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In Focus Spotlight on the May 17 Issue Robert A. Gross, MD, PhD, FAAN Editor-in-Chief, Neurology® Clinical outcomes of ...

Author: Robert A. Gross | MD | PhD | FAAN

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In Focus Spotlight on the May 17 Issue Robert A. Gross, MD, PhD, FAAN Editor-in-Chief, Neurology®

Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy The authors assessed clinical outcomes and identified variables associated with survival in 35 patients with natalizumab-associated progressive multifocal leukoencephalopathy (PML). At the time of analysis, 25 patients (71%) had survived. These data suggest that earlier diagnosis through enhanced clinical vigilance and aggressive management may improve outcomes in natalizumabassociated PML. See p. 1697

From editorialist David B. Clifford: “PML must be understood as a major risk, but it is also somewhat manageable through early diagnosis and aggressive treatment. Neither exaggeration nor minimization of the risks of this complication will serve our patients well.” See p. 1688

A case of multiple sclerosis presenting with inflammatory cortical demyelination Neurologic examination, MRI, CSF and serologic analyses, and brain biopsy were performed in a patient with an active solitary cortical lesion. This case provides pathologic evidence of relapsing-remitting multiple sclerosis and emphasizes the importance of considering demyelinating disease in the differential diagnosis of patients presenting with a solitary cortical enhancing lesion. See p. 1705

Diffusion-weighted MRI hyperintensity patterns

Clinical features and APOE genotype of pathologically proven early-onset Alzheimer disease The authors examined clinical data (age at onset, family history, clinical presentation, diagnostic delay, diagnosis) and APOE genotype of neuropathologically confirmed early-onset Alzheimer disease in 40 patients. Fully one-third of pathologically proven early-onset Alzheimer disease cases presented atypically. See p. 1720

Are networks for residual language function and recovery consistent across aphasic patients? Functional neuroimaging studies were reviewed, which used language tasks in both patients with chronic aphasia after stroke (N ⫽ 105) and control subjects (N ⫽ 129). Activation likelihood estimation meta-analysis determined areas of consistent activity in each group. These findings may guide development of treatment protocols that can be applied to aphasic patients who share common attributes. See p. 1726

Outcomes and prognostic factors of intracranial unruptured vertebrobasilar artery dissection Presentations, treatments, outcomes and prognostic factors were analyzed in 191 patients with symptomatic intracranial unruptured vertebrobasilar artery dissection (siu-VBD). Clinical outcomes were favorable in all patients without ischemic symptoms and in most patients with ischemic presentation. This study may offer a guideline for the management of siu-VBD. See p. 1735

differentiate CJD from other rapid dementias This study examined the sensitivity and specificity of brain MRI for prion disease among a cohort of CJD and other rapidly progressive dementias (RPDs). Authors found the pattern of FLAIR/DWI hyperintensity and restricted diffusion differentiates sporadic CJD from other RPDs with high sensitivity and specificity and propose new sCJD MRI criteria. See p. 1711

CLINICAL/SCIENTIFIC NOTES

Fractal dimension of the retinal vasculature and risk of stroke: A nested case-control study Retinal vascular fractal dimension could mirror the complexity in the cerebral micro-vasculature. Lower retinal fractal dimension predicted higher stroke risk, independent of traditional factors. This automated measure could be a stroke risk marker. See p. 1766

NB: “Resident & Fellow Book Review: Pediatric Epilepsy, Third Edition,” see p. e99. To check out other Resident & Fellow Book Review submissions, point your browser to http://www.neurology.org and watch for more book reviews over the next several months. Podcasts can be accessed at www.neurology.org

Copyright © 2011 by AAN Enterprises, Inc.

1685

EDITORIAL

CMT2A The name doesn’t tell the whole story

Steven S. Scherer, MD, PhD

Address correspondence and reprint requests to Dr. Steven Scherer, Department of Neurology, The University of Pennsylvania School of Medicine, Philadelphia, PA 19104 [email protected]

