of onset and

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penetrance for Huntington’s disease based on CAG length. Clin Genet 2004;65:267–277. Ashburner J. A fast diffeomorphic image registration algorithm. Neuroimage 2007;38:95–113. Ashburner J, Friston KJ. Voxel-based morphometry: the methods. Neuroimage 2000;11:805–821. Wright IC, McGuire PK, Poline JB, et al. A voxel-based method for the statistical analysis of gray and white matter density applied to schizophrenia. Neuroimage 1995;2:244–252. Bishop C. Pattern Recognition and Machine Learning. New York: Springer; 2006. Deichmann R, Schwarzbauer C, Turner R. Optimisation of the 3D MDEFT sequence for anatomical brain imaging: technical implications at 1.5 and 3 T. Neuroimage 2004;21:757–767. Reading SA, Yassa MA, Bakker A, et al. Regional white matter change in pre-symptomatic Huntington’s disease: a diffusion tensor imaging study. Psychiatry Res 2005;140: 55–62. Rosas HD, Tuch DS, Hevelone ND, et al. Diffusion tensor imaging in presymptomatic and early Huntington’s disease: selective white matter pathology and its relationship to clinical measures. Mov Disord 2006;21:1317– 1325. Rosas HD, Hevelone ND, Zaleta AK, Greve DN, Salat DH, Fischl B. Regional cortical thinning in preclinical Huntington disease and its relationship to cognition. Neurology 2005;65:745–747. Aylward EH, Sparks BF, Field KM, et al. Onset and rate of striatal atrophy in preclinical Huntington disease. Neurology 2004;63:66–72. Douaud G, Gaura V, Ribeiro MJ, et al. Distribution of grey matter atrophy in Huntington’s disease patients: a combined ROI-based and voxel-based morphometric study. Neuroimage 2006;32:1562–1575. Paulsen JS, Langbehn DR, Stout JC, et al. Detection of Huntington’s disease decades before diagnosis: the Predict HD study. J Neurol Neurosurg Psychiatry 2008;79:874– 880. Fan Y, Batmanghelich N, Clark CM, Davatzikos C. Spatial patterns of brain atrophy in MCI patients, identified via highdimensional pattern classification, predict subsequent cognitive decline. Neuroimage 2008;39: 1731–1743. Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 1998;17:857–872.

No Charge for Color Figures Neurology® is committed to presenting data in the most descriptive way for the benefit of our readers. To make possible the publication of a greater number of color figures, we have elimated our color figure charges to authors.

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Incidence and remaining lifetime risk of Parkinson disease in advanced age

Jane A. Driver, MD, MPH Giancarlo Logroscino, MD, PhD J. Michael Gaziano, MD, MPH Tobias Kurth, MD, ScD

Address correspondence and reprint request to Dr. Jane A. Driver, Division of Aging, Brigham and Women’s Hospital, 1620 Tremont St., Boston, MA 02120 [email protected]

ABSTRACT

Objective: To estimate the incidence and lifetime risk (LTR) of Parkinson disease (PD) in a large cohort of men.

Background: Age is the strongest risk factor for PD, but whether its incidence continues to increase after age 80 years remains unclear. Methods: Prospective cohort of 21,970 US male physicians aged 40 – 84 years at baseline who did not report PD before study entry. Participants self-reported PD on yearly follow-up questionnaires, and all deaths were confirmed. We calculated incidence rates and cumulative incidence using a modified Kaplan–Meier analysis. LTR was estimated by adjusting cumulative incidence for competing risks of death. Results: Five hundred sixty-three cases of PD were identified over 23 years of follow-up. The crude incidence rate of PD was 121 cases/100,000 person-years. Age-specific incidence rates increased sharply beginning at age 60 years, peaked in those aged 85– 89 years, and declined beginning at age 90 years. Cumulative incidence substantially overestimated the long-term risk of PD, particularly in those aged 80 years and older. Cumulative incidence was 9.9% (95% confidence interval [CI] 8.48%–11.30%) from ages 45 to 100 years, whereas LTR for the same period was 6.7% (95% CI 6.01%–7.43%). The incidence and LTR of PD decreased with increasing exposure to smoking. Conclusions: Our study provides evidence that the incidence of Parkinson disease (PD) in men increases through age 89 years. Whether the subsequent decline represents a true decrease in risk remains to be established. A history of smoking substantially decreased the incidence and lifetime risk of PD. Incidence studies that do not adjust for competing risks of death may overestimate the true risk of PD in the elderly. Neurology® 2009;72:432–438 GLOSSARY AD ⫽ Alzheimer disease; CI ⫽ confidence interval; LTR ⫽ lifetime risk; PD ⫽ Parkinson disease; PHS ⫽ Physicians’ Health Study.

The burden of Parkinson disease (PD) in developing nations is expected to double over the next generation as the result of increasing life expectancy.1 People aged 85 years and older are currently the fastest growing segment of the US population.2 Age is the strongest risk factor for PD, with a nearly exponential increase in incidence between ages 55 and 79 years. However, the incidence of PD in advanced age remains controversial.3 The majority of prior studies have combined those aged 80 or 85 years and older together because of low numbers of participants in that age group, obscuring the relationship between PD and advanced age. Accurate predic-

From the Divisions of Aging (J.A.D., J.M.G., T.K.) and Preventive Medicine (J.M.G., T.K.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; Department of Neurology and Psychiatry (G.L.), School of Medicine, University of Bari, Italy; Department of Epidemiology (T.K.), Harvard School of Public Health, Boston, MA; and Massachusetts Veterans Epidemiology Research Information Center (J.M.G.), VA Boston Healthcare System, Boston, MA. The Physicians’ Health Study is supported by grants CA-34944, CA-40360, and CA-097193 from the National Cancer Institute and grants HL26490 and HL-34595 from the National Heart, Lung, and Blood Institute, Bethesda, MD. J.A.D. is supported by a grant from the Parkinson’s Disease Foundation. Disclosure: Author disclosures are provided at the end of the article. 432

Copyright © 2009 by AAN Enterprises, Inc.

tions of the future population burden of PD depend on whether its incidence continues to increase, plateaus, or declines in those aged 80 years and older. To appreciate the actual risk of an age-related neurodegenerative disease, it is necessary to adjust for competing risks of death, as was first shown in Alzheimer disease (AD).4 By taking into account the mortality rate of the population, the lifetime risk method estimates the absolute risk of developing a disease before dying of some other cause. Such estimates are useful for predicting individual risk, health education, and population health planning.5 Only one prior estimate of lifetime risk in PD has been published.6 To further investigate the incidence of PD in advanced age, we estimated its agespecific incidence and remaining lifetime risk in a large prospective cohort of men with more than 23 years of follow-up. METHODS The Physicians’ Health Study (PHS) was a randomized trial of aspirin and ␤-carotene for the primary prevention of cardiovascular disease and cancer among 22,071 US male physicians. Detailed descriptions of the study design and findings have been published previously.7,8 All participants provided written informed consent, and the trial was approved by the institutional review board of the Brigham and Women’s Hospital. At study entry in 1982, participants were aged between 40 and 84 years and had no history of cardiovascular disease, cancer (with the exception of nonmelanoma skin cancer), or other serious illnesses. Ninety-two percent of the participants identified their race as white. Baseline information was self-reported and collected by a mailed questionnaire that asked about risk factors for disease as well as lifestyle variables. Participants were sent follow-up questionnaires asking about study outcomes and other medical information twice in the first year and then yearly. Posttrial follow up is ongoing.9 Follow-up information through March 30, 2007, was used in this analysis.

Ascertainment of PD. We identified all participants who reported a new diagnosis of PD on their annual survey between 1982 and 2006. To evaluate the accuracy of the physicians’ selfreport of PD, we performed a validation study using the available medical records of 73 participants who indicated a new PD diagnosis, as previously reported.10 In the PHS, medical records were obtained for each reported study outcome (cardiac event, TIA, stroke, cancer, pulmonary embolism, or death). A physician (J.A.D.) reevaluated medical records of participants who selfreported PD before developing an outcome event. The records were then reviewed independently by two trained neurologists (T.K., G.L.). The clinical diagnosis of PD was considered valid if record review revealed one or more of the following: 1) established diagnosis of PD in the medical record or PD as cause of death on the death certificate; 2) current use of PD medication such as DOPA or a DOPA agonist; 3) neurologic examination with physical findings consistent with parkinsonism (at least two of the following: rest tremor, rigidity, bradykinesia or postural instability)

with no evidence of a secondary cause of parkinsonism such as stroke, history of encephalitis, brain tumor, or neuroleptic treatment in the year before disease onset; patients who developed dementia or severe dysautonomia within the first year of PD diagnosis were also not considered valid cases of PD; 4) patient followed up by a neurologist or a movement disorders specialist for PD. Of the 73 patients with available medical records, the selfreported PD diagnosis was found to be valid in 90% (66 patients). Of these, 26 patients had an established diagnosis, had a confirmatory neurologic examination, and were taking PD medication. Thirty-six patients had an established diagnosis and were taking PD medication, and 8 had an established diagnosis or were taking PD medication. In 7% (5 patients), criteria for a clinical diagnosis of parkinsonism was present, but a secondary cause could not be ruled out. The diagnosis was found to be incorrect in only 3% (2 patients): one patient had intention tremor and the other did not have adequate evidence for a diagnosis of PD.

Statistical analysis. We used a modified life-table method to determine the crude and age-specific incidence rates of PD. An actuarial method was used in calculating person-time. A weight of 0.5 was given to all observations censored during a given age, and a weight of 1 was given to all other observations. Age (in years) was used as the time scale. Follow-up began at age at study entry, and we censored individuals at the age they developed PD, died, or reached the end of follow-up. Because few participants lived beyond their 10th decade, we censored data for those aged 100 years and older. We calculated 1-year crude incidence rates (per 100,000 personyears) for each age and then collapsed them into 5- or 10-year age groups. We calculated PD incidence in smokers and nonsmokers and then estimated age-adjusted incidence rates using direct standardization to the distribution of person-years in the overall group. We chose to stratify lifetime risk estimates by smoking because, with age, it is the best established factor associated with PD risk and a major predictor of mortality. We estimated the cumulative incidence of PD conditional on survival to age 45 years using a modified Kaplan–Meier method.11 We calculated lifetime risk, an adjusted cumulative

Table 1

Age group, y

Age-specific and overall annual incidence rates of Parkinson disease per 100,000 person-years No. of PD cases

Person-years

Incidence rate

40 – 44

0

12,553.0

0.0

45–49

2

34,324.0

5.83

50–54

9

54,448.5

16.53

55–59

28

72,172.0

38.80

60–64

57

84,889.0

67.15

65–69

101

75,356.5

134.03

70–74

111

58,443.0

189.93

75–79

101

39,660.0

254.67

80–84

80

22,512.5

355.36

85–89

59

9,597.5

614.74

15

3,361.0

446.30

563

467,316.5

120.48

90–99 Total

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incidence for the competing risk of death from other causes, by a method described by Gaynor et al.12 We calculated the remaining lifetime risk of PD for those who reached the baseline ages of 45, 55, 65, 75, and 85 years free of the disease of interest. Incidence estimates were produced using the Practical Incidence Estimators Macro, which has been described in detail elsewhere.13 All statistical calculations were performed using SAS statistical software (SAS Institute, Inc., version 9.1).

Over 23.1 years of median follow-up (437,316.5 person-years), participants reported 563 cases of incident PD. The median age of PD onset was 73.1 years (range 45.7–93.9 years). Men who developed PD during follow-up were older at baseline (median age 59.8 vs 52.3 years) than men without PD. The percentage of ever-smokers at baseline was slightly lower in those who developed PD (48.9% vs 50.4%). They were also less likely to be current smokers at baseline (6.8% vs 11.1%) and to smoke more than 2 packs per day (3.7% vs 7.2%). The crude annual incidence rate of PD in our population was 120.5 cases/100,000 person-years. The agespecific incidence rate increased sharply beginning at age 60 years, peaked in those aged 85– 89 years at 614.7 cases/100,000 person-years, and declined in those aged 90 –99 years. Overall and age-specific incidence rates are shown in table 1. The figure (A) shows the effect of adjustment for the competing risk of mortality on the cumulative incidence of PD. The curves begin to di-

RESULTS

Figure

verge after age 70 years, and the adjustment is greatest for those aged 85 years and older because of their high mortality rate. Cumulative incidence from ages 45 to 100 years is 9.89 (95% confidence interval [CI] 8.48 – 11.30), whereas lifetime risk for the same period is 6.72 (95% CI 6.01–7.43). Table 2 shows mortality-adjusted risk estimates for the development of PD from different ages reached free of the disease. The lifetime risk, which was 1 in 15 at age 45 years, remained relatively stable at ages 55 and 65 years and then declined to 1 in 18 at age 75 years and 1 in 25 at age 85 years. The age-adjusted incidence rate in ever-smokers at baseline (113 cases/100,000 person-years) was lower than among never-smokers (127 cases/100,000 personyears). Table 2 displays mortality-adjusted short-term, intermediate, and lifetime risks for PD in never- and ever-smokers. Both incidence and lifetime risks of PD decreased as the level of smoking exposure increased (table 3). The figure (B and C) shows the cumulative incidence and lifetime risk curves for PD according to baseline smoking status. Further stratification of smoking exposure into four categories reveals a substantial difference in lifetime risk between heavy smokers and never-smokers (figure, D). To better understand the relationship between smoking and lifetime risk for PD and to explore the

Cumulative incidence and lifetime risk curves

(A) Unadjusted cumulative incidence vs mortality-adjusted lifetime risk of Parkinson disease (PD) for the entire cohort. (B) Cumulative incidence of PD in never- vs ever-smokers. (C) Lifetime risk of PD in never- vs ever-smokers. (D) Lifetime risk of PD by four categories of baseline smoking status (never, past, current ⬍20 cigarettes/day, current ⱖ20 cigarettes/day). 434

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Table 2

Age-specific, mortality-adjusted risk estimates for the development of Parkinson disease in men of different ages reached free of Parkinson disease Short-term, intermediate, and lifetime risks (95% CI)

Age, y

10-y risk

20-y risk

30-y risk

Lifetime risk

45

0.11 (0.04–0.17)

0.62 (0.49–0.74)

2.04 (1.81–2.27)

6.72 (6.01–7.43)

55

0.51 (0.41–0.63)

1.96 (1.73–2.18)

4.23 (3.83–4.63)

6.72 (6.00–7.45)

65

1.51 (1.30–1.71)

3.87 (3.46–4.27)

6.46 (5.72–7.21)

6.46 (5.72–7.21)

75

2.63 (2.24–3.01)

5.52 (4.72–6.32)

85

3.91 (2.96–4.86)

Overall population

5.52 (4.72–6.32) 3.91 (2.96–4.86)

Never-smokers 45

0.17 (0.05–0.28)

0.68 (0.49–0.86)

2.33 (1.97–2.68)

7.76 (6.55–8.96)

55

0.52 (0.36–0.67)

2.19 (1.85–2.53)

4.49 (3.87–5.10)

7.70 (6.48–8.91)

65

1.73 (1.41–2.05)

4.09 (3.48–4.71)

7.42 (6.17–8.66)

7.42 (6.17–8.66)

75

2.58 (2.00–3.17)

6.20 (4.88–7.52)

85

4.59 (3.07–6.10)

6.20 (4.88–7.52) 4.59 (3.07–6.10)

Ever-smokers 45

0.04 (0.00–0.10)

0.54 (0.38–0.71)

1.76 (1.47–2.05)

5.81 (4.98–6.64)

55

0.51 (0.35–0.67)

1.76 (1.47–2.05)

3.99 (3.46–4.52)

5.90 (5.05–6.74)

65

1.31 (1.05–1.57)

3.65 (3.13–4.18)

5.66 (4.78–6.53)

5.66 (4.78–6.53)

75

2.66 (2.14–3.19)

4.93 (3.98–5.88)

85

3.23 (2.10–4.38)

4.93 (3.98–5.88) 3.23 (2.10–4.38)

CI ⫽ confidence interval.

possibility that the inclusion of cases of vascular parkinsonism influenced our results, we repeated the analysis after excluding 5,251 participants with confirmed cardiovascular disease. The study findings did not change substantially. Smokers still had a lower age-adjusted incidence than nonsmokers (101.5 cases/100,000 person-years vs 116.1 cases/100,000 person-years). Lifetime risk of PD for the overall population was 6.6% (95% CI 5.69%–7.57%), 7.8% among nonsmokers and 5.6% among smokers. DISCUSSION In this large prospective cohort study among male physicians, the average annual incidence of PD was 121 cases/100,000 person-years. The agespecific incidence increased steeply through age 89 years and then declined in the 10th decade of life. Unadjusted cumulative incidence substantially over-

Table 3

estimated the true risk of PD in those aged 80 years and older. The lifetime risk curve for PD reached a plateau by age 90 years. The cumulative incidence and lifetime risks of PD decreased substantially with increasing smoking exposure. Our study has several strengths, including its large number of participants and outcome events, prospective design, and well-defined population with a long follow-up. We were able to adjust cumulative incidence for competing risks using mortality information from the same population and could perform stratified analyses by smoking status. A number of limitations should be considered in the interpretation of our results. First, our diagnosis of PD was based on self-reports. However, prior work has shown the self-reported diagnosis of PD to

Incidence, cumulative incidence, and remaining lifetime risk of Parkinson disease by baseline smoking status

Smoking status

Participants (no. of PD cases)

Person-years

Crude incidence

Cumulative incidence (95% CI)

Lifetime risk (95% CI)

Never

10,901 (288)

229,772.5

125.34

10.79 (8.58–12.99)

7.76 (6.55–8.96)

8,662 (237)

178,238.0

132.97

9.35 (7.58–11.13)

6.43 (5.44–7.40)

Past Current <1 pack/day

847 (17)

17,648.5

96.33

8.01 (3.32–12.70)

5.45 (2.58–8.31)

Current >1 pack/day

1,560 (21)

29,626.5

70.88

3.47 (1.59–5.35)

2.26 (1.21–3.31)

PD ⫽ Parkinson disease; CI ⫽ confidence interval. Neurology 72

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Table 4

Comparison of the Physicians’ Health Study with studies using widely accepted diagnostic criteria that report crude annual incidence of Parkinson disease in men

Reference

Population

Study years

Age range, y

Person-years

Unadjusted incidence rate per 100,000 person-years

Current article

US national

1982–2007

ⱖ65

208,931

224

15

Rotterdam

1990–1999

ⱖ65

11,105

261

18

Central Spain

1994–1998

ⱖ65

5,284

360

20

US, Manhattan

1988–1991

ⱖ65

14,238

119

US, Rochester, Minnesota

1976–1991

ⱖ65

49,723

113

21

US, California

1994–1995

ⱖ60

261,074

100

17

Italy

1992–1996

ⱖ65

6,285

461

5

be highly valid in a population of health professionals.14 Direct validation of more than 10% of selfreported PD diagnoses using available medical records revealed an accuracy of 90%, which is similar to that found in validation studies of self-reported hypercholesterolemia and hypertension in the PHS.15 However, despite this good validation, misclassification of PD remains possible. A number of factors limit the generalizability of our results to other populations. Our cohort was composed of white men of the same educational level and profession who were motivated to modify their risks for disease. They also may have higher rates of disease diagnosis than nonphysicians because of easier access to medical care. However, our incidence estimates for PD were similar to that of a population-based study with direct ascertainment.16 We were unable to estimate the incidence and risk of PD in women. Prior estimates of PD incidence have varied widely depending on nationality, sex, population age distribution, and case ascertainment methods. General populations have an average estimate of 13 cases/ 100,000 (range 1.5–26),17 whereas populations aged 65 years and older have an average of 180 cases/ 100,000 (range 89 –332).16,18-22 We recalculated the incidence rates of studies that evaluated most or all population members using accepted diagnostic criteria and reported age-specific incidence in older white men (table 4). The rate obtained in our cohort (224 cases/100,000 person-years) was similar to that of the Rotterdam Study (261 cases/100,000 person-years),16 a primarily white population-based cohort in which the diagnosis of PD was obtained by direct screening followed by a detailed clinical workup. Thirty-nine percent of PD cases were newly diagnosed by study physicians, demonstrating the substantial number of patients with PD who are missed when case finding is based on medical records alone. Despite the fact that our participants are physicians with easy access to medical care, our rate was lower than that of two door-todoor studies of elders in Italy and Spain, in which PD 436

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was directly ascertained.18,19 Finally, our rate was higher than that in three US-based studies in which no population screening was performed and cases were found through health care providers or medical records systems.6,21,22 In our cohort, PD incidence increases through age 89 years and then declines in the 10th decade of life. In the majority of studies reporting age-specific incidence in white men, incidence increases through the oldest age group,16,18,19,21-23 as it does in our study when those aged 85 years and older are combined. However, a number of well-conducted studies show a decline in PD incidence in men after age 75 or 79 years.6,23-25 Similar results have been found for AD in a cohort characterized by exceptional longevity in which the incidence of AD in men began to decline in their early 90s.26 It is unclear whether the observed decline represents a true decrease in the risk of PD or is simply due to underdiagnosis. Older patients may become lost to follow-up, particularly in studies with lessintensive cohort surveillance.23 Because parkinsonian signs as well as comorbidities increase markedly with age,27 the decline of PD in the oldest old may also reflect the difficulty of distinguishing idiopathic PD from other causes of parkinsonism.20 In the Rochester Epidemiology Project, the incidence of PD declined in men after age 79 years when strict diagnostic criteria were used, but continued to increase through age 99 years when broad criteria were used.28 When we included PD patients with concurrent dementia, the incidence rate increased slightly but still declined after age 89 years (data not shown). Our study provides evidence that PD incidence increases at least to age 90 years, thus shifting to the right the age where we can be confident that incidence is still increasing. Cumulative incidence is often used to provide a measure of long-term disease risk. However, it overestimates the incidence when the disease has a prevalence of 10% or greater, or the competing risk of

mortality is high.29 The lifetime risk method adjusts the incidence rate of a disease by the all-cause mortality rate in the population. It thus provides the actual risk of developing the disease before dying of some other cause, assuming one has survived free of that disease to a specified age. Lifetime risk estimates are helpful as an absolute measure of long-term individual risk and are easily understood by the lay public. They are increasingly being used by researchers and policy makers to predict population risks30 and develop clinical practice guidelines.31,32 Our study illustrates the importance of adjusting for the competing risk of death when estimating the incidence of a disease in an older population. The cumulative incidence of PD from ages 45 to 100 years was 9.9% (1 in 10), but mortality-adjusted lifetime risk for the same period was 6.7% (1 in 15). Our estimate of lifetime cumulative incidence at age 40 years was remarkably similar to that of the Rochester Epidemiology Project (10.9%), but our estimates of lifetime risk were higher. This likely reflects the increased longevity of our cohort, which has a life expectancy of 49.3 additional years at age 40 years, 12 years longer than that of 40-year-old men in the general US population.33 Populations with a longer life expectancy have a longer period at risk; thus, lifetime risk estimates cannot be compared across different populations unless they have similar mortality rates. Although smoking is known to decrease PD risk,34 it increases the risk of many other major diseases and of death. The cumulative incidence of PD decreased as the level of smoking exposure increased, suggesting a dose–response relationship between smoking and protection from PD. The lifetime risk of PD followed the same pattern (figure, D), and lifetime risk in heavy smokers (2.3%) was substantially less than in never-smokers (7.8%). The difference in lifetime risk curves between ever- and never-smokers was accounted for by increased mortality from cardiovascular disease, cancer, and pulmonary disease among smokers (data not shown). Because we had relatively few current smokers in the cohort, smoking-associated mortality rates were lower than might be found in a general population. In a cohort with a higher smoking exposure, both cumulative incidence and lifetime risks of PD among smokers might be even lower. It is worth emphasizing that while smoking may decrease the incidence of PD by some protective factors, it decreases the lifetime risk of PD by substantially increasing the risk of death from smoking-related diseases. We were unable to address the incidence and lifetime risk of PD in women. Women are known to have a twofold decreased risk of PD compared with

men,20 which seems to persist even to very old ages.18 On the other hand, older women have increased longevity compared with men and are less likely to be smokers. Thus, although incidence in men is higher at all ages, the difference in lifetime risk between men and women likely decreases with age.6 Further studies of lifetime risk in elderly women are needed. Our results illustrate the sensitivity of PD incidence and risk estimates to a number of factors, including the age and longevity of the population, methods of case finding, the strictness of PD criteria, and the prevalence of smoking. In this population of health-conscious male physicians with exceptional longevity, PD incidence increased sharply to age 90 years, and lifetime risk was as high as 1 in 15 at age 40 years. As life expectancy increases worldwide, similar lifetime risks can be expected in general populations. AUTHOR CONTRIBUTIONS Statistical analysis was conducted by J.A.D.

ACKNOWLEDGMENT The authors thank the staff of the Physician’s Health Study and the 22,071 dedicated physicians who made this project possible.

DISCLOSURE While we believe that we have no conflict of interest that could inappropriately influence (or bias) our decisions, work, or writing of the manuscript with regard to the specific matter of the submitted paper, we report a full disclosure for the last 5 years for each of the authors below. J.A.D. has nothing to disclose. G.L. has received investigator-initiated research funding from the NIH and has received honoraria from Pfizer and Lilly Pharmaceutical for speaking engagements in 2003. J.M.G. has received investigator-initiated research funding and support as Principal Investigator from the NIH, BASF, DSM Pharmaceuticals, Wyeth Pharmaceuticals, McNeil Consumer Products, and Pliva; has received honoraria from Bayer and Pfizer for speaking engagements; and is a consultant for Bayer, McNeil Consumer Products, Wyeth Pharmaceuticals, Merck, Nutraquest, and GlaxoSmithKline. T.K. has received investigator-initiated research funding as Principal or Co-Investigator from the NIH, Bayer AG, McNeil Consumer and Specialty Pharmaceuticals, Merck, and Wyeth Consumer Healthcare; is a consultant to i3 Drug Safety; and has received honoraria from Genzyme for educational lectures and from Organon for contributing to an expert panel.

Received July 14, 2008. Accepted in final form October 24, 2008. REFERENCES 1. Dorsey ER, Constantinescu R, Thompson JP, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 2007;68:384–386. 2. US Department of Health and Human Services. A Profile of Older Americans: 2005. Washington, DC: Department of Health and Human Services; 2005. 3. Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R. How common are the “common” neurologic disorders? Neurology 2007;68:326–337. 4. Seshadri S, Wolf PA, Beiser A, et al. Lifetime risk of dementia and Alzheimer’s disease: the impact of mortality on risk estimates in the Framingham Study. Neurology 1997; 49:1498–1504. Neurology 72

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Seshadri S, Wolf PA. Lifetime risk of stroke and dementia: current concepts, and estimates from the Framingham Study. Lancet Neurol 2007;6:1106–1114. Elbaz A, Bower JH, Maraganore DM, et al. Risk tables for parkinsonism and Parkinson’s disease. J Clin Epidemiol 2002;55:25–31. Final report on the aspirin component of the ongoing Physicians’ Health Study. Steering Committee of the Physicians’ Health Study Research Group. N Engl J Med 1989; 321:129–135. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:1145–1149. Christen WG, Gaziano JM, Hennekens CH. Design of Physicians’ Health Study II: a randomized trial of betacarotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials. Ann Epidemiol 2000; 10:125–134. Driver JA, Kurth T, Buring JE, Gaziano JM, Logroscino G. Prospective case-control study of nonfatal cancer preceding the diagnosis of Parkinson’s disease. Cancer Causes Control 2007;18:705–711. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. Gaynor J, Feuer E, Tan C, et al. On the use of causespecific failure and conditional failure probabilities: examples from clinical oncology data. J Am Stat Assoc 1993;88: 400–409. Beiser A, D’Agostino RB Sr, Seshadri S, Sullivan LM, Wolf PA. Computing estimates of incidence, including lifetime risk: Alzheimer’s disease in the Framingham Study—the Practical Incidence Estimators (PIE) macro. Stat Med 2000;19:1495–1522. Chen H, Zhang SM, Schwarzschild MA, Hernan MA, Ascherio A. Physical activity and the risk of Parkinson disease. Neurology 2005;64:664–669. Camargo CA Jr, Hennekens CH, Gaziano JM, Glynn RJ, Manson JE, Stampfer MJ. Prospective study of moderate alcohol consumption and mortality in US male physicians. Arch Intern Med 1997;157:79–85. de Lau LM, Giesbergen PC, de Rijk MC, Hofman A, Koudstaal PJ, Breteler MM. Incidence of parkinsonism and Parkinson disease in a general population: the Rotterdam Study. Neurology 2004;63:1240–1244. Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies of Parkinson’s disease. Mov Disord 2003;18:19–31. Baldereschi M, Di Carlo A, Rocca WA, et al. Parkinson’s disease and parkinsonism in a longitudinal study: two-fold higher incidence in men. ILSA Working Group. Italian Longitudinal Study on Aging. Neurology 2000;55:1358–1363. Benito-Leon J, Bermejo-Pareja F, Morales-Gonzalez JM, et al. Incidence of Parkinson disease and parkinsonism in three elderly populations of central Spain. Neurology 2004;62:734–741.

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Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence and distribution of parkinsonism in Olmsted County, Minnesota, 1976 –1990. Neurology 1999;52: 1214–1220. Mayeux R, Marder K, Cote LJ, et al. The frequency of idiopathic Parkinson’s disease by age, ethnic group, and sex in northern Manhattan, 1988-1993. Am J Epidemiol 1995;142:820–827. Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 2003;157:1015–1022. Morens DM, Davis JW, Grandinetti A, Ross GW, Popper JS, White LR. Epidemiologic observations on Parkinson’s disease: incidence and mortality in a prospective study of middle-aged men. Neurology 1996;46:1044–1050. Granieri E, Carreras M, Casetta I, et al. Parkinson’s disease in Ferrara, Italy, 1967 through 1987. Arch Neurol 1991; 48:854–857. Kuopio AM, Marttila RJ, Helenius H, Rinne UK. Changing epidemiology of Parkinson’s disease in southwestern Finland. Neurology 1999;52:302–308. Miech RA, Breitner JC, Zandi PP, Khachaturian AS, Anthony JC, Mayer L. Incidence of AD may decline in the early 90s for men, later for women: the Cache County Study. Neurology 2002;58:209–218. Bennett DA, Beckett LA, Murray AM, et al. Prevalence of parkinsonian signs and associated mortality in a community population of older people. N Engl J Med 1996;334:71–76. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Influence of strict, intermediate, and broad diagnostic criteria on the age- and sex-specific incidence of Parkinson’s disease. Mov Disord 2000;15:819–825. Schouten LJ, Straatman H, Kiemeney LA, Verbeek AL. Cancer incidence: life table risk versus cumulative risk. J Epidemiol Community Health 1994;48:596–600. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008;117:e25–e146. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106: 3143–3421. Wood D, De Backer G, Faergeman O, Graham I, Mancia G, Pyorala K. Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Atherosclerosis 1998;140:199–270. Arias E. United States life tables, 2003. Natl Vital Stat Rep 2006;54:1–40. Hernan MA, Takkouche B, Caamano-Isorna F, GestalOtero JJ. A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson’s disease. Ann Neurol 2002;52:276–284.

Randomized, double-blind, placebo-controlled study of XP13512/ GSK1838262 in patients with RLS C.A. Kushida, MD, PhD P.M. Becker, MD A.L. Ellenbogen, DO, MPH D.M. Canafax, PharmD R.W. Barrett, PhD The XP052 Study Group

Address correspondence and reprint requests to Dr. Clete A. Kushida, Stanford University Center of Excellence for Sleep Disorders, 401 Quarry Road, Suite 3301, Stanford, CA 943055730 [email protected]

ABSTRACT

Objective: To assess the efficacy and tolerability of the nondopaminergic agent XP13512/ GSK1838262 in adults with moderate to severe primary restless legs syndrome (RLS).

Methods: Patient Improvements in Vital Outcomes following Treatment in Restless Legs Syndrome I was a 12-week, multicenter, randomized, double-blind, placebo-controlled trial of XP13512 1,200 mg or placebo taken once daily at 5:00 PM with food. Coprimary endpoints were mean change from baseline International Restless Legs Scale (IRLS) total score and proportion of investigator-rated responders (very much improved or much improved on the Clinical Global Impression–Improvement scale) at week 12 (last observation carried forward). Tolerability was assessed using adverse events, vital signs, and clinical laboratory parameters.

Results: A total of 222 patients were randomized (XP13512 ⫽ 114, placebo ⫽ 108) and 192 patients (XP13512 ⫽ 100, placebo ⫽ 92) completed the study. At week 12, the mean change from baseline IRLS total score was greater with XP13512 (⫺13.2) compared with placebo (⫺8.8). Analysis of covariance, adjusted for baseline score and pooled site, demonstrated a mean treatment difference of ⫺4.0 (95% confidence interval [CI], ⫺6.2 to ⫺1.9; p ⫽ 0.0003). More patients treated with XP13512 (76.1%) were responders compared with placebo (38.9%; adjusted OR 5.1; 95% CI, 2.8 to 9.2; p ⬍ 0.0001). Significant treatment effects for both coprimary measures were identified at week 1, the earliest time point measured. The most commonly reported adverse events were somnolence (XP13512 27%, placebo 7%) and dizziness (XP13512 20%, placebo 5%), which were mild to moderate in intensity and generally remitted. Conclusions: XP13512 1,200 mg, taken once daily, significantly improved restless legs syndrome (RLS) symptoms compared with placebo and was generally well tolerated in adults with moderate to severe primary RLS. Neurology® 2009;72:439–446 GLOSSARY AE ⫽ adverse event; ANCOVA ⫽ analysis of covariance; CGI-I ⫽ Clinical Global Impression–Improvement; CI ⫽ confidence interval; ESS ⫽ Epworth Sleepiness Scale; IRLS ⫽ International Restless Legs Scale; LOCF ⫽ last observation carried forward; LS ⫽ least squares; MITT ⫽ modified intent-to-treat population; MOS ⫽ Medical Outcomes Study; NNT ⫽ numbers needed to treat; OR ⫽ odds ratio; PghSD ⫽ Pittsburgh Sleep Diary; PSQ ⫽ post-sleep questionnaire; RLS ⫽ restless legs syndrome; RLSQoL ⫽ RLS Quality of Life; SAE ⫽ serious adverse events; SOS ⫽ Sudden Onset of Sleep questionnaire; TST ⫽ total sleep time; WASO ⫽ wake time after sleep onset.

Restless legs syndrome (RLS) is a sensorimotor disorder characterized by an urge to move the legs, usually caused by uncomfortable sensations that begin or worsen at rest and in the evening or at bedtime, and are temporarily relieved by movement.1 Sleep complaints are common among patients with moderate to severe RLS; approximately 75% of these patients report difficulties with sleep initiation, maintenance, or awakenings.2 Approximately 2% to 3% of the US population reports RLS symptoms that may require pharmacologic treatment.2 Dopamine agonists are the only Food and Drug Administration–approved treatments for RLS, although other drug classes have been used.3-12 Dopamine agonists have been associated with adverse events (AEs) such as nausea and vomiting, impulse control issues, early morning Supplemental data at www.neurology.org From the Stanford University Center of Excellence for Sleep Disorders (C.A.K.), Stanford, CA; Sleep Medicine Associates of Texas (P.M.B.), Dallas, TX; Quest Research Institute (A.L.E.), Bingham Farms, MI; and XenoPort, Inc. (D.M.C., R.W.B.), Santa Clara, CA. Disclosure: Author disclosures are provided at the end of the article. Copyright © 2009 by AAN Enterprises, Inc.

439

rebound, and augmentation—a paradoxical increase in symptom severity, migration of symptoms to other limbs, and symptoms occurring earlier than before in the day or night.13 Treatment guidelines suggest that patients who do not tolerate current therapies may benefit from changing to another class of medication.11,12 An early clinical study and case reports suggest that gabapentin may be effective in improving RLS symptoms.14-19 The mechanism of action of gabapentin in RLS is unknown. However, the antiepileptic and pain relief properties of ␣2-␦ ligands, such as gabapentin, have been demonstrated.20,21 Gabapentin pharmacokinetic studies report interpatient variability in absorption and plasma exposure due to saturable absorption in the upper intestine.22 XP13512/GSK1838262, absorbed by high-capacity nutrient transporters throughout the gastrointestinal tract, is rapidly converted to gabapentin23 and overcomes the pharmacokinetic limitations of gabapentin.24,25 XP13512 delays time to peak plasma concentration, improves gabapentin absorption, and provides dose-proportional exposure. The 1,200 mg dose was selected based on results from two phase 2 studies of XP13512 in patients with RLS.26 This study compares the efficacy and tolerability of once-daily XP13512 1,200 mg with placebo in patients with moderate to severe primary RLS. METHODS Design. This study (XenoPort, Inc. protocol #XP052, clinical trials.gov identifier NCT00298623; Patient Improvements in Vital Outcomes following Treatment in Restless Legs Syndrome I [PIVOT RLS-I]) was a randomized, double-blind, parallel-group comparison of XP13512 1,200 mg and placebo, conducted between March 2006 and February 2007 at 22 US centers (see the appendix for a list of investigators and institutions at which trials were performed).

Patient population. Men and women aged 18 years or older with a diagnosis of moderate to severe primary RLS using International Restless Legs Syndrome Study Group diagnostic criteria1 were recruited. Eligible patients had RLS symptoms ⱖ15 days during the month prior to screening (or, if on treatment, similar symptom frequency before treatment initiation) and symptoms on ⱖ4 nights during the 7-day baseline period. Prior RLS treatment was discontinued at least 2 weeks prior to baseline. Patients also had an International Restless Legs Scale (IRLS) total score ⱖ15 at the beginning and end of the baseline period. To eliminate the potential to confound the assessment of treatment response, patients were excluded if they had evidence 440

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of secondary RLS; had a body mass index ⱖ34 kg/m2; were currently experiencing or being treated for moderate to severe depression, other primary sleep disorders, or neurologic disease or movement disorders; or had a history of RLS symptom augmentation or end-of-dose rebound with previous dopaminergic treatment. Pregnant patients were excluded. Although presence of daytime RLS symptoms (between 10:00 AM and 6:00 PM) for ⱖ2 days during the week prior to baseline was originally an exclusion criterion, this restriction was removed after enrollment of approximately 30% of the total study population to improve the generalizability of study results. All patients provided written informed consent prior to study participation. The study was conducted in accordance with good clinical practice guidelines and the 1996 version of the Declaration of Helsinki. The protocol was reviewed and approved by a local or regional institutional review board, depending upon center requirements.

Protocol. Patients were randomized 1:1 to receive placebo or XP13512 1,200 mg once daily at 5:00 PM with food, using a blocked randomization schedule stratified by study site. Patients took one placebo or XP13512 600-mg extended-release tablet on days 1 to 3 and two placebo or 600-mg extended-release tablets on days 4 to 84. Eligible patients then entered an extension study or started a 7-day taper period (one placebo or XP13512 600-mg extended-release tablet). Blinding was ensured by the use of matching placebo and XP13512 tablets. If patients developed intolerable AEs during titration, the dose was maintained until the AE abated, decreased to the prior dose level, or withheld for a few days and then reinitiated to achieve the target dose. Clinic visits took place on days ⫺7 and 1 (baseline), and at weeks 1, 2, 3, 4, 6, 8, 10, and 12.

Outcome measures. Efficacy assessments. The primary efficacy measures were the IRLS rating scale,1 administered at every clinic visit, and the investigator-rated Clinical Global Impression–Improvement (CGI-I scale),27 administered at weeks 1, 2, 4, 8, and 12. Secondary efficacy measures included several validated patient-rated scales: the CGI-I,27 the Johns Hopkins RLS Quality of Life (RLSQoL) questionnaire,28 and the Medical Outcomes Study (MOS) sleep scale.29 The Pittsburgh Sleep Diary (PghSD)30,31 (to assess total sleep time [TST] and wake time after sleep onset [WASO]) and RLS pain scale (pain associated with RLS symptoms; 11-point scale: 0 ⫽ no pain, 10 ⫽ most intense pain imaginable) were completed for 7 days prior to visits via electronic diary. An investigator-designed, exploratory, fivequestion post-sleep questionnaire (PSQ) queried sleep quality, next-day functioning, number of nights with RLS symptoms, number of nighttime awakenings from RLS symptoms, and duration of time awake from RLS symptoms over the previous week. Patients completed the CGI-I, PghSD, RLS pain scale, RLSQoL, MOS sleep scale, and PSQ at weeks 1, 2 (CGI-I and PghSD only), 4, 8, and 12. Patients also maintained a 24-hour diary, beginning at 8:00 AM daily, to record the onset and severity of RLS symptoms and sleep intervals at the end of weeks 1, 2, and 12. Tolerability assessments. The incidence and intensity of treatment-emergent AEs and serious AEs (SAEs) were recorded. Vital signs, including orthostatic blood pressure, were assessed at each visit. Laboratory tests and electrocardiography were performed at weeks 1, 2 (laboratory tests only), 4, 8, and 12. Daytime sleepiness was assessed at weeks 1, 4, 8, and 12 using the Epworth Sleepiness Scale (ESS),32 which measured the likelihood of dozing during eight prespecified activities. The

Table 1

Demographic and clinical characteristics at baseline (safety population)

Placebo (n ⴝ 108)

XP13512 1,200 mg (n ⴝ 113)

Total (n ⴝ 221)

50.2 (12.79)

52.0 (12.80)

51.1 (12.80)

Male

43 (40)

46 (41)

89 (40)

Female

65 (60)

67 (59)

132 (60)

Demographic characteristics

Statistical analyses. Statistical analysis was supervised by

Age, mean (SD), y Gender, n (%)

Race, n (%) White or Caucasian*

106 (98)

108 (96)

214 (97)

Asian

0

1 (1)

1 (1)

Black or African American

2 (2)

3 (3)

5 (2)

American Indian or Native Alaskan*

1 (1)

1 (1)

2 (1)

5.4 (1.15)

5.3 (1.15)

5.3 (1.15)

Mean (SD)

14.5 (12.91)

13.6 (14.63)

14.1 (13.79)

Median (range)

RLS history 7-day RLS record,† mean (SD), d Duration of RLS symptoms, y

10.0 (0.6–59.3)

9.8 (0.4–65.9)

9.9 (0.4–65.9)

Baseline IRLS scale total score, mean (SD)

22.6 (4.91)

23.1 (4.86)

22.8 (4.87)

Moderate (IRLS score 11–20), n (%)

39 (36.1)

44 (38.9)

83 (37.6)

Severe (IRLS score 21–30), n (%)

60 (55.6)

61 (54.0)

121 (54.8)

Very severe (IRLS score 31–40), n (%)

9 (8.3)

8 (7.1)

17 (7.7)

No previous treatment, n (%)

70 (64.8)

81 (71.7)

151 (68.3)

Discontinued prior to washout,‡ n (%)

10 (9.3)

16 (14.2)

26 (11.8)

28 (25.9)

16 (14.2)

44 (19.9)

Daytime somnolence (mean [SD] score)

35.6 (21.10)

37.7 (18.66)

Sleep adequacy, mean (SD) score

32.3 (22.37)

32.8 (22.43)

Sleep disturbance, mean (SD) score

50.7 (19.65)

50.4 (22.29)

Sleep quantity, mean (SD) time, h

5.9 (1.15)

5.9 (1.32)

95 (88.0)

101 (90.2)

RLS treatment history

§

Discontinued during washout, n (%) Baseline sleep characteristics (MOS sleep scale)

Baseline pain characteristics

sponsor developed a Sudden Onset of Sleep (SOS) questionnaire33 to record possible sleep attacks (defined as “a sudden onset of sleep that is irresistible and overwhelming and comes without warning”) and the activities during which they occurred. Positive responses on the SOS questionnaire were assessed by the investigator.

Patients with pain at baseline, n (%) ¶

Mean (SD) baseline pain score

4.1 (1.94)

4.3 (1.98)

Patients with pain score >4 at baseline, n (%)

51 (47.2)

61 (54.5)

Mean (SD) baseline pain score¶ in patients with pain score >4

5.5 (1.19)

5.6 (1.16)

*One patient in the placebo group reported two races (white or Caucasian and American Indian or Native Alaskan). † Number of days RLS symptoms expressed. Once 4 days was achieved, patients could stop recording. ‡ Patients discontinued previous RLS treatment prior to the month before starting study medication. § Patients discontinued previous RLS treatment within the month before starting study medication. Data from modified intent-to-treat population. ¶ RLS pain score (pain associated with RLS symptoms; 11-point scale: 0 ⫽ no pain, 10 ⫽ most intense pain imaginable) collected for 7 days prior to visit. RLS ⫽ restless legs syndrome; IRLS ⫽ International Restless Legs Scale; MOS ⫽ Medical Outcomes Study.

Daniel Bonzo, PhD, Senior Director and Head, Biometrics and Data Management, XenoPort, Inc. The sample size was determined for each of the two primary measures using the results of Phase 2 studies.26 A sample size of 105 patients per treatment group was considered sufficient to detect, with overall 81% power, a treatment difference of ⫺4.0 in mean change from baseline IRLS total score at the 0.05 significance level using a two-sided t test, assuming a SD of 8.8, and a response difference of 23% on the investigator-rated CGI-I (XP13512 68%, placebo 45%; odds ratio [OR] 2.6). Positive evidence of efficacy required both coprimary tests to be significant (p ⬍ 0.05). All efficacy analyses were performed on the modified intentto-treat population (MITT; all patients who took at least one dose of study medication and completed a baseline and at least one on-treatment IRLS assessment) using last observation carried forward (LOCF) as an imputation method. Coprimary efficacy endpoints were the mean change from baseline IRLS total score and the proportion of responders on the investigator-rated CGI-I at week 12 LOCF. The primary efficacy measures were also analyzed using observed cases at each time point, as secondary endpoints. Least squares (LS) mean treatment difference was calculated for the mean change from baseline IRLS total score using an analysis of covariance (ANCOVA) model adjusted for pooled site and baseline scores. Logistic regression, with treatment and pooled site as explanatory factors, was used to analyze the proportions of responders on investigator- and patient-rated CGI-I. Subgroup analysis of pain outcomes was performed on patients with a baseline RLS pain score ⱖ4. Median time of first onset of RLS symptoms was derived from 24-hour diary data. No adjustments for multiple comparisons were made for secondary efficacy endpoints. As differences in study site sample sizes could affect the statistical power and generalizability of the overall study findings, study sites were pooled regionally to form six larger consolidated sites before performing analyses that included adjustment for site. Continuous efficacy variables were analyzed using an ANCOVA model with treatment and pooled site as main effects and baseline as a covariate. Dichotomous endpoints were analyzed by logistic regression using treatment and pooled site as explanatory factors. Numbers needed to treat (NNT) for the coprimary endpoints were calculated post hoc using the smallest integer greater than or equal to one divided by the difference in response rates using LOCF. For IRLS total score, response was defined as a six-point decrease from baseline and a score ⬍15. ESS was also analyzed post hoc using the same method described for the continuous efficacy variables. Treatment compliance was defined as the ratio between the actual number of pills taken and the expected number of pills taken during the study period. Patients were considered compliant if the ratio was 0.8 to 1.2. RESULTS Patient disposition. In total, 222 patients were randomized to receive XP13512 1,200 mg (n ⫽ 114) or placebo (n ⫽ 108) (figure e-1 on the Neurology® Web site at www.neurology.org). Two patients Neurology 72

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441

Figure 1

Mean (ⴞ2 SE) change from baseline International Restless Legs Scale (IRLS) total score by visit

week 1 assessment. Study completion rates were similar in the two groups. Patient characteristics. Baseline demographics, RLS

history, and IRLS scores were similar across treatment groups (table 1) and reflected moderate to severe disease severity. The majority of patients (68.3%) were treatment naı¨ve. Compliance rates were 95.4% (XP13512) and 85.8% (placebo). The mean number of days on study drug was similar with XP13512 (77.6 days) and placebo (76.2 days). Outcome measures. Primary efficacy outcomes. The

Coprimary endpoint: adjusted mean treatment difference (week 12, last observation carried forward [LOCF]): ⫺4.0 (analysis of covariance [ANCOVA]: 95% confidence interval: ⫺6.2 to ⫺1.9; p ⫽ 0.0003). ***p ⬍ 0.0001 vs placebo, **p ⫽ 0.0001 vs placebo, †p ⫽ 0.0003 vs placebo; ANCOVA with baseline as covariate and treatment and pooled site as main effects. Unadjusted mean change from baseline at week 12 (LOCF): XP13512 ⫽ ⫺13.2; placebo ⫽ ⫺8.8.

(XP13512) withdrew prematurely and were excluded from the MITT population. One had a conflicting work schedule, did not receive study drug, and was also excluded from the safety population. The other developed somnolence and withdrew prior to the

Figure 2

Investigator-rated responders on the Clinical Global Impression– Improvement (CGI-I) by visit (last observation carried forward)

Coprimary endpoint (week 12, last observation carried forward): OR: 5.1; 95% confidence interval: 2.8 to 9.2; p ⬍ 0.0001. ***p ⬍ 0.0001 vs placebo. Logistic regression adjusted for pooled site. Responders defined as patients with an investigator rating of much improved or very much improved on the CGI-I. 442

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mean (SD) change from baseline IRLS total score at week 12 (LOCF) was greater with XP13512 (⫺13.2 [9.21]) compared with placebo (⫺8.8 [8.63]) (adjusted mean treatment difference: ⫺4.0; 95% CI, ⫺6.2 to ⫺1.9; p ⫽ 0.0003) (figure 1). More patients treated with XP13512 (76.1%) were rated by investigators as responders at week 12 (LOCF) compared with placebo (38.9%) (adjusted OR: 5.1; 95% CI, 2.8 to 9.2; p ⬍ 0.0001) (figure 2). The post hoc NNT to gain one response benefit was 6 (95% CI, 3.1 to 14.3) for the IRLS total score, 3 (95% CI, 2.0 to 4.0) for the investigator-rated CGI-I, and 4 (95% CI, 2.4 to 6.5) when both primary endpoints were considered. Secondary efficacy outcomes. At week 1, the mean [SD] change from baseline IRLS total score was greater with XP13512 (⫺10.7 [8.01]) compared with placebo (⫺4.4 [7.21]) (adjusted treatment difference: ⫺6.0; 95% CI, ⫺7.9 to ⫺4.1; p ⬍ 0.0001). Similarly, at week 1, more patients treated with XP13512 (57.9%) were rated by investigators as responders compared with placebo (24.8%; p ⬍ 0.0001). At week 12, more patients treated with XP13512 (73.6%) rated themselves as responders compared with placebo (42.6%; p ⬍ 0.0001). Similar results were reported at week 1 (61.7% vs 24.0%; p ⬍ 0.0001). XP13512 increased the average daily TST at weeks 2 (LS treatment difference 0.3; p ⫽ 0.0033) and 4 (LS treatment difference 0.2; p ⫽ 0.0246), but not at week 12 (LS treatment difference 0.2; p ⫽ 0.1870) compared with placebo. Mean (SD) change from baseline average daily WASO was greater at week 12 with XP13512 (⫺17.6 [29.28]) compared with placebo (⫺11.8 [24.91]; LS treatment difference ⫺6.5; p ⫽ 0.0033). Mean reduction in average daily RLS pain score in patients with baseline RLS pain score ⱖ4 was greater at week 12 with XP13512 (⫺3.7) compared with placebo (⫺1.9) (LS treatment difference ⫺1.7; 95% CI, ⫺2.6 to ⫺0.9; p ⬍ 0.0001).

Figure 3

Time to onset of restless legs syndrome symptoms (over 24 hours beginning at 8:00 AM) at baseline and at week 12

Time to onset of first restless legs syndrome symptoms analyzed using the Kaplan-Meier method; log-rank test used to compare treatments.

XP13512 improved RLSQoL scores at week 12 compared with placebo (mean [SD] change from baseline: XP13512, 21.4 [17.00]; placebo, 14.1 [17.32]; LS treatment difference 7.8; p ⬍ 0.0001). All MOS sleep scale domains improved with XP13512 at week 12 compared with placebo. XP13512-treated patients had greater mean [SD] changes from baseline to week 12 compared with placebo-treated patients in daytime somnolence (⫺17.4 [19.39] vs ⫺9.6 [17.18]; p ⫽ 0.0018), sleep quantity (0.8 [1.24] vs 0.4 [1.38]; p ⫽ 0.0084), sleep adequacy (27.7 [29.89] vs 13.4 [27.42]; p ⬍ 0.0001), and sleep disturbance (⫺29.1 [23.84] vs ⫺15.5 [21.79]; p ⬍ 0.0001). All PSQ sleep outcomes improved with XP13512 at week 12 compared with placebo (sleep quality p ⬍ 0.0001, next day functioning p ⫽ 0.0002, number of nights with RLS symptoms p ⬍ 0.0001, number of nighttime awakenings from RLS symptoms p ⫽ 0.0429, and number of hours awake due to RLS symptoms p ⫽ 0.0189). At baseline, the median time to onset of first RLS symptoms based on the 24-hour patient diary was 6.0 hours in both treatment groups, and almost all patients exhibited symptoms by the end of the 24hour period (figure 3). XP13512 increased the median time to onset of first symptoms to 13.3 hours at week 2 and to ⬎23.5 hours at week 12 compared with placebo (9.0 hours at week 2, p ⫽ 0.0006; 11.5 hours at week 12, p ⬍ 0.0001). At week 12, 50.5% of patients treated with XP13512 were symptom-free at 24 hours compared with placebo (17.7%). Tolerability. Treatment-emergent AEs were reported by 93 (82%) patients receiving XP13512 and by 80 (74%) patients receiving placebo (table 2). The

most commonly reported AEs with XP13512 were somnolence and dizziness; these occurrences were reported as mild or moderate in intensity. Twentyseven of 30 first somnolence events and 19 of 22 first dizziness events occurred during the first 2 weeks of XP13512 treatment compared with five of eight first somnolence events and three of five first dizziness events with placebo. The median duration of somnolence was 14.5 days (XP13512) and 17.0 days (placebo); the median duration of dizziness was 5.5 days (XP13512) and 9.0 days (placebo) (calculation includes patients who discontinued treatment due to these AEs). One patient (XP13512) withdrew due to somnolence prior to the week 1 assessment. Nine further patients (XP13512) withdrew due to AEs: somnolence (n ⫽ 2), dizziness (n ⫽ 2), elevated hepatic enzymes (n ⫽ 1), sedation (n ⫽ 1), dyspepsia (n ⫽ 1), deep vein thrombosis (n ⫽ 1), and a combination of nausea, dizziness, and vomiting (n ⫽ 1). Three patients (placebo) withdrew due to AEs: chest tightness (n ⫽ 1), vomiting and diarrhea (n ⫽ 1), and a combination of mood changes, insomnia, and facial swelling (n ⫽ 1). AEs leading to study withdrawal were considered by investigators to be treatment related and resolved upon discontinuation. One SAE occurred in a patient (placebo) who developed appendicitis, which resolved and was not considered treatment related; the patient continued in the study. Mean [SD] ESS scores decreased during treatment with XP13512 (baseline: 9.8 [4.89]; week 12: 6.1 [4.69]) and with placebo (baseline: 9.2 [4.48]; week 12: 7.0 [4.61]); differences between treatment groups at weeks 4, 8, or 12 were not significant. One Neurology 72

February 3, 2009

443

Table 2

Patients with treatment-emergent adverse events by investigatorrated intensity*† Placebo (n ⴝ 108)

XP13512 (n ⴝ 113)

Adverse event

Mild

Moderate

Severe

Mild

Moderate

Severe

Somnolence

8 (7.4)

0

0

Dizziness

3 (2.8)

1 (0.9)

1 (0.9)

11 (9.7)

19 (16.8)

0

11 (9.7)

11 (9.7)

0

Headache

8 (7.4)

4 (3.7)

0

Fatigue

2 (1.9)

0

0

8 (7.1)

8 (7.1)

0

5 (4.4)

5 (4.4)

1 (0.9)

Nausea

1 (0.9)

2 (1.9)

Nasopharyngitis

4 (3.7)

2 (1.9)

0

5 (4.4)

4 (3.5)

0

0

4 (3.5)

2 (1.8)

1 (0.9)

Feeling abnormal

0

Irritability

0

1 (0.9)

0

5 (4.4)

0

0

0

0

5 (4.4)

0

0

Sedation

0

0

0

1 (0.9)

3 (2.7)

1 (0.9)

Dyspepsia

0

2 (1.9)

1 (0.9)

2 (1.8)

2 (1.8)

0

Muscle spasms

1 (0.9)

0

0

1 (0.9)

3 (2.7)

0

Myalgia

0

0

0

3 (2.7)

1 (0.9)

0

Sinus congestion

2 (1.9)

0

0

4 (3.5)

0

0

Vertigo

0

0

0

3 (2.7)

1 (0.9)

0

Vomiting

0

1 (0.9)

1 (0.9)

1 (0.9)

3 (2.7)

0

Back pain

1 (0.9)

1 (0.9)

0

2 (1.8)

1 (0.9)

0

Cough

2 (1.9)

0

0

2 (1.8)

0

1 (0.9)

Dry eye

0

0

0

2 (1.8)

1 (0.9)

0

Flatulence

0

0

0

3 (2.7)

0

0

Increased appetite

1 (0.9)

0

0

2 (1.8)

0

1 (0.9)

Insomnia

2 (1.9)

1 (0.9)

1 (0.9)

3 (2.7)

0

0

Lethargy

0

0

0

1 (0.9)

2 (1.8)

0

Libido decreased

1 (0.9)

0

0

1 (0.9)

2 (1.8)

0

Pain

2 (1.9)

1 (0.9)

0

1 (0.9)

2 (1.8)

0

Rash

1 (0.9)

0

0

2 (1.8)

1 (0.9)

0

Upper respiratory tract infection

6 (5.6)

1 (0.9)

0

1 (0.9)

2 (1.8)

0

Values are n (%). Adverse events (AEs) reported as MedDRA-preferred term. *Reported by ⱖ3 patients (2%) in active treatment group (safety population); patients could experience ⬎1 AE. † Intensity was rated by the investigator as mild (AE did not interfere in a significant manner with the subject’s normal function; it was an annoyance), moderate (AE produced some impairment of function, but was not hazardous to health; it was uncomfortable), or severe (AE produced significant impairment of function or incapacitation; it was a hazard to the subject’s health).

patient (placebo) reported an episode of SOS at week 8, which was confirmed by the investigator. The patient fell asleep while talking and riding as a passenger in a car. There were no clinically significant changes in hematologic, chemistry, or urinalysis parameters in either treatment group. Mean changes in supine and standing systolic and diastolic blood pressure and pulse rate were relatively small and comparable between treatment groups. No clinically significant abnormal electrocardiography results were reported in either treatment group. 444

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XP13512 1,200 mg, taken once daily, significantly improved RLS symptoms compared with placebo on both coprimary endpoints: mean change from baseline IRLS total score and proportion of responders on the investigator-rated CGI-I. Significant improvements on these measures occurred as early as week 1, the earliest time point examined, after only 4 days at the target dose. XP13512 also significantly improved patientreported sleep outcomes and painful RLS symptoms. The improvement in RLS symptoms with XP13512 1,200 mg after 12 weeks of treatment was similar to that of the dopamine agonists.7,8,34,35 The mean XP13512 treatment difference in IRLS total score at week 12 is comparable with the mean treatment differences observed with ropinirole (0.25 mg to 4 mg)7,8,34 and pramipexole (0.25 mg, 0.5 mg, and 0.75 mg).35 Placebo response in the present study was also similar to that reported in the 12-week dopamine agonist trials.7,8,34,35 More than threequarters of XP13512-treated patients were rated as responders by investigators after 12 weeks of treatment, also similar to responder rates reported with ropinirole7,8,34 and pramipexole.35 More than half of XP13512-treated patients were considered responders at week 1. This onset of action may be a consequence of the pharmacokinetics of XP13512 or its short titration schedule.24 The robust efficacy demonstrated suggests reconsideration of the etiology of underlying RLS. Sleep disturbance and pain are among the most troubling symptoms reported by patients with RLS.2,36 XP13512 significantly improved patientreported sleep outcomes on all MOS sleep scale domains and PSQ items compared with placebo, in addition to improving WASO. While the observed sleep benefits in this study were based on subjective measures, polysomnography data from a small crossover study of XP13512 1,800 mg suggested an improvement on sleep architecture in XP13512-treated patients with RLS after 14 days of treatment compared with placebo.37 XP13512 also significantly improved pain associated with RLS symptoms in those patients who entered the study with pain scores ⬎4. Overall, XP13512 was generally well tolerated during 12 weeks of treatment. Somnolence was the most commonly reported AE with XP13512 and these episodes were rated as mild or moderate in intensity. Most events occurred within the first 2 weeks of treatment and generally remitted. ESS findings showed that XP13512 did not increase daytime sleepiness relative to baseline and was similar to placebo. There were no confirmed episodes of sudden onset of sleep with XP13512. Tolerability of XP13512 was similar to that previously reported DISCUSSION

with oral gabapentin38 and different from those observed with dopamine agonists,9,10 likely due to the different mechanism of action of XP13512. AUTHOR CONTRIBUTIONS Drs. Kushida, Becker, and Ellenbogen contributed to the conception and design (protocol advice), acquisition of data (study investigator), and data analysis and interpretation of the study. Drs. Canafax and Barrett contributed to the conception and design (protocol advice) and data analysis and interpretation.

2.

3.

4.

ACKNOWLEDGMENT The authors acknowledge Barbara Wilson, MEd (GlaxoSmithKline, Research Triangle Park, NC) for editorial coordination and Kathy McIvor, BS (Envision Pharma, Inc., Philadelphia, PA) for writing and editorial assistance.

DISCLOSURE The study was funded by XenoPort, Inc., Santa Clara, CA. Research funding for design and conduct of this study; collection, management, analysis, and interpretation of the data were sponsored by XenoPort, Inc. Preparation, review, and approval of the manuscript were sponsored by XenoPort, Inc. and GlaxoSmithKline, Research Triangle Park, NC. Clete A. Kushida and Philip M. Becker have received grants from the sponsor for other research or activities not reported in this research article that were in excess of $10,000 per year. Aaron L. Ellenbogen has received grants from the sponsor for other research or activities not reported in this research article that were less than $10,000 per year. Philip M. Becker has received honoraria from the sponsor during the course of the study for a speaker’s bureau and advising in excess of $10,000 per year. Ronald W. Barrett is a current employee of the study sponsor and Daniel M. Canafax is a former employee. Ronald W. Barrett and Daniel M. Canafax have equity or ownership interest in the sponsor of the study that is valued at more than $10,000.

APPENDIX Investigators and institutions at which trials were performed: Donald Ayres, MD (Ayres & Assoc. Clinical Trials, Lebanon, NH); Philip M. Becker, MD (Sleep Medicine Associates of Texas, P.A., Dallas); Eileen Brady, MD (Lovelace Scientific Resources, Albuquerque, NM); David Chen, MD (Beacon Clinical Research, LLC, Brockton, MD); John Cochran, MD (Alexandria Fairfax Neurology, PC, VA); Aaron Ellenbogen, DO, MPH (Quest Research Institute, Bingham Farms, MI); William Ellison, MD (Radiant Research, Greer, SC); Ramedevi Gourineni, MD (Northwestern Medical Faculty Foundation, Chicago, IL); Dennis Hill, MD (Central Carolina Neurology & Sleep, Salisbury, NC); John Hudson, MD (Future Search Trials, Austin, TX); David Kudrow, MD (Neurological Research Institute, Santa Monica, CA); Clete A. Kushida, MD, PhD (Stanford Center for Human Research, Palo Alto, CA); Antoinette Pragalos, MD (Community Research & Sleep Management Institute, Cincinnati, OH); Marc Raphaelson, MD, PA (Community Clinical Trials, Frederick, MD); Albert Razzetti, MD (University Clinical Research Deland, Inc., Deland, FL); Paul Scheinberg, MD (Atlanta Pulmonary Group–Research, GA); Markus Schmidt, MD, PhD (Ohio Sleep Medicine & Neuroscience Institute, Inc., Dublin, OH); Susan Steen, MD (Axiom Clinical Research of Florida, Tampa, FL); Stephen G. Thein, PhD (Pacific Research Network, San Diego, CA); Alberto Vasquez, MD (Suncoast Neuroscience Assoc, Inc., St. Petersburg, FL); Jan Westerman, MD (Jasper Summit Research, LLC, Jasper, AL); David Winslow, MD (Kentucky Research Group, Louisville, KY).

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

Received June 11, 2008. Accepted in final form October 24, 2008. 16. REFERENCES 1. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology: A report from the restless legs syndrome diagnosis and epide-

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Clinical and electrodiagnostic correlates of peroneal intraneural ganglia

Nathan P. Young, DO Eric J. Sorenson, MD Robert J. Spinner, MD Jasper R. Daube, MD

ABSTRACT

Objective: Intraneural ganglia (IG) are an underappreciated but treatable cause of common peroneal neuropathy (CPN). This study was designed to determine if there are clinical measures that distinguish CPN caused by IG from CPN without a clear proximate cause.

Methods: Clinical and electrodiagnostic features of 22 cases of IG were compared in a caseAddress correspondence and reprint requests to Dr. Nathan Young, Department of Neurology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905 [email protected]

control study to 11 cases of CPN with imaging negative for IG.

Results: The IG group had a greater body mass index (30 vs 24; p ⬍ 0.005), more pain at the knee (52% of 22 vs 0% of 11; p ⬍ 0.005) or in the peroneal distribution (76% of 21 vs 27% of 1; p ⬍ 0.02), more frequent fluctuating weakness (48% of 21 vs 4% of 29; p ⬍ 0.01) with weight bearing (38%, p ⬍ 0.05), or a palpable mass (47% of 20, p ⬍ 0.01) at the fibular head. The IG group was less likely to present with a history of weight loss (0% vs 36%; p ⬍ 0.01), immobility (0% vs 21%; p ⬍ 0.03), or leg crossing (0% vs 80%; p ⬍ 0.05). There were no significant electrophysiologic differences.

Conclusions: Presenting clinical features increase the likelihood of intraneural ganglia and may assist selection of patients with common peroneal neuropathy for diagnostic peroneal nerve imaging. Neurology® 2009;72:447–452 GLOSSARY AFO ⫽ ankle-foot orthosis; BMI ⫽ body mass index; CMAP ⫽ compound muscle action potential; CPN ⫽ common peroneal neuropathy; EDB ⫽ extensor digitorum brevis; IG ⫽ intraneural ganglia; NCS ⫽ nerve conduction study; PL ⫽ peroneus longus; TA ⫽ tibialis anterior.

Intraneural ganglia (IG) are likely an underrecognized cause of common peroneal neuropathy (CPN).1-3 IG of the peroneal nerve develop from the superior tibio-fibular joint when disruption of the capsule allows dissection of synovial fluid along the articular branch of the peroneal nerve.4,5 IG were detected by ultrasound in 5 of 28 (18%) cases of CPN in a series of consecutive patients presenting with foot drop2 and by MRI in 6 of 10 (60%) consecutive patients with CPN without a clear cause.1 Early routine imaging of the peroneal nerve with ultrasound2 or MRI1,6,7 to identify IG has been promoted because targeted surgical treatment of IG is associated with improvement of pain, function, and prevention of recurrence.3,4,8,9 It is not known whether clinical or electrodiagnostic factors can reliably distinguish CPN due to IG from other causes. This retrospective case-control study compares the clinical and electrodiagnostic features of CPN due to IG to CPN without a clear proximate cause to better define early signs of this treatable condition. METHODS Patients with CPN due to IG and CPN controls without IG were identified by retrospective review of Mayo medical records from 1998 to 2007 with approval of the Mayo Institutional Review Board and consent of all patients to review their medical record.

Inclusion criteria. Men and women ages 18 –75 with CPN were included if there was a clinical history, neurologic examination, and EMG/nerve conduction study (NCS) documented in the Mayo Clinic record. The diagnosis of CPN required motor and sensory symptoms or signs limited to the distribution of the common peroneal nerve, abnormal peroneal motor or sensory nerve conduction

From the Departments of Neurology (N.P.Y., E.J.S., J.R.D.) and Neurosurgery (R.J.S.), Mayo Clinic, Rochester, MN. Disclosure: The authors report no disclosures. Copyright © 2009 by AAN Enterprises, Inc.

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study, and needle electromyographic abnormalities confined to the peroneal innervated muscles below the knee. Inclusion required normal EMG findings in the short head of the biceps femoris, medial gastrocnemius, lumbar paraspinal (when examined in cases of suspected L5 radiculopathy), and any additional non-peroneal innervated muscles examined. CPN cases with IG had an IG on knee MRI or highresolution ultrasound imaging and pathologic confirmation at surgery. CPN controls had no evidence of IG on knee MRI. The majority of IG patients in this study have been reported in MRI studies of IG.3,9,11,12

Figure

Images of peroneal intraneural ganglia

Exclusion criteria. Patients were excluded if they had residual deficit from lumbar spine disease, previous spine, peroneal, or sciatic nerve surgery, a central cause of foot drop, acute CPN from blunt trauma, or any evidence of non-peroneal neurologic disease.

Clinical variables. Demographic variables included age, gender, and body mass index (BMI). Time data included onset of symptoms to time of EMG/NCS studies and temporal profile of onset—acute (less than 24 hours), subacute (less than 6 weeks), chronic (greater than 6 weeks), fluctuating, or indeterminate. The presence and severity of pain (mild, moderate, and severe) at the knee or neuropathic pain (burning, stabbing, shock-like, uncomfortable pins and needles sensation) in the peroneal nerve distribution and the use of pain medications were noted. The weakness and sensory loss at the time of presentation was recorded on an ordinal scale from 0 (normal), 1 (25% of normal; mild), 2 (50% of normal, moderate), 3 (75% of normal, severe), to 4 (paralysis). The presence of fluctuating weakness with weight bearing, a mass at the knee, and Tinel sign were recorded. History of leg crossing, local compression by a brace or other device, degree of weight loss, diabetes, recent surgery and type, direct minor trauma, immobility (bedridden), critical illness, and history of contralateral peroneal neuropathy were recorded as present, absent, or not documented.

Nerve conduction studies. Standard nerve conduction studies were performed in all patients: 1) ipsilateral and contralateral peroneal motor recording at extensor digitorum brevis (EDB); 2) peroneal motor recording over tibialis anterior (TA) if the EDB response was absent or at the discretion of the electromyographer; 3) tibial motor recording at the abductor hallucis muscle; 4) bilateral peroneal sensory; and 5) sural sensory. All peroneal motor studies included stimulation at the ankle and 5 cm proximal and distal to the fibular head. Upper limb nerve conduction studies were also performed in cases referred for possible generalized peripheral neuropathy. In addition, we evaluated peroneal motor amplitude at ankle, fibula, and knee (recording EDB or tibialis anterior), the presence and degree of conduction block, the peroneal sensory amplitude and the peroneal motor and sensory conduction velocities and distal latencies. Electromyography. Fibrillation potentials, motor unit duration increase, and recruitment reduction were graded on an ordinal scale from 0 to 4. The findings in the tibialis anterior, peroneus longus, and other peroneal innervated done at the discretion of the electromyographer were recorded. At least one proximal L4 and L5 innervated muscle were examined. Data analysis. Fisher exact test compared categorical variables between groups; Wilcoxon rank sums test compared continuous variables. The primary analysis compared the electrodiagnostic, clinical, and historical factors of cases with IG to controls without IG (MRI negative). A second analysis compared control sub448

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(A) Axial T2-weighted MRI demonstrating an intraneural ganglion cyst (*) arising from the superior tibiofibular joint (arrow) and displacing the common peroneal neuropathy (arrowhead) near the fibular head. (B) Intraoperative photograph of the intraneural ganglia (*) arising from the articular branch to the superior tibiofibular joint (arrow) expanding the common peroneal neuropathy at the fibular head (arrowhead). (C) Longitudinal high-resolution ultrasound image of intraneural ganglia (“cyst”) dissecting along the peroneal nerve (“P Nerve”) near the fibular head.

jects to another group with CPN improved at last follow-up but without knee MRI to exclude IG. The secondary analysis was performed to determine if our control group represented an unbiased sampling from all cases of CPN. If any variable was not documented in the medical record then it was not assumed to be absent and was excluded from analysis of that variable.

Thirty cases of IG were identified. Most patients (77%) were referred for a surgical opinion from one of the authors (R.J.S.). All patients demonstrated an intraneural ganglion by MRI (figure, A), at the time of surgery (figure, B), and pathologically. A cystic mass consistent with IG was demonstrated in two of three patients who also underwent high-resolution ultrasonography (figure, C). Ultrasound in the third patient showed nerve en-

RESULTS Cases.

Table 1

Comparison of clinical features

IG (n ⴝ 22)

MRI negative CPN (n ⴝ 11)

p

Mean months to first presentation (95% CI)

1.5 (0.8–2.3)

1.4 (0.7–2.0)

NS

Mean months to Mayo presentation (95% CI)

8.4 (3.0–14.0)

1.6 (–4.4–7.7)

⬍0.006

Mean age, y (range)

45 (17–65)

49 (24–78)

NS

M:F

3.4 (17:5)

BMI (range)

30 (27–33)

1.75 (7:4) 24 (22–26)

NS ⬍0.005

Knee pain, n (%)

11 of 22 (52)

0 of 11

⬍0.005

Neuropathic pain, n (%)

16 of 21 (76)

3 of 11 (27)

⬍0.02

Palpable mass at fibular head, n (%)

10 of 20 (47)

0 of 10

⬍0.01

Fluctuating deficit, n (%)

10 of 21 (48)

0 of 10

⬍0.01

Fluctuating deficit with weight bearing, n (%)

6 of 16 (38)

0 of 9

⬍0.05

Weight loss (lbs), n (%)

0 of 19 (0)

4 of 11 (36)

⬍0.01

Leg crossing, n (%)

0 of 7 (0)

4 of 5 (80)

⬍0.005

Immobility, n (%)

0 of 22 (0)

6 of 29 (21)

⬍0.03

AFO, n (%)

12 of 22 (55)

Sensory subjective/ objective, n (%)

20 of 21 (95)/16 of 22 (73)

6 of 11 (55)

Tinel at fibular head, n (%)

16 of 17 (94)

5 of 7 (71)

NS

Clinical weakness: TA > PL, n (%)

15 of 22 (68)

6 of 9 (66)

NS

11 of 11 (100)/9 of 11 (82)

distribution symptoms, one had focal pain with fibular head palpation, and all had MRI evidence of a non-cystic mass (ultrasound was not performed). Two patients with systemic vasculitis had acute onset of the peroneal neuropathy (mixture of conduction block and axonal degeneration), one bilateral, associated with concurrent facial numbness in one and generalized arthralgia, hemoptysis, and renal failure in another (peroneal nerve imaging was not performed). No patients presented with isolated or predominant CPN due to multifocal motor neuropathy or focal CIDP. Fifty total controls without a clear proximate cause CPN were eligible for inclusion. Eleven of the 50 cases had an MRI of the knee negative for IG and were included as controls. Eighteen of the remaining 39 cases without MRI had documented improvement as the treating neurologist expected and were utilized for the secondary analysis. Twenty-one of the 39 had no available follow-up data.