Neurology® 2011;76:1686–1687

Charcot-Marie-Tooth disease (CMT) is named for the physicians who first described the families that we now recognize as having a dominantly inherited peripheral neuropathy. In the subsequent 120 years, the term CMT has become increasing complex, incorporating different inherited forms (X-linked, recessive, and dominant), clinical phenotypes, and primary pathologic processes (demyelination vs axonal loss), as well as the differential involvement of sensory or motor axons. The identification of more than 30 genes that cause CMT (and surely a greater number remain to be discovered), and the realization that mutations of the same gene can cause different phenotypes, are further complications. Incorporating these complexities has resulted in cumbersome classification schemes that emphasize the genetics over the clinical features of the patients, thereby causing confusion among clinicians, and the inefficient usage of genetic testing. Mutations in MFN2 cause CMT2A,1 the most common kind of dominantly inherited axonal neuropathy. In this issue of Neurology®, Feely et al.2 evaluate 126 patients with CMT2: 99 patients from one clinic in the United States and 27 patients from another clinic in the United Kingdom. Altogether, 21% (27/126) had a MFN2 mutation that was deemed responsible for their neuropathy; this figure is similar to other studies. By using the CMT Neuropathy Score, the investigators demonstrated that patients with CMT2A were more severely affected than patients with CMT2 without MFN2 mutations: 17/27 patients with CMT2A had severe neuropathy, and 5 more adolescents had moderate neuropathy and were likely to progress to severe neuropathy by adulthood. Of these 27 adult patients with CMT2A, 23 (91%) were nonambulatory by 21 years. These severely affected patients with CMT2A comprised the vast majority of patients with CMT2 with severe neuropathy (17/19 patients from 15/17 families), and typically had de novo mutations. In accord with these findings, the mean age at onset of

patients with CMT2A was 4.4 years (range 1–33 years); it was 41.4 years (range 1– 82 years) for patients with CMT2 without MFN2 mutations, most of whom had a dominant family history. Although it had been appreciated that most patients with CMT2A had a severe, early-onset axonal neuropathy,3– 6 that they constituted the majority of such patients with CMT2 had not been rigorously validated. Feely et al. also found that some patients appeared to have a motor neuropathy, whereas others also had a prominent sensory ataxia. In many patients, the sensory findings appeared later than the motor findings, but a relative lack of sensory findings was still evident in 2 middle-aged patients (44 and 55 years old). These phenotypic subtypes of CMT2A had not been emphasized previously, and understanding this genotype–phenotype association, as well as why some mutations cause optic atrophy and myelopathy, merits further investigation. MFN2 and the related MFN1 encode mitofusin 2 and 1, respectively, which are intrinsic membrane proteins that mediate mitochondrial fusion. All disease-causing mutations described by Feely et al. were missense mutations, resulting in amino acid substitutions. Of the 14 different mutations they found, only 6 were previously described. The mutations affected the GTPase domain, the coiled-coil domains, or another highly conserved (R3) domain of the protein. The authors postulate that MFN2 mutants associated with severe, early-onset axonal neuropathy, but not those associated with milder, late-onset axonal neuropathy, have dominantnegative effects on wild-type MFN2. In light of these results, it makes sense to test for MFN2 mutations in individuals who have a severe, early-onset axonal neuropathy that affects both sensory and motor or just motor axons, especially if there is no family history of CMT. If the patients do not harbor MFN2 mutations, then testing for recessive GDAP1, LMNA, MED25, and NEFL mutations could be considered. Conversely, it does not make

See page 1690 e-Pub ahead of print on April 20, 2011, at www.neurology.org. From the Department of Neurology, The University of Pennsylvania School of Medicine, Philadelphia. Disclosure: Author disclosures are provided at the end of the editorial. 1686

Copyright © 2011 by AAN Enterprises, Inc.

sense to test routinely for MFN2 mutations in patients with adult-onset axonal neuropathies because the yield is too low, and even if a mutation is found, determining whether it is a polymorphism or a disease-associated mutation can be challenging. A productive strategy for screening adult-onset axonal neuropathies will require a much more complete collection of the mutations that cause this phenotype. Fortunately, whole-exome7 and even whole-genome8 sequencing may soon enable pinpointing the missing genetic causes and provide a faster and cheaper alternative to the current strategy of sequencing candidate genes. DISCLOSURE Dr. Scherer serves on the editorial boards of ASN Neuro, Cell and Tissue Research, Experimental Neurology, Journal of Neuroscience Research, Journal of the Peripheral Nervous System, Neuron Glia Biology, The Journal of Neuroscience, and The Journal of the Neurological Sciences; and receives research support from the NIH, the National Multiple Sclerosis Society, and the Muscular Dystrophy Association.