NS

Presenting clinical features. A summary of the pre-

NS/NS

senting clinical features and comparison between groups are presented in table 1. There was no difference in presenting age or gender. The onset and progression of symptoms in both groups was usually subacute over days (IG 72% vs controls 90%) with a lower frequency of acute (hours) and chronic (weeks) presentations. There was no difference in the degree of weakness, use of AFO, proportion with sensory symptoms or signs, or greater weakness in the distribution of the deep peroneal nerve (68% vs 66%). A prior history of probable minor trauma to the fibular head (n ⫽ 3) and repetitive squatting (n ⫽ 3) was documented in patients with IG. No patient with IG presented with a history of weight loss (0% of 19 vs 36% of 11, p ⬍ 0.01), immobility (0% of 22 vs 21% of 11, p ⬍ 0.03), or leg crossing (0% of 7 vs 80% of 5, p ⬍ 0.005). The median weight loss in the control group was 32 pounds (range 20 –72). IG were more likely to present with pain at the knee (52% of 22 vs 0%; p ⬍ 0.005) or neuropathic pain in the peroneal distribution (76% of 21 vs 27% of 1; p ⬍ 0.02), fluctuating weakness (48% of 21 vs 4% of 29; p ⬍ 0.01) usually with weight bearing (38%, p ⬍ 0.05), and greater mean BMI (30 vs 24; p ⬍ 0.005) even after excluding control patients with a history of weight loss. A palpable mass was only detected in 47% of 20 patients with IG. Two patients presented without pain.

IG ⫽ intraneural ganglia; CI ⫽ confidence interval; CPN ⫽ common peroneal neuropathy; BMI ⫽ body mass index; AFO ⫽ ankle-foot orthosis; TA ⫽ tibialis anterior; PL ⫽ peroneus longus.

largement without a cyst which was clearly seen on MRI. Eight patients were excluded because of unavailable clinical history (n ⫽ 2), normal EMG/NCS (n ⫽ 1), EMG/NCS abnormalities in the tibial distribution, or peripheral neuropathy (n ⫽ 5). Eight additional patients were excluded from the electrodiagnostic analysis because of peroneal surgical intervention prior to referral for evaluation and treatment of recurrent IG. A total of 22 patients were included in the study of presenting clinical variables and 13 patients were included in the study of presenting electrodiagnostic variables. Controls. Of 310 potential controls, 260 were ex-

cluded: generalized peripheral neuropathy (91), lumbar radiculopathy (51), tibial or sciatic neuropathy (40), known major leg trauma (i.e., knee dislocation) (31), incomplete documentation of clinical data (12), normal EMG or no CPN (10), motor neuron disease (6), myopathy (6), neuromuscular junction disorder (3), peroneal tumor (4), compartment syndrome (3), femoral neuropathy (2), or necrotizing fascitis (1). All patients with a tumor (perineurioma, probable schwannoma, lipoma, and low-grade sarcoma) presented with chronic progressive peroneal

Electrodiagnostic features. A summary of the present-

ing electrodiagnostic features is presented in table 2. The time from onset to electrodiagnostic testing was longer in the IG group (4.8 months vs 1.6 months; p ⬍ 0.01). There was no difference between the Neurology 72

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449

Table 2

Comparison of electrodiagnostic data IG (n ⴝ 13)

Mean months from onset to EMG (range)

4.9 (3.4–6.4)

MRI-negative CPN (n ⴝ 11)

p

1.6 (1–2.2)

⬍0.01

Mean peroneal amplitude (EDB), mV* (range)

0.60 (0–2.7)

1.9 (0–5.1)

NS

Mean peroneal amplitude (TA), mV* (range)

0.78 (0.2–2.5); n ⫽ 6

1.5; n ⫽ 1

NS

4 (25)

7 (64)

NS

7.2 (0–16)

9.2 (0–17)

NS

7 of 10 (70)

NS

Conduction block fibular head, n (%) Peroneal sensory amplitude, ␮V (range) Normal peroneal sensory amplitude, n (%)

8 of 14 (57)

Fibrillation potentials: TA > PL, n (%)

13 (87)

7 (64)

NS

Reduced recruitment: TA > PL, n (%)

10 (71)

7 (64)

NS

*Stimulating above fibular head. IG ⫽ intraneural ganglia; CPN ⫽ common peroneal neuropathy; EDB ⫽ extensor digitorum brevis; TA ⫽ tibialis anterior; PL ⫽ peroneus longus.

mean compound motor amplitude recorded over the EDB muscle, the superficial peroneal sensory amplitudes, or the presence of an abnormal superficial peroneal sensory study on the symptomatic side. There was no difference in the grade of fibrillation potentials, motor unit duration, or recruitment in individual muscles between groups. The majority of patients in both groups had a higher grade of fibrillation potentials and reduced recruitment in the tibialis anterior muscle than the peroneus longus muscle consistent with predominant involvement of the deep branch of the common peroneal nerve. There was a trend toward an increased frequency of conduction block at the fibular head identified in controls (64% vs 25%; p ⬍ 0.06). Controls compared to clinically improving CPN without imaging. No significant differences were noted in

demographic, historical, or clinical variables between control patients with or without an MRI of the symptomatic nerve. Conduction block was more frequent in those without MR imaging (95% v 64%, p ⬍ 0.02) but there was no difference in other electrodiagnostic variables. To our knowledge, this is the largest series of patients with IG reported with detailed clinical and electrophysiologic description and comparison to control subjects. One prior study compared five patients with peroneal IG to patients with CPN due to other causes and found that patients with IG were more likely to present with greater weakness, with lower peroneal compound muscle action potential (CMAP) amplitudes, and without typical risk factors for CPN.2 We did not confirm a difference in the degree of weakness or mean peroneal CMAP in

DISCUSSION

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this study. Our findings are similar to anecdotal observations from case studies.3-5,8-10,13 Surgical treatment of peroneal IG has been associated with improved clinical outcomes, but a randomized controlled study has not been performed. In the largest series of surgically treated IG (n ⫽ 24), which included patients described in this study, pain improved in all patients (70% complete, 30% moderate improvement), there was no evidence of recurrence or worsening of weakness, and the mean MRC grade of strength of deep peroneal innervated muscles improved from 2.5 to 3.3 (mean follow-up 3.5 years; range 1–10 years).4 The mild improvement of strength may have reflected the long duration of symptoms prior to surgery (mean 15 months; range 3 months to 3 years) and referral bias. It is not known whether early diagnosis and surgical treatment of IG at the time of diagnosis of CPN would lead to a better outcome in cases with IG. We found axonal degeneration in all cases; therefore, early intervention before further axonal loss occurs may increase the probability of a better recovery of strength. A prospective natural history study of CPN with or without IG has not been performed to help answer whether all or a subset of patients with CPN should have an MRI or peroneal ultrasound at the time of diagnosis, or whether imaging should be deferred until there is lack of the expected improvement.14,15 The studies of surgical decompression of the peroneal nerve without IG are retrospective, unblended, and do not include a control group of untreated patients to help define the time to expected improvement of CPN without IG.16-18 Suggestions that patients with CPN without IG and conduction block from compression (i.e., leg crossing) should improve in 2 to 3 months, and after 4 – 6 months if the injury is predominantly axonal, are based on the probable pathophysiologic mechanism of improvement (i.e., remyelination or axonal regeneration and reinnervation).15 The findings in this study suggest that clinical features, especially pain at the knee or neuropathic pain in the peroneal distribution, a mass lesion, and fluctuating deficit can help clinicians select patients for early imaging for IG, especially if there is no history of weight loss, immobility, leg crossing, or a clear proximate cause. The precise predictive value of the presence or absence of each clinical variable cannot be reliability assessed because of the design of this study. IG can be clearly demonstrated with MRI or ultrasound imaging,1,2 but the sensitivity and specificity of each test are unknown. We describe a single case in which the cyst was visualized on MRI but not by ultrasound, suggesting that MRI is a more sensitive test. However, ultrasound is often a more accessible, cost-effective, bedside screening test2 that could

be performed in the electrodiagnostic laboratory when CPN is identified. The technical limitations of ultrasound suggest that MRI may still be required to exclude IG when there is a high index of suspicion. Very few cases of CPN due to IG have been reported with detailed neurophysiology.2,19 Three patients were reported with possible inexcitability of the peroneal nerve perhaps due to the underlying fluid collection.2 We did not observe inexcitability of the nerve in any case. However, in one prospective case in which the IG extended 8 cm proximal to the fibular head we could not elicit a response above the knee with surface bipolar stimulation. Needle stimulation was required to reliably stimulate the nerve which excluded conduction block and inexcitability in this single case. Rare cases of IG extending proximally into the sciatic or “crossing over” and descending into the tibial nerve support the possibility that a prolonged region of conduction block or relative inexcitability may be present in cases with proximal extension of the cyst.20 The control group in this study was chosen to reflect the typical CPN that neurologists are frequently asked to evaluate and treat. We used MRI negative controls because IG may be more common than previously recognized, even in patients with risk factors for CPN such as leg crossing.1 We assessed for selection bias in the control group by performing a secondary comparison of controls to a group of patients with improving CPN without a clear proximate cause or MRI excluding IG. Conduction block (63% v 94%; p ⬍ 0.02) was more common in the secondary control group than the primary control group. It is possible that the absence of a conduction block influenced the clinician’s decision to obtain an MRI in our primary control group. There was greater significance of all findings in the secondary analysis suggesting that controls with or without MRI excluding cyst had similar clinical and electrodiagnostic features. Although selection bias limits our ability to draw conclusions on the presence of conduction block, the borderline significance in the primary analysis suggests that IG are less likely, but not excluded, when conduction block is identified. BMI was significantly greater in patients with IG than in controls. A history of obesity was found in 4 of the 10 patients studied with MRI, 6 of whom had an IG.1 Elevated BMI supports the articular branch hypothesis of IG pathogenesis, which predicts that increased weight places a greater impact on the knee and superior tibiofibular joints, thus increasing risk of synovial disruption, cyst development, and dissection along the articular branch of the peroneal nerve.4 Fluctuation of symptoms with weight bearing may also have the same mechanism.

Despite the potential limitations of investigator and referral bias, this study defines the clinical factors that should raise the index of suspicion for IG and assist in selection of patients for MRI or ultrasound. Imaging of the peroneal nerve should be considered in patients with idiopathic CPN presenting with knee pain or neuropathic pain in the distribution of the peroneal nerve, who have not had weight loss, leg crossing, immobility, palpable mass near the fibular head, worsening of neurologic deficit with weight bearing, and absence of conduction block at the fibular head.3,7,8,10 The risk of CPN due to IG appears to be increased in patients with an elevated BMI. Since 53% of patients with IG in this study did not have a palpable mass near the fibular head, the absence of a mass alone does not exclude IG. It remains unclear whether IG are an underrecognized cause of CPN that warrants routine imaging of the peroneal nerve with MRI or ultrasound in all or a subset of patients with CPN. A prospective study assessing the frequency of IG as a cause of CPN and the association between historical risk factors, presenting symptoms, EMG/NCS, and imaging of the nerve with ultrasound and MRI is needed. AUTHOR CONTRIBUTIONS Statistical analysis was performed by N.P.Y. and E.J.S.

Received August 18, 2008. Accepted in final form October 24, 2008.

REFERENCES 1. Iverson DJ. MRI detection of cysts of the knee causing common peroneal neuropathy. Neurology 2005;65:1829– 1831. 2. Visser LH. High-resolution sonography of the common peroneal nerve: detection of intraneural ganglia. Neurology 2006;67:1473–1475. 3. Spinner RJ, Desy NM, Rock MG, Amrami KK. Peroneal intraneural ganglia: part I: techniques for successful diagnosis and treatment. Neurosurg Focus 2007;22:E16. 4. Spinner RJ, Atkinson JL, Scheithauer BW, et al. Peroneal intraneural ganglia: the importance of the articular branch: clinical series. J Neurosurg 2003;99:319–329. 5. Spinner RJ, Atkinson JL, Tiel RL. Peroneal intraneural ganglia: the importance of the articular branch: a unifying theory. J Neurosurg 2003;99:330–343. 6. Weig SG, Waite RJ, McAvoy K. MRI in unexplained mononeuropathy. Pediatr Neurol 2000;22:314–317. 7. Kim JY, Ihn YK, Kim JS, Chun KA, Sung MS, Cho KH. Non-traumatic peroneal nerve palsy: MRI findings. Clin Radiol 2007;62:58–64. 8. Lowenstein J, Towers J, Tomaino MM. Intraneural ganglion of the peroneal nerve: importance of timely diagnosis. Am J Orthop 2001;30:816–819. 9. Spinner RJ, Desy NM, Rock MG, Amrami KK. Peroneal intraneural ganglia: part II: lessons learned and pitfalls to avoid for successful diagnosis and treatment. Neurosurg Focus 2007;22:E27. Neurology 72

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Petit-Lacour MC, Pico F, Rappoport N, Gagey O, Said G. Fluctuating peroneal nerve palsy caused by an intraneural cyst. J Neurol 2002;249:490–491. 11. Spinner RJ, Desy NM, Amrami KK. Cystic transverse limb of the articular branch: a pathognomonic sign for peroneal intraneural ganglia at the superior tibiofibular joint. Neurosurgery 2006;59:157–166. 12. Spinner RJ, Luthra G, Desy NM, Anderson ML, Amrami KK. The clock face guide to peroneal intraneural ganglia: critical “times” and sites for accurate diagnosis. Skeletal Radiol 2008;37:1091–1099. 13. Poppi M, Nasi MT, Giuliani G, Acciarri N, Montagna P. Intraneural ganglion of the peroneal nerve: an unusual presentation: case report. Surg Neurol 1989;31:405–406. 14. Aprile I, Padua L, Padua R, et al. Peroneal mononeuropathy: predisposing factors, and clinical and neurophysiological relationships. Neurol Sci 2000;21:367–371. 15. Katirji B. Peroneal neuropathy. Neurol Clin 1999;17:567–591.

16.

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19. 20.

Humphreys DB, Novak CB, Mackinnon SE. Patient outcome after common peroneal nerve decompression. J Neurosurg 2007;107:314–318. Garozzo D, Ferraresi S, Buffatti P. Surgical treatment of common peroneal nerve injuries: indications and results: a series of 62 cases. J Neurosurg Sci 2004;48:105–112. Kim DH, Murovic JA, Tiel RL, Kline DG. Management and outcomes in 318 operative common peroneal nerve lesions at the Louisiana State University Health Sciences Center. Neurosurgery 2004;54:1421–1428, discussion 1428 –1429. Bakshi N, Chan KM, Wirganowicz PZ. Peroneal intraneural ganglion. Neurology 2005;65:1753. Spinner RJ, Amrami KK, Angius D, Wang H, Carmichael SW. Peroneal and tibial intraneural ganglia: correlation between intraepineurial compartments observed on magnetic resonance images and the potential importance of these compartments. Neurosurg Focus 2007;22:E17.

Calling All Artists! Submit Your Art to Help Raise Money for Neurologic Research Are you an artist? The AAN Foundation invites you to donate your work to the Art for Research: An AAN Gallery Show. Pieces will be displayed at the Annual Meeting in Seattle and put on sale with proceeds going to support clinical research training in neuroscience. Academy members and/or their families may donate pieces for the show. The show accepts paintings, sculptures, textiles, ceramics, and more. Choose how to make your donations: ● Donate a piece of art for the Academy to sell at the meeting ● Sell a piece of art with 20% of the proceeds going to support research ● Submit your art for showcase only for a $50.00 fee For additional details on this event and to learn how to contribute, visit www.aan.com/art.

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Executive dysfunction in frontotemporal dementia and corticobasal syndrome

E.D. Huey, MD E.N. Goveia, BS S. Paviol, BS M. Pardini, BS F. Krueger, PhD G. Zamboni, MD M.C. Tierney, MA E.M. Wassermann, MD J. Grafman, PhD

Address correspondence and reprint requests to Dr. J. Grafman, Chief, Cognitive Neuroscience Section, NINDS, NIH, Bldg. 10, Room 7D43, MSC 1440, Bethesda, MD 20892-1440 [email protected]

ABSTRACT

Objective: To determine the pattern of executive dysfunction in frontotemporal dementia (FTD) and corticobasal syndrome (CBS) and to determine the brain areas associated with executive dysfunction in these illnesses.

Method: We administered the Delis-Kaplan Executive Function System (D-KEFS), a collection of standardized executive function tests, to 51 patients with behavioral-variant FTD and 50 patients with CBS. We also performed a discriminant analysis on the D-KEFS to determine which executive function tests best distinguished the clinical diagnoses of FTD and CBS. Finally, we used voxel-based morphometry (VBM) to determine regional gray matter volume loss associated with executive dysfunction. Results: Patients with FTD and patients with CBS showed executive dysfunction greater than memory dysfunction. Executive function was better preserved in the patients with CBS than the patients with FTD with the exception of tests that required motor, visuospatial ability, or both. In patients with CBS, dorsal frontal and parietal and temporal-parietal cortex was associated with executive function. In FTD, tests with a language component (Verbal Fluency) were associated with left perisylvian cortex, sorting with the left dorsolateral prefrontal cortex, and reasoning (the Twenty Questions task) with the left anterior frontal cortex. The Twenty Questions test best distinguished the clinical diagnoses of CBS and FTD.

Conclusions: The neuroanatomic findings (especially in frontotemporal dementia [FTD]) agree with the previous literature on this topic. Patients with FTD and patients with corticobasal syndrome (CBS) show disparate performance on higher-order executive functions, especially the Twenty Questions test. It may be difficult to distinguish motor and visuospatial ability from executive function in patients with CBS using tests with significant motor and visuospatial demands such as Trail Making. Neurology® 2009;72:453–459 GLOSSARY bv-FTD ⫽ behavioral variant FTD; CBS ⫽ corticobasal syndrome; D-KEFS ⫽ Delis-Kaplan Executive Function System; FDR ⫽ false discovery rate; FTD ⫽ frontotemporal dementia; FWE ⫽ family wise error; MDRS2 ⫽ Mattis Dementia Rating Scale 2; NINDS ⫽ National Institute of Neurological Disorders and Stroke; ROI ⫽ region of interest; VBM ⫽ voxel-based morphometry; WMS-III ⫽ Wechsler Memory Scale–third edition.

Frontotemporal dementia (FTD) is a progressive neurodegenerative disease that primarily affects the frontal and anterior temporal lobes, resulting in changes in behavior, language, and cognition.1 Corticobasal syndrome (CBS) is a disorder characterized by progressive asymmetric apraxia and rigidity with other findings of cortical (e.g., alien limb, cortical sensory loss, myoclonus) and basal ganglia (e.g., bradykinesia and increased resistance to passive movement) dysfunction.2,3 Both disorders can be associated with pathologic tau aggregation.1-5 Patients with FTD and patients with CBS often have deficits in executive function,6-9 a term that encompasses complex cognitive functions such as planning, judgment, reasoning, problem Supplemental data at www.neurology.org From the Cognitive Neuroscience Section (E.D.H., E.N.G., S.P., M.P., F.K., G.Z., M.C.T., E.M.W., J.G.) and Brain Stimulation Unit (E.M.W.), National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD; Litwin-Zucker Research Center for the Study of Alzheimer’s Disease and Memory Disorders (E.D.H.), Feinstein Institute for Medical Research, Manhasset, NY; Departimento di Neuroscienze, Oftalmologia e Genetica (M.P.), Universita` di Genova; and Departimento di Neuroscienze (G.Z.), Universita` di Modena e Reggio Emilia, Modena, Italy. Supported by the intramural program of the NIH/National Institute of Neurological Disorders and Stroke. Disclosure: The authors report no disclosures. Copyright © 2009 by AAN Enterprises, Inc.

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Table 1

Mean (SD) demographic and clinical characteristics of 51 patients with FTD and 50 patients with CBS

Male/female

Mean age at onset, y

Mean age at testing, y

R/L handed

Mean education, y

Body side affected

FTD

26/25

54.7 (7.8)

59.6 (7.9)

46/5

15.6 (2.9)

—

CBS

25/25

61.1 (8.4)

65.6 (8.2)

43/6/1 ambidextrous

14.9 (3.0)

25 L/21R/4 unclear

NA

60.1 (6.4)

14/0

16.9 (3.7)

NA

Normal controls

7/7

FTD ⫽ frontotemporal dementia; CBS ⫽ corticobasal syndrome.

solving, organization, attention, abstraction, and mental flexibility.10 Several questions, however, remain unanswered: How do the patterns of executive dysfunction of behavioral variant FTD (bv-FTD) and CBS compare? What brain areas are associated with specific symptoms of executive dysfunction in bv-FTD and CBS? These are important questions for several reasons: executive dysfunction is a clinically important symptom in FTD11 and CBS,7 but little is known about its neurobiological basis in these disorders; and insights from patients with deficits in executive function can elucidate the neuroanatomic basis of executive function in healthy people. The distributions of atrophy observed in FTD and CBS are ideal to determine the relative contributions of regions of the frontal and parietal cortexes to executive function. A review of the brain areas involved in the performance of executive function tests is beyond the scope of this article, but in summary, while intact executive function requires more fundamental cognitive abilities in other parts of the brain (including the parietal lobe12), the prefrontal cortex, especially on the left, is prominently associated with executive functions.13 Patients with FTD had high numbers of rule violations on the Tower Test compared to patients with Alzheimer disease and healthy controls,14 and impaired performance on a sorting task associated with decreased left frontal lobe volume.15 Performance on the Twenty Questions test has been shown to be impaired in patients with prefrontal cortex lesions,16 and letter fluency is impaired in patients with left prefrontal17 lesions. Patients with FTD who had progressive disease were especially impaired on digit span and inhibition of prepotent responses.18 The Delis-Kaplan Executive Function System (D-KEFS) is a battery of nine standardized executive function tests (Trail Making, 454

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Verbal Fluency, Design Fluency, Color-Word Interference, Sorting, Twenty Questions, Word Context, Tower, and Proverb interpretation) designed to comprehensively assess higher cognitive function.19 In this study, we compared D-KEFS scores between the patients with CBS and patients with FTD and determined which areas of the brain are associated with these executive functions using voxel-based morphometry (VBM) of MRI. Based on the findings discussed above and the brain areas affected in FTD and CBS, we hypothesized that patients with FTD would show more severe executive dysfunction than the patients with CBS and that this executive dysfunction would be associated with left prefrontal atrophy in the patients with FTD and left prefrontal and parietal atrophy in the patients with CBS. METHODS Participants. A total of 51 patients with behavioral variant FTD (bv-FTD) and 50 patients with CBS participated in this study. Patients with language-variant FTD (i.e., semantic dementia or primary progressive aphasia) were excluded from this study in order to remove the potential confound of the effect of language deficits on testing executive functions. Subjects were seen as part of an ongoing research study on FTD and CBS in the Cognitive Neuroscience Section of the National Institute of Neurological Disorders and Stroke (NINDS) of the NIH, Bethesda, MD. They were either selfreferred or referred by outside neurologists. Patients arrived at the NIH with a caregiver and were diagnosed based on an initial clinical evaluation and examination by a neurologist (E.M.W.) by standard clinical criteria.2,20 They then spent 9 days participating in extensive neuropsychological and neurologic testing and imaging studies. Their diagnoses were re-evaluated by a neuropsychologist (J.G.) based on the results of the testing done at the NIH. However, in all but one case, the final diagnosis agreed with the initial diagnosis, suggesting that the executive function testing performed at NINDS very rarely changed the initial diagnosis. We required all subjects to have an assigned research durable power of attorney prior to admission to the protocol and the assigned individuals gave written informed consent for the study. The patients gave assent for the study. All aspects of the study and the consent procedure were approved by the NINDS Institutional Review Board. Demographic and clinical data on the patients is presented in table 1. Since the time of testing, one

patient with FTD and five patients with CBS have died and their diagnoses were confirmed by autopsy.5,20 The 14 control subjects were recruited locally with an advertisement and paid for their participation in the study. They were age-matched to the patients. They were free of any neurologic or psychiatric illness at the time of evaluation and not taking any neurologic or psychiatric medications (table 1).

Materials. The D-KEFS is a standardized battery of nine executive function tests.19 It has good reliability and validity and it has been standardized with large normative and patient samples.19,21,22 The patients also received the Mattis Dementia Rating Scale 2 (MDRS2), a test of general cognitive function designed for patients with cognitive impairment,23 and the Wechsler Memory Scale–third edition (WMS-III), a memory test.24 Principal components analysis of executive function tests. A principal components analysis (using Varimax with Kaiser normalization) of the D-KEFS scores was conducted. In pilot testing, many of our patients had difficulty completing some of the more difficult D-KEFS tests (Proverbs, Color-word interference, Design Fluency, and Word Context). Thus, of the nine D-KEFS tests, we administered and analyzed the five tests the patients were best able to complete: Trail Making, Verbal Fluency, Sorting, Twenty Questions, and the Tower Test. We performed a principal components analysis for three reasons: to reduce the data as there are too many subtests of the D-KEFS to reasonably perform imaging analyses on each; because there is accumulating evidence that executive function is comprised of categories of functions that do not necessarily correspond to a particular test10; and to objectively provide summary measures for the VBM analysis—the D-KEFS tests do not have a single summary score and the principal components analysis provides a better summary of a component of executive function than an arbitrarily chosen D-KEFS subscore. All Primary Measures of the D-KEFS tests (excluding measures that are derived from other Primary Measures, see table 2) for the 101 patients were used in the analysis (20 variables) performed in SPSS 15.0. Optional Measures were not used in the analysis. Scaled D-KEFS scores were used in the analysis. The sample size (⬎100 subjects) and ratio of subjects to variables (⬎5 to 1) satisfies guidelines for principal components analysis.25-27 The factor scores obtained from this analysis were used as the measures of interest in the VBM analyses. Discriminant analysis. To determine which tests of the D-KEFS best distinguish FTD and CBS, a standard (not stepwise) linear discriminant analysis was performed in SPSS 15.0 on the same 20 D-KEFS variables on which the factor analyses were performed (see table 2). Cases with missing values were excluded. Imaging. A 1.5-T GE MRI scanner (GE Medical Systems, Milwaukee, WI) and standard quadrature head coil were used to obtain all images. A T1-weighted spoiled gradient echo sequence was used to generate 124 contiguous 1.5-mm-thick axial slices (repetition time ⫽ 6.1 msec; echo time ⫽ min full; flip angle ⫽ 20°; field of view ⫽ 240 mm; 124 slices, slices’ thickness 1.5 mm; matrix size ⫽ 256 ⫻ 256 ⫻ 124). Imaging analysis. VBM analysis of the data was performed with SPM5 (http://www.fil.ion.ucl.ac.uk/spm/software/spm5) and followed the principles outlined by Ridgway et al.28 Except as noted below, all default SPM5 options were used. Images were segmented into gray matter, white matter, and CSF. In SPM5, spatial normalization, segmentation, and modulation are processed using a unified segmentation algorithm.29 This algorithm, in contrast to optimized VBM used in SPM2 in which the steps are completed sequentially, simultaneously calculates image registration, tissue classification, and bias correction using our par-

ticipants’ structural MR images combined with the tissue probability maps provided in SPM5. The segmented and modulated normalized gray matter images were smoothed with a 12 mm full width at half-maximum Gaussian kernel. An explicit mask encompassing the entire brain was used in the analyses to control for background signal outside the brain. This mask was downloaded from the SPM5 Anatomic Automatic Labeling toolbox (www.cyceron.fr/freeware). A 0.05 explicit absolute threshold for masking was used in the SPM second-level model interface.30 Total intracranial volume was calculated in SPM5 from the unsmoothed, modulated gray matter, white matter, and CSF images from each patient and used as a nuisance variable to account for the possible effect of varying brain volumes. Finally, in all our analyses we corrected the statistical significance thresholds for multiple comparisons correction using two methods widely used in the neuroimaging community: the false discovery rate (FDR) and family wise error (FWE) corrections. The FDR is the proportion of false positives among those tests for which the null hypothesis is rejected31 while the FWE correction, which computes a correction for all voxels controlling for the chance of any false positives, is the most stringent correction for multiple comparisons available in SPM.32 We were interested in elucidating the different brain areas associated with each executive function score between the patients with FTD and patients with CBS. Thus, the CBS and bv-FTD patient groups were analyzed separately. Two sets of analyses were performed. First, the scans from each patient group were compared to the scans of a group of 14 age-matched healthy control subjects using a two-sample t test. Statistical threshold for this analysis was set at p ⬍ 0.05 FWE-corrected for multiple comparisons. All subsequent analyses were limited to these areas of significant gray matter volume reduction (figure e-1 on the Neurology® Web site at www.neurology.org). The relationship between voxel values and each Component Score from the principal components analysis was examined using five separate one-tailed t tests (one for each Component Score), assuming that decreasing performance in executive function performance would be associated with decreased tissue density. Total intracranial volume was added as covariate of no interest. For all these analyses, we considered as significant those voxels surviving both a threshold of p ⬍ 0.001 uncorrected at voxel level and of p ⬍ 0.05 FDR-corrected for multiple comparisons (except for those reported in the figure, D); however, many of the reported areas also survived the more stringent FWE correction with a threshold p ⬍ 0.05 FWE. All clusters reported were composed of at least 30 voxels. For one analysis (component 4), we used a left frontal region of interest (ROI) that we did not use for the other analyses. While this increases the power of this analysis over the others, the rationale was that previous findings have demonstrated that the left side is associated with executive functions,13 and we wanted to power this analysis sufficiently to detect any associations between this component and the left frontal lobe. The left frontal ROI was selected from the WFU Pickatlas (http://fmri.wfubmc.edu/cms/software).

Measures of the correlation between the variables were good, indicating that a principal components analysis is appropriate (the Kaiser-Meyer-Olkin measure was 0.852 and Barlett’s Test of Sphericity had a ␹2 of 921.2, df 190, p ⬍ 0.001). Five components with eigenvalues greater than 1.0 were found (i.e., satisfied the Kaiser-Guttman rule), demonstrating that each RESULTS Principal components analysis.

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Table 2

Neuropsychological test results from patients with FTD and patients with CBS for selected D-KEFS, MDRS2, and WMS-III tests

FTD

CBS

t-Test p value

Discriminant function coefficients

D-KEFS (scaled scores) Sorting test Free sorting confirmed correct

6.44 (⫾3.89)

8.47 (⫾3.35)

0.013*

0.232

Free sorting description

5.44 (⫾3.77)

7.60 (⫾3.08)

0.005*

0.256

Sort recognition description

5.18 (⫾3.27)

6.80 (⫾2.74)

0.018*

0.194

Tower Test Total achievement

4.60 (⫾3.96)

5.74 (⫾3.75)

0.157

11.25 (⫾4.18)

9.05 (⫾3.64)

0.009*

⫺0.229

Time Per-move ratio

6.00 (⫾4.65)

3.67 (⫾3.28)

0.007*

⫺0.242

Move accuracy ratio

12.23 (⫾2.71)

11.40 (⫾2.33)

0.124

⫺0.008

7.25 (⫾3.23)

9.60 (⫾1.81)

Mean first move time

Rule Violations Per-Item Ratio

⬍0.001*

0.072

0.406

Trail Making Test Visual scanning

6.06 (⫾4.15)

3.50 (⫾3.28)

0.001*

⫺0.390

Number sequencing

5.13 (⫾4.03)

4.00 (⫾3.35)

0.155

⫺0.234

Letter sequencing

4.63 (⫾4.34)

4.37 (⫾3.88)

0.765

⫺0.127

Number-letter switching

5.86 (⫾4.73)

4.97 (⫾4.34)

0.409

⫺0.110

Motor speed

7.09 (⫾3.86)

6.05 (⫾4.01)

0.221

⫺0.159

Initial abstraction

6.24 (⫾2.44)

9.77 (⫾3.94)

⬍0.001*

0.372

Total questions asked

4.71 (⫾4.25)

8.57 (⫾4.06)

⬍0.001*

0.348

Total weighted achievement

4.87 (⫾3.99)

10.11 (⫾8.44)

⬍0.001*

0.414

Twenty Questions Test

Verbal Fluency Test ⫺0.007

Letter fluency

4.08 (⫾3.81)

4.92 (⫾3.39)

0.253

Category fluency

3.46 (⫾3.31)

5.71 (⫾3.23)

0.001*

0.190

Total correct responses

3.90 (⫾3.81)

5.90 (⫾3.89)

0.012*

0.115

Total switching accuracy

4.24 (⫾3.83)

6.39 (⫾6.75)

0.006*

0.139

Total

3.96 (2.96)

5.38 (3.67)

0.039*

Attention

7.66 (3.83)

8.16 (3.97)

0.522

Initiation/perseveration

4.10 (3.17)

4.75 (2.94)

0.295

MDRS2 (t scores)

Construction

7.34 (3.00)

4.23 (3.30)

⬍0.001*

Conceptualization

5.82 (3.15)

8.69 (2.71)

⬍0.001*

Memory

5.52 (3.82)

7.51 (4.07)

0.014*

78.75 (20.19)

88.53 (16.49)

0.014*

WMS-III (index scores) Auditory immediate Visual immediate

74.11 (16.02)

86.65 (15.11)

⬍0.001*

Immediate memory

72.88 (19.12)

85.50 (17.35)

0.002*

Auditory delayed

81.18 (20.35)

89.60 (16.62)

0.034*

Visual delayed

72.93 (15.52)

88.56 (17.62)

⬍0.001*

Auditory recognition delayed

77.50 (19.87)

93.62 (19.38)

⬍0.001*

General memory

73.93 (19.17)

88.41 (18.09)

⬍0.001*

Working memory

79.58 (18.77)

83.35 (18.12)

0.339

Means with standard deviations are reported with results from two-tailed t tests between the patient groups (not corrected for multiple comparisons). All D-KEFS scores are scaled. Ten is the mean for healthy subjects on the D-KEFS tests and the MDRS index scores with a standard deviation of 3. One hundred is the mean for healthy subjects on the WMS-III index scores with a standard deviation of 15. *p ⬍ 0.05. FTD ⫽ frontotemporal dementia; CBS ⫽ corticobasal syndrome; D-KEFS ⫽ Delis-Kaplan Executive Function System; MDRS2 ⫽ Mattis Dementia Rating Scale 2; WMS-III ⫽ Wechsler Memory Scale–third edition. 456

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Figure

Brain areas associated with executive dysfunction in frontotemporal dementia and corticobasal syndrome

an absolute value greater than 0.70 on the rotated component matrix (table e-1).27 Each of the five components found in the principal components analysis corresponded to only one of the five D-KEFS tests. Thus, each of the components was named by the D-KEFS test with which it corresponded (i.e., Sorting, Tower, Trail Making, Twenty Questions, and Verbal Fluency). Discriminant analysis. A good eigenvalue of 1.64 was

obtained. A discriminant function was calculated. The value of this function was significantly different between the patients with FTD and patients with CBS (␹2 ⫽ 47.5, df ⫽ 20, p ⬍ 0.001). Five variables had a p value less than, or equal to, 0.001 to distinguish the groups: all three Twenty Questions test measures (Initial Abstraction Score, Total Questions Asked, Total Weighted Achievement Score), the Tower Test Rule-Violations-Per-Item Ratio, and the Trail Making test Visual Scanning Score (table 2). Of these, the patients with CBS performed better than the patients with FTD on the Tower and Twenty Questions variables, but worse than the patients with FTD on the Trail Making Score. Overall, 86.9% of the patients (89.3% of patients with FTD and 84.8% of patients with CBS) were correctly distinguished using the discriminant function.