REFERENCES 1. Zu¨chner S, Mersiyanova IV, Muglia M, et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-

2.

3.

4.

5.

6.

7.

8.

Marie-Tooth neuropathy type 2A. Nat Genet 2004;36: 449 – 451. Feely SME, Laura M, Siskind CE, et al. MFN2 mutations cause severe phenotypes in most patients with CMT2A. Neurology 2011;76:1690 –1696. Kijima K, Numakura C, Izumino H, et al. Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet 2005;116:23–27. Chung KW, Kim SB, Park KD, et al. Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain 2006;129:2103– 2118. Verhoeven K, Claeys KG, Zu¨chner S, et al. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain 2006;129:2093– 2102. Ouvrier R, Geevasingha N, Ryan MM. Autosomalrecessive and X-linked forms of hereditary motor and sensory neuropathy in childhood. Muscle Nerve 2007;36: 131–143. Montenegro G, Powell E, Huang J, et al. Exome sequencing allows for rapid gene identification in a CharcotMarie-Tooth family. Ann Neurol Epub 2011 Jan 20. Lupski JR, Reid JG, Gonzaga-Jauregui C, et al. Wholegenome sequencing in a patient with Charcot-MarieTooth neuropathy. N Engl J Med 2010;362:1181–1191.

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EDITORIAL

Time is brain for infections too?

David B. Clifford, MD

Address correspondence and reprint requests to Dr. David B. Clifford, Department of Neurology, Washington University in St. Louis, Box 8111, Neurology, 660 South Euclid Avenue, St. Louis, MO 63110 [email protected]

Neurology® 2011;76:1688–1689

Progressive multifocal leukoencephalopathy (PML) is a serious neurologic condition caused by the JC virus, which generally develops in chronically immunosuppressed patients. The emergence of this devastating disease in the setting of natalizumab therapy for multiple sclerosis (MS) has challenged neurologists.1 Better therapy for MS is urgently needed, and clinical trials suggest that natalizumab can markedly reduce the magnetic resonance– demonstrated activity associated with MS, as well as slow progression of disability.2,3 Sadly, a very significant risk of PML is now clearly associated with use of this therapy. Neurologists must gather the needed information to honorably carry out their task of framing therapeutic choices for patients, as well as coming to terms with when they recommend such a therapy. While therapies including lethal complications are commonly used in other disciples of medicine such as oncology and surgery, they have been rare in neurology. At a minimum, neurologists require data concerning potential benefits, the frequency of serious complications, and severity of outcomes if the complications are encountered. Clinical trials with natalizumab suggest that it provides a significant benefit to MS control, although direct head-to-head comparisons with alternative treatments would be more reassuring. The risk of PML in natalizumab-treated patients was estimated early on as approximately 1 case per 1,000 patient exposures, an estimate that appears accurate.1 The January 2011 Biogen update notes 85 confirmed PML cases and an overall incidence of 1.06 cases per 1,000 exposed individuals (95% confidence interval 0.85–1.31 per 1,000) (https:// medinfo.biogenidec.com/medinfo/download?doc⫽ Tysabri&type⫽monup&Continue⫽Continue). In this issue of Neurology®, Vermersch et al.4 summarize observations from the first 35 cases of natalizumab-associated PML, emphasizing outcomes, that help the clinician understand the implications of this 0.1% risk of PML. The report is the product of assessments from treating clinicians, organized by the company that markets natalizumab.

Some of the observations will not be surprising; older, sicker, and more extensively affected patients had worse outcomes. However, several important lessons emerge. PML is not a death sentence. PML prognosis has evolved rapidly, differing substantially with setting. In the early part of the AIDS epidemic, it was an almost uniformly fatal disease. The assumption that such outcomes are intrinsic to this disease can lead to fatalistic behaviors by patients, families, and physicians. This is not warranted. With modern HIV therapy, more than 50% of patients with HIVassociated PML survive.5 PML in patients with MS treated with natalizumab appears to have survival exceeding 70%, probably because the underlying immune system is competent in this setting, and can be reactivated by removal of the drug that, by design, limits immune responses to the CNS.6,7 Making this diagnosis quickly has substantial benefits and is at the heart of optimizing outcomes. Even with a few patients, Vermersch found that the prognosis was better when the diagnosis was recognized earlier: a median 3-week quicker diagnosis was associated with better prognosis. While not proven by this retrospective analysis, the clinically relevant implication is that early diagnosis allows reversing immunosuppression earlier, arresting ongoing viral associated demyelination, and limiting the extent of brain damage. To achieve this with clinical surveillance, patients and clinicians must be prepared to evaluate new definite symptoms promptly. At a minimum, skilled clinical assessment of new complaints, followed by prompt magnetic resonance evaluation of the brain, can generally determine if PML is possible, while CSF analysis with an ultrasensitive PCR assay for JC viral DNA can generally confirm the diagnosis.6,8 Neurologists might well apply the “time is brain” mantra to this aggressive infectious disease as well as to vascular disease. Many clinicians are also performing MRI surveillance brain scans for new lesions consistent with PML in an effort to make the diagnosis before symp-