Areas of significantly lower gray matter density associated with the Delis-Kaplan Executive Function System components shown in table e-1. For the statistical thresholds of the individual analysis, see Methods. Significant areas of correlations are shown in green for the patients with frontotemporal dementia and in red for the patients with corticobasal syndrome. (A) Component 1, Verbal Fluency; (B) Component 2, Trail Making; (C) Component 3, Sorting; (D) Component 4, Twenty Questions.

component explained a considerable portion of the total variance. Together, they accounted for 72.8% of the total variance. A loading of a D-KEFS subtest with a component was considered significant if it had

VBM analysis. Deficits in Verbal Fluency (component 1) are associated with decreased gray matter volume in the left frontal operculum (BA 47) (table e-1; figure, A) in FTD and in the dorsal frontal and parietal and temporal-parietal cortex, and the thalamus, in CBS (table e-1; figure, A). A similar pattern was observed with Trail Making (component 2) in CBS (table e-1; figure, B). Deficits in Sorting (component 3) are associated with decreased volume in the left frontal operculum extending to dorsolateral prefrontal cortex (BA 6, 47) and thalamus in FTD and, in patients with CBS, with decreased volume in the left mesial frontal lobe (table e-1; figure, C). The analysis of component 4 (Twenty Questions) did not yield significant areas of association. However, if one limits the analysis to a left frontal lobe ROI, one area of decreased gray matter volume is found in the patients with FTD to have a significant association with the component: the left anterior middle frontal gyrus (BA 47) (table e-1; figure, D). Using a left frontal lobe ROI for component 4 for the patients with CBS does not yield significant results, nor does using right frontal lobe or left parietal ROIs for component 4 for patients with FTD or CBS.

Our hypothesis that patients with FTD would show relatively greater executive dys-

DISCUSSION

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function than patients with CBS was mostly supported (table 2); patients with FTD performed significantly worse than patients with CBS on the majority of the Sorting, Twenty Questions, and Verbal Fluency measures (table 2). The patients with CBS performed significantly worse than the patients with FTD on one of the Trail Making measures, and on the two timed measures of the Tower Test (table 2). The relatively poor performance of the patients with CBS on Trail Making and the timed measures of the Tower Test could be due, in part, to the motor and visuospatial demands of these tests. A similar pattern was observed on the MDRS2: patients with CBS performed significantly better than the patients with FTD overall, but significantly worse than the patients with FTD on the Construction subtest, which requires motor and visuospatial abilities to draw shapes (table 2). This finding corroborates previous studies which found that tau⫹ patients with frontotemporal lobar degeneration (including patients with CBD) had greater visuospatial deficits than tau– patients with frontotemporal lobar degeneration (a group that did not include patients with CBD),8,9 and likely reflects the greater involvement of brain areas involved in motor and visuospatial function in CBS than in FTD. Executive function appears to be selectively impaired in both disorders. When the D-KEFS scores are converted to the same scale (normed at 100 points, SD of 15 points) as the WMS-III,24 a memory test, the mean D-KEFS score of the patients with bv-FTD (60.8) and CBS (69.0) is approximately one SD lower than the mean WMS-III score for the patients with FTD (76.4) and CBS (88.0). This finding in patients with CBS replicates a study7 that reported that patients with CBD have relatively preserved memory function. The patients with bv-FTD performed significantly worse than the patients with CBS on the majority of the WMS-III memory measures even though preservation of memory is a diagnostic criterion of FTD.20 This could reflect the negative effects of behavioral symptoms and executive dysfunction (i.e., deficits in motivation, attention, and strategic search) on memory testing, or that the disease has progressed in the patients with bvFTD to involve the medial temporal lobes. On the principal components analysis, the D-KEFS variables cluster well by test, indicating that the separate tests of the D-KEFS correspond to separable executive functions. The VBM results affirm the hypothesized importance of the left frontal lobe in executive function. In the patients with CBS posterior and right-sided areas were also associated with executive function. This could be because these areas selectively contribute to 458

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executive function in CBS, or, more likely, because the patients with CBS’s motor and visuospatial deficits interfere with the assessment of executive function (especially on the Trail Making test, which has significant motor and visuospatial components).8,9 The patients with FTD show regionally specific associations: Verbal Fluency (with a significant language component) was associated with left frontal perisylvian cortex, Sorting with dorsolateral prefrontal cortex, and Twenty Questions, a reasoning task, with left anterior frontal cortex. These findings fit well with a large previous literature on the neuroanatomic localization of these specific executive functions.13,19 A limitation of this study is that we were unable to completely rule out the effects of general cognitive dysfunction and disease severity. However, since the D-KEFS was designed (and validated) to isolate executive functions,19,22 and imaging differences between the components were observed within the same patient group, we are confident that our results are valid. On the discriminant analysis, the greatest discrepancy between the patients with FTD and CBS is on tests that require higher-order executive functions such as reasoning, planning, and abstraction (the Twenty Questions and Tower Tests), on which the patients with FTD perform worse than the patients with CBS.14 This finding corresponds well to the brain areas affected in FTD and CBS. FTD is more likely than CBS to affect the anterior frontal lobes,1,2 which are thought to be preferentially involved in higher-order executive functions.33 While the anterior PFC appears to have a key role in mediating executive function, it is also important for other kinds of processes not evaluated in this study, including social cognition. ACKNOWLEDGMENT The authors thank Alyson Cavanagh and Karen Detucci for patient testing, the Clinical Center nurses for patient care, and Bernadino Ghetti and Salvatore Spina for neuropathologic examinations.

Received May 20, 2008. Accepted in final form October 23, 2008. REFERENCES 1. Neary D, Snowden J, Mann D. Frontotemporal dementia. Lancet Neurol 2005;4:771–780. 2. Boeve BF. Corticobasal degeneration: the syndrome and the disease. In: Litvan I, ed. Atypical Parkinsonian Disorders: Clinical and research aspects. Totowa, NJ: Humana Press Inc.; 2005:309–334. 3. Litvan I, Bhatia KP, Burn DJ, et al. Mov Disord Society Scientific Issues Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Disord 2003;18:467–486. 4. Cairns NJ, Bigio EH, Mackenzie IR, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Fron-

totemporal Lobar Degeneration. Acta Neuropathol (Berl) 2007;114:5–22. 5. Dickson DW, Bergeron C, Chin SS, et al. Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 2002;61:935–946. 6. Elderkin-Thompson V, Boone KB, Hwang S, Kumar A. Neurocognitive profiles in elderly patients with frontotemporal degeneration or major depressive disorder. J Int Neuropsychol Soc 2004;10:753–771. 7. Murray R, Neumann M, Forman MS, et al. Cognitive and motor assessment in autopsy-proven corticobasal degeneration. Neurology 2007;68:1274–1283. 8. Grossman M, Libon DJ, Forman MS, et al. Distinct antemortem profiles in patients with pathologically defined frontotemporal dementia. Arch Neurol 2007;64:1601– 1609. 9. Grossman M, Xie SX, Libon DJ, et al. Longitudinal decline in autopsy-defined frontotemporal lobar degeneration. Neurology 2008;70:2036–2045. 10. Stuss DT, Alexander MP. Is there a dysexecutive syndrome? Philos Trans R Soc Lond B Biol Sci 2007;362: 901–915. 11. Bozeat S, Gregory CA, Ralph MA, Hodges JR. Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer’s disease? J Neurol Neurosurg Psychiatry 2000; 69:178–186. 12. Goethals I, Audenaert K, Van de Wiele C, Dierckx R. The prefrontal cortex: insights from functional neuroimaging using cognitive activation tasks. Eur J Nucl Med Mol Imaging 2004;31:408–416. 13. Stuss DT, Alexander MP, Floden D, et al. Fractionation and localization of distinct frontal lobe processes: evidence from focal lesions in humans. In: Stuss DT, Knight RT, eds. Principals of Frontal Lobe Function. New York, NY: Oxford University Press; 2002:392–407. 14. Carey CL, Woods SP, Damon J, et al. Discriminant validity and neuroanatomical correlates of rule monitoring in frontotemporal dementia and Alzheimer’s disease. Neuropsychologia 2008;46:1081–1087. 15. Fine EM, Delis DC, Dean D, et al. Left frontal lobe contributions to concept formation: a quantitative MRI study of performance on the Delis-Kaplan Executive Function System Sorting Test. J Clin Exp Neuropsychol Epub ahead of print 2008 Nov 24. 16. Baldo JV, Delis DC, Wilkins DP, Shimamura AP. Is it bigger than a breadbox? Performance of patients with prefrontal lesions on a new executive function test. Arch Clin Neuropsychol 2004;19:407–419. 17. Baldo JV, Schwartz S, Wilkins D, Dronkers NF. Role of frontal versus temporal cortex in verbal fluency as revealed

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by voxel-based lesion symptom mapping. J Int Neuropsychol Soc 2006;12:896–900. Hornberger M, Piguet O, Kipps C, et al. Executive function in progressive and nonprogressive behavioral variant frontotemporal dementia. Neurology 2008; 71:1481–1488. Delis DC, Kaplan E, Kramer JH. The Delis-Kaplan Executive Function System: Examiner’s Manual. San Antonio: The Psychological Corporation; 2001. Clinical and neuropathological criteria for frontotemporal dementia: The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry 1994;57:416–418. Homack S, Lee D, Riccio CA. Test review: Delis-Kaplan executive function system. J Clin Exp Neuropsychol 2005; 27:599–609. Delis DC, Kramer JH, Kaplan E, Holdnack J. Reliability and validity of the Delis-Kaplan Executive Function System: an update. J Int Neuropsychol Soc 2004;10:301– 303. Mattis S. Mental Status examination for organic mental syndrome in the elderly patient. In: Bellack L, Karusu TB, eds. Geriatric Psychiatry. New York: Grune & Stratton; 1976:77–121. Wechsler D. Wechsler Memory Scale Revised. San Antonio: Harcourt Brace Jovanovich, Inc.; 1987. Hutchenson G, Sofroniou N. The Multivariate Social Scientist: Introductory Statistics Using Generalized Linear Models. Thousand Oaks, CA: Sage Publications; 1999. Kline P. An Easy Guide to Factor Analysis. London: Routledge; 1994. Bryant FB, Yarnold PR. Reading and Understanding Multivariate Analysis. Washington, DC: American Psychological Association Books; 1995. Ridgway GR, Henley SM, Rohrer JD, Scahill RI, Warren JD, Fox NC. Ten simple rules for reporting voxel-based morphometry studies. Neuroimage 2008;40:1429–1435. Ashburner J, Friston KJ. Unified segmentation. Neuroimage 2005;26:839–851. Ashburner J, Friston KJ. Why voxel-based morphometry should be used. Neuroimage 2001;14:1238–1243. Genovese CR, Lazar NA, Nichols T. Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage 2002;15:870–878. Friston KJ, Ashburner JT, Stefan JK, Nichols TE, Penny WD. Statistical Parametric Mapping: The Analysis of Functional Brain Images, first edition. London: Academic Press; 2007. Koechlin E, Summerfield C. An information theoretical approach to prefrontal executive function. Trends Cogn Sci 2007;11:229–235.

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Educational attainment and cognitive decline in old age

R.S. Wilson, PhD L.E. Hebert, ScD P.A. Scherr, ScD, PhD L.L. Barnes, PhD C.F. Mendes de Leon, PhD D.A. Evans, MD

Address correspondence and reprint requests to Dr. Robert S. Wilson, Rush Alzheimer’s Disease Center, Rush University Medical Center, 600 South Paulina Avenue, Suite 1038, Chicago, IL 60612 [email protected]

ABSTRACT

Background: Level of education is a well-established risk factor for Alzheimer disease but its relation to cognitive decline, the principal clinical manifestation of the disease, is uncertain.

Methods: More than 6,000 older residents of a community on the south side of Chicago were interviewed at approximately 3-year intervals for up to 14 years. The interview included administration of four brief tests of cognitive function from which a previously established composite measure of global cognition was derived. We estimated the associations of education with baseline level of cognition and rate of cognitive change in a series of mixed-effects models.

Results: In an initial analysis, higher level of education was related to higher level of cognition at baseline, but there was no linear association between education and rate of change in cognitive function. In a subsequent analysis with terms to allow for nonlinearity in education and its relation to cognitive decline, rate of cognitive decline at average or high levels of education was slightly increased during earlier years of follow-up but slightly decreased in later years in comparison to low levels of education. Findings were similar among black and white participants. Cognitive performance improved with repeated test administration, but there was no evidence that retest effects were related to education or attenuated education’s association with cognitive change.

Conclusions: The results suggest that education is robustly associated with level of cognitive function but not with rate of cognitive decline and that the former association primarily accounts for education’s correlation with risk of dementia in old age. Neurology® 2009;72:460–465 GLOSSARY AD ⫽ Alzheimer disease.

Risk of dementia and Alzheimer disease (AD) in old age is reduced in persons with higher levels of educational attainment compared to those with lower levels.1-4 This finding is due in part to the well-established correlation of education with cognitive test performance at all ages. Thus, persons with more schooling, relative to those with less, are likely to begin old age at a higher level of cognitive function and so would need to experience more cognitive decline before reaching a level of impairment meeting dementia criteria. Another way in which education might influence risk of dementia is by a correlation with late life cognitive decline, the primary clinical manifestation of AD. Consistent with this idea, several studies have reported an association of higher educational attainment with reduced cognitive decline.5-23 However, this research is mostly based on change between two measurement points. Although this approach can provide an estimate of rate of change in cognitive function, it has a fundamental limitation: even with statistical adjustments, change in function between two time points is hard to

From Rush Alzheimer’s Disease Center (R.S.W., L.L.B.), Rush Institute for Healthy Aging (L.E.H., C.F.M.d.L., D.A.E.), and Departments of Neurological Sciences (R.S.W., L.L.B., D.A.E.), Behavioral Sciences (R.S.W., L.L.B.), and Internal Medicine (L.E.H., C.F.M.d.L., D.A.E.), Rush University Medical Center, Chicago, IL; and National Center for Chronic Disease Prevention and Health Promotion (P.A.S.), Centers for Disease Control and Prevention, Atlanta, GA. Supported by National Institute on Aging grants AG 11101 and AG10161 and by National Institute of Environmental Health Sciences grant ES 10902. Disclosure: The authors report no disclosures. Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. 460

Copyright © 2009 by AAN Enterprises, Inc.

securely distinguish from level of function at either point.24 This limitation is especially telling when the predictor of interest is highly correlated with the outcome as in the present case. Importantly, therefore, such studies are not well positioned to separate the estimate of education’s correlation with cognitive decline from its strong correlation with level of cognition. Assessment of cognition at three or more points in time permits separation of initial level of cognition from rate of change, but fewer of these studies have been published and their findings on the relation of higher educational attainment to cognitive decline have been mixed.12,17,19,21,25-28 Other factors may be contributing to this inconsistency. For example, education has been quantified in different ways (e.g., categorically vs continuously, linearly vs nonlinearly) and its association with cognitive decline may be modified by other variables (e.g., preexisting cognitive impairment, practice effects, race/ethnicity). In the present study, we test the hypothesis that higher level of education is associated with reduced rate of cognitive decline in old age using data from the Chicago Health and Aging Project, a longitudinal populationbased study of aging and AD. Participants are more than 6,000 older African American and white residents of a community on the south side of Chicago. At approximately 3-year intervals for up to 14 years, they completed four brief tests of cognitive performance from which a previously established composite measure of global cognition was derived. We used mixed-effects models to characterize person-specific paths of cognitive change and to test the relation of education to initial level of cognition and annual rate of change. In subsequent analyses, we examined other socioeconomic indicators and tested whether the association of education with change in cognitive function was modified by race, cognitive impairment, or repeated exposure to the cognitive tests. METHODS Participants. To date, 10,186 older community residents have participated in the baseline interview; 118 (1%) were missing data on education or cognitive function. Of the remaining 10,068 people, 1,552 died before the first follow-up interview and 1,580 had not yet reached the date

scheduled for the first follow-up. Among the 6,936 eligible for follow-up, 6,533 (94%) completed at least one follow-up interview. Analyses are based on this group. They completed a mean of 3.0 (SD ⫽ 1.1) interviews during a mean of 6.5 (SD ⫽ 3.6) years of observation. They had a mean age at baseline of 72.2 years (SD ⫽ 6.1) and a mean of 12.2 years of formal education (SD ⫽ 3.6); 61% were women and 67% were African American.

Assessment of cognitive function. Four brief tests of cognitive function were administered as part of the in home interview. Immediate and delayed recall of 12 ideas contained in the East Boston Story were used to assess episodic memory. A modified version of the oral form of the Symbol Digit Modalities Test was used to assess perceptual speed. Global cognition was assessed with the Mini-Mental State Examination, a widely used mental status test. In a principal-components factor analysis of baseline data, these four measures loaded on a single factor that accounted for approximately 74% of the variance in the individual tests.29 Therefore, we formed a composite measure of global cognition by converting raw scores on each test to z scores, using the baseline mean and SD in the population, and then averaging the z scores to get the composite score, as described in previous publications.29-31

Assessment of other covariates. Educational attainment was expressed as years of formal schooling completed, as reported by the participant. Race was assessed with the US Census questions. Income was assessed by asking participants to choose one of 10 levels of total family income from a “show card.” Lifetime occupation was quantified using the perceived occupational prestige scale of Featherman and Hauser.32 Data on five chronic medical conditions was obtained from self report of heart attack or myocardial infarction, hypertension, stroke, diabetes mellitus, and cancer.

Data analysis. The statistical analyses were performed by Kenneth Tonnissen under the supervision of Dr. Hebert. We used mixed-effects models to characterize individual paths of change in cognitive function and to test the association of education with baseline level of cognition and rate of change. The initial model had terms for time (in years since baseline) and time squared to allow for nonlinear change. We then added terms for education, education ⫻ time, and education ⫻ time squared. This and all subsequent models also included terms for age, sex, race, and their interactions with time. We conducted identical analyses substituting first income and then occupation for education. Next, we repeated the analysis adding terms for education squared, education squared ⫻ time, and education squared ⫻ time squared. We repeated this latter model with terms added for chronic conditions and their interactions with time; with terms added for the interactions among race, education, and time; and with persons with low baseline levels of cognition excluded. To evaluate retest effects, we added indicators for the first, second, third, and fourth retestings (i.e., first, second, third, and fourth follow-ups), as previously described,33,34 and terms for the interaction of education with each indicator to see if retest effects varied by education. We also repeated analyses after excluding the first observation. Models were graphically and analytically validated.

Years of education had a mean of 12.2 (SD ⫽ 3.6) and an approximately normal distribution (skewness ⫽ 0.0; range: 0 to 30). Higher education was associated with younger age (r ⫽ ⫺0.16,

RESULTS

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Figure 1

Predicted individual paths of change in global cognition estimated for a 3% random sample of the population

p ⬍ 0.001) and white race (t[6,532] ⫽ 28.9, p ⬍ 0.001) but not with sex (t[6,536] ⫽ 0.7, p ⫽ 0.493). Change in cognitive function. At baseline, the com-

posite measure of global cognition ranged from ⫺3.50 to 1.66 (mean ⫽ 0.24, SD ⫽ 0.74), with higher scores indicating better cognitive functioning. To assess change in cognitive function during the study period, we constructed a mixed-effects model with terms for time (in years since baseline) and time squared to allow for nonlinear change in cognition. The effects of time (estimate ⫽ ⫺0.036, SE ⫽ 0.009, p ⬍ 0.001) and time squared (estimate ⫽ ⫺0.001, SE ⬍ 0.001, p ⬍ 0.001) indicate that on average cognition declined at a gradually accelerating rate. To examine individual differences, we plotted the estimated paths for a 3% random sample of the population (figure 1). Substantial heterogeneity is evident with some persons rapidly declining and others showing little decline or slightly improving. Education and change in cognitive function. To test

whether education was associated with these individual differences in cognitive decline, we constructed a new model with terms added for education and its interaction with time (table 1, model A). This and all subsequent analyses also included terms to control for the potentially confounding effects of age, sex, Table 1

and race on initial level of cognition and rate of cognitive change. Higher level of education was associated with higher level of cognition at baseline, as shown by the term for education in table 1. There was no interaction between education and time, however, indicating that people with different levels of education did not differ in rate of cognitive decline. Substituting other socioeconomic indicators, income and lifetime occupation, yielded similar results: they were related to higher level of cognition at baseline but were unrelated to cognitive decline (data not shown). The association of education with cognition is probably not linear. Therefore, we repeated the analysis with four additional terms: the interaction of education with time squared, which allows the association of education with change in cognitive function to shift with time, plus a quadratic term for education and terms for its interactions with time and time squared (table 1, model B). It was only after the addition of these terms that education had any association with cognitive change. To better understand the complex interactions between time and education that emerged in this model, we plotted the predicted 12-year cognitive trajectories at three different levels of education (figure 2). Substantial differences are apparent in level of cognitive performance. Rates of cognitive change are broadly similar, but those with low education (8 years, 10th percentile) appear to be declining slightly less than persons with average (12 years, 50th percentile) or high (16 years, 90th percentile) levels of education but only in the early years of follow-up. By contrast, in the later years of follow-up there is a slight benefit of higher education though it is too small to be apparent in the figure. To see if differences in health affected findings, we repeated the analysis with indicators for the presence of five chronic conditions during the study period (heart disease, hypertension,

Relation of education to change in cognitive function*

Model term

Model A estimate (SE); p

Model B estimate (SE); p

Time

⫺0.049 (0.004); ⬍0.001

⫺0.053 (0.004); 0.001

⫺0.051 (0.004); ⬍0.001

2

⫺0.001 (⬍0.001); ⬍0.001

⫺0.001 (⬍0.001); ⬍0.001

⫺0.001 (⬍0.001); 0.001

Education

0.072 (0.002); ⬍0.001

0.075 (0.002); ⬍0.001

Time

Education ⴛ time

⫺0.001 (⬍0.001); 0.205

Education ⴛ time2 Education

2

Education2 ⴛ time 2

2

Education ⴛ time

Model C estimate (SE); p

0.073 (0.002); ⬍0.001

⫺0.002 (0.001); 0.027

⫺0.002 (0.001); 0.020

⬍0.001 (⬍0.001); 0.097

⬍0.001 (⬍0.001); 0.120

⫺0.004 (⬍0.001); ⬍0.001

⫺0.004 (⬍0.001); ⬍0.001

⬍0.001 (⬍0.001); 0.001

⬍0.001 (⬍0.001); 0.001

⬎⫺0.001 (⬍0.001); 0.005

⬎⫺0.001 (⬍0.001); 0.005

*From mixed-effects models. In addition to the terms shown in the table, each model included terms to control for the effects of age, sex, and race, and model C also adjusted for chronic medical conditions. 462

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Figure 2

Predicted 12-year paths of change in global cognition in persons with 8 (solid line), 12 (dotted line), or 16 (dashed line) years of education, adjusted for age, sex, and race

Table 2

Retest effects and their relation to education*

Model term

Estimate

Standard error

p

Retest 1

0.012

0.059

0.837

Retest 2

0.175

0.089

0.050

Retest 3

0.303

0.106

0.004

0.567

0.134

⬍0.001

Education ⴛ retest 1

⫺0.004

0.017

0.793

Education ⴛ retest 2

⫺0.002

0.025

0.940

Education ⴛ retest 3

0.002

0.030

0.959

Education ⴛ retest 4

⬍⫺0.001

0.039

0.990

Retest 4

*From a mixed-effects model adjusted for age, sex, race, and education.

stroke, diabetes, cancer), and results were unchanged (table 1, model C). Because little is known about the relation of education to cognitive decline in African Americans, we repeated the analysis (model B) with terms to allow for interactions among race, education, and time. The overall goodness of fit for this model was reduced compared to the original analysis, suggesting that the association of education with change in cognitive function did not vary by race. Impact of cognitive impairment. Among people with

dementia, higher level of education has been associated with more rapid cognitive decline,35,36 suggesting that the presence of individuals with dementia or cognitive impairment in the population might obscure an association of higher education with slower decline in the remainder. To test this possibility, we repeated the analysis (model B) excluding those whose cognitive score at baseline was at or below the 10th percentile, and then conducted similar analyses using the 20th and then 30th percentiles as cutpoints. With these exclusions, which tended to remove people with low education and short followup, higher education was associated with slightly less rapid cognitive decline early in follow-up but with slightly more rapid decline later in follow-up. Impact of retesting. Repeated administration of cognitive tests can improve performance. If such retest effects were related to education, they might obscure an association with change in cognitive function. We investigated this possibility in two ways. First, to evaluate retest effects across the range of follow-up, we added indicators for the first, second, third, and fourth retestings and their interactions with education (table 2). The terms for the second, third, and fourth indicators were positive and significant, meaning that cognitive test performance improved with repeated test administration. These retest effects were not associated with education, however, as

shown by the interaction terms in table 2. Second, to test whether education had a disproportionate impact on the initial testing experience, we repeated the primary model with the baseline observation removed. In this analysis, education’s association with change in cognitive function was eliminated. DISCUSSION In more than 6,000 community dwelling old persons, we examined the relation of education to rate of change in cognitive function during up to 14 years of observation. Level of educational attainment was robustly related to level of cognitive function at study onset. By contrast, we found little evidence that education is associated with cognitive decline. When associations were observed, they were invariably small, with the presence and direction of effects conditional on other variables. In the context of previous work, the findings suggest that education affects risk of late life dementia primarily by virtue of its association with level of cognition and not by an association with rate of cognitive decline. A simple tally of prior research tends to support an association between higher educational attainment and reduced cognitive decline, with nearly half of published studies reporting the association,5-11,13-15,22,23 and about one quarter finding mixed evidence of it.12,16-21 In the negative studies,25-28,37,38 however, change was more likely to be based on three or more cognitive assessments rather than only two (4/8 vs 2/19, p ⫽ 0.059, Fisher exact test) and on 6 or more years of observation rather than less than 6 (5/11 vs 0/14, p ⫽ 0.003, Fisher exact test). Further, in each of three projects that published two articles on education and cognitive decline, education was related to cognitive decline in the earlier publication,15,21,22 but not in the later publication despite additional data collection.25,26,28 In research with three or more assessments of cognition, evidence linking higher level Neurology 72

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of education with reduced cognitive decline has been limited, with four studies reporting no association25-28 and four finding it to be conditional on some other variable (e.g., sex,12 cognitive outcome12,17,19). In short, the studies best equipped to assess change in cognitive function, by virtue of measuring it more often during a longer period of time, were the least likely to find an association with education. This is the opposite of the pattern that one would expect if education were truly related to change in cognitive function. Instead, we propose that education has little or no association with change in cognition and that evidence to the contrary mainly reflects difficulty disentangling level of cognition, which is robustly related to education, from change. Little is known about education and cognitive decline in black persons.39 In this biracial population, the association of education with cognitive decline was comparable in black and white participants. Repeated administration of cognitive tests leads to improved performance,33,34 and such retest effects might influence the association of education with cognitive change.27 One prior study did find that lower education was associated with greater improvement from the first to second testing and that after controlling for this apparent retest effect, higher education predicted less cognitive decline during the remainder of the study.21 However, cognitive retest effects are known to persist beyond a single retesting34 and education was not related to retest effects across the range of follow-up in this population, consistent with previous research.34 There was a differential effect of the first observation, but deleting it eliminated education’s association with cognitive change rather than enlarging it. Because education’s association with change in cognitive function may shift as impairment in cognition begins to emerge,40 the presence of cognitive impairment within a cohort might obscure a protective effect of education. In this population, however, excluding persons with low cognitive function at baseline did not have this effect: although higher education was associated with reduced cognitive decline in the early years of follow-up, it was associated with more rapid decline in later years. Confidence in these findings is strengthened by several factors. First, they are based on a geographically defined and racially diverse population of older persons. Second, the availability of a psychometrically sound composite measure of cognition administered at regular intervals with high follow-up participation in survivors enhanced our ability to reliably assess individual differences in rate of cognitive change and their relation to education. Finally, the 464

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long follow-up period enhanced our ability to distinguish initial level of cognition from rate of change, and the large cohort size made it possible to identify even small effects. This study also has important limitations. Because results are based on a measure of global cognition, we cannot rule out the possibility that education is related to decline in some cognitive domains but not others. In addition, the measure of educational attainment, years of schooling, assumes an equivalence of educational quality across persons and time that is unlikely to be true. Incorporating data on educational quality (e.g., spending per pupil in county) with amount of schooling might provide further insight into the association of education with age-related cognitive decline. ACKNOWLEDGMENT The authors thank the residents of Morgan Park, Washington Heights, and Beverly who participated in the study. They also thank Ann Marie Lane for community development and oversight of project coordination, Michelle Bos, Holly Hadden, Flavio LaMorticella, and Jennifer Tarpey for coordination of the study, Kenneth Tonnissen for analytic programming, and the staff of the Rush Institute for Healthy Aging.

Received June 25, 2008. Accepted in final form October 23, 2008.

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Farmer ME, Kittner SJ, Rae DS, Bartko JJ, Regier DA. Education and change in cognitive function: the Epidemiologic Catchment Area Study. Ann Epidemiol 1995;5: 1–7. Evans DA, Beckett LA, Albert MS, et al. Level of education and change in cognitive function in a community population of older persons. Ann Epidemiol 1993;3: 71–77. Colsher PL, Wallace RB. Longitudinal application of cognitive function measures in a defined population of community-dwelling elders. Ann Epidemiol 1991;1:215– 230. Liang J, Borawski-Clark E, Liu X, Sugisawa H. Transitions in cognitive status among the aged in Japan. Soc Sci Med 1996;43:325–337. White L, Katzman R, Losonczy K, et al. Association of education with incidence of cognitive impairment in three established populations for epidemiologic studies of the elderly. J Clin Epidemiol 1994;47:363–374. Christensen H, Korten AE, Jorm AF, Henderson AS, Jacomb PA, Rodgers B. Education and decline in cognitive performance: compensatory but not protective. Int J Geriatr Psychiatry 1997;12:323–330. Butler SM, Ashford JW, Snowdon DA. Age, education, and changes in the Mini-Mental State Exam scores of older women: findings from the Nun Study. J Am Geriatr Soc 1996;44:675–681. Alley D, Suthers K, Crimmins E. Education and cognitive decline in older Americans: results from the AHEAD sample. Res Aging 2007;29:73–94. Schmand B, Smit J, Lindeboom J, et al. Low education is a genuine risk factor for accelerated memory decline and dementia. J Clin Epidemiol 1997;50:1025–1033. Anstey KJ, Hofer SM, Luszcz MA. A latent growth curve analysis of late-life sensory and cognitive function over 8 years: evidence for specific and common factors underlying change. Psychol Aging 2003;18:714–726. Arbuckle TY, Maag U, Pushkar D, Chaikelson JS. Individual differences in trajectory of intellectual development over 45 years of adulthood. Psychol Aging 1998;13:663–675. Jacqmin-Gadda H, Fabrigoule C, Commenges D, Dartigues J-F. A 5-year longitudinal study of the Mini-Mental State Examination in normal aging. Am J Epidemiol 1997;145: 498–506. Albert MS, Jones K, Savage CR, et al. Predictors of cognitive changes in older persons: MacArthur studies of successful aging. Psychol Aging 2005;10:578–589. Koster A, Penninx BWJH, Bosma H, et al. Socioeconomic differences in cognitive decline and the role of biomedical factors. Ann Epidemiol 2005;15:564–571. Morris MC, Evans DA, Hebert LE, Bienias JL. Methodological issues in the study of cognitive decline. Am J Epidemiol 1999;149:789–793. Christensen H, Hofer SM, Mackinnon AJ, Korten AE, Jorm AF, Henderson AS. Age is no kinder to the better educated: absence of an association investigated using latent growth techniques in a community sample. Psychol Med 2001;31:15–28.

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Seeman TE, Huang M-H, Bretsky P, Crimmins E, Launer L, Guralnik JM. Education and APOE-␧4 in longitudinal cognitive decline: MacArthur studies of successful aging. J Gerontol Psychol Sci 2005;60B:P74–P83. Van Dijk KRA, Van Gerven PWM, Van Boxtel MPJ, Van der Elst W, Jolles J. No protective effects of education during normal cognitive aging: results from the 6-year follow-up of the Maastricht Aging Study. Psychol Aging 2008;23:119–130. Winnock M, Letenneur L, Jacqmin-Gadda H, Dallongeville J, Amouyel P, Dartigues JF. Longitudinal analysis of the effect of apolipoprotein E ⑀4 and education on cognitive performance in elderly subjects: the PAQUID study. J Neurol Neurosurg Psychiatry 2002;72:794–797. Wilson RS, Bennett DA, Beckett LA, et al. Cognitive activity in older persons from a geographically defined population. J Gerontol Psychol Sci Soc Sci 1999;54: P155–P160. Wilson RS, Mendes de Leon CF, Bennett DA, Bienias JL, Evans DA. Depressive symptoms and cognitive decline in a community population of older persons. J Neurol Neurosurg Psychiatry 2004;75:126–129. Wilson RS, Bennett DA, Mendes de Leon CF, Bienias JL, Morris MC, Evans DA. Distress proneness and cognitive decline in a population of older persons. Psychoneuroendocrinology 2005;30:11–17. Featherman DL, Hauser RM. The measurement of occupation in social surveys. In: Hauser RM, Featherman DL, eds. The Process of Stratification. Academic Press: Orlando; 1977. Wilson RS, Beckett LA, Barnes LL, et al. Individual differences in rates of change in cognitive abilities of older persons. Psychol Aging 2002;17:179–193. Wilson RS, Li Y, Bienias JL, Bennett DA. Cognitive decline in old age: separating retest effects from the effects of growing older. Psychol Aging 2006;21:774–789. Wilson RS, Li Y, Aggarwal NT, et al. Education and the course of cognitive decline in Alzheimer’s disease. Neurology 2004;63:1198–1202. Scarmeas N, Albert SM, Manly JJ, Stern Y. Education and rates of cognitive decline in incident Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2006;77:308–316. Shadlen M-F, Larson EB, Wang L, et al. Education modifies the effect of apolipoprotein epsilon 4 on cognitive decline. Neurobiol Aging 2005;26:17–24. Hultsch DF, Hertzog C, Small BJ, Dixon RA. Use it or lose it: engaged lifestyle as a buffer of cognitive decline in aging? Psychol Aging 1999;14:245–263. Callahan CM, Hall KS, Hui SL, Musick BS, Unverzagt FW, Hendrie HC. Relationship of age, education, and occupation with dementia among a community based sample of African Americans. Arch Neurol 1996;53: 134–140. Hall CB, Derby C, LeVally A, Katz MJ, Verghese J, Lipton RB. Education delays accelerated decline on a memory test in persons who develop dementia. Neurology 2007;69:1657–1664.

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Clinical/Scientific Notes

J. Wagner, MD C. Schankin, MD T. Birnbaum, MD G. Po¨pperl, MD A. Straube, MD

OCULAR MOTOR AND LID APRAXIA AS INITIAL SYMPTOM OF ANTI-Ma1/Ma2-ASSOCIATED ENCEPHALITIS

Antibodies against Ma1/Ma2 antigens are typically associated with paraneoplastic neurologic disease. Most common are the involvement of the limbic and diencephalic system and the brainstem. We report a case of anti-Ma1 and anti-Ma2-positive encephalitis with predominant frontoparietal cortical involvement. The main initial clinical symptom was an ocular motor and lid apraxia. Case report. We report on a 49-year-old man who presented with blurred vision and drooping eyelids bilaterally. The symptoms had progressed over a period of 3 months. When we first saw the patient, he also had dysphagia and apathy. The patient was previously healthy and did not take any regular medication. Two weeks before the onset of symptoms, he had been vaccinated against tick-borne encephalitis. On examination of the ocular motor system, the patient had a downward deviation of the bulbi and

Figure

an inability to elicit voluntary horizontal or vertical saccades and the optokinetic reflex. Reflexive saccades were preserved. Gaze holding, vergence, and smooth pursuit were impaired and vertical ocular motility was limited. The deficit could be overcome via the vestibulo-ocular reflex, indicating a supranuclear origin. Furthermore, the patient showed apraxia of lid opening, keeping his eyes closed most of the time although opening of the eyes was still possible. Trying to open the eyes manually caused the patient to forcefully squeeze the eyelids shut. A thorough neuropsychological examination revealed deficits of attention, memory, verbal fluency, visuoconstruction, and executive function as well as simultanagnosia. Repeated cranial MRIs including thin sectioning of the brainstem were unremarkable. In the CSF, the total cell count was slightly raised (16/3/cmm [normal ⬍15/3/cmm]) and total protein was significantly elevated (81 mg/dL [normal ⬍50 mg/dL]) with CSF-specific oligoclonal bands. Furthermore, serum and CSF anti-Ma1 and anti-Ma2 antibodies

FDG-PET revealing frontoparietal hypometabolism

Cranial FDG-PET (A) showed hypometabolism in the frontoparietal cortex (left more than right) with a focal hypermetabolic spot in the right frontal cortex. A normal FDG-PET (B) is shown for comparison. 466

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as detected by indirect immunofluorescence were positive, while anti-Yo/-Ri/-Hu/-CV2/CRMP5/amphiphysin/-purkinje cell antibodies were absent. A cranial FDG-PET (figure) showed hypometabolism in the frontoparietal cortex (left more than right). The limbic system and subcortical structures including the basal ganglia and the cerebellum were unremarkable in the PET examination. A total-body FDG-PET-CT did not reveal any neoplasia. Neither did a total-body CT scan, a gastroscopy, a colonoscopy, an abdominal sonography, or a urologic examination. The patient was treated with IV prednisone (5 ⫻ 500 mg). Due to further deterioration of his neurologic status, a 5-day course of IV immunoglobulins (0.4 g/kg per day) was administered, followed by oral prednisone and azathioprine (150 mg/ day). With this regimen, the symptoms remained stable but without sign of remission. Discussion. Ma1 and Ma2 are omnipresent intraneuronal antigens. Antibodies against Ma1/Ma2 are associated with paraneoplastic neurologic disease. In most cases of anti-Ma1 positive encephalitis testicular tumors are found, whereas in patients in whom both anti-Ma1 and anti-Ma2 antibodies are detected the underlying tumors are more diverse. The most frequent manifestations are signs of limbic (shortterm memory loss, seizures, personality changes), diencephalic (excessive daytime sleepiness, hyperthermia, endocrine dysfunction), brainstem (cranial neuropathy including ophthalmoplegia, dysarthria, dysphagia), and cerebellar involvement and opsoclonus-myoclonus.1 Our patient presented with signs of diencephalic and brainstem involvement as commonly recognized features of paraneoplastic encephalitis. The most prominent symptom, however, was ocular motor and lid apraxia. In the FDG-PET, this patient showed prominent hypometabolism in the fronto-parietal cortex compatible with residual postencephalitic defects whereas the limbic system and subcortical structures were unaltered. Ocular motor apraxia has been described before in patients with frontoparietal lesions.2-4 It has been attributed to involvement of the frontal and parietal

Richard F. Lewis, MD Aisha S. Traish, MD Simmons Lessell, MD

ATYPICAL VOLUNTARY NYSTAGMUS

Voluntary nystagmus, once considered rare, may actually occur in as much as 8% of the population.1 We recently observed a child who appeared to have voluntary nystagmus but the eye movements had distinct slow and fast phases rather than the rapid back-to-back saccades that typify voluntary nystagmus. Analysis of the eye movements revealed that the patient’s nystag-

eye fields.5 Cases with predominant involvement of the frontoparietal cortex are rare in anti-Ma1/Ma2 associated encephalitis. Histologic changes in the frontal lobe have been described in few patients.1,6 Possibly some of the patients previously described to have complete gaze paresis due to brainstem involvement might have had ocular motor apraxia as a sign of frontoparietal dysfunction. Anti-Ma1/Ma2 associated encephalitis may cause predominant involvement of the frontoparietal cortex. Ocular motor and lid apraxia can result from frontoparietal cortical dysfunction. Hence, these signs may constitute the initial presentation in Mapositive encephalitis. Acquired ocular motor and lid apraxia in adulthood therefore warrants a thorough search for antineuronal antibodies. From the Departments of Neurology (J.W., C.S., T.B., A.S.) and Nuclear Medicine (G.P.), Klinikum Grosshadern, LudwigMaximilians University, Munich, Germany. Disclosure: The authors report no disclosures. Received June 18, 2008. Accepted in final form August 29, 2008. Address correspondence and reprint requests to Dr. Judith Wagner, Department of Neurology, Ludwig-Maximilians University, Klinikum Grosshadern, Marchioninistraße 15, D-81366 Munich, Germany; [email protected] Copyright © 2009 by AAN Enterprises, Inc. 1.

2.

3.

4.

5. 6.

Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004;127:1831– 1844. Pierrot-Deseilligny C, Gautier JC, Loron P. Acquired ocular motor apraxia due to bilateral frontoparietal infarcts. Ann Neurol 1988;23:199–202. Monaco F, Pirisi A, Sechi GP, Cossu G. Acquired ocularmotor apraxia and right-sided cortical angioma. Cortex 1980;16:159–167. Genc BO, Genc E, Acik L, Ilhan S, Paksoy Y. Acquired ocular motor apraxia from bilateral frontoparietal infarcts associated with Takayasu arteritis. J Neurol Neurosurg Psychiatry 2004;75:1651–1652. Pierrot-Deseilligny C, Gaymard B, Muri R, Rivaud S. Cerebral ocular motor signs. J Neurol 1997;244:65–70. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000;123:1481–1494.

mus showed features of both voluntary nystagmus and a rare form of congenital nystagmus in which the patient can suppress the adventitious movements at will. Case report. A 27-month-old girl was referred because of nystagmus. Her family was free of neurologic and nonrefractive eye disorders. Apart from surgery for tear duct obstruction, she had been healthy. At age 9 months, her mother observed intermittent bursts of Neurology 72

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Figure

Horizontal eye position (A) and velocity (B) plotted vs time

The nystagmus has a frequency of about 4.0 Hz and has clearly delineated slow and quick phases. The waveform of the slow phases suggests a velocity-increasing morphology, particularly early in the run of the nystagmus, although the slow phases become more linear as they decelerate. No foveation periods are evident. Right is positive and left is negative. The quick phases were clipped on the velocity plot for clarity. There was no significant vertical component to the nystagmus (data not shown).

Supplemental data at www.neuurology.org

468

horizontal eye movements lasting seconds. It later became evident that she could produce these movements whenever requested. Except for 2 months during which no nystagmus was observed, episodes continued several times a day. Her general neurologic examination was unremarkable. Uncorrected visual acuities were 20/30 in each eye and her visual fields were full to confrontation testing. The anterior segments, pupils, eyelids, and fundi were normal. She had full ductions and versions and was orthophoric. Fixation, saccades, vergence, gaze holding, pursuit, and optokinetic responses were normal. No spontaneous nystagmus was observed in the light or dark and no nystagmus was produced by covering one eye, horizontal head-shaking, or changing head orientation. When she was asked to perform her “eye trick,” she diverged her eyes slightly and produced a burst of right-beating horizontal nystagmus (video on the Neurology ® Web site at www. neurology.org). She could produce nystagmus looking straight ahead or eccentrically and the rate and direction of the nystagmus did not depend on orbital eye position. No null position was evident and there were no other adventitious movements. When her eye movements were observed in the dark with an infrared camera, there was no spontaneous nystagmus in any direction of gaze. Even in the dark, however, the patient could produce horizontal nystagmus upon request. Neurology 72

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An EEG and brain MRI were normal. Her nystagmus was recorded with standard DC electrooculography (figure) with the eyes opened in complete darkness. The recordings demonstrate the transient divergence of the eyes which appears necessary to initiate the nystagmus (at about 2 seconds on the trace), followed by a conjugate jerk nystagmus with leftward slow phases. Examination of the position and velocity traces demonstrates that the initial slow phases were velocityincreasing, but shifted toward a linear (constantvelocity) waveform after the first several beats of nystagmus. Discussion. The eye movements observed and recorded in this patient are of uncertain origin. This could be a form of voluntary nystagmus, but the eye movements in this syndrome consist of back-to-back saccades and have never been described to have slow and quick phases like those observed in this subject. The initiation of the nystagmus with a change of vergence angle, however, has been described as a feature of voluntary nystagmus.2 The velocity-increasing morphology evident in the initial slow phases suggests that the patient may have congenital nystagmus with voluntary control3 although similar slow phases have been described in acquired nystagmus4 and hence are not pathognomonic for congenital nystagmus. Unlike other patients described with this rare syndrome, she had no spontaneous nystagmus in the dark, no latent nystagmus induced by monocular vision, and her nystagmus was not modulated by changes in orbital eye position. The exact mechanism underlying her nystagmus is therefore uncertain. The divergence that initiates the nystagmus and the velocity-increasing slow phases suggest that she may have instability in the velocity-to-position neural integrator in the brainstem and cerebellum,5 and that this may be under a form of voluntary control that is associated with ocular alignment. The abnormal eye movements in this patient share some features of voluntary nystagmus and some features of voluntary suppression of congenital nystagmus. She is the first patient to be described with this combination of findings. From the Department of Otology and Laryngology (R.F.L.) and Department of Ophthalmology (A.S.T., S.L.), Harvard Medical School and the Massachusetts Eye and Ear Infirmary, Boston. Disclosure: The authors report no disclosures. Received May 10, 2008. Accepted in final form September 10, 2008. Address correspondence and reprint requests to Dr. Richard Lewis, Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114; [email protected] Copyright © 2009 by AAN Enterprises, Inc. 1.

Miller NR, Newman NJ, ed. Walsh and Hoyt’s Neuroophthalmology. 5th ed. Baltimore: Williams & Wilkins; 1998: 1490, 1777, 1779.

2.

3.

M. Liguori, MD, PhD* R. Mazzei, PhD* C. Ungaro, PhD I.L. Simone, MD A. Gambardella, MD I. Plasmati, MD F. Fera, MD U. Aguglia, MD P. Lanza, MD F. Bono, MD L. Chiumarulo, MD F.L. Conforti, PhD D. Consoli, MD A. Quattrone, MD

Hotson JR. Convergence-initiated voluntary flutter: a normal intrinsic capability in man. Brain Res 1984;294:299– 304. Tusa RJ, Zee DS, Hain TC, Simonsz HJ. Voluntary control of congenital nystagmus. Clin Vis Sci 1992;7:195–210.

CONVENTIONAL MRI AND NOTCH3 GENE SCREENING IN SPORADIC CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a small vessels disease caused by mutations in the NOTCH3 gene,1 is considered the most frequent cause of genetically determined stroke. The age at onset ranges between the fourth and the third decade, and the cardinal symptoms comprise stroke, migraine headaches with or without aura, and cognitive decline, with additional features including psychiatric disturbances and epileptic seizures.2 Imaging studies summarized the CADASIL pattern as a combination of T2-hyperintensities in the periventricular white matter, anterior temporal pole, external capsule, basal ganglia, and brainstem.Hemosiderin deposits (microbleeds) have been described, primarily in the thalamic regions.3,4 The extent of radiologic CADASIL abnormalities, however, greatly differs among subjects and increases with age4 or other factors, sometimes impeding identification of CADASIL in a subject. In patients with CADASIL, causative mutations have been reported spanning the NOTCH3 gene; since it is a quite expensive and time-consuming analysis,5 a common strategy is to perform a complete gene screening only on patients with a positive familial history of CADASIL. We investigated whether sporadic patients with brain MRI suggestive of CADASIL may carry mutations in the entire NOTCH3 gene, even in the absence of a positive familial history. Methods. We reviewed brain MRIs of patients suspected of having cerebrovascular disease referred to the Institute of Neurological Sciences (Mangone) and the Department of Neuroradiology (Bari). Eligible images presented confluent periventricular T2-hyperintensity in addition to 1) an increased T2-signal from the external capsule or 2) the anterior temporal lobe, or 3) thalamic microbleeds, all of these signs considered highly suggestive of CADASIL.3,4 Patients with at least two of these MRI features underwent the mutational screening of the entire NOTCH3 gene. These patients were asked to partic-

4. 5.

Zee DS, Leigh RJ, Mathieu-Millaire F. Cerebellar control of ocular gaze stability. Ann Neurol 1980;7:37–40. Arnold DB, Robinson DA, Leigh RJ. Nystagmus induced by pharmacological inactivation of the brainstem ocular motor integrator in monkey. Vision Res 1999;39:4286–4295.

ipate in the prospective study for peripheral blood collection, and detailed pedigrees spanning at least three generations were obtained. All patients gave written informed consent under the institutional review board–approved protocol. Genomic DNA was extracted by standard procedures. The NOTCH3 gene mutation analysis consisted of PCRs followed by denaturing highperformance liquid chromatography and direct sequencing of the suspected exons. Results. MRIs from 641 patients were screened; the scans of 31 patients (4.8%) were considered highly suggestive of CADASIL, since they all displayed T2hyperintensities of external capsule, 73% with additional temporal pole impairment and 32% also with thalamic microbleeds (table). Twenty-two of these patients underwent the blood collection; at the time of the enrollment, none of them reported having relatives who had CADASIL symptoms. In three of them (13.6%), we identified three NOTCH3 gene mutations involving a cysteine residue, precisely in exon 10 (C531S), in exon 11 (Y574C), and in exon 19 (R1006C) (table). Additionally, two nucleotide substitutions were detected, both leading to amino acid changes not involving a cysteine residue (in exons 4 and 12). No skin biopsies were performed. Clinical features of the 22 patients (mean current age: 69.32 ⫾ 9.06 years) are reported in the table; no difference has been found in the occurrence of conventional vascular risk factors between the patients carrying or not the NOTCH3 mutations (Fisher test: p ⫽ 0.99). Discussion. This observation shows that 13.6% of the patients with MRI suggestive of CADASIL and apparently negative familial history for the disease carry the typical NOTCH3 gene mutations involving the cysteine residues within the epidermal growth factor (EGF)–like repeats of the protein.1 Two further mutations not involving the cysteine residues were identified, but their pathogenic interest is under investigation. To date, evidence indicates that the prevalence of CADASIL may be underestimated, mostly because of incomplete family histories2; i.e., either the patient is unable to accurately report the existence of the disease in other family members or they were not diagNeurology 72

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Table

Demographic and clinical features of patients who underwent the NOTCH3 gene mutation screening Conventional MRI features

Patient 1

Gender M

Age at onset, y

Cardiovascular risk factor

Symptoms at onset

Periventricular confluence

54

⫹

Seizures

⫹

NOTCH3 gene screening

Anterior temporal pole

External Thalamic capsule microbleeds

Mutation site

Amino acid change*

⫹

⫹

c.529 (C⬎G)

Q151E

⫹

2

F

48

⫺

Stroke

⫹

⫹

⫹

3

F

58

⫹

Minor stroke

⫹

⫹

⫹

⫹

4

M

55

⫺

Stroke

⫹

5

F

43

⫹

Migraine

⫹

⫹

6

F

57

⫺

Migraine ⫹ cognitive decline

⫹

7

F

46

⫹

Stroke

⫹

8

F

60

⫺

Migraine ⫹ minor stroke

⫹

9

M

59

⫹

Cognitive decline

⫹

⫹

10

M

54

⫺

Psychiatric disturbances

⫹

⫹

⫹ ⫹

⫹

— —

—

—

c.3094 (C⬎T)

R1006C

c.1799 (A⬎G)

Y574C

—

—

c.1670 (G⬎C)

C531S

⫹

—

—

⫹

—

—

⫹

⫹ ⫹

— —

⫹

⫹

11

F

61

⫺

Migraine ⫹ seizures

⫹

⫹

⫹

—

—

12

F

56

⫺

Seizures

⫹

⫹

⫹

—

—

13

M

60

⫹

Stroke

⫹

—

—

14

M

58

⫹

Migraine ⫹ cognitive decline

⫹

⫹

⫹

—

—

15

F

55

⫺

Stroke

⫹

⫹

⫹

—

—

16

M

56

⫺

Stroke

⫹

⫹

⫹

—

—

17

M

50

⫹

Stroke

⫹

⫹

⫹

—

—

18

M

56

⫺

Stroke

⫹

⫹

⫹

—

—

19

M

55

⫹

Minor stroke

⫹

⫹

⫹

—

—

20

F

59

⫹

Cognitive decline

⫹

⫹

⫹

—

—

21

F

48

⫺

Migraine

⫹

⫹

⫹

—

—

22

F

20

⫺

Migraine

⫹

⫹

⫹

c.2009 (T⬎A)

V644D

⫹

⫹

*International nomenclature for amino acid identification: Q ⫽ glutamine; E ⫽ glutamate; R ⫽ arginine; C ⫽ cysteine; Y ⫽ tyrosine; S ⫽ serine; V ⫽ valine; D ⫽ aspartate.

nosed owing to the non-specificity of symptoms. Alternatively, relatives of the patients might complain of suggestive neurologic signs later in their lives. Otherwise, de novo mutations of NOTCH3 gene have been already described.6 Some authors tried to identify incident CADASIL by screening patients with lacunar stroke at MRI but, since they previously found NOTCH3 mutations only in four exons of the gene, they limited the molecular testing to these exons even in sporadic cases, with an overall mutation frequency of 0.05%.7 As reported here, this approach can lead to a missed diagnosis of CADASIL in the sporadic leukoencephalopathies. We suggest that the mutation screening of the entire NOTCH3 gene should be considered in patients with brain MRI indicative of CADASIL and (apparently) negative familial history of the disease, although formal genetic counseling is recommended. 470

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e-Pub ahead of print on December 3, 2008, at www.neurology.org. *These authors contributed equally. From the Institute of Neurological Sciences (M.L., R.M., C.U., P.L., F.L.C., A.Q.), National Research Council, Mangone; Departments of Neurological and Psychiatric Sciences (I.L.S., I.P.) and Neuroradiology (L.C.), University of Bari; Institute of Neurology (A.G., U.A., F.B., A.Q.) and Institute of Neuroradiology (F.F.), University “Magna Graecia,” Catanzaro; and Presidio Ospedaliero “Jazzolino” (D.C.), Vibo Valentia, Italy. Disclosure: The authors report no disclosures. Received May 2, 2008. Accepted in final form September 2, 2008. Address correspondence and reprint requests to Prof. Aldo Quattrone, Institute of Neurological Sciences, National Research Council, Contrada Burga, 87050 Mangone (CS), Italy; [email protected] Copyright © 2009 by AAN Enterprises, Inc. 1.

2.

Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707–710. Razvi SS, Davidson R, Bone I, Muir KW. Is inadequate family history a barrier to diagnosis in CADASIL? Acta Neurol Scand 2005;112:323–326.

3.

4.

Auer DP, Putz B, Gossl C, Elbel G, Gasser T, Dichgans M. Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic leukoencephalopathy: MR imaging study with statistical parametric group comparison. Radiology 2001;218:443–451. van den Boom R, Lesnik Oberstein SA, Ferrari MD, Haan J, van Buchem MA. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR imaging findings at different ages—3rd– 6th decades. Radiology 2003;229:683–690.

5.

6.

7.

Dotti MT, Federico A, Mazzei R, et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry 2005;76:736–738. Joutel A, Dodick DD, Parisi JE, Cecillion M, TournierLasserve E, Bousser MG. De Novo mutations in the Notch3 gene causing CADASIL. Ann Neurol 2000;47:388– 391. Dong Y, Hassan A, Zhang Z, et al. Yield of screening for CADASIL mutations in lacunar stroke and leukoaraiosis. Stroke 2003;34:203–206.

From the AAN History Library Collection Dana’s Text-book of Nervous Diseases and Psychiatry (1892) New York neurologist Charles Loomis Dana (1852–1935), Professor of Diseases of the Mind and Nervous System at the New York Post-Graduate Hospital (1884 –1895) and later Professor of Diseases of the Nervous System at the newly founded Cornell University medical College (1898 until his retirement in the mid-1920s), served twice as President of the American Neurological Association (1892 and1928). Dana’s Text-book of Nervous Diseases (1892)1 was one of the most popular and influential general neurology texts from the end of the 19th century through the first quarter of the 20th century. This single-author text was first published in 1892 and went through 10 editions, the last published in 1925. As noted by Jelliffe in his obituary of Dana, the continued popularity of this text was “an unprecedented event in neurology.”2–3 As recently as 1975, McDowell and Denny-Brown remarked that “the quality of the first edition [of Dana’s text] was outstanding, and it was undoubtedly the first well-organized neurological textbook by an American neurologist . . .. The quality of the tenth and last edition of this book is impressive even when compared with contemporary neurological texts. Having been written by one man it stands out even more as a monumental achievement.”4 This illustration from Dana’s textbook shows elicitation of the triceps jerk with Dana’s modification (c.1892) of a triangular-headed Taylor (c.1888) reflex hammer.5 Douglas J. Lanska, MD, MS, MSPH, FAAN Chairman, AAN History Section 1. Dana CL. Text-book of Nervous Diseases and Psychiatry for the Use of Students and Practioners of Medicine. New York: Wood, 1892. 2. Jelliffe SE. Charles Loomis Dana, M.D. J Nerv Ment Dis 1926;83:622– 637. 3. Jelliffe SE. Charles Loomis Dana, M.D.: 1852–1935. Trans Am Berik Assic 1936;62:187–193. 4. McDowell F, Denny-Brown D. Charles Loomis Dana: 1852–1935. In: Denny-Brown D, Rose AS, Sahs AL, eds. Centennial Anniversary Volume of the American Neurological Association: 1875–1975. New York: Springer, 1975:96 –101. 5. Lanska DJ. The Dana reflex hammer (c.1892). J Child Neurol 1995;10:367–368. The American Academy of Neurology (AAN) Library Collection originated with a long-term donation of several thousand neurology-related books, many of them rare, by H. Richard Tyler, MD. The collection comprises more than 3,500 books, making it one of the world’s most significant research resources for the history of neurology and neurosciences. All the materials in the AAN collection are organized, processed, and easily retrievable for research. AAN members may use the collection by contacting Lilla Vekerdy, Librarian, at [email protected] or (314) 362-4235. If you have a passion for the history of neurology, consider applying for the H. Richard Tyler Award from the AAN which was established to encourage historical research using the AAN Library Collection at the Bernard Becker Medical Library at the Washington University School of Medicine in St. Louis. The award provides up to $1,200 for research expenses and is open to AAN members and non-members. For more information about the award, visit www.aan.com/libv or contact Jeff Sorenson at [email protected] or (651) 695-2728.

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Clinical/Scientific Notes

J. Wagner, MD C. Schankin, MD T. Birnbaum, MD G. Po¨pperl, MD A. Straube, MD

OCULAR MOTOR AND LID APRAXIA AS INITIAL SYMPTOM OF ANTI-Ma1/Ma2-ASSOCIATED ENCEPHALITIS

Antibodies against Ma1/Ma2 antigens are typically associated with paraneoplastic neurologic disease. Most common are the involvement of the limbic and diencephalic system and the brainstem. We report a case of anti-Ma1 and anti-Ma2-positive encephalitis with predominant frontoparietal cortical involvement. The main initial clinical symptom was an ocular motor and lid apraxia. Case report. We report on a 49-year-old man who presented with blurred vision and drooping eyelids bilaterally. The symptoms had progressed over a period of 3 months. When we first saw the patient, he also had dysphagia and apathy. The patient was previously healthy and did not take any regular medication. Two weeks before the onset of symptoms, he had been vaccinated against tick-borne encephalitis. On examination of the ocular motor system, the patient had a downward deviation of the bulbi and

Figure

an inability to elicit voluntary horizontal or vertical saccades and the optokinetic reflex. Reflexive saccades were preserved. Gaze holding, vergence, and smooth pursuit were impaired and vertical ocular motility was limited. The deficit could be overcome via the vestibulo-ocular reflex, indicating a supranuclear origin. Furthermore, the patient showed apraxia of lid opening, keeping his eyes closed most of the time although opening of the eyes was still possible. Trying to open the eyes manually caused the patient to forcefully squeeze the eyelids shut. A thorough neuropsychological examination revealed deficits of attention, memory, verbal fluency, visuoconstruction, and executive function as well as simultanagnosia. Repeated cranial MRIs including thin sectioning of the brainstem were unremarkable. In the CSF, the total cell count was slightly raised (16/3/cmm [normal ⬍15/3/cmm]) and total protein was significantly elevated (81 mg/dL [normal ⬍50 mg/dL]) with CSF-specific oligoclonal bands. Furthermore, serum and CSF anti-Ma1 and anti-Ma2 antibodies

FDG-PET revealing frontoparietal hypometabolism

Cranial FDG-PET (A) showed hypometabolism in the frontoparietal cortex (left more than right) with a focal hypermetabolic spot in the right frontal cortex. A normal FDG-PET (B) is shown for comparison. 466

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as detected by indirect immunofluorescence were positive, while anti-Yo/-Ri/-Hu/-CV2/CRMP5/amphiphysin/-purkinje cell antibodies were absent. A cranial FDG-PET (figure) showed hypometabolism in the frontoparietal cortex (left more than right). The limbic system and subcortical structures including the basal ganglia and the cerebellum were unremarkable in the PET examination. A total-body FDG-PET-CT did not reveal any neoplasia. Neither did a total-body CT scan, a gastroscopy, a colonoscopy, an abdominal sonography, or a urologic examination. The patient was treated with IV prednisone (5 ⫻ 500 mg). Due to further deterioration of his neurologic status, a 5-day course of IV immunoglobulins (0.4 g/kg per day) was administered, followed by oral prednisone and azathioprine (150 mg/ day). With this regimen, the symptoms remained stable but without sign of remission. Discussion. Ma1 and Ma2 are omnipresent intraneuronal antigens. Antibodies against Ma1/Ma2 are associated with paraneoplastic neurologic disease. In most cases of anti-Ma1 positive encephalitis testicular tumors are found, whereas in patients in whom both anti-Ma1 and anti-Ma2 antibodies are detected the underlying tumors are more diverse. The most frequent manifestations are signs of limbic (shortterm memory loss, seizures, personality changes), diencephalic (excessive daytime sleepiness, hyperthermia, endocrine dysfunction), brainstem (cranial neuropathy including ophthalmoplegia, dysarthria, dysphagia), and cerebellar involvement and opsoclonus-myoclonus.1 Our patient presented with signs of diencephalic and brainstem involvement as commonly recognized features of paraneoplastic encephalitis. The most prominent symptom, however, was ocular motor and lid apraxia. In the FDG-PET, this patient showed prominent hypometabolism in the fronto-parietal cortex compatible with residual postencephalitic defects whereas the limbic system and subcortical structures were unaltered. Ocular motor apraxia has been described before in patients with frontoparietal lesions.2-4 It has been attributed to involvement of the frontal and parietal

Richard F. Lewis, MD Aisha S. Traish, MD Simmons Lessell, MD

ATYPICAL VOLUNTARY NYSTAGMUS

Voluntary nystagmus, once considered rare, may actually occur in as much as 8% of the population.1 We recently observed a child who appeared to have voluntary nystagmus but the eye movements had distinct slow and fast phases rather than the rapid back-to-back saccades that typify voluntary nystagmus. Analysis of the eye movements revealed that the patient’s nystag-

eye fields.5 Cases with predominant involvement of the frontoparietal cortex are rare in anti-Ma1/Ma2 associated encephalitis. Histologic changes in the frontal lobe have been described in few patients.1,6 Possibly some of the patients previously described to have complete gaze paresis due to brainstem involvement might have had ocular motor apraxia as a sign of frontoparietal dysfunction. Anti-Ma1/Ma2 associated encephalitis may cause predominant involvement of the frontoparietal cortex. Ocular motor and lid apraxia can result from frontoparietal cortical dysfunction. Hence, these signs may constitute the initial presentation in Mapositive encephalitis. Acquired ocular motor and lid apraxia in adulthood therefore warrants a thorough search for antineuronal antibodies. From the Departments of Neurology (J.W., C.S., T.B., A.S.) and Nuclear Medicine (G.P.), Klinikum Grosshadern, LudwigMaximilians University, Munich, Germany. Disclosure: The authors report no disclosures. Received June 18, 2008. Accepted in final form August 29, 2008. Address correspondence and reprint requests to Dr. Judith Wagner, Department of Neurology, Ludwig-Maximilians University, Klinikum Grosshadern, Marchioninistraße 15, D-81366 Munich, Germany; [email protected] Copyright © 2009 by AAN Enterprises, Inc. 1.

2.

3.

4.

5. 6.

Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004;127:1831– 1844. Pierrot-Deseilligny C, Gautier JC, Loron P. Acquired ocular motor apraxia due to bilateral frontoparietal infarcts. Ann Neurol 1988;23:199–202. Monaco F, Pirisi A, Sechi GP, Cossu G. Acquired ocularmotor apraxia and right-sided cortical angioma. Cortex 1980;16:159–167. Genc BO, Genc E, Acik L, Ilhan S, Paksoy Y. Acquired ocular motor apraxia from bilateral frontoparietal infarcts associated with Takayasu arteritis. J Neurol Neurosurg Psychiatry 2004;75:1651–1652. Pierrot-Deseilligny C, Gaymard B, Muri R, Rivaud S. Cerebral ocular motor signs. J Neurol 1997;244:65–70. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000;123:1481–1494.

mus showed features of both voluntary nystagmus and a rare form of congenital nystagmus in which the patient can suppress the adventitious movements at will. Case report. A 27-month-old girl was referred because of nystagmus. Her family was free of neurologic and nonrefractive eye disorders. Apart from surgery for tear duct obstruction, she had been healthy. At age 9 months, her mother observed intermittent bursts of Neurology 72

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467

Figure

Horizontal eye position (A) and velocity (B) plotted vs time

The nystagmus has a frequency of about 4.0 Hz and has clearly delineated slow and quick phases. The waveform of the slow phases suggests a velocity-increasing morphology, particularly early in the run of the nystagmus, although the slow phases become more linear as they decelerate. No foveation periods are evident. Right is positive and left is negative. The quick phases were clipped on the velocity plot for clarity. There was no significant vertical component to the nystagmus (data not shown).

Supplemental data at www.neuurology.org

468

horizontal eye movements lasting seconds. It later became evident that she could produce these movements whenever requested. Except for 2 months during which no nystagmus was observed, episodes continued several times a day. Her general neurologic examination was unremarkable. Uncorrected visual acuities were 20/30 in each eye and her visual fields were full to confrontation testing. The anterior segments, pupils, eyelids, and fundi were normal. She had full ductions and versions and was orthophoric. Fixation, saccades, vergence, gaze holding, pursuit, and optokinetic responses were normal. No spontaneous nystagmus was observed in the light or dark and no nystagmus was produced by covering one eye, horizontal head-shaking, or changing head orientation. When she was asked to perform her “eye trick,” she diverged her eyes slightly and produced a burst of right-beating horizontal nystagmus (video on the Neurology ® Web site at www. neurology.org). She could produce nystagmus looking straight ahead or eccentrically and the rate and direction of the nystagmus did not depend on orbital eye position. No null position was evident and there were no other adventitious movements. When her eye movements were observed in the dark with an infrared camera, there was no spontaneous nystagmus in any direction of gaze. Even in the dark, however, the patient could produce horizontal nystagmus upon request. Neurology 72

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An EEG and brain MRI were normal. Her nystagmus was recorded with standard DC electrooculography (figure) with the eyes opened in complete darkness. The recordings demonstrate the transient divergence of the eyes which appears necessary to initiate the nystagmus (at about 2 seconds on the trace), followed by a conjugate jerk nystagmus with leftward slow phases. Examination of the position and velocity traces demonstrates that the initial slow phases were velocityincreasing, but shifted toward a linear (constantvelocity) waveform after the first several beats of nystagmus. Discussion. The eye movements observed and recorded in this patient are of uncertain origin. This could be a form of voluntary nystagmus, but the eye movements in this syndrome consist of back-to-back saccades and have never been described to have slow and quick phases like those observed in this subject. The initiation of the nystagmus with a change of vergence angle, however, has been described as a feature of voluntary nystagmus.2 The velocity-increasing morphology evident in the initial slow phases suggests that the patient may have congenital nystagmus with voluntary control3 although similar slow phases have been described in acquired nystagmus4 and hence are not pathognomonic for congenital nystagmus. Unlike other patients described with this rare syndrome, she had no spontaneous nystagmus in the dark, no latent nystagmus induced by monocular vision, and her nystagmus was not modulated by changes in orbital eye position. The exact mechanism underlying her nystagmus is therefore uncertain. The divergence that initiates the nystagmus and the velocity-increasing slow phases suggest that she may have instability in the velocity-to-position neural integrator in the brainstem and cerebellum,5 and that this may be under a form of voluntary control that is associated with ocular alignment. The abnormal eye movements in this patient share some features of voluntary nystagmus and some features of voluntary suppression of congenital nystagmus. She is the first patient to be described with this combination of findings. From the Department of Otology and Laryngology (R.F.L.) and Department of Ophthalmology (A.S.T., S.L.), Harvard Medical School and the Massachusetts Eye and Ear Infirmary, Boston. Disclosure: The authors report no disclosures. Received May 10, 2008. Accepted in final form September 10, 2008. Address correspondence and reprint requests to Dr. Richard Lewis, Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114; [email protected] Copyright © 2009 by AAN Enterprises, Inc. 1.

Miller NR, Newman NJ, ed. Walsh and Hoyt’s Neuroophthalmology. 5th ed. Baltimore: Williams & Wilkins; 1998: 1490, 1777, 1779.

2.

3.

M. Liguori, MD, PhD* R. Mazzei, PhD* C. Ungaro, PhD I.L. Simone, MD A. Gambardella, MD I. Plasmati, MD F. Fera, MD U. Aguglia, MD P. Lanza, MD F. Bono, MD L. Chiumarulo, MD F.L. Conforti, PhD D. Consoli, MD A. Quattrone, MD

Hotson JR. Convergence-initiated voluntary flutter: a normal intrinsic capability in man. Brain Res 1984;294:299– 304. Tusa RJ, Zee DS, Hain TC, Simonsz HJ. Voluntary control of congenital nystagmus. Clin Vis Sci 1992;7:195–210.

CONVENTIONAL MRI AND NOTCH3 GENE SCREENING IN SPORADIC CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a small vessels disease caused by mutations in the NOTCH3 gene,1 is considered the most frequent cause of genetically determined stroke. The age at onset ranges between the fourth and the third decade, and the cardinal symptoms comprise stroke, migraine headaches with or without aura, and cognitive decline, with additional features including psychiatric disturbances and epileptic seizures.2 Imaging studies summarized the CADASIL pattern as a combination of T2-hyperintensities in the periventricular white matter, anterior temporal pole, external capsule, basal ganglia, and brainstem.Hemosiderin deposits (microbleeds) have been described, primarily in the thalamic regions.3,4 The extent of radiologic CADASIL abnormalities, however, greatly differs among subjects and increases with age4 or other factors, sometimes impeding identification of CADASIL in a subject. In patients with CADASIL, causative mutations have been reported spanning the NOTCH3 gene; since it is a quite expensive and time-consuming analysis,5 a common strategy is to perform a complete gene screening only on patients with a positive familial history of CADASIL. We investigated whether sporadic patients with brain MRI suggestive of CADASIL may carry mutations in the entire NOTCH3 gene, even in the absence of a positive familial history. Methods. We reviewed brain MRIs of patients suspected of having cerebrovascular disease referred to the Institute of Neurological Sciences (Mangone) and the Department of Neuroradiology (Bari). Eligible images presented confluent periventricular T2-hyperintensity in addition to 1) an increased T2-signal from the external capsule or 2) the anterior temporal lobe, or 3) thalamic microbleeds, all of these signs considered highly suggestive of CADASIL.3,4 Patients with at least two of these MRI features underwent the mutational screening of the entire NOTCH3 gene. These patients were asked to partic-

4. 5.