See page 1697 From the Department of Neurology, Washington University in St. Louis, St. Louis, MO. Disclosure: Author disclosures are provided at the end of the editorial. 1688

Copyright © 2011 by AAN Enterprises, Inc.

toms occur. While the clinically explosive course of this infection suggested this might be an impractical approach, observation of a lesion in a clinically eloquent region visible on scan as much as 4 months prior to symptom onset suggests that scans at 6- to 12-month intervals might be expected to detect some lesions before symptoms are apparent.9 Particularly for patients with a history of prior immunosuppression who appear at higher risk of PML, such surveillance may be reasonable. This report also emphasizes the serious nature of PML. A third of survivors had devastating brain injuries that left them in a dependent condition, and an additional third had very serious increase in their disability. Given the risk of such injury, along with more than 20% mortality, aggressive MS treatment cannot be casually recommended. Only when MS is clearly diagnosed and is judged to be active enough to warrant aggressive therapy should such risks be recommended. However, where patients face life with a disabling disease while effective therapies are available, much good can be done by assuming calculated and real risks. The description of outcomes of PML from this report will help neurologists and patients realistically frame the risk of natalizumab therapy. PML must be understood as a major risk, but it is also somewhat manageable through early diagnosis and aggressive treatment. Neither exaggeration nor minimization of the risks of this complication will serve our patients well. DISCLOSURE Dr. Clifford serves/has served on scientific advisory boards for Biogen Idec, Elan Corporation, Roche, Forest Laboratories, Inc., Genentech, Inc., GlaxoSmithKline, Millennium Pharmaceuticals, Inc., ScheringPlough Corp., Bristol-Meyers Squibb, and Genzyme Corporation;

received speaker honoraria and funding for travel from GlaxoSmithKline, Millennium Pharmaceuticals, Inc., and Genentech Inc.; has received research support from Pfizer Inc, Schering-Plough Corp., Bavarian Nordic, NeurogesX, GlaxoSmithKline, Tibotec Therapeutics, Boehringer Ingelheim, and Gilead Sciences, Inc.; and receives research support from the NIH (NIMH, NINDS, NIAID, and Fogarty Institutes).

REFERENCES 1. 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. 2. 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. 3. 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. 4. Vermersch P, Kappos L, Gold R, et al. Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy. Neurology 2011;76:1697–1704. 5. Cinque P, Koralnik IJ, Gerevini S, Miro JM, Price RW. Progressive multifocal leukoencephalopathy in HIV-1 infection. Lancet Infect Dis 2009;9:625– 636. 6. Clifford DB, DeLuca A, Simpson DM, Arendt G, Giovannoni G, Nath A. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010;9: 438 – 446. 7. Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009;72:402– 409. 8. 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. 9. Lindå H, von Heijne A, Major EO, et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med 2009;361:1081–1087.

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ARTICLES

MFN2 mutations cause severe phenotypes in most patients with CMT2A

S.M.E. Feely, MS M. Laura, MD C.E. Siskind, MS S. Sottile, BA M. Davis, PhD V.S. Gibbons, PhD M.M. Reilly M.E. Shy

Address correspondence and reprint requests to Dr. Michael E. Shy, Wayne State University, 421 Ea Canfield, Detroit, MI 48201 [email protected]

ABSTRACT

Background: Charcot-Marie-Tooth disease type 2A (CMT2A), the most common form of CMT2, is caused by mutations in the mitofusin 2 gene (MFN2), a nuclear encoded gene essential for mitochondrial fusion and tethering the endoplasmic reticulum to mitochondria. Published CMT2A phenotypes have differed widely in severity.