Zee DS, Leigh RJ, Mathieu-Millaire F. Cerebellar control of ocular gaze stability. Ann Neurol 1980;7:37–40. Arnold DB, Robinson DA, Leigh RJ. Nystagmus induced by pharmacological inactivation of the brainstem ocular motor integrator in monkey. Vision Res 1999;39:4286–4295.

ipate in the prospective study for peripheral blood collection, and detailed pedigrees spanning at least three generations were obtained. All patients gave written informed consent under the institutional review board–approved protocol. Genomic DNA was extracted by standard procedures. The NOTCH3 gene mutation analysis consisted of PCRs followed by denaturing highperformance liquid chromatography and direct sequencing of the suspected exons. Results. MRIs from 641 patients were screened; the scans of 31 patients (4.8%) were considered highly suggestive of CADASIL, since they all displayed T2hyperintensities of external capsule, 73% with additional temporal pole impairment and 32% also with thalamic microbleeds (table). Twenty-two of these patients underwent the blood collection; at the time of the enrollment, none of them reported having relatives who had CADASIL symptoms. In three of them (13.6%), we identified three NOTCH3 gene mutations involving a cysteine residue, precisely in exon 10 (C531S), in exon 11 (Y574C), and in exon 19 (R1006C) (table). Additionally, two nucleotide substitutions were detected, both leading to amino acid changes not involving a cysteine residue (in exons 4 and 12). No skin biopsies were performed. Clinical features of the 22 patients (mean current age: 69.32 ⫾ 9.06 years) are reported in the table; no difference has been found in the occurrence of conventional vascular risk factors between the patients carrying or not the NOTCH3 mutations (Fisher test: p ⫽ 0.99). Discussion. This observation shows that 13.6% of the patients with MRI suggestive of CADASIL and apparently negative familial history for the disease carry the typical NOTCH3 gene mutations involving the cysteine residues within the epidermal growth factor (EGF)–like repeats of the protein.1 Two further mutations not involving the cysteine residues were identified, but their pathogenic interest is under investigation. To date, evidence indicates that the prevalence of CADASIL may be underestimated, mostly because of incomplete family histories2; i.e., either the patient is unable to accurately report the existence of the disease in other family members or they were not diagNeurology 72

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Table

Demographic and clinical features of patients who underwent the NOTCH3 gene mutation screening Conventional MRI features

Patient 1

Gender M

Age at onset, y

Cardiovascular risk factor

Symptoms at onset

Periventricular confluence

54

⫹

Seizures

⫹

NOTCH3 gene screening

Anterior temporal pole

External Thalamic capsule microbleeds

Mutation site

Amino acid change*

⫹

⫹

c.529 (C⬎G)

Q151E

⫹

2

F

48

⫺

Stroke

⫹

⫹

⫹

3

F

58

⫹

Minor stroke

⫹

⫹

⫹

⫹

4

M

55

⫺

Stroke

⫹

5

F

43

⫹

Migraine

⫹

⫹

6

F

57

⫺

Migraine ⫹ cognitive decline

⫹

7

F

46

⫹

Stroke

⫹

8

F

60

⫺

Migraine ⫹ minor stroke

⫹

9

M

59

⫹

Cognitive decline

⫹

⫹

10

M

54

⫺

Psychiatric disturbances

⫹

⫹

⫹ ⫹

⫹

— —

—

—

c.3094 (C⬎T)

R1006C

c.1799 (A⬎G)

Y574C

—

—

c.1670 (G⬎C)

C531S

⫹

—

—

⫹

—

—

⫹

⫹ ⫹

— —

⫹

⫹

11

F

61

⫺

Migraine ⫹ seizures

⫹

⫹

⫹

—

—

12

F

56

⫺

Seizures

⫹

⫹

⫹

—

—

13

M

60

⫹

Stroke

⫹

—

—

14

M

58

⫹

Migraine ⫹ cognitive decline

⫹

⫹

⫹

—

—

15

F

55

⫺

Stroke

⫹

⫹

⫹

—

—

16

M

56

⫺

Stroke

⫹

⫹

⫹

—

—

17

M

50

⫹

Stroke

⫹

⫹

⫹

—

—

18

M

56

⫺

Stroke

⫹

⫹

⫹

—

—

19

M

55

⫹

Minor stroke

⫹

⫹

⫹

—

—

20

F

59

⫹

Cognitive decline

⫹

⫹

⫹

—

—

21

F

48

⫺

Migraine

⫹

⫹

⫹

—

—

22

F

20

⫺

Migraine

⫹

⫹

⫹

c.2009 (T⬎A)

V644D

⫹

⫹

*International nomenclature for amino acid identification: Q ⫽ glutamine; E ⫽ glutamate; R ⫽ arginine; C ⫽ cysteine; Y ⫽ tyrosine; S ⫽ serine; V ⫽ valine; D ⫽ aspartate.

nosed owing to the non-specificity of symptoms. Alternatively, relatives of the patients might complain of suggestive neurologic signs later in their lives. Otherwise, de novo mutations of NOTCH3 gene have been already described.6 Some authors tried to identify incident CADASIL by screening patients with lacunar stroke at MRI but, since they previously found NOTCH3 mutations only in four exons of the gene, they limited the molecular testing to these exons even in sporadic cases, with an overall mutation frequency of 0.05%.7 As reported here, this approach can lead to a missed diagnosis of CADASIL in the sporadic leukoencephalopathies. We suggest that the mutation screening of the entire NOTCH3 gene should be considered in patients with brain MRI indicative of CADASIL and (apparently) negative familial history of the disease, although formal genetic counseling is recommended. 470

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e-Pub ahead of print on December 3, 2008, at www.neurology.org. *These authors contributed equally. From the Institute of Neurological Sciences (M.L., R.M., C.U., P.L., F.L.C., A.Q.), National Research Council, Mangone; Departments of Neurological and Psychiatric Sciences (I.L.S., I.P.) and Neuroradiology (L.C.), University of Bari; Institute of Neurology (A.G., U.A., F.B., A.Q.) and Institute of Neuroradiology (F.F.), University “Magna Graecia,” Catanzaro; and Presidio Ospedaliero “Jazzolino” (D.C.), Vibo Valentia, Italy. Disclosure: The authors report no disclosures. Received May 2, 2008. Accepted in final form September 2, 2008. Address correspondence and reprint requests to Prof. Aldo Quattrone, Institute of Neurological Sciences, National Research Council, Contrada Burga, 87050 Mangone (CS), Italy; [email protected] Copyright © 2009 by AAN Enterprises, Inc. 1.

2.

Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707–710. Razvi SS, Davidson R, Bone I, Muir KW. Is inadequate family history a barrier to diagnosis in CADASIL? Acta Neurol Scand 2005;112:323–326.

3.

4.

Auer DP, Putz B, Gossl C, Elbel G, Gasser T, Dichgans M. Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic leukoencephalopathy: MR imaging study with statistical parametric group comparison. Radiology 2001;218:443–451. van den Boom R, Lesnik Oberstein SA, Ferrari MD, Haan J, van Buchem MA. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR imaging findings at different ages—3rd– 6th decades. Radiology 2003;229:683–690.

5.

6.

7.

Dotti MT, Federico A, Mazzei R, et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry 2005;76:736–738. Joutel A, Dodick DD, Parisi JE, Cecillion M, TournierLasserve E, Bousser MG. De Novo mutations in the Notch3 gene causing CADASIL. Ann Neurol 2000;47:388– 391. Dong Y, Hassan A, Zhang Z, et al. Yield of screening for CADASIL mutations in lacunar stroke and leukoaraiosis. Stroke 2003;34:203–206.

From the AAN History Library Collection Dana’s Text-book of Nervous Diseases and Psychiatry (1892) New York neurologist Charles Loomis Dana (1852–1935), Professor of Diseases of the Mind and Nervous System at the New York Post-Graduate Hospital (1884 –1895) and later Professor of Diseases of the Nervous System at the newly founded Cornell University medical College (1898 until his retirement in the mid-1920s), served twice as President of the American Neurological Association (1892 and1928). Dana’s Text-book of Nervous Diseases (1892)1 was one of the most popular and influential general neurology texts from the end of the 19th century through the first quarter of the 20th century. This single-author text was first published in 1892 and went through 10 editions, the last published in 1925. As noted by Jelliffe in his obituary of Dana, the continued popularity of this text was “an unprecedented event in neurology.”2–3 As recently as 1975, McDowell and Denny-Brown remarked that “the quality of the first edition [of Dana’s text] was outstanding, and it was undoubtedly the first well-organized neurological textbook by an American neurologist . . .. The quality of the tenth and last edition of this book is impressive even when compared with contemporary neurological texts. Having been written by one man it stands out even more as a monumental achievement.”4 This illustration from Dana’s textbook shows elicitation of the triceps jerk with Dana’s modification (c.1892) of a triangular-headed Taylor (c.1888) reflex hammer.5 Douglas J. Lanska, MD, MS, MSPH, FAAN Chairman, AAN History Section 1. Dana CL. Text-book of Nervous Diseases and Psychiatry for the Use of Students and Practioners of Medicine. New York: Wood, 1892. 2. Jelliffe SE. Charles Loomis Dana, M.D. J Nerv Ment Dis 1926;83:622– 637. 3. Jelliffe SE. Charles Loomis Dana, M.D.: 1852–1935. Trans Am Berik Assic 1936;62:187–193. 4. McDowell F, Denny-Brown D. Charles Loomis Dana: 1852–1935. In: Denny-Brown D, Rose AS, Sahs AL, eds. Centennial Anniversary Volume of the American Neurological Association: 1875–1975. New York: Springer, 1975:96 –101. 5. Lanska DJ. The Dana reflex hammer (c.1892). J Child Neurol 1995;10:367–368. The American Academy of Neurology (AAN) Library Collection originated with a long-term donation of several thousand neurology-related books, many of them rare, by H. Richard Tyler, MD. The collection comprises more than 3,500 books, making it one of the world’s most significant research resources for the history of neurology and neurosciences. All the materials in the AAN collection are organized, processed, and easily retrievable for research. AAN members may use the collection by contacting Lilla Vekerdy, Librarian, at [email protected] or (314) 362-4235. If you have a passion for the history of neurology, consider applying for the H. Richard Tyler Award from the AAN which was established to encourage historical research using the AAN Library Collection at the Bernard Becker Medical Library at the Washington University School of Medicine in St. Louis. The award provides up to $1,200 for research expenses and is open to AAN members and non-members. For more information about the award, visit www.aan.com/libv or contact Jeff Sorenson at [email protected] or (651) 695-2728.

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471

Clinical/Scientific Notes

J. Wagner, MD C. Schankin, MD T. Birnbaum, MD G. Po¨pperl, MD A. Straube, MD

OCULAR MOTOR AND LID APRAXIA AS INITIAL SYMPTOM OF ANTI-Ma1/Ma2-ASSOCIATED ENCEPHALITIS

Antibodies against Ma1/Ma2 antigens are typically associated with paraneoplastic neurologic disease. Most common are the involvement of the limbic and diencephalic system and the brainstem. We report a case of anti-Ma1 and anti-Ma2-positive encephalitis with predominant frontoparietal cortical involvement. The main initial clinical symptom was an ocular motor and lid apraxia. Case report. We report on a 49-year-old man who presented with blurred vision and drooping eyelids bilaterally. The symptoms had progressed over a period of 3 months. When we first saw the patient, he also had dysphagia and apathy. The patient was previously healthy and did not take any regular medication. Two weeks before the onset of symptoms, he had been vaccinated against tick-borne encephalitis. On examination of the ocular motor system, the patient had a downward deviation of the bulbi and

Figure

an inability to elicit voluntary horizontal or vertical saccades and the optokinetic reflex. Reflexive saccades were preserved. Gaze holding, vergence, and smooth pursuit were impaired and vertical ocular motility was limited. The deficit could be overcome via the vestibulo-ocular reflex, indicating a supranuclear origin. Furthermore, the patient showed apraxia of lid opening, keeping his eyes closed most of the time although opening of the eyes was still possible. Trying to open the eyes manually caused the patient to forcefully squeeze the eyelids shut. A thorough neuropsychological examination revealed deficits of attention, memory, verbal fluency, visuoconstruction, and executive function as well as simultanagnosia. Repeated cranial MRIs including thin sectioning of the brainstem were unremarkable. In the CSF, the total cell count was slightly raised (16/3/cmm [normal ⬍15/3/cmm]) and total protein was significantly elevated (81 mg/dL [normal ⬍50 mg/dL]) with CSF-specific oligoclonal bands. Furthermore, serum and CSF anti-Ma1 and anti-Ma2 antibodies

FDG-PET revealing frontoparietal hypometabolism

Cranial FDG-PET (A) showed hypometabolism in the frontoparietal cortex (left more than right) with a focal hypermetabolic spot in the right frontal cortex. A normal FDG-PET (B) is shown for comparison. 466

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as detected by indirect immunofluorescence were positive, while anti-Yo/-Ri/-Hu/-CV2/CRMP5/amphiphysin/-purkinje cell antibodies were absent. A cranial FDG-PET (figure) showed hypometabolism in the frontoparietal cortex (left more than right). The limbic system and subcortical structures including the basal ganglia and the cerebellum were unremarkable in the PET examination. A total-body FDG-PET-CT did not reveal any neoplasia. Neither did a total-body CT scan, a gastroscopy, a colonoscopy, an abdominal sonography, or a urologic examination. The patient was treated with IV prednisone (5 ⫻ 500 mg). Due to further deterioration of his neurologic status, a 5-day course of IV immunoglobulins (0.4 g/kg per day) was administered, followed by oral prednisone and azathioprine (150 mg/ day). With this regimen, the symptoms remained stable but without sign of remission. Discussion. Ma1 and Ma2 are omnipresent intraneuronal antigens. Antibodies against Ma1/Ma2 are associated with paraneoplastic neurologic disease. In most cases of anti-Ma1 positive encephalitis testicular tumors are found, whereas in patients in whom both anti-Ma1 and anti-Ma2 antibodies are detected the underlying tumors are more diverse. The most frequent manifestations are signs of limbic (shortterm memory loss, seizures, personality changes), diencephalic (excessive daytime sleepiness, hyperthermia, endocrine dysfunction), brainstem (cranial neuropathy including ophthalmoplegia, dysarthria, dysphagia), and cerebellar involvement and opsoclonus-myoclonus.1 Our patient presented with signs of diencephalic and brainstem involvement as commonly recognized features of paraneoplastic encephalitis. The most prominent symptom, however, was ocular motor and lid apraxia. In the FDG-PET, this patient showed prominent hypometabolism in the fronto-parietal cortex compatible with residual postencephalitic defects whereas the limbic system and subcortical structures were unaltered. Ocular motor apraxia has been described before in patients with frontoparietal lesions.2-4 It has been attributed to involvement of the frontal and parietal

Richard F. Lewis, MD Aisha S. Traish, MD Simmons Lessell, MD

ATYPICAL VOLUNTARY NYSTAGMUS

Voluntary nystagmus, once considered rare, may actually occur in as much as 8% of the population.1 We recently observed a child who appeared to have voluntary nystagmus but the eye movements had distinct slow and fast phases rather than the rapid back-to-back saccades that typify voluntary nystagmus. Analysis of the eye movements revealed that the patient’s nystag-

eye fields.5 Cases with predominant involvement of the frontoparietal cortex are rare in anti-Ma1/Ma2 associated encephalitis. Histologic changes in the frontal lobe have been described in few patients.1,6 Possibly some of the patients previously described to have complete gaze paresis due to brainstem involvement might have had ocular motor apraxia as a sign of frontoparietal dysfunction. Anti-Ma1/Ma2 associated encephalitis may cause predominant involvement of the frontoparietal cortex. Ocular motor and lid apraxia can result from frontoparietal cortical dysfunction. Hence, these signs may constitute the initial presentation in Mapositive encephalitis. Acquired ocular motor and lid apraxia in adulthood therefore warrants a thorough search for antineuronal antibodies. From the Departments of Neurology (J.W., C.S., T.B., A.S.) and Nuclear Medicine (G.P.), Klinikum Grosshadern, LudwigMaximilians University, Munich, Germany. Disclosure: The authors report no disclosures. Received June 18, 2008. Accepted in final form August 29, 2008. Address correspondence and reprint requests to Dr. Judith Wagner, Department of Neurology, Ludwig-Maximilians University, Klinikum Grosshadern, Marchioninistraße 15, D-81366 Munich, Germany; [email protected] Copyright © 2009 by AAN Enterprises, Inc. 1.

2.

3.

4.

5. 6.

Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004;127:1831– 1844. Pierrot-Deseilligny C, Gautier JC, Loron P. Acquired ocular motor apraxia due to bilateral frontoparietal infarcts. Ann Neurol 1988;23:199–202. Monaco F, Pirisi A, Sechi GP, Cossu G. Acquired ocularmotor apraxia and right-sided cortical angioma. Cortex 1980;16:159–167. Genc BO, Genc E, Acik L, Ilhan S, Paksoy Y. Acquired ocular motor apraxia from bilateral frontoparietal infarcts associated with Takayasu arteritis. J Neurol Neurosurg Psychiatry 2004;75:1651–1652. Pierrot-Deseilligny C, Gaymard B, Muri R, Rivaud S. Cerebral ocular motor signs. J Neurol 1997;244:65–70. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000;123:1481–1494.

mus showed features of both voluntary nystagmus and a rare form of congenital nystagmus in which the patient can suppress the adventitious movements at will. Case report. A 27-month-old girl was referred because of nystagmus. Her family was free of neurologic and nonrefractive eye disorders. Apart from surgery for tear duct obstruction, she had been healthy. At age 9 months, her mother observed intermittent bursts of Neurology 72

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Figure

Horizontal eye position (A) and velocity (B) plotted vs time

The nystagmus has a frequency of about 4.0 Hz and has clearly delineated slow and quick phases. The waveform of the slow phases suggests a velocity-increasing morphology, particularly early in the run of the nystagmus, although the slow phases become more linear as they decelerate. No foveation periods are evident. Right is positive and left is negative. The quick phases were clipped on the velocity plot for clarity. There was no significant vertical component to the nystagmus (data not shown).

Supplemental data at www.neuurology.org

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horizontal eye movements lasting seconds. It later became evident that she could produce these movements whenever requested. Except for 2 months during which no nystagmus was observed, episodes continued several times a day. Her general neurologic examination was unremarkable. Uncorrected visual acuities were 20/30 in each eye and her visual fields were full to confrontation testing. The anterior segments, pupils, eyelids, and fundi were normal. She had full ductions and versions and was orthophoric. Fixation, saccades, vergence, gaze holding, pursuit, and optokinetic responses were normal. No spontaneous nystagmus was observed in the light or dark and no nystagmus was produced by covering one eye, horizontal head-shaking, or changing head orientation. When she was asked to perform her “eye trick,” she diverged her eyes slightly and produced a burst of right-beating horizontal nystagmus (video on the Neurology ® Web site at www. neurology.org). She could produce nystagmus looking straight ahead or eccentrically and the rate and direction of the nystagmus did not depend on orbital eye position. No null position was evident and there were no other adventitious movements. When her eye movements were observed in the dark with an infrared camera, there was no spontaneous nystagmus in any direction of gaze. Even in the dark, however, the patient could produce horizontal nystagmus upon request. Neurology 72

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An EEG and brain MRI were normal. Her nystagmus was recorded with standard DC electrooculography (figure) with the eyes opened in complete darkness. The recordings demonstrate the transient divergence of the eyes which appears necessary to initiate the nystagmus (at about 2 seconds on the trace), followed by a conjugate jerk nystagmus with leftward slow phases. Examination of the position and velocity traces demonstrates that the initial slow phases were velocityincreasing, but shifted toward a linear (constantvelocity) waveform after the first several beats of nystagmus. Discussion. The eye movements observed and recorded in this patient are of uncertain origin. This could be a form of voluntary nystagmus, but the eye movements in this syndrome consist of back-to-back saccades and have never been described to have slow and quick phases like those observed in this subject. The initiation of the nystagmus with a change of vergence angle, however, has been described as a feature of voluntary nystagmus.2 The velocity-increasing morphology evident in the initial slow phases suggests that the patient may have congenital nystagmus with voluntary control3 although similar slow phases have been described in acquired nystagmus4 and hence are not pathognomonic for congenital nystagmus. Unlike other patients described with this rare syndrome, she had no spontaneous nystagmus in the dark, no latent nystagmus induced by monocular vision, and her nystagmus was not modulated by changes in orbital eye position. The exact mechanism underlying her nystagmus is therefore uncertain. The divergence that initiates the nystagmus and the velocity-increasing slow phases suggest that she may have instability in the velocity-to-position neural integrator in the brainstem and cerebellum,5 and that this may be under a form of voluntary control that is associated with ocular alignment. The abnormal eye movements in this patient share some features of voluntary nystagmus and some features of voluntary suppression of congenital nystagmus. She is the first patient to be described with this combination of findings. From the Department of Otology and Laryngology (R.F.L.) and Department of Ophthalmology (A.S.T., S.L.), Harvard Medical School and the Massachusetts Eye and Ear Infirmary, Boston. Disclosure: The authors report no disclosures. Received May 10, 2008. Accepted in final form September 10, 2008. Address correspondence and reprint requests to Dr. Richard Lewis, Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114; [email protected] Copyright © 2009 by AAN Enterprises, Inc. 1.

Miller NR, Newman NJ, ed. Walsh and Hoyt’s Neuroophthalmology. 5th ed. Baltimore: Williams & Wilkins; 1998: 1490, 1777, 1779.

2.

3.

M. Liguori, MD, PhD* R. Mazzei, PhD* C. Ungaro, PhD I.L. Simone, MD A. Gambardella, MD I. Plasmati, MD F. Fera, MD U. Aguglia, MD P. Lanza, MD F. Bono, MD L. Chiumarulo, MD F.L. Conforti, PhD D. Consoli, MD A. Quattrone, MD

Hotson JR. Convergence-initiated voluntary flutter: a normal intrinsic capability in man. Brain Res 1984;294:299– 304. Tusa RJ, Zee DS, Hain TC, Simonsz HJ. Voluntary control of congenital nystagmus. Clin Vis Sci 1992;7:195–210.

CONVENTIONAL MRI AND NOTCH3 GENE SCREENING IN SPORADIC CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a small vessels disease caused by mutations in the NOTCH3 gene,1 is considered the most frequent cause of genetically determined stroke. The age at onset ranges between the fourth and the third decade, and the cardinal symptoms comprise stroke, migraine headaches with or without aura, and cognitive decline, with additional features including psychiatric disturbances and epileptic seizures.2 Imaging studies summarized the CADASIL pattern as a combination of T2-hyperintensities in the periventricular white matter, anterior temporal pole, external capsule, basal ganglia, and brainstem.Hemosiderin deposits (microbleeds) have been described, primarily in the thalamic regions.3,4 The extent of radiologic CADASIL abnormalities, however, greatly differs among subjects and increases with age4 or other factors, sometimes impeding identification of CADASIL in a subject. In patients with CADASIL, causative mutations have been reported spanning the NOTCH3 gene; since it is a quite expensive and time-consuming analysis,5 a common strategy is to perform a complete gene screening only on patients with a positive familial history of CADASIL. We investigated whether sporadic patients with brain MRI suggestive of CADASIL may carry mutations in the entire NOTCH3 gene, even in the absence of a positive familial history. Methods. We reviewed brain MRIs of patients suspected of having cerebrovascular disease referred to the Institute of Neurological Sciences (Mangone) and the Department of Neuroradiology (Bari). Eligible images presented confluent periventricular T2-hyperintensity in addition to 1) an increased T2-signal from the external capsule or 2) the anterior temporal lobe, or 3) thalamic microbleeds, all of these signs considered highly suggestive of CADASIL.3,4 Patients with at least two of these MRI features underwent the mutational screening of the entire NOTCH3 gene. These patients were asked to partic-

4. 5.

Zee DS, Leigh RJ, Mathieu-Millaire F. Cerebellar control of ocular gaze stability. Ann Neurol 1980;7:37–40. Arnold DB, Robinson DA, Leigh RJ. Nystagmus induced by pharmacological inactivation of the brainstem ocular motor integrator in monkey. Vision Res 1999;39:4286–4295.

ipate in the prospective study for peripheral blood collection, and detailed pedigrees spanning at least three generations were obtained. All patients gave written informed consent under the institutional review board–approved protocol. Genomic DNA was extracted by standard procedures. The NOTCH3 gene mutation analysis consisted of PCRs followed by denaturing highperformance liquid chromatography and direct sequencing of the suspected exons. Results. MRIs from 641 patients were screened; the scans of 31 patients (4.8%) were considered highly suggestive of CADASIL, since they all displayed T2hyperintensities of external capsule, 73% with additional temporal pole impairment and 32% also with thalamic microbleeds (table). Twenty-two of these patients underwent the blood collection; at the time of the enrollment, none of them reported having relatives who had CADASIL symptoms. In three of them (13.6%), we identified three NOTCH3 gene mutations involving a cysteine residue, precisely in exon 10 (C531S), in exon 11 (Y574C), and in exon 19 (R1006C) (table). Additionally, two nucleotide substitutions were detected, both leading to amino acid changes not involving a cysteine residue (in exons 4 and 12). No skin biopsies were performed. Clinical features of the 22 patients (mean current age: 69.32 ⫾ 9.06 years) are reported in the table; no difference has been found in the occurrence of conventional vascular risk factors between the patients carrying or not the NOTCH3 mutations (Fisher test: p ⫽ 0.99). Discussion. This observation shows that 13.6% of the patients with MRI suggestive of CADASIL and apparently negative familial history for the disease carry the typical NOTCH3 gene mutations involving the cysteine residues within the epidermal growth factor (EGF)–like repeats of the protein.1 Two further mutations not involving the cysteine residues were identified, but their pathogenic interest is under investigation. To date, evidence indicates that the prevalence of CADASIL may be underestimated, mostly because of incomplete family histories2; i.e., either the patient is unable to accurately report the existence of the disease in other family members or they were not diagNeurology 72

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Table

Demographic and clinical features of patients who underwent the NOTCH3 gene mutation screening Conventional MRI features

Patient 1

Gender M

Age at onset, y

Cardiovascular risk factor

Symptoms at onset

Periventricular confluence

54

⫹

Seizures

⫹

NOTCH3 gene screening

Anterior temporal pole

External Thalamic capsule microbleeds

Mutation site

Amino acid change*

⫹

⫹

c.529 (C⬎G)

Q151E

⫹

2

F

48

⫺

Stroke

⫹

⫹

⫹

3

F

58

⫹

Minor stroke

⫹

⫹

⫹

⫹

4

M

55

⫺

Stroke

⫹

5

F

43

⫹

Migraine

⫹

⫹

6

F

57

⫺

Migraine ⫹ cognitive decline

⫹

7

F

46

⫹

Stroke

⫹

8

F

60

⫺

Migraine ⫹ minor stroke

⫹

9

M

59

⫹

Cognitive decline

⫹

⫹

10

M

54

⫺

Psychiatric disturbances

⫹

⫹

⫹ ⫹

⫹

— —

—

—

c.3094 (C⬎T)

R1006C

c.1799 (A⬎G)

Y574C

—

—

c.1670 (G⬎C)

C531S

⫹

—

—

⫹

—

—

⫹

⫹ ⫹

— —

⫹

⫹

11

F

61

⫺

Migraine ⫹ seizures

⫹

⫹

⫹

—

—

12

F

56

⫺

Seizures

⫹

⫹

⫹

—

—

13

M

60

⫹

Stroke

⫹

—

—

14

M

58

⫹

Migraine ⫹ cognitive decline

⫹

⫹

⫹

—

—

15

F

55

⫺

Stroke

⫹

⫹

⫹

—

—

16

M

56

⫺

Stroke

⫹

⫹

⫹

—

—

17

M

50

⫹

Stroke

⫹

⫹

⫹

—

—

18

M

56

⫺

Stroke

⫹

⫹

⫹

—

—

19

M

55

⫹

Minor stroke

⫹

⫹

⫹

—

—

20

F

59

⫹

Cognitive decline

⫹

⫹

⫹

—

—

21

F

48

⫺

Migraine

⫹

⫹

⫹

—

—

22

F

20

⫺

Migraine

⫹

⫹

⫹

c.2009 (T⬎A)

V644D

⫹

⫹

*International nomenclature for amino acid identification: Q ⫽ glutamine; E ⫽ glutamate; R ⫽ arginine; C ⫽ cysteine; Y ⫽ tyrosine; S ⫽ serine; V ⫽ valine; D ⫽ aspartate.

nosed owing to the non-specificity of symptoms. Alternatively, relatives of the patients might complain of suggestive neurologic signs later in their lives. Otherwise, de novo mutations of NOTCH3 gene have been already described.6 Some authors tried to identify incident CADASIL by screening patients with lacunar stroke at MRI but, since they previously found NOTCH3 mutations only in four exons of the gene, they limited the molecular testing to these exons even in sporadic cases, with an overall mutation frequency of 0.05%.7 As reported here, this approach can lead to a missed diagnosis of CADASIL in the sporadic leukoencephalopathies. We suggest that the mutation screening of the entire NOTCH3 gene should be considered in patients with brain MRI indicative of CADASIL and (apparently) negative familial history of the disease, although formal genetic counseling is recommended. 470

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e-Pub ahead of print on December 3, 2008, at www.neurology.org. *These authors contributed equally. From the Institute of Neurological Sciences (M.L., R.M., C.U., P.L., F.L.C., A.Q.), National Research Council, Mangone; Departments of Neurological and Psychiatric Sciences (I.L.S., I.P.) and Neuroradiology (L.C.), University of Bari; Institute of Neurology (A.G., U.A., F.B., A.Q.) and Institute of Neuroradiology (F.F.), University “Magna Graecia,” Catanzaro; and Presidio Ospedaliero “Jazzolino” (D.C.), Vibo Valentia, Italy. Disclosure: The authors report no disclosures. Received May 2, 2008. Accepted in final form September 2, 2008. Address correspondence and reprint requests to Prof. Aldo Quattrone, Institute of Neurological Sciences, National Research Council, Contrada Burga, 87050 Mangone (CS), Italy; [email protected] Copyright © 2009 by AAN Enterprises, Inc. 1.

2.

Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707–710. Razvi SS, Davidson R, Bone I, Muir KW. Is inadequate family history a barrier to diagnosis in CADASIL? Acta Neurol Scand 2005;112:323–326.

3.

4.

Auer DP, Putz B, Gossl C, Elbel G, Gasser T, Dichgans M. Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic leukoencephalopathy: MR imaging study with statistical parametric group comparison. Radiology 2001;218:443–451. van den Boom R, Lesnik Oberstein SA, Ferrari MD, Haan J, van Buchem MA. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR imaging findings at different ages—3rd– 6th decades. Radiology 2003;229:683–690.

5.

6.

7.

Dotti MT, Federico A, Mazzei R, et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry 2005;76:736–738. Joutel A, Dodick DD, Parisi JE, Cecillion M, TournierLasserve E, Bousser MG. De Novo mutations in the Notch3 gene causing CADASIL. Ann Neurol 2000;47:388– 391. Dong Y, Hassan A, Zhang Z, et al. Yield of screening for CADASIL mutations in lacunar stroke and leukoaraiosis. Stroke 2003;34:203–206.

From the AAN History Library Collection Dana’s Text-book of Nervous Diseases and Psychiatry (1892) New York neurologist Charles Loomis Dana (1852–1935), Professor of Diseases of the Mind and Nervous System at the New York Post-Graduate Hospital (1884 –1895) and later Professor of Diseases of the Nervous System at the newly founded Cornell University medical College (1898 until his retirement in the mid-1920s), served twice as President of the American Neurological Association (1892 and1928). Dana’s Text-book of Nervous Diseases (1892)1 was one of the most popular and influential general neurology texts from the end of the 19th century through the first quarter of the 20th century. This single-author text was first published in 1892 and went through 10 editions, the last published in 1925. As noted by Jelliffe in his obituary of Dana, the continued popularity of this text was “an unprecedented event in neurology.”2–3 As recently as 1975, McDowell and Denny-Brown remarked that “the quality of the first edition [of Dana’s text] was outstanding, and it was undoubtedly the first well-organized neurological textbook by an American neurologist . . .. The quality of the tenth and last edition of this book is impressive even when compared with contemporary neurological texts. Having been written by one man it stands out even more as a monumental achievement.”4 This illustration from Dana’s textbook shows elicitation of the triceps jerk with Dana’s modification (c.1892) of a triangular-headed Taylor (c.1888) reflex hammer.5 Douglas J. Lanska, MD, MS, MSPH, FAAN Chairman, AAN History Section 1. Dana CL. Text-book of Nervous Diseases and Psychiatry for the Use of Students and Practioners of Medicine. New York: Wood, 1892. 2. Jelliffe SE. Charles Loomis Dana, M.D. J Nerv Ment Dis 1926;83:622– 637. 3. Jelliffe SE. Charles Loomis Dana, M.D.: 1852–1935. Trans Am Berik Assic 1936;62:187–193. 4. McDowell F, Denny-Brown D. Charles Loomis Dana: 1852–1935. In: Denny-Brown D, Rose AS, Sahs AL, eds. Centennial Anniversary Volume of the American Neurological Association: 1875–1975. New York: Springer, 1975:96 –101. 5. Lanska DJ. The Dana reflex hammer (c.1892). J Child Neurol 1995;10:367–368. The American Academy of Neurology (AAN) Library Collection originated with a long-term donation of several thousand neurology-related books, many of them rare, by H. Richard Tyler, MD. The collection comprises more than 3,500 books, making it one of the world’s most significant research resources for the history of neurology and neurosciences. All the materials in the AAN collection are organized, processed, and easily retrievable for research. AAN members may use the collection by contacting Lilla Vekerdy, Librarian, at [email protected] or (314) 362-4235. If you have a passion for the history of neurology, consider applying for the H. Richard Tyler Award from the AAN which was established to encourage historical research using the AAN Library Collection at the Bernard Becker Medical Library at the Washington University School of Medicine in St. Louis. The award provides up to $1,200 for research expenses and is open to AAN members and non-members. For more information about the award, visit www.aan.com/libv or contact Jeff Sorenson at [email protected] or (651) 695-2728.

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NEUROIMAGES

Direct visualization of remyelination in multiple sclerosis using T2-weighted high-field MRI Figure

Demyelinated (block arrow) and partially remyelinated (red arrow ⴝ demyelinated; blue arrows ⴝ remyelinated) lesions in postmortem multiple sclerosis brain

Spin-echo MRI (relaxation time ⫽ 3,000 msec, echo time ⫽ 60 msec, field of view ⫽ 30 ⫻ 30 mm2, matrix size 256 ⫻ 256 [⬃117 ␮m2 in-plane resolution], 16 averages). The corresponding histologic section was immunostained for myelin basic protein.

In multiple sclerosis (MS), remyelination may restore conduction and prevent axonal degeneration.1 Ability to monitor remyelination in MS in vivo would benefit natural history studies and clinical trials of novel drugs.2 High-field MRI (ⱖ3 T) is a promising tool to detect remyelination. We scanned a block of postmortem MS brain at 9.4 T. Histology revealed two areas of demyelination, and one showing remyelination. These findings corresponded to distinct changes visible on the T2-weighted MRI (figure). As human high-field MRI systems become increasingly widespread, remyelination in patients with MS may become detectable on T2-weighted scans. Klaus Schmierer, PhD, Harold G. Parkes, PhD, Po-Wah So, PhD, London, UK Supported by the Wellcome Trust (grant 075941) and the Multiple Sclerosis Society of Great Britain & Northern Ireland. Disclosure: The authors report no disclosures. Address correspondence and reprint requests to Dr. Klaus Schmierer, Institute of Neurology, University College London, Department of Neuroinflammation, NMR Research Unit, Queen Square, London WC1N 3BG, UK; [email protected] 1. 2.

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Rodriguez M. Effectors of demyelination and remyelination in the CNS: implications for multiple sclerosis. Brain Pathol 2007;17:219–229. Zhao C, Zawadzka M, Roulois AJA, Bruce CC, Franklin RJM. Promoting remyelination in multiple sclerosis by endogenous adult neural stem/precursor cells: Defining cellular targets. J Neurol Sci 2008;265:12–16.

Copyright © 2009 by AAN Enterprises, Inc.

RESIDENT & FELLOW SECTION Section Editor Mitchell S.V. Elkind, MD, MS

Sarah I. Sheikh, MD, MRCP

Address correspondence and reprint requests to Dr. Sarah I. Sheikh, Neurology Resident, WACC 835, MGH, 55 Fruit St., Boston, MA 02114 [email protected]

International Issues: Of saints and sickness A neurology elective in India

Standing at the top of Humayun’s Tomb (figure 1), I had a wonderful view over Delhi. It was the end of February. Spring had suddenly struck and the thermometer climbed. Kites in the hundreds rode the thermals and green parrots filled the air with their screeches. It was a peaceful scene of a building on which the Taj Mahal was modeled and is the final resting place of the 16th century Moghul ruler Humayun, who fell to his death while descending the steps of his library. It was the perfect place to stand back, think about a fascinating month, and distance myself from a sense of being overwhelmed by sheer numbers of people, impressions, and contrasts. A resident, halfway through my 3-year neurology residency, I had come to India to spend an elective rotation in neurology at the All India Institute of Medical Sciences in Delhi, known to the locals as AIIMS (figure 2). It is considered to be one of India’s finest government medical institutions, serving not only the citizens of a multi-million bustling metropolis but also those in search of a cure from all over India. Battling through the dust and traffic on my 1-hour drive to the hospital in the morning, I pass a daily repeating scene: small Suzuki Marutis jostling for space with motor scooters, cycle rickshaws, cyclists, pedestrians, and the occasional tractor or elephant; cows munching on rubbish in the middle of the road, the barber shaving a man at his roadside stand, throngs of small uniformed children on their way to school. A cyclist with a monkey perched calmly on the cycle rack, a man with a red turban on a scooter, a young lady balancing herself elegantly on the back and adjusting her flowing dress in the wind. I would arrive to dozens of people, young and old, crouching in the dust in front of the hospital building, lying on pieces of cardboard, wrapped in woolen shawls, cotton wool in their ears to fend off the morning chill. Whole family scenes unfolded here: food was eaten from metal tiffin carriers, children were washed and wounds dressed, monkeys and stray dogs joining this organic me´lange.

From Massachusetts General Hospital, Boston. Disclosure: The author reports no disclosures. e24

Copyright © 2009 by AAN Enterprises, Inc.

Patients would come from all over India, perhaps as far as 3 days’ journey away, to seek help from an AIIMS doctor, revered as among the most knowledgeable and dedicated in the country. Our postgraduate education might be considered to be long but theirs is even longer: after medical school, a year’s internship, and 3 years in internal medicine, a specialty training position is awarded usually based on rankings in national examinations (AIIMS has a separate entrance examination). It is a highly competitive process and medical specialties, such as cardiology and radiology, I was told, were currently more sought after than surgical ones. There were around a dozen residents spread over a 3-year program. Split into two teams and supervised by around 10 rotating attendings, they covered roughly 70 inpatients and 200 outpatients per day. The residents usually had 10- to 12-hour days and Saturday was considered a normal working day, as it seemed to be for most other professions in India. Overnight calls were split evenly between the residents, and usually a junior and a senior resident took calls together to cover the wards, new admissions, emergency room, and ward consultations. Communication was entirely by cell phone and pagers had been relegated to history. On a bad call day, they might admit 10 patients, see up to 30 emergency room patients, and get another 20 consults in addition to attending their own ward rounds, teaching rounds, and outpatient clinic. And all this with only one computer dedicated to the residents. How do they do it, I wondered. Over the next few weeks, I had a chance to see and learn how they coped in a system so very different from what I was used to. Being a government hospital, care is free, though tests and medications have to be paid for and procured by the patient. Hardly anybody has health insurance and an interesting mix of schemes and offers has developed: there are government hospitals, essentially free but usually underfunded; private hospitals,

Figure 1

Humayun’s tomb

such as the Apollo hospital chain, whose marbled corridors cater to the local rich as well as international medical “tourists” (traveling from Kenya for cardiac bypass surgery or from the United Kingdom for a knee replacement); and then there are private clinics. Most tend to prefer these smaller private clinics, found in plenty in all neighborhoods, advertising their services with gleaming white boards and neon colors. These small clinics might be run by a husband and wife Figure 2

team, have a few nurses, a dietician, perhaps a social worker and physical therapist, such as the clinic run by a couple I met who came from an entire medical family. Of five sisters, all were doctors married to doctors of a specialty complementary to theirs. Back at AIIMS, the waiting room is full. I barely manage to squeeze through roughly 200 people who fill the large atrium in front of the clinic corridors. They stand in lines, divided into old and new patients, and have to register before 10:30 AM so that their files can be pulled for the day’s clinic. Everybody seems preoccupied with their own worries and thoughts and despite the crowds there is a hushed silence. There are two residents, in white coats, holding simultaneous reign over one small clinic room. It is still quite cold this morning but there are no provisions for heating. The paint is peeling from the walls in large strips and the tap drips a steady rhythm. There is a metal stretcher in one corner of the room, a blood pressure cuff, and a scale. The doctors sit on opposite sides of a table, stacks of notes between them. The patients’ names are hurtled into the waiting room, the cry taken up by all those waiting to try and spur the lucky next patient into the consultation room. A few patients just walk in without being asked, standing by the door patiently until they can catch the doctor’s eye to ask for a signature, a repeat prescription, or a consultation. With great concentration and gusto the two residents dive into their pile of notes and start seeing patients. There is no privacy. No curtain to hide the

Neurology inpatient ward at the All India Institute of Medical Sciences

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wasted leg which one man reveals, dropping his trousers (he has wasted leg syndrome, a tropical form of anterior horn cell disease), or to conceal the depigmented lesions on another man’s torso (he has leprosy). Histories are taken in Hindi in front of a large audience of relatives, other patients, and drug reps, who keep coming into the room unsolicited. The notes are then written in English into the cardboard bound paper charts and communication among the doctors themselves is a curious mix of English and Hindi. They are kind to include me by translating snippets of the conversation into English. A young woman, threatened with marriage by her parents, comes with difficulty walking but without objective neurologic deficits, and the mother confirms that she will have the girl married “as soon as she can walk again.” A 22-year-old woman complains of sudden early morning jerking preceding generalized seizures: juvenile myoclonic epilepsy. She is started on valproate and can choose to come for follow-up on Tuesday, Thursday, or Saturday, the clinic days of this particular team. A 27-year-old man comes with a first seizure; his neurologic examination is non-focal. He, like so many other patients, clutches an old plastic bag containing all his notes and a CT scan. This shows multiple small, calcified lesions with minimal edema. He has neurocysticercosis. The scan cost him around 200 rupees ($5 or about 2 days’ earnings for taxi drivers, such as mine). An MRI would cost around 2,000 rupees ($50), the IV contrast another 800 rupees. There is no routine handwashing but there is alcohol hand rub in the room, which is used rarely. The tea lady interrupts us and brings small paper cups filled with fragrant cardamon chai, which she carries in an old sugar box. That day, we also see tuberculomas, more epilepsy, Parkinson disease, carpal tunnel syndrome, headache, conversion disorder, strokes, and intracranial abscess, but no brain tumor (these go directly to neurosurgery). Occasionally, I partake in inpatient teaching rounds; they are quite an experience. Three attendings preside over case presentations and one resident gets picked to discuss the case and then has to answer a barrage of questions on the presumed pathophysiology, anatomy, differential diagnosis, and the merits and shortcomings of chosen investigations. If he fails to provide acceptable answers, the Socratic baton gets passed to the next victim. Perhaps this is not the most comfortable way of learning but it certainly seems to be effective. On the wards, men and women share the same rooms. There are no curtains to pretend that there is even a modicum of privacy. Each patient has a relae26

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tive by the bedside who helps with daily care, and goes to fetch any devices or medications which might be needed. Few medications are in stock on the ward, so if IV fluids or medications are required, the doctor hands the relative a piece of paper with the name of the desired medication and the relative then disappears, to return a few minutes later with the required goods, miraculously procured from the local bazaar. Although some medications might be expensive, most families will do their utmost to scrape together what they have to help. We see meningococcal meningitis, subacute sclerosing panencephalitis, severe Parkinson disease, multisystem atrophy, tuberculous meningitis (sputum is not tested routinely to see whether there is lung tuberculosis), subacute stroke, varicella zoster encephalitis, and intracerebral hemorrhage with intraventricular extension. None of these patients is in the intensive care unit. They have a high dependency unit in which ventilated and nonventilated patients are monitored more closely. Only one bed has a monitor, but I see no pulse oximeter for the ventilated patients. It is still light outside as I wander out of the hospital. Groups of huddled waiting patients are getting ready to spend another night in front of the hospital or to go and visit one of the saints that so many people in Delhi revere and seek help from in times of need. One such tomb, that of Nizamuddin, lies in a marble complex at the end of a winding street in the old town. A fascinating mix of people, religions, and classes rub shoulders there, among them some of my patients. Around this area, too, some of the traditional medicine doctors, practicing Unani medicine in the ancient Greek tradition or Aryuvedic medicine, are also found, but on this visit, I do not get a chance to see one in action. I only hear patients’ accounts who combine the advice of a traditional healer with that of the AIIMS doctor in an attempt to cover all bases. I learned a lot during my Delhi medical travels: a lot of medicine and neurology, but also how doctors and patients cope in a very different medical system. These talented doctors could easily choose to work at higher paid institutions elsewhere. Instead they choose to dedicate themselves to caring for the underprivileged and often illiterate groups of society. Their rewards are a rich clinical experience: in numbers, in diagnoses, and in human encounters. This unique combination of efficiently delivered technology at reasonably affordable cost and dedicated physicians and health care workers is a great example of providing extraordinary care in extraordinarily challenging circumstances. ACKNOWLEDGMENT The author thanks Professor Madhuri Behari and her colleagues at the AIIMS Department of Neurology for allowing her to visit their department and learn from their expertise.

RESIDENT & FELLOW SECTION Section Editor Mitchell S.V. Elkind, MD, MS

Max R. Lowden, MD David Gill, MD

Teaching NeuroImage: Idiopathic hypertrophic spinal pachymeningitis Figure 1

Sagittal and axial MRI T2-weighted images

Figure 2

Hematoxylin and eosin stain of dural mass showing a chronic inflammatory infiltrate consisting of plasma cells and lymphocytes

Address correspondence and reprint requests to Dr. Max R. Lowden, Department of Neurology, The Pennsylvania State University Milton S. Hershey Medical Center, 30 Hope Drive, Hershey, PA 17033 [email protected]

(A) Sagittal MRI T2-weighted image showing a dural lesion of low signal intensity within the spinal canal at levels T2 to T5 extending anteriorly. (B) Axial MRI T2-weighted image at T3 and T4 level showing a dural mass (white arrow) in the anterior aspect of the spinal canal.

A 42-year-old woman had progressive numbness from both feet to mid chest for 2 weeks. Examination showed a sensory level at T8, no weakness, and brisk reflexes throughout. MRI showed T2–T5 dural thickening (figure 1). Testing revealed an elevated sedimentation rate and normal chest x-ray, CSF analyses, and tests for rheumatologic diseases and infections. Dural biopsy showed an inflammatory infiltrate (figure 2). Idiopathic hypertrophic pachymeningitis is a diagnosis of exclusion since it is associated with trauma, infection, and autoimmune diseases.

There is also fibrosis and reactive fibroblasts throughout.

Treatment consists of corticosteroids and steroid sparing agents.1 It is usually found intracranially and rarely involves cervical and higher thoracic levels.2 REFERENCES 1. Kupersmith MJ, Martin V, Heller G, Shah A, Mitnick HS. Idiopathic hypertrophic pachymeningitis. Neurology 2004;62:686–694. 2. Pai S, Welsh CT, Patel S, Rumboldt Z. Idiopathic hypertrophic spinal pachymeningitis: report of two cases with typical MR imaging findings. Am J Neuroradiol 2007;28: 590–592.

From the Department of Neurology, The Pennsylvania State University Milton S. Hershey Medical Center College of Medicine. Disclosure: The authors report no disclosures.

Copyright © 2009 by AAN Enterprises, Inc.

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Correspondence

THE ALS/PDC SYNDROME OF GUAM AND THE CYCAD HYPOTHESIS

To the Editor: In their review of the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) syndrome of Guam, Steele and McGeer1 argue against the cycad hypothesis of causation, noting the persistence of this disorder after 1950 when the regular consumption of cycad flour (fadang) among the native Chamorros ceased. The rapid decline in incidence of both ALS and PDC beginning in the 1950s and persisting for more than 50 years is well established.2 The occasional observation of new cases by Steele and McGeer is consistent with a disappearing syndrome resulting from a point exposure in the 1940s. Analysis of the 29 cases of PDC identified in our 2003 island-wide prevalence study reveals that all subjects were born before 1940 and would have had ample opportunity to be exposed to an environmental toxin in the 1940s.3 Steele and McGeer state that our findings of an association of cycad exposure with PDC, MCI, and Guam dementia (GD) “are inconsistent with any reasonable theory regarding fadang toxicity,” because of a protective effect of exposure in childhood and lack of association in adulthood.1 We pointed out that the protective effect in childhood is likely due to recall bias related to study design.4 Our findings of significantly elevated odds ratios for picking, processing, and eating fadang in early adulthood for all three outcomes (GD, MCI, and PDC) are consistent with a point-source exposure. These findings are also consistent with epidemiologic evidence showing a preponderance of affected men as well as reflecting a commonality in causation of all three disorders. The fact that adult exposures were not associated is likely due to the rapid decline in exposure rates of Chamorros to cycad during the 1960s and later when subjects reached adulthood, reducing the statistical power to detect an effect.4 Long-term cycad toxicity is plausible, based on recent studies that implicate toxins other than BMAA. For example, phytosterol glucosides that result in the excitotoxic release of glutamate lead to motor neuron and Parkinsonian phenotypes and pathology in cycad extract-fed mice.5

While alternative hypotheses are welcome, there are negligible data to support them. Steele and McGeer1 suggest that an infection that causes retinopathy may predispose to ALS/PDC. The infectious agent has never been identified, and there is no evidence that infectious retinal diseases trigger tangle formation in widespread regions of brain and spinal cord. Finally, the rapid decline in incidence is inconsistent with either a genetic or persisting environmental exposure. Amy R. Borenstein, Tampa, FL; James A. Mortimer, Gerard D. Schellenberg, Philadelphia, PA; Douglas Galasko, San Diego, CA Disclosure: The authors report no disclosures.

To the Editor: We read with interest the review by Steele and McGeer1 but disagree with their contention that cycads do not deserve serious consideration as possible causes of ALS/PDC in Guam. In what might be better labeled “the cyanobacteria/BMAA hypothesis,” cyanobacteria resident in specialized cycad roots produce the amino acid BMAA.6 This potent excitotoxin, produced by diverse species of cyanobacteria, is found in cycad seed flour and in animals which forage on cycad seeds, as well as in water supplies contaminated with Cyanobacteria.7 BMAA can biomagnify in the food chain, and occurs in a protein-bound form at concentrations 50 –100 times greater than as a free amino acid,6,8 which may explain previous negative reports. BMAA was found in blinded brain tissues of patients with ALS/PDC from Guam and in brain tissues of patients with Alzheimer disease (AD) from North America, but not in healthy controls.8 Researchers recently independently replicated the 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC)-tag method of BMAA analysis with high performance liquid chromatography with fluorescence detection (HPLC-FD), and found protein-bound BMAA in brain tissues of North American patients with AD and ALS.9 Patients with ALS (n ⫽ 13) had 134 ⫾ 13 ␮g/g mean BMAA concentration, patients with AD (n⫽12) had 111 ⫾ 15 ␮g/g mean BMAA concentration, while BMAA was undetected in 22/24 samples from 12 control patients (limit of detection ⫽ 2 ng Neurology 72

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on column), but was detected at 45 and 36 ␮g/g in 2/24 samples.9 Similar to how patients with phenylketonuria accumulate rather than metabolize the amino acid phenylalanine, vulnerable individuals may accumulate BMAA, which can then trigger latent neurodegeneration. It might seem surprising that two different clinicopathologic diseases—ALS and AD—may arise from the action of one environmental neurotoxin. However, there are several instances where a single gene mutation causes different diseases defined clinicopathologically (e.g., ALS, frontotemporal dementia, corticobasal degeneration, AD, Parkinson disease from mutations of progranulin and MAPT genes, limb girdle muscular dystrophy, and several different distal myopathies from mutations of dysferlin gene). Chamorros are exposed to BMAA through consumption of cycad flour, flying foxes, and other animals which forage on cycad seeds. Elsewhere in the world, BMAA exposure comes primarily from water contaminated with cyanobacteria. The cyanobacteria hypothesis suggests that a worldwide environmental neurotoxin precipitates sporadic ALS and AD, generates testable predictions, and offers new approaches to prevention and therapy. Walter G. Bradley, Sandra Anne Banack, Paul Alan Cox, Miami, FL Disclosure: The authors report no disclosures.

To the Editor: A recent article on ALS-PDC of Guam reviews some of the recent epidemiologic, genetic, and pathologic findings on this intriguing disorder and rightfully underscores its relevance as an important geographic isolate that might shed light on similar disorders elsewhere.1 In their examination of the etiologic factors, Steele and McGeer also revisit some of the environmental hypothesis and refute the cycad hypothesis. The authors state that the cycad hypothesis lacks scientific merit due to lack of supportive evidence. As an example of these failures, a brief discussion of the widely criticized cyanobacteria ␤-methylamino-Lalanine (BMAA) biomagnification hypothesis is presented. However, to further refute the cycad hypothesis, the authors omit scientific literature. A basic PubMed search reveals at least 25% of the published articles on this subject in the last 5 years including a feature review.10 Whatever the flaws in the recent article by Borenstein et al.,4 this study recapitulates the original conclusions of Whiting and others. The authors of the current review present their objections based on age at cycad exposure and use the apparent discrepancies to dismiss the entire hypothe474

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sis. However, age-dependent impacts of neurotoxins are well known. We have published over a dozen original articles clearly demonstrating an ALS-PDC phenotype in vivo and plausible putative neurotoxins in vivo and in vitro. The in vivo studies have shown that chronic dietary exposure to cycad flour leads to neurodegeneration in mice after prolonged exposure.11 These data confirm earlier observations on macaque monkeys fed washed and unwashed cycad flour. In addition, we have identified water-insoluble molecules that could be responsible for cycad neurotoxicity.12 We welcome critiques of the hypothesis that cycad toxins are not causal to ALS-PDC. Reyniel Cruz-Aguado, Christopher A. Shaw, Vancouver, BC, Canada Disclosure: The authors report no disclosures.

To the Editor: Steele and McGeer1 acknowledge the possible role of environmental factors in the etiology of the “Guam syndrome” while refuting the cycad hypothesis (specifically the minor cycad component L-BMAA) as a plausible environmental etiology for this prototypical neurodegenerative disease complex. The authors present incomplete cycad exposure information for the Japanese residents of the diseaseaffected region of Kii Peninsula of Honshu Island and the absence of any consideration of the comparable neurodegenerative disease focus in Auyu and Jaqai linguistic groups of West Papua, Indonesia. The only common environmental factor in these three genetically distinct, ALS/PDC-affected populations is the use of raw, non-detoxified Cycas spp seed for medicinal purposes. It is used as a poultice for open wounds in New Guinea and Guam, and as an oral tonic in the Kii Peninsula.13,14 Food use of poorly detoxified cycad seed is an additional historical exposure factor on Guam yet fully detoxified cycad products (stem and/or seed) have been used for food in the Japanese Ryukyu Islands and Northern Australia where Guam-like neurodegenerative disease foci are absent.14 There is a strong epidemiologic relationship for sampled Guam villages between the concentration of residual methylazoxymethanol (MAM, the aglycone of the principal cycad neurotoxin cycasin) in washed cycad flour and the 10-year age-adjusted incidence of ALS and PD. Cycad components and cycasin produce motor system disease in adult cattle.14 MAM is an established developmental neurotoxin in rodents, where it induces formation of ectopic, multinucleated Purkinje-like cells comparable to those reported in the cerebellum of deceased Guam and Kii ALS patients.14 It also damages rodent neuronal DNA and modulates tau expression in vitro15 and induces the

accumulation of synuclein in the brain of young mice.16 The ability of MAM to disrupt the metabolism of both synuclein and tau (including its phosphorylation) is evidence that is consistent with the classification of ALS/PDC as a synucleinopathy and tauopathy. Contrary to the view expressed by Steele and McGeer,1 these facts demonstrate the plausibility of a cycad hypothesis for Western Pacific ALS/PDC that emphasizes the role of the plant’s principal neurotoxin, MAM-beta-glucoside, while not excluding a role for BMAA. Peter S. Spencer, Valerie Palmer, Glen Kisby, Portland, OR Disclosure: The authors report no disclosures.

Reply from the Authors: Borenstein et al. defend the inconsistencies in their epidemiologic study as recall bias. We drew attention in our review to the difficulty of reaching firm conclusions based on remembering details of events that took place over 50 years previously. In this case-control study, the subjects were elderly Chamorros who in some cases had dementia. However, this is not the main reason for rejecting the notion that the consumption of cycad flour, or the picking of its seeds, could be responsible for the Guam disease. It is the gap, amounting to orders of magnitude, between the amounts of cycad that Chamorros must have had to consume and the amounts required to produce even weak toxicity in animals. If exposure to cycad itself fails for this reason, then exposure to its minor constituents also fails. This applies to the BMAA hypothesis put forward by Bradley et al., the ß-sitosterol glucoside (BSSG) hypothesis put forward by Cruz-Aguado et al., and the methylazoxymethanol (MAM) hypothesis put forward by Spencer et al. Bradley et al. have gone beyond the BMAA hypothesis as a cause of the Guam syndrome by proposing that BMAA, produced by cyanobacteria, is contaminating worldwide water supplies, causing AD and ALS. They describe BMAA as “this potent excitotoxin.” However, BMAA is not a potent excitotoxin. For example, rats were not seriously harmed by a continuous infusion of 100 mg/kg/day of BMAA over a 2-week period.17 Humans would have to consume a dose of about 5 kilograms per day of Cycas micronesica to be exposed even to these minimally effective levels of BMAA. Potent excitotoxins, such as kainic and ibotenic acids, have a dicarboxylic acid structure similar to glutamate so that they produce a neurotoxic action at glutamate receptors.18 BMAA, as a monocarboxylic acid, lacks the necessary structure. Bradley et al. quote astonishingly high

BMAA levels in the brains of Guam ALS/PDC as well as AD and ALS cases. The levels are at least four times higher than those obtained in the high dose BMAA rat infusion experiments. Significantly, there was no BMAA retained in the brain in these experiments.17 This argues against the protein binding theory proposed by Bradley et al. Such binding would not be expected in any event since BMAA lacks the prosthetic groups normally involved in hydrogen bonding to proteins. In our review, we pointed out that Montine et al., using a well established analytical technique, failed to detect any BMAA in the brains of AD cases, controls, or Chamorros with and without PDC. This indicates serious discrepancies in the analytical methods used for detecting BMAA. Those discrepancies need to be resolved. Bradley et al. state they have put forward a testable hypothesis. Since AD and ALS tissue is widely available, investigators will be able to determine whether or not their results can be replicated. Cruz-Aguado et al. hypothesize that chronic exposure to BSSG induces an ALS/PDC phenotype yet overlooked the extremely low concentrations of this material that have been found in cycad preparations. Originally, only 7.3 mg was obtained from 200 grams of washed flour.19 The authors fed mice 1 mg/ day of synthetic BSSG for 15 weeks. This would be equivalent to humans eating 2.5 grams per day of this constituent. If the original report of its concentration in cycad is anywhere near quantitative, this would require a human to consume 68,000 grams of cycad flour per day. The mice survived this regimen and the authors did not identify motor deficits in their mice in such measures as open field behavior and motor strength, although they did report reduced counts of spinal motor neurons on autopsy. We do not consider that these results constitute an ALS PDC phenotype. Like the BMAA hypothesis, we do not consider that this hypothesis merits serious scientific consideration. Spencer and colleagues propose that the toxic constituent in cycad flour is methylazoxymethanol (MAM). They suggest that the MAM hypothesis explains not just the Guam disease, but also the Kii Peninsula disease and possibly a similar but unproven disease in West Papua, New Guinea. Kisby et al. injected a dose of 43 mg/kg of MAM to newborn mice and then observed small developmental changes in the cerebellum.12 That dose would be equivalent to more than 2 grams of MAM to a human. MAM comes from cycasin, which constitutes 2– 4% of unwashed cycad flour and 0.004 –75.93 ␮g/g of washed cycad flour.11 Since Guamanians were known to eat only washed cycad flour, this would translate to a conNeurology 72

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sumption of between 1,300 and 250,000,000,000 grams of washed flour. Studies of adult rats fed cycasin or raw cycad flour failed to demonstrate major pathologic changes or deficits in behavior.20 In the Kii Peninsula, there are two small foci each of five villages with ALS/PDC separated by 200 km with no neurologic disorders in other coastal and inland villages between them. Kuzuhara et al.21 concluded that the epidemiologic, clinical, pathologic, and immunologic features of ALS/PDC were the same on Guam and in the Kii Peninsula. In October 2007, Kuzahara et al.22 wrote: “None of the patients had the habit of eating the cycad, flying fox, or any other odd materials.” We do not agree that the data presented by Spencer et al. demonstrate the plausibility of a cycad hypothesis. Patrick L. McGeer, John C. Steele, Vancouver, BC, Canada Disclosure: The authors report no disclosures.

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Copyright © 2009 by AAN Enterprises, Inc. 1.

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Steele JC, McGeer PL. The ALS/PDC syndrome of Guam and the cycad hypothesis. Neurology 2008;70: 1984 –1990. Plato CC, Garruto RM, Galasko D, et al. Amyotrophic lateral sclerosis and Parkinsonism-dementia complex of Guam: changing incidence rates during the past 60 years. Am J Epidemiol 2003;157:149 –157. Galasko D, Salmon D, Gamst A, et al. Prevalence of dementia in Chamorros on Guam: relationship to age, gender, education and APOE. Neurology 2007;68:1772–1781. Borenstein AR, Mortimer E, Schofield E, et al. Cycad exposure and risk of dementia, MCI and PDC in the Chamorro population of Guam. Neurology 2007;68: 1764 –1771. Wilson J, Shaw CA. Commentary on: Return of the cycad hypothesis: does the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health? Neuropathol Appl Neurobiol 2006;32:341–343. Cox PA, Banack SA, Murch SJ. Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proc Natl Acad Sci USA 2003;100:13380 –13383. Metcalf JS, Banack SA, Lindsay J, Morrison LF, Cox PA, Codd GA. Co-occurrence of beta-N-methylamino-Lalanine, a neurotoxic amino acid, with other cyanobacterial toxins in British waterbodies, 1990 –2004. Environ Microbiol 2008;10:702–708. Murch SJ, Cox PA, Banack SA. A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc Natl Acad Sci USA 2004;101:12228 –12231. Mash D, Pablo J, Banack SA, et al. Neurotoxic nonprotein amino acid BMAA in brain from patients dying with ALS and Alzheimer’s disease: American Academy of Neurology annual meeting: P06.127. Neurology 2008; 70(suppl 1):A329. Miller G. Guam’s deadly stalker: on the loose worldwide? Science 2006;313:428 – 431.

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Wilson JM, Khabazian I, Wong MC, et al. Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour. Neuromolecular Med 2002;1:207–221. Tabata RC, Wilson JM, Ly P, et al. Chronic exposure to dietary sterol glucosides is neurotoxic to motor neurons and induces an ALS-PDC phenotype. Neuromolecular Med 2008;7:24 –39. Spencer PS, Palmer VS, Ludolph AC. On the decline and etiology of high-incidence motor system disease in West Papua (southwest New Guinea). Mov Disord 2005;20: S119 –126. Spencer PS, Kisby GE, Palmer VS, Obendorf P. Cycasin, methylazoxymethanol and related compounds. In: Spencer PS, Schaumburg HH, eds. Experimental and Clinical Neurotoxicology, 2nd edition. New York: Oxford University Press; 2000:436 – 446. Esclaire F, Kisby G, Spencer P, Milne J, Lesort M, Hugon J. The Guam cycad toxin methylazoxymethanol damages neuronal DNA and modulates tau mRNA expression and excitotoxicity. Exp Neurol 1999;155:11–21. Kisby GE, Standley M, Park T, et al. Proteomic analysis of the genotoxicant methylazoxymethanol (MAM) induced changes in the developing cerebellum. J Proteome Res 2006;5:2656 –2665. Duncan MW, Nelly E, Villacreses PG, et al. 2-Amino-3(methylamino)-propanoic acid (BMAA) pharmacokinetics and blood-brain barrier permeability in the rat. J Pharm Exp Ther 1991;258:27–35. McGeer EG, Olney J, McGeer PL, eds. Kainic Acid as a Tool in Neurobiology. New York: Raven Press; 1978. Khabazian I, Bains JS, Williams DE, et al. Isolation of various forms of sterol B-D-glucoside from the seed of Cycas circinalis: neurotoxicity and implications for the ALSparkinsonian dementia complex. J Neurochem 2002;82: 516 –528. Campbell ME, Mickelsen O, Yang MG, Laqueur GL, Keresztesy JC. Effects of strain, age and diet on the response of rats to the ingestion of Cycas circinalis. J Nutr 1966;88:115–124. Kuzuhara S, Kokubo Y, Sasaki R, et al. Familial Amyotrophic lateral sclerosis and Parkinsonism-dementia complex of the Kii Peninsula of Japan: Clinical and neuropathological study and tau analysis. Ann Neurol 2001;49:501–511. Kuzuhara S. Revisit to Kii ALS: the innovated concept of ALS/Parkinsonism-dementia complex, clinicopathological features, epidemiology and etiology (in Japanese with English abstract). Brain Nerve 2007;59:1065–1074.

IS IT TIME FOR NEUROHOSPITALISTS?

To the Editor: We read the invited article by Freeman et al.1 regarding the advantages of neurohospitalists, which represents an emerging field of neurology serving cost-effective, high-quality medical care to the inpatient population. The authors postulated potential advantages of improved logistical efficiency leading to improved patient outcome but how this is achieved was not explained. In our 400-bed academic medical center at the University of California, Irvine (UCI), the Hospitalist Program consists of 16 board-certified hospitalists

physicians from nine medical specialties: internal medicine, family medicine, pediatrics, neurology, geriatrics, palliative care, adult infectious disease, pediatric infectious disease, and critical care. One of us (G.Y.C.) joined the UCI Hospitalist Program as the first full-time neurohospitalist more than 2 years ago. Although no previous comparable data are available, our experience in forming a true multidisciplinary Hospitalist Program with specialists from various medical disciplines located in the same office and attending required hospitalist faculty meetings and hospitalist-oriented weekly conferences has enhanced inpatient based communication and facilitated a more collaborative approach to patient care and education. We also instituted daily critical care hospitalist– neurohospitalist “handshake rounds” in which the two hospitalist teams (neurohospitalist attending plus housestaff and critical care hospitalist attendings plus housestaff) meet briefly during morning rounds to discuss clinical data as well as medical–legal and ethical aspects of patient care. This is more difficult to accomplish in the traditional approach. We agree with the authors that the neurohospitalist model will continue to expand and grow. Our experience of adding a neurohospitalist to our multidisciplinary Hospitalist Program has been advantageous for patient care, education of our trainees, and developing collaborative, progressive models of multidisciplinary inpatient care processes. Gregory Y. Chang, Alpesh Amin, Orange, CA Disclosure: The authors report no disclosures.

Reply from the Authors: Drs. Chang and Amin inquire about the method by which neurohospitalists provide improved outcomes in health care delivery to medicine or pediatric hospitalists. Neurohospitalists provide similar if not equal outcomes as other hospitalists by standardizing quality measures (i.e., deep vein thrombosis prevention), providing improved emergency department coverage, and reducing length of hospitalization.2– 4 We note the authors’ review of their experience at UCI Hospitalist Practice. We acknowledge there are different and diverse hospitalist systems that can achieve similar patient outcomes and quality results in the current US healthcare system. William D. Freeman, Gary Gronseth, Benjamin H. Eidelman, Jacksonville, FL Disclosure: Drs. Freeman and Eidelman report no conflicts of interest. Dr. Gronseth is a member of Boehringer Ingelheim Pharmaceutical’s speaker’s bureau. Copyright © 2009 by AAN Enterprises, Inc. 1. 2.

3.

4.

Freeman WD, Gronseth G, Eidelman BH. Is it time for neurohospitalists? Neurology 2008;70:1282–1288. Auerbach AD, Wachter RM, Katz P, et al. Implementation of a voluntary hospitalist service at a community teaching hospital: improved clinical efficiency and patient outcomes. Ann Intern Med 2002;137:859 – 865. Coffman J, Rundall TG. The impact of hospitalists on the cost and quality of inpatient care in the United States: a research synthesis. Med Care Res Rev 2005;62:379 – 406. Davis KM, Koch KE, Harvey JK, Wilson R, Englert J, Gerard PD. Effects of hospitalists on cost, outcomes, and patient satisfaction in a rural health system. Am J Med 2000;108:621– 626.

AAN CME: Quick, Convenient, Smart. The AAN makes earning your continuing medical education (CME) credits more convenient than ever with a host of unparalleled CME opportunities. Whether you choose online, print, or classroom, rest assured that AAN CME is designed by top experts in neurology specifically to help you fulfill your Maintenance of Certification requirements and stay current in the field. Quick and convenient has never been so smart. • Neurology Online CME • Continuum: Lifelong Learning in Neurology® • Quintessentials® • Online CME Tracker • 2009 Winter Conference, Lake Buena Vista, FL • 2009 AAN Annual Meeting, Seattle, WA • More Learn more at www.aan.com/cme.

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Correspondence

THE ALS/PDC SYNDROME OF GUAM AND THE CYCAD HYPOTHESIS

To the Editor: In their review of the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) syndrome of Guam, Steele and McGeer1 argue against the cycad hypothesis of causation, noting the persistence of this disorder after 1950 when the regular consumption of cycad flour (fadang) among the native Chamorros ceased. The rapid decline in incidence of both ALS and PDC beginning in the 1950s and persisting for more than 50 years is well established.2 The occasional observation of new cases by Steele and McGeer is consistent with a disappearing syndrome resulting from a point exposure in the 1940s. Analysis of the 29 cases of PDC identified in our 2003 island-wide prevalence study reveals that all subjects were born before 1940 and would have had ample opportunity to be exposed to an environmental toxin in the 1940s.3 Steele and McGeer state that our findings of an association of cycad exposure with PDC, MCI, and Guam dementia (GD) “are inconsistent with any reasonable theory regarding fadang toxicity,” because of a protective effect of exposure in childhood and lack of association in adulthood.1 We pointed out that the protective effect in childhood is likely due to recall bias related to study design.4 Our findings of significantly elevated odds ratios for picking, processing, and eating fadang in early adulthood for all three outcomes (GD, MCI, and PDC) are consistent with a point-source exposure. These findings are also consistent with epidemiologic evidence showing a preponderance of affected men as well as reflecting a commonality in causation of all three disorders. The fact that adult exposures were not associated is likely due to the rapid decline in exposure rates of Chamorros to cycad during the 1960s and later when subjects reached adulthood, reducing the statistical power to detect an effect.4 Long-term cycad toxicity is plausible, based on recent studies that implicate toxins other than BMAA. For example, phytosterol glucosides that result in the excitotoxic release of glutamate lead to motor neuron and Parkinsonian phenotypes and pathology in cycad extract-fed mice.5

While alternative hypotheses are welcome, there are negligible data to support them. Steele and McGeer1 suggest that an infection that causes retinopathy may predispose to ALS/PDC. The infectious agent has never been identified, and there is no evidence that infectious retinal diseases trigger tangle formation in widespread regions of brain and spinal cord. Finally, the rapid decline in incidence is inconsistent with either a genetic or persisting environmental exposure. Amy R. Borenstein, Tampa, FL; James A. Mortimer, Gerard D. Schellenberg, Philadelphia, PA; Douglas Galasko, San Diego, CA Disclosure: The authors report no disclosures.

To the Editor: We read with interest the review by Steele and McGeer1 but disagree with their contention that cycads do not deserve serious consideration as possible causes of ALS/PDC in Guam. In what might be better labeled “the cyanobacteria/BMAA hypothesis,” cyanobacteria resident in specialized cycad roots produce the amino acid BMAA.6 This potent excitotoxin, produced by diverse species of cyanobacteria, is found in cycad seed flour and in animals which forage on cycad seeds, as well as in water supplies contaminated with Cyanobacteria.7 BMAA can biomagnify in the food chain, and occurs in a protein-bound form at concentrations 50 –100 times greater than as a free amino acid,6,8 which may explain previous negative reports. BMAA was found in blinded brain tissues of patients with ALS/PDC from Guam and in brain tissues of patients with Alzheimer disease (AD) from North America, but not in healthy controls.8 Researchers recently independently replicated the 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC)-tag method of BMAA analysis with high performance liquid chromatography with fluorescence detection (HPLC-FD), and found protein-bound BMAA in brain tissues of North American patients with AD and ALS.9 Patients with ALS (n ⫽ 13) had 134 ⫾ 13 ␮g/g mean BMAA concentration, patients with AD (n⫽12) had 111 ⫾ 15 ␮g/g mean BMAA concentration, while BMAA was undetected in 22/24 samples from 12 control patients (limit of detection ⫽ 2 ng Neurology 72

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on column), but was detected at 45 and 36 ␮g/g in 2/24 samples.9 Similar to how patients with phenylketonuria accumulate rather than metabolize the amino acid phenylalanine, vulnerable individuals may accumulate BMAA, which can then trigger latent neurodegeneration. It might seem surprising that two different clinicopathologic diseases—ALS and AD—may arise from the action of one environmental neurotoxin. However, there are several instances where a single gene mutation causes different diseases defined clinicopathologically (e.g., ALS, frontotemporal dementia, corticobasal degeneration, AD, Parkinson disease from mutations of progranulin and MAPT genes, limb girdle muscular dystrophy, and several different distal myopathies from mutations of dysferlin gene). Chamorros are exposed to BMAA through consumption of cycad flour, flying foxes, and other animals which forage on cycad seeds. Elsewhere in the world, BMAA exposure comes primarily from water contaminated with cyanobacteria. The cyanobacteria hypothesis suggests that a worldwide environmental neurotoxin precipitates sporadic ALS and AD, generates testable predictions, and offers new approaches to prevention and therapy. Walter G. Bradley, Sandra Anne Banack, Paul Alan Cox, Miami, FL Disclosure: The authors report no disclosures.

To the Editor: A recent article on ALS-PDC of Guam reviews some of the recent epidemiologic, genetic, and pathologic findings on this intriguing disorder and rightfully underscores its relevance as an important geographic isolate that might shed light on similar disorders elsewhere.1 In their examination of the etiologic factors, Steele and McGeer also revisit some of the environmental hypothesis and refute the cycad hypothesis. The authors state that the cycad hypothesis lacks scientific merit due to lack of supportive evidence. As an example of these failures, a brief discussion of the widely criticized cyanobacteria ␤-methylamino-Lalanine (BMAA) biomagnification hypothesis is presented. However, to further refute the cycad hypothesis, the authors omit scientific literature. A basic PubMed search reveals at least 25% of the published articles on this subject in the last 5 years including a feature review.10 Whatever the flaws in the recent article by Borenstein et al.,4 this study recapitulates the original conclusions of Whiting and others. The authors of the current review present their objections based on age at cycad exposure and use the apparent discrepancies to dismiss the entire hypothe474

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sis. However, age-dependent impacts of neurotoxins are well known. We have published over a dozen original articles clearly demonstrating an ALS-PDC phenotype in vivo and plausible putative neurotoxins in vivo and in vitro. The in vivo studies have shown that chronic dietary exposure to cycad flour leads to neurodegeneration in mice after prolonged exposure.11 These data confirm earlier observations on macaque monkeys fed washed and unwashed cycad flour. In addition, we have identified water-insoluble molecules that could be responsible for cycad neurotoxicity.12 We welcome critiques of the hypothesis that cycad toxins are not causal to ALS-PDC. Reyniel Cruz-Aguado, Christopher A. Shaw, Vancouver, BC, Canada Disclosure: The authors report no disclosures.

To the Editor: Steele and McGeer1 acknowledge the possible role of environmental factors in the etiology of the “Guam syndrome” while refuting the cycad hypothesis (specifically the minor cycad component L-BMAA) as a plausible environmental etiology for this prototypical neurodegenerative disease complex. The authors present incomplete cycad exposure information for the Japanese residents of the diseaseaffected region of Kii Peninsula of Honshu Island and the absence of any consideration of the comparable neurodegenerative disease focus in Auyu and Jaqai linguistic groups of West Papua, Indonesia. The only common environmental factor in these three genetically distinct, ALS/PDC-affected populations is the use of raw, non-detoxified Cycas spp seed for medicinal purposes. It is used as a poultice for open wounds in New Guinea and Guam, and as an oral tonic in the Kii Peninsula.13,14 Food use of poorly detoxified cycad seed is an additional historical exposure factor on Guam yet fully detoxified cycad products (stem and/or seed) have been used for food in the Japanese Ryukyu Islands and Northern Australia where Guam-like neurodegenerative disease foci are absent.14 There is a strong epidemiologic relationship for sampled Guam villages between the concentration of residual methylazoxymethanol (MAM, the aglycone of the principal cycad neurotoxin cycasin) in washed cycad flour and the 10-year age-adjusted incidence of ALS and PD. Cycad components and cycasin produce motor system disease in adult cattle.14 MAM is an established developmental neurotoxin in rodents, where it induces formation of ectopic, multinucleated Purkinje-like cells comparable to those reported in the cerebellum of deceased Guam and Kii ALS patients.14 It also damages rodent neuronal DNA and modulates tau expression in vitro15 and induces the

accumulation of synuclein in the brain of young mice.16 The ability of MAM to disrupt the metabolism of both synuclein and tau (including its phosphorylation) is evidence that is consistent with the classification of ALS/PDC as a synucleinopathy and tauopathy. Contrary to the view expressed by Steele and McGeer,1 these facts demonstrate the plausibility of a cycad hypothesis for Western Pacific ALS/PDC that emphasizes the role of the plant’s principal neurotoxin, MAM-beta-glucoside, while not excluding a role for BMAA. Peter S. Spencer, Valerie Palmer, Glen Kisby, Portland, OR Disclosure: The authors report no disclosures.

Reply from the Authors: Borenstein et al. defend the inconsistencies in their epidemiologic study as recall bias. We drew attention in our review to the difficulty of reaching firm conclusions based on remembering details of events that took place over 50 years previously. In this case-control study, the subjects were elderly Chamorros who in some cases had dementia. However, this is not the main reason for rejecting the notion that the consumption of cycad flour, or the picking of its seeds, could be responsible for the Guam disease. It is the gap, amounting to orders of magnitude, between the amounts of cycad that Chamorros must have had to consume and the amounts required to produce even weak toxicity in animals. If exposure to cycad itself fails for this reason, then exposure to its minor constituents also fails. This applies to the BMAA hypothesis put forward by Bradley et al., the ß-sitosterol glucoside (BSSG) hypothesis put forward by Cruz-Aguado et al., and the methylazoxymethanol (MAM) hypothesis put forward by Spencer et al. Bradley et al. have gone beyond the BMAA hypothesis as a cause of the Guam syndrome by proposing that BMAA, produced by cyanobacteria, is contaminating worldwide water supplies, causing AD and ALS. They describe BMAA as “this potent excitotoxin.” However, BMAA is not a potent excitotoxin. For example, rats were not seriously harmed by a continuous infusion of 100 mg/kg/day of BMAA over a 2-week period.17 Humans would have to consume a dose of about 5 kilograms per day of Cycas micronesica to be exposed even to these minimally effective levels of BMAA. Potent excitotoxins, such as kainic and ibotenic acids, have a dicarboxylic acid structure similar to glutamate so that they produce a neurotoxic action at glutamate receptors.18 BMAA, as a monocarboxylic acid, lacks the necessary structure. Bradley et al. quote astonishingly high

BMAA levels in the brains of Guam ALS/PDC as well as AD and ALS cases. The levels are at least four times higher than those obtained in the high dose BMAA rat infusion experiments. Significantly, there was no BMAA retained in the brain in these experiments.17 This argues against the protein binding theory proposed by Bradley et al. Such binding would not be expected in any event since BMAA lacks the prosthetic groups normally involved in hydrogen bonding to proteins. In our review, we pointed out that Montine et al., using a well established analytical technique, failed to detect any BMAA in the brains of AD cases, controls, or Chamorros with and without PDC. This indicates serious discrepancies in the analytical methods used for detecting BMAA. Those discrepancies need to be resolved. Bradley et al. state they have put forward a testable hypothesis. Since AD and ALS tissue is widely available, investigators will be able to determine whether or not their results can be replicated. Cruz-Aguado et al. hypothesize that chronic exposure to BSSG induces an ALS/PDC phenotype yet overlooked the extremely low concentrations of this material that have been found in cycad preparations. Originally, only 7.3 mg was obtained from 200 grams of washed flour.19 The authors fed mice 1 mg/ day of synthetic BSSG for 15 weeks. This would be equivalent to humans eating 2.5 grams per day of this constituent. If the original report of its concentration in cycad is anywhere near quantitative, this would require a human to consume 68,000 grams of cycad flour per day. The mice survived this regimen and the authors did not identify motor deficits in their mice in such measures as open field behavior and motor strength, although they did report reduced counts of spinal motor neurons on autopsy. We do not consider that these results constitute an ALS PDC phenotype. Like the BMAA hypothesis, we do not consider that this hypothesis merits serious scientific consideration. Spencer and colleagues propose that the toxic constituent in cycad flour is methylazoxymethanol (MAM). They suggest that the MAM hypothesis explains not just the Guam disease, but also the Kii Peninsula disease and possibly a similar but unproven disease in West Papua, New Guinea. Kisby et al. injected a dose of 43 mg/kg of MAM to newborn mice and then observed small developmental changes in the cerebellum.12 That dose would be equivalent to more than 2 grams of MAM to a human. MAM comes from cycasin, which constitutes 2– 4% of unwashed cycad flour and 0.004 –75.93 ␮g/g of washed cycad flour.11 Since Guamanians were known to eat only washed cycad flour, this would translate to a conNeurology 72

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sumption of between 1,300 and 250,000,000,000 grams of washed flour. Studies of adult rats fed cycasin or raw cycad flour failed to demonstrate major pathologic changes or deficits in behavior.20 In the Kii Peninsula, there are two small foci each of five villages with ALS/PDC separated by 200 km with no neurologic disorders in other coastal and inland villages between them. Kuzuhara et al.21 concluded that the epidemiologic, clinical, pathologic, and immunologic features of ALS/PDC were the same on Guam and in the Kii Peninsula. In October 2007, Kuzahara et al.22 wrote: “None of the patients had the habit of eating the cycad, flying fox, or any other odd materials.” We do not agree that the data presented by Spencer et al. demonstrate the plausibility of a cycad hypothesis. Patrick L. McGeer, John C. Steele, Vancouver, BC, Canada Disclosure: The authors report no disclosures.

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Steele JC, McGeer PL. The ALS/PDC syndrome of Guam and the cycad hypothesis. Neurology 2008;70: 1984 –1990. Plato CC, Garruto RM, Galasko D, et al. Amyotrophic lateral sclerosis and Parkinsonism-dementia complex of Guam: changing incidence rates during the past 60 years. Am J Epidemiol 2003;157:149 –157. Galasko D, Salmon D, Gamst A, et al. Prevalence of dementia in Chamorros on Guam: relationship to age, gender, education and APOE. Neurology 2007;68:1772–1781. Borenstein AR, Mortimer E, Schofield E, et al. Cycad exposure and risk of dementia, MCI and PDC in the Chamorro population of Guam. Neurology 2007;68: 1764 –1771. Wilson J, Shaw CA. Commentary on: Return of the cycad hypothesis: does the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health? Neuropathol Appl Neurobiol 2006;32:341–343. Cox PA, Banack SA, Murch SJ. Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proc Natl Acad Sci USA 2003;100:13380 –13383. Metcalf JS, Banack SA, Lindsay J, Morrison LF, Cox PA, Codd GA. Co-occurrence of beta-N-methylamino-Lalanine, a neurotoxic amino acid, with other cyanobacterial toxins in British waterbodies, 1990 –2004. Environ Microbiol 2008;10:702–708. Murch SJ, Cox PA, Banack SA. A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc Natl Acad Sci USA 2004;101:12228 –12231. Mash D, Pablo J, Banack SA, et al. Neurotoxic nonprotein amino acid BMAA in brain from patients dying with ALS and Alzheimer’s disease: American Academy of Neurology annual meeting: P06.127. Neurology 2008; 70(suppl 1):A329. Miller G. Guam’s deadly stalker: on the loose worldwide? Science 2006;313:428 – 431.

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Wilson JM, Khabazian I, Wong MC, et al. Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour. Neuromolecular Med 2002;1:207–221. Tabata RC, Wilson JM, Ly P, et al. Chronic exposure to dietary sterol glucosides is neurotoxic to motor neurons and induces an ALS-PDC phenotype. Neuromolecular Med 2008;7:24 –39. Spencer PS, Palmer VS, Ludolph AC. On the decline and etiology of high-incidence motor system disease in West Papua (southwest New Guinea). Mov Disord 2005;20: S119 –126. Spencer PS, Kisby GE, Palmer VS, Obendorf P. Cycasin, methylazoxymethanol and related compounds. In: Spencer PS, Schaumburg HH, eds. Experimental and Clinical Neurotoxicology, 2nd edition. New York: Oxford University Press; 2000:436 – 446. Esclaire F, Kisby G, Spencer P, Milne J, Lesort M, Hugon J. The Guam cycad toxin methylazoxymethanol damages neuronal DNA and modulates tau mRNA expression and excitotoxicity. Exp Neurol 1999;155:11–21. Kisby GE, Standley M, Park T, et al. Proteomic analysis of the genotoxicant methylazoxymethanol (MAM) induced changes in the developing cerebellum. J Proteome Res 2006;5:2656 –2665. Duncan MW, Nelly E, Villacreses PG, et al. 2-Amino-3(methylamino)-propanoic acid (BMAA) pharmacokinetics and blood-brain barrier permeability in the rat. J Pharm Exp Ther 1991;258:27–35. McGeer EG, Olney J, McGeer PL, eds. Kainic Acid as a Tool in Neurobiology. New York: Raven Press; 1978. Khabazian I, Bains JS, Williams DE, et al. Isolation of various forms of sterol B-D-glucoside from the seed of Cycas circinalis: neurotoxicity and implications for the ALSparkinsonian dementia complex. J Neurochem 2002;82: 516 –528. Campbell ME, Mickelsen O, Yang MG, Laqueur GL, Keresztesy JC. Effects of strain, age and diet on the response of rats to the ingestion of Cycas circinalis. J Nutr 1966;88:115–124. Kuzuhara S, Kokubo Y, Sasaki R, et al. Familial Amyotrophic lateral sclerosis and Parkinsonism-dementia complex of the Kii Peninsula of Japan: Clinical and neuropathological study and tau analysis. Ann Neurol 2001;49:501–511. Kuzuhara S. Revisit to Kii ALS: the innovated concept of ALS/Parkinsonism-dementia complex, clinicopathological features, epidemiology and etiology (in Japanese with English abstract). Brain Nerve 2007;59:1065–1074.

IS IT TIME FOR NEUROHOSPITALISTS?

To the Editor: We read the invited article by Freeman et al.1 regarding the advantages of neurohospitalists, which represents an emerging field of neurology serving cost-effective, high-quality medical care to the inpatient population. The authors postulated potential advantages of improved logistical efficiency leading to improved patient outcome but how this is achieved was not explained. In our 400-bed academic medical center at the University of California, Irvine (UCI), the Hospitalist Program consists of 16 board-certified hospitalists

physicians from nine medical specialties: internal medicine, family medicine, pediatrics, neurology, geriatrics, palliative care, adult infectious disease, pediatric infectious disease, and critical care. One of us (G.Y.C.) joined the UCI Hospitalist Program as the first full-time neurohospitalist more than 2 years ago. Although no previous comparable data are available, our experience in forming a true multidisciplinary Hospitalist Program with specialists from various medical disciplines located in the same office and attending required hospitalist faculty meetings and hospitalist-oriented weekly conferences has enhanced inpatient based communication and facilitated a more collaborative approach to patient care and education. We also instituted daily critical care hospitalist– neurohospitalist “handshake rounds” in which the two hospitalist teams (neurohospitalist attending plus housestaff and critical care hospitalist attendings plus housestaff) meet briefly during morning rounds to discuss clinical data as well as medical–legal and ethical aspects of patient care. This is more difficult to accomplish in the traditional approach. We agree with the authors that the neurohospitalist model will continue to expand and grow. Our experience of adding a neurohospitalist to our multidisciplinary Hospitalist Program has been advantageous for patient care, education of our trainees, and developing collaborative, progressive models of multidisciplinary inpatient care processes. Gregory Y. Chang, Alpesh Amin, Orange, CA Disclosure: The authors report no disclosures.

Reply from the Authors: Drs. Chang and Amin inquire about the method by which neurohospitalists provide improved outcomes in health care delivery to medicine or pediatric hospitalists. Neurohospitalists provide similar if not equal outcomes as other hospitalists by standardizing quality measures (i.e., deep vein thrombosis prevention), providing improved emergency department coverage, and reducing length of hospitalization.2– 4 We note the authors’ review of their experience at UCI Hospitalist Practice. We acknowledge there are different and diverse hospitalist systems that can achieve similar patient outcomes and quality results in the current US healthcare system. William D. Freeman, Gary Gronseth, Benjamin H. Eidelman, Jacksonville, FL Disclosure: Drs. Freeman and Eidelman report no conflicts of interest. Dr. Gronseth is a member of Boehringer Ingelheim Pharmaceutical’s speaker’s bureau. Copyright © 2009 by AAN Enterprises, Inc. 1. 2.

3.

4.

Freeman WD, Gronseth G, Eidelman BH. Is it time for neurohospitalists? Neurology 2008;70:1282–1288. Auerbach AD, Wachter RM, Katz P, et al. Implementation of a voluntary hospitalist service at a community teaching hospital: improved clinical efficiency and patient outcomes. Ann Intern Med 2002;137:859 – 865. Coffman J, Rundall TG. The impact of hospitalists on the cost and quality of inpatient care in the United States: a research synthesis. Med Care Res Rev 2005;62:379 – 406. Davis KM, Koch KE, Harvey JK, Wilson R, Englert J, Gerard PD. Effects of hospitalists on cost, outcomes, and patient satisfaction in a rural health system. Am J Med 2000;108:621– 626.

AAN CME: Quick, Convenient, Smart. The AAN makes earning your continuing medical education (CME) credits more convenient than ever with a host of unparalleled CME opportunities. Whether you choose online, print, or classroom, rest assured that AAN CME is designed by top experts in neurology specifically to help you fulfill your Maintenance of Certification requirements and stay current in the field. Quick and convenient has never been so smart. • Neurology Online CME • Continuum: Lifelong Learning in Neurology® • Quintessentials® • Online CME Tracker • 2009 Winter Conference, Lake Buena Vista, FL • 2009 AAN Annual Meeting, Seattle, WA • More Learn more at www.aan.com/cme.

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Section Editors Christopher J. Boes, MD Kenneth J. Mack, MD, PhD

Book Review

THE COMATOSE PATIENT

edited by Eelco F. M. Wijdicks, 584 pp., New York, Oxford University Press, 2008, $125 Dr. Wijdicks’ book provides a tour de force on impaired consciousness for neurologists, neurosurgeons, and others who see comatose patients. The book is divided into two principal sections. The first is concerned with the evolution of basic concepts of consciousness and unconsciousness from historical, basic science, clinical, and neuroimaging perspectives. The historical section on the evolution of the clinical concepts of coma is masterful, beginning with clinical-pathologic correlations of signs and structural brain lesions. Concepts of herniation evolved from early postmortem descriptions that overemphasized the role of uncal herniation until neuroimaging provided more in vivo concepts of lateral shift of supratentorial midline structures by Fisher and Ropper. Metabolic aspects of coma began with early descriptions of renal failure by Bright and hepatic failure with Adams and Florey. Conversely, wakefulness without awareness was recognized as a special type of unresponsiveness and concepts of consciousness became dichotomized into alertness and awareness. Basic neuroscience insights into consciousness at first mirrored clinical-pathologic correlations in humans, but animal studies clarified the anatomic structures with associated neurochemistry involved in wakefulness, arousal, sleep, and a glimpse at awareness (still not understood). The clinical, radiologic, and pathologic aspects of major syndromes of impaired consciousness include brain death, coma, stupor, and vegetative states. General aspects of decision making, medical man-

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agement, and supportive care are included. The ethical, religious, cultural, and medicolegal implications of organ donation after neurologic and cardiac death are also discussed. There is even a review of coma in the media and popular culture. The second part of the book is devoted to practical aspects of individual causes of coma: gunshot wounds, traumatic brain injury, intracranial hemorrhages and venous thromboses, primary and secondary tumors, hydrocephalus, demyelination, transplantation, status epilepticus, nutritional disorders, organ failure, some inborn errors of metabolism, intoxications, glucose disturbances, complications of pregnancy, and many others. These discussions begin with an illustrative case followed by a brief review of the topic and key references. Length of each topic is short, 2–7 pages. The book also includes a DVD with 5 chapters, including the FOUR score (a promising coma scoring system developed and validated by Dr. Wijdicks), selected neurologic findings in comatose patients (including excellent examples of eye movement abnormalities), seizures vs pseudoseizures, states of impaired consciousness, and neurologic determination of death. Strengths of the book include its clear, thorough, current, and well-illustrated presentations, uniformity of style, and avoidance of reduplication and redundancy. By its very nature it cannot treat all coma-producing conditions in detail, but there is enough for a good overview and references to help and interest the busy clinician. Reviewed by G. Bryan Young, MD, FAAN Disclosure: The author reports no disclosures. Copyright © 2009 by AAN Enterprises, Inc.

Calendar

Neurology® publishes short announcements of meetings and courses related to the field. Items must be received at least 6 weeks before the first day of the month in which the initial notice is to appear. Send Calendar submissions to Calendar, Editorial Office, Neurology®, Suite 214, 20 SW 2nd Ave., P.O. Box 178, Rochester, MN 55903 [email protected]

2009 FEB. 9 –11 Case Studies in Epilepsy Surgery will be held at the Silver Tree and Snowmass Conference Center in Snowmass, CO. Contact Martha Tobin at (216) 445-3449 or (800) 2232273, ext 53449, or at [email protected] for seminar details. FEB. 9 –13 The 22nd Annual Practicing Physician’s Approach to the Difficult Headache Patient will be held at the Camelback Inn, Scottsdale, AZ. Approved for AMA PRA Category 1 credit. Diamond Headache Clinic Research & Educational Foundation: tel (877) 706-6363 or (733) 883-2062; [email protected]; www.dhc-fdn.org. FEB. 16 –17 Fifth Annual Update Symposium on Clinical Neurology and Neurophysiology will be held in Tel Aviv, Israel. Presented by Weill Cornell Medical College, Department of Neurology, and Tel Aviv University, Adams Brain Supercenter. www.neurophysiology-symposium.com. FEB. 20 –22 International Symposium on Stereotactic Body Radiation Therapy and Stereotactic Radiosurgery will be held at the Floridian Resort & Spa in Lake Buena Vista, FL. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details.

MAY 8 The Office of Continuing Medical Education at the University of Michigan Medical School is sponsoring a CME conference entitled: Movement Disorders: A Practical Approach. It is located at The Inn at St. John’s in Plymouth, Michigan. tel (734) 763-1400; fax (734) 936-1641. MAY 11–12 Music and the Brain will be held at the InterContinental Hotel & Bank of America Conference Center in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details. MAY 15–17 The Fifth International Conference on Alzheimer’s Disease and Related Disorders in the Middle East will be held in Limassol, Cyprus. www.worldeventsforum.com/alz. MAY 28 –30 6th International Headache Seminary. Focus on Headaches: New Frontier in Mechanisms and Management will be held at the Grand Hotel des Iles Borromees in Stresa (Italy); tel/fax 02 7063 8067; [email protected]. JUN. 8 –12 Leksell Gamma Knife® Perfexion™ Introductory Course will be held at the Gamma Knife Center in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details.

APR. 2– 4 The Innsbruck Colloquium on Status Epilepticus 2009 will be held at the Congress Innsbruck, Austria. [email protected]; www.innsbruck-SE2009.eu.

JUN. 12 Mellen Center Regional Symposium on Multiple Sclerosis will be held at the InterContinental Hotel & Bank of America Conference Center in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details.

APR. 3 5th Annual Contemporary Issues in Pituitary: Casebase Management Update will be held at the Cleveland Clinic Lerner Research Institute in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details.

JUN. 19 –24 Epileptology Symposium will be held at the InterContinental Hotel & Bank of America Conference Center, in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details.

APR. 20 –22 Leksell Gamma Knife® Perfexion™ Upgrade Course will be held at the Gamma Knife Center in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 2232273, ext 53449, or at [email protected] for seminar details. APR. 25–MAY 2 AAN Annual Meeting will be held in Seattle, Washington State Convention & Trade Center, WA. American Academy of Neurology: tel (800) 879-1960; www.aan.com/am. MAY 3– 6 2nd International Epilepsy Colloquium, Pediatric Epilepsy Surgery Cite´ Internationale will be held in Lyon, France. http://epilepsycolloquium2009ams.fr. MAY 6 –10 International SFEMG Course and Xth Quantitative EMG conference will be held in Venice, Italy. tel 39041-951112; [email protected]; www.congressvenezia.it.

JUL. 7–10 SickKids Centre for Brain & Behaviour International Symposium. [email protected]; www.sickkids.ca/ learninginstitute. JUL. 16 –18 Mayo Clinic Neurology in Clinical Practice2009 will be held at the InterContinental Hotel, Chicago, IL. Mayo CME: tel: (800) 323-2688; [email protected]; http:// www.mayo.edu/cme/neurology-neurologic-surgery.html. JUL. 21–27 Cleveland Spine Review 2009 will be held at the Embassy Suites Cleveland–Rockside Hotel in Independence, OH. Contact Martha Tobin at (216) 445-3449 or (800) 2232273, ext 53449, or at [email protected] for seminar details. AUG. 17–19 Leksell Gamma Knife® Perfexion™ Upgrade Course will be held at the Gamma Knife Center in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 2232273, ext 53449, or at [email protected] for seminar details. Neurology 72

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SEP. 12–15 13th Congress of the European Federation of Neurological Societies will be held in Florence, Italy. For more information: tel ⫹41 22 908 0488; http://www.kenes.com/efns2009/ index.asp; [email protected]. SEP. 25 Practical Pearls in Neuro-Ophthalmology–International Symposium in Honour of Dr. James Sharpe will be held on September 25, 2009 at the University of Toronto Conference Centre, Toronto, Ontario. For further information contact the Office of Continuing Education & Professional Development, Faculty of Medicine, University of Toronto: tel (416) 978-2719; (888) 5128173; fax (416) 946-7028; [email protected]; http:// events.cmetoronto.ca/website/index/OPT0907. OCT. 8 –11 The Third World Congress on Controversies in Neurology. Full information is available at: ComtecMed - Medical Congresses, PO Box 68, Tel-Aviv, 61000 Israel; tel ⫹972– 3-5666166; fax ⫹972–3-5666177; [email protected]; www.comtecmed.com/cony. OCT. 24 –30 19th World Congress of Neurology, WCN 2009, will be held in Bangkok, Thailand. www.wcn2009bangkok.com.

NOV. 19 –22 The Sixth International Congress on Vascular Dementia will be held Barcelona, Spain. For further details, please contact: Kenes International 17 Rue du Cendrier, P.O. Box 1726, CH-1211, Geneva 1, Switzerland; tel ⫹41 22 908 0488; fax ⫹41 22 732 2850; [email protected]; http://www. kenes.com/vascular. DEC. 3– 6 Neuromodulation 2009 Encore will be held at Wynn Las Vegas in NV. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details. DEC. 7–11 Leksell Gamma Knife® Perfexion™ Introductory Course will be held at the Gamma Knife Center in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details.

2010 MAY 2–7 11th International Child Neurology Congress will be held in Cairo, Egypt; http://www.icnc2010.com/.

Save These Dates for AAN CME Opportunities! Mark these upcoming dates on your calendar for these exciting continuing education opportunities, where you can catch up on the latest neurology information. AAN Annual Meetings ● April 25—May 2, 2009, Seattle, Washington State Convention & Trade Center ● April 10 –17, 2010, Toronto, Ontario, Canada, Toronto Convention Centre

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Section Editor Robert J. Joynt, MD, PhD

Changes ● People ● Comments

CHANGES

ABPN certification update

The following have successfully completed the subspecialty certification requirements of the American Board of Psychiatry and Neurology (ABPN). ABPN certifications expire on December 31 (10 years following the date of examination). Neurology (9/19/08): Francena Abendroth; Aiesha Ahmed; Ziad Alaani; Hazem Ali; Lilyana Amezcua; Aruna Arora; Yekaterina Axelrod; Daniel Becker; Jennifer Bickel; Suur Biliciler; Roberto Bomprezzi; Laura Bonds; Salima Brillman; Shonte Byrd; Richard Callison; Shereen Chang; Jason Chang; Marcello Cherchi; Richard Cho; Michael Connor; Jesse Corry; Khashayar Dashtipour; Caryl Dellinger; Melissa DeRosa; Dan Dumitru; Eric Farbman; Jeremy Fields; Clyde Finch; Nicholas Galifianakis; Robert Gardner; Nicolette Gebhardt; Nupur Ghoshal; Harpaul Gill; Sangeeta Goel; Edward Goldberg; Tanya Harlow; Matthew Harms; Martha Haykin; Mei He; William Hills; David Isaradisaikul; Nilanee Karikaran; Berneet Kaur; Aneesa Keya; Saud Khan; May Kim; Anthony Kim; James Ko; Kalyani Korabathina; Suparna Krishnaiengar; Kenneth Kudelko; Jayalekshmy Kumar; Wayne Lai; Beth Lo; Yuanyuan Long; Lynne Love; Jose Lujan Palma; Jianxin Ma; Achraf Makki; Michael Marmura; Jesus Martinez; Leslie Masood; Shyamal Mehta; Ravi Menon; Kathleen Messenger; Guillermo Moguel-Cobos; Muhammad Naeem; Glen Nagasawa; Deepa Nidhiry; Arbi Ohanian; Edward Olson; Erik Ortega; Dakshesh Patel; Richard Plowey; Ashvini Premkumar; Faisal Qazi; Daniel Rabinovitch; Satish Rao; Daniel Reich; Luisa Rojas Estupinan; Malcolm Roland; Juan Ros-Escalante; Jenny Saket; Syed Salahuddin; Milan Sanghavi; Adrian Santamaria; Cordelia Schwarz; Brian Scott; David Searls; John Simmons; James Southwell; Rebecca Spiegel; David Teeple; Jeffrey Thornton; Diego Torres-Russotto; Lynn Trotti; Jeffrey Tsai; Vanessa Tseng; Kenneth VanOwen; George Veech; Jaymes Venema; Harrison Walker; Grant Warmouth; Michael Xu; and Toby Yaltho. Neuromuscular (9/8/08): Hoda Abdel-Hamid; Senda Ajroud-Driss; Roula Al-Dahhak; Zakir Ali; Muhammad AlLozi; Majeed Al-Mateen; Ahmad Al-Sadat; Anthony Amato; MaryAlice Ambrose; Carl Ansevin; Padmaja Aradhya; Carmel Armon; Robert Baloh; George Baquis; Richard Barohn; Jitendra Baruah; Bassam Bassam; Said Beydoun; Eteri Bibileishvili; Phyllis Bieri; Wilson Bryan; William Burnette; Stephanus Busono; Joseph Campellone; Doris Cardenas; Scott Carlson; Jasvinder Chawla; Rossitza Chichkova; Rabia Choudry; Mary Chu; Gwendolyn Claussen; Thomas Cochrane; Jeffrey Cohen; William Corn; Basil Darras; William David; Jose De Ocampo; Eduardo De Sousa; Jose DeSousa; Mazen Dimachkie; George Dmytrenko; James Dowling; Bakri Elsheikh; Erik Ensrud; Tanya Fatimi; Dominic Fee; Kevin Felice; Jose Fernandes Filho; Mark Ferrante; Richard Finkel; Mary Floeter; Miriam Freimer; Robert Freundlich; Robert Friedman; James Gaffney; Moham-

med Ghabra; Namita Goyal; Patrick Grogan; David Hammond; Anwarul Haq; Daragh Heitzman; Steven Herskovitz; Lisa Hobson-Webb; Stuart Hoffman; Neil Holland; James Hora; Aatif Husain; Mohammad Ikramuddin; Eliud Irizarry Claudio; Agnes Jani-Acsadi; Joshua Johnson; Lyell Jones; Vern Juel; Peter Kang; Peter Karachunski; Bashar Katirji; Lara Katzin; Seth Kaufman; Praful Kelkar; Iftikhar Khan; Octavia Kincaid; John Kissel; Aphrodite Konstantinidou; Daniel Koontz; Roger Kula; Bangaruswamy Kumar; Jerome Kurent; Abraham Kuruvilla; Justin Kwan; Shafeeq Ladha; Dale Lange; Kerry Levin; Jin Li; Heidi Loganbill; Glenn Lopate; Steven Lovitt; Carlos Luciano; Jin Luo; Glenn Mackin; Alan Martin; Robert McMichael; April McVey; Gregg Meekins; Daniel Menkes; Matthew Meriggioli; Daniel Miller; Mark Milstein; Shri Mishra; Christopher Mitchell; Jonathan Moravek; Brett Morrison; Tahseen Mozaffar; Suraj Muley; William Musser; Christopher Nance; Thambirajah Nandakumar; Rachel Nardin; Samer Nasher-Alneam; Kussay Nassr; Kevin Nelson; Daniel Newman; Kenkichi Nozaki; John O’Connor; Lee Osborne; Bjo¨rn Oskarsson; Carlos Otero Rodriguez; Richard Palmer; Luis Pary; Mamatha Pasnoor; Dhruvkumar Patel; Amanda Peltier; Alan Pestronk; Noor Pirzada; Milvia Pleitez; David Polston; David Preston; M. Purino; Muhammad Rahman; Goran Rakocevic; Keshav Rao; Chitharanjan Rao; Ananthi Rathinam; John Ravits; David Rosenfield; James Russell; Mohammad Salajegheh; Hamid Sami; David Saperstein; Robert Schwendimann; Valeria Serban; Aziz Shaibani; Teena Shetty; Perry Shieh; Steven Shook; Peter Siao Tick Chong; Ericka Simpson; David Simpson; Mark Sivak; Kumaraswamy Sivakumar; John Sladky; Michael Snyder; Madhu Soni; Rodney Sorensen; Nizar Souayah; Jayashri Srinivasan; Naganand Sripathi; Jeffrey Steier; James Strong; Vahid Taghavi; Rup Tandan; Patrick Tessman; Pariwat Thaisetthawatkul; Timothy Thomas; Sandra Torres; Jaya Trivedi; Bryan Tsao; Eroboghene Ubogu; Vettaikorumakankav Vedanarayanan; Yedatore Venkatesh; Ashok Verma; Mervat Wahba; Annabel Wang; Zeng Wang; Peter Warinner; Jacqueline Washington; Thurman Wheeler; Charles Whitaker; Gil Wolfe; Muhammad Zaidi; Lan Zhou; and Simon Zimnowodzki. Child neurology (9/19/08): Raafat Iskander. PEOPLE

Dr. Larry Faulkner is the Executive Vice-President of the ABPN. He is the former dean of the University of South Carolina School of Medicine and was a board member of ABPN for 7 years beDr. Larry Faulkner fore assuming his present position in 2006. In a telephone interview, he explained the reasons for recent changes in the certification process and some plans for the future. He said that eliminating Copyright © 2009 by AAN Enterprises, Inc.

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COMMENTS

have reread James Lipton’s little book An Exaltation of Larks several times. I imagine the provenance of most of these cannot be traced, such as a dazzle of zebras, a shrewdness of apes, a parliament of owls, a cete of badgers, and an ostentation of peacocks. There is the old story of a group of Oxford dons encountering an early morning gathering of some ladies of the night and trying to assign collective nouns to the bunch. They came up with “an anthology of Trollopes” and “an introduction of Great Expectations.” I have come up with a few, maybe not original but overheard: a void of urologists (oxymoronic), a rash of dermatologists (slam dunk), a comminution of orthopedists, an arrogance of surgeons (or maybe you met the one humble one in the country), a tuck of plastic surgeons, a confusion of consultants (I have been there), a clot of hematologists, and a disclaimer of health care insurers. I did not do very well with neurologist as a synapse or a ganglia, but a burst of electroencephalographers or a train of electrophysiologists. Here, I leave you on your own as I likely acquired a boredom of readers.

I have always liked collective nouns; they are an ingenious and amusing part of the English language. I

Robert J. Joynt, MD, PhD

the oral examination was done only after long consideration by the board. They had the example from other boards which had previously made this change. He cited two principal reasons: reliability of the testing and advances in test construction and administration with advances in computer technology. He also pointed out that the administration with patient participation was becoming unwieldy. The replacement is the local assessment of the candidate in interviewing, examination, and professionalism. This assessment is done during the residency so that deficiencies in the candidate’s performance can be detected early so that remediation can be accomplished. He said that the ABPN is working on programs to train the examiners or the candidates in the certifying process. He also spoke about maintenance of certification. Now, all 24 boards of the American Board of Medical Specialties have this requirement. There is now a Web site set up by the ABPN to explain the details and to allow individual members of the board to find where they are in the process (http://www.abpn. com/verifycert/verifycert.Asp).

Neurology® publishes news about professionals in the neurological community. Please send items of interest including news of chair and endowed professorship appointments and awards to the Neurology® Newsletter Editor, Robert Joynt, MD, PhD, at [email protected] or fax 651-332-8603.

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In the next issue of Neurology® Volume 72, Number 6, February 10, 2009 www.neurology.org THE MOST WIDELY READ AND HIGHLY CITED PEER-REVIEWED NEUROLOGY JOURNAL

THIS WEEK IN Neurology®

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Highlights of the February 10 issue

EDITORIALS

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How much expansion to be diseased? Toward repeat size and myotonic dystrophy type 2 Benedikt Schoser and Tetsuo Ashizawa

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Mom and me: Brain metabolism links Alzheimer disease to maternal genes Vijay Dhawan and David Eidelberg

IN MEMORIAM

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Raymond D. Adams, MD (1911–2008) Walter J. Koroshetz

VIEWS & REVIEWS

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A neurologist’s guide to genome-wide association studies S.A. Mullen, D.E. Crompton, P.W. Carney, et al.

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Epistasis: Multiple sclerosis and the major histocompatibility complex Sreeram V. Ramagopalan and George C. Ebers

CLINICAL/SCIENTIFIC NOTES

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Urine heteroplasmy is the best predictor of clinical outcome in the m.3243A⬎G mtDNA mutation R.G. Whittaker, J.K. Blackwood, C.L. Alston, et al.

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Neural signatures in patients with neuropathic pain A.L. Green, S. Wang, J.F. Stein, E.A.C. Pereira, et al.

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Ocular tilt reaction: A clinical sign of cerebellar infarctions? Bernhard Baier and Marianne Dieterich

ARTICLES

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Premutation allele pool in myotonic dystrophy type 2 L.L. Bachinski, T. Czernuszewicz, et al.

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Transcranial magnetic stimulation in ALS: Utility of central motor conduction tests A.G. Floyd, Q.P. Yu, P. Piboolnurak, M.X. Tang, et al.

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Warm and cold complex regional pain syndromes: Differences beyond skin temperature? T. Eberle, B. Doganci, H.H. Kra ¨mer, C. Geber, et al.

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Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease L. Mosconi, R. Mistur, R. Switalski, M. Brys, et al.

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Predictors of driving safety in early Alzheimer disease J.D. Dawson, S.W. Anderson, E.Y. Uc, et al.

REFLECTIONS: NEUROLOGY AND THE HUMANITIES

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A punder in Catch-22 C.J. Hammond, H.H. Fernandez, and M.S. Okun

NEUROIMAGES

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Bilateral radial nerve palsy in a newborn C.T. Lundy, S. Goyal, S. Lee, and T. Hedderly

RESIDENT & FELLOW SECTION

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Pearls and Oy-sters: Evaluation of peripheral neuropathies Michelle L. Mauermanns and Ted M. Burns

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Teaching NeuroImage: MRI of diabetic lumbar plexopathy treated with local steroid injection A. Cianfoni, M. Luigetti, F. Madia, A. Conte, et al.

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Increased striatal dopamine (D2/D3) receptor availability and delusions in Alzheimer disease S. Reeves, R. Brown, R. Howard, and P. Grasby

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Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS J.A. Cohen, et al., for the ACT Investigators

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Early MRI in optic neuritis: The risk for disability J.K. Swanton, K.T. Fernando, C.M. Dalton, et al.

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Nonviolent elaborate behaviors may also occur in REM sleep behavior disorder D. Oudiette, V.C. De Cock, S. Lavault, et al.

FUTURE ISSUES

CORRESPONDENCE

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Motor cortex stimulation for chronic pain Micturition-induced reflex epilepsy Antihypertensives and risk of PD Changing concepts in PD

Abstracts In the Next Issue of Neurology®

Subject to change.

THE OFFICIAL JOURNAL OF THE AMERICAN ACADEMY OF NEUROLOGY