Methods: To determine the prevalence and phenotypes of CMT2A within our clinics we performed genetic testing on 99 patients with CMT2 evaluated at Wayne State University in Detroit and on 27 patients with CMT2 evaluated in the National Hospital for Neurology and Neurosurgery in London. We then preformed a cross-sectional analysis on our patients with CMT2A. Results: Twenty-one percent of patients had MFN2 mutations. Most of 27 patients evaluated with CMT2A had an earlier onset and more severe impairment than patients without CMT2A. CMT2A accounted for 91% of all our severely impaired patients with CMT2 but only 11% of mildly or moderately impaired patients. Twenty-three of 27 patients with CMT2A were nonambulatory prior to age 20 whereas just one of 78 non-CMT2A patients was nonambulatory after this age. Eleven patients with CMT2A had a pure motor neuropathy while another 5 also had profound proprioception loss. MFN2 mutations were in the GTPase domain, the coiled-coil domains, or the highly conserved R3 domain of the protein.

Conclusions: We find MFN2 mutations particularly likely to cause severe neuropathy that may be primarily motor or motor accompanied by prominent proprioception loss. Disruption of functional domains of the protein was particularly likely to cause neuropathy. Neurology® 2011;76:1690–1696 GLOSSARY CMAP ⫽ compound muscle action potential; CMT2A ⫽ Charcot-Marie-Tooth disease type 2A; CMTNS ⫽ Charcot-MarieTooth Neuropathy Score; ER ⫽ endoplasmic reticulum; NCS ⫽ nerve conduction studies; SNAP ⫽ sensory nerve action potential; WSU ⫽ Wayne State University.

Charcot-Marie-Tooth disease 2A (CMT2A) is the most frequent form of CMT2, comprising ⬃20% of patients and families,1 and is caused by mutations in the nuclear encoded mitochondrial gene mitofusin 2 (MFN2).2 MFN2 is a highly conserved, nuclear encoded mitochondrial GTPase that is a component of the outer mitochondrial membrane and an essential regulator of fusion of mitochondria to each other3,4 or to membranes of the endoplasmic reticulum (ER).5 The phenotypic characteristics of CMT2A remain poorly understood. Some studies suggest that CMT2A, like all forms of CMT2, presents with slowly progressive length-dependent weakness and sensory loss.6 However, CMT2A cases have been described that severely affect infants and children as well as those with milder phenotypes that affect mainly adults.2,7,8 Several MFN2 mutations cause optic atrophy and neuropathy (CMT6)1 or have brain MRI Editorial, page 1686 e-Pub ahead of print on April 20, 2011, at www.neurology.org. From the Department of Neurology (S.M.E.F., C.E.S., S.S., M.E.S.) and Center for Molecular Medicine and Genetics (M.E.S.), Wayne State University, Detroit, MI; and MRC Centre for Neuromuscular Diseases (M.L., M.D., V.S.G., M.M.R.), Department of Molecular Neurosciences, UCL Institute of Neurology, London, UK. Study funding: Supported by the Muscular Dystrophy Association, the Charcot-Marie-Tooth Association, the NINDS/ORD (1U54NS065712-01), the Medical Research Council (MRC), and the Muscular Dystrophy Campaign. In the United Kingdom, this work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme. Disclosure: Author disclosures are provided at the end of the article. 1690

Copyright © 2011 by AAN Enterprises, Inc.

abnormalities or clinical pyramidal tract findings suggestive of CNS as well as PNS abnormalities (CMT5). We find that, unlike previous reports, almost all patients with CMT2A that we have evaluated have had severe early-onset neuropathies with most nonambulatory by age 20. Interestingly, some patients presented with pure motor abnormalities whereas other patients had profound proprioception loss in addition to weakness. As has been found in other series,2,9 most of the mutations affecting our patients were in either the GTPase or coiled-coil domains of MFN2, although we also identified a group of severely affected patients within the conserved R3 domain of the protein. METHODS Patient ascertainment and evaluation. We defined CMT2 as inherited axonal neuropathies in which nerve conduction velocities in the upper extremities were ⬎38 m/s.10,11 This value was used as a cutoff for both the Detroit and London patients. Compound muscle action potential (CMAP) or sensory nerve action potential (SNAP) amplitudes were reduced or absent, though in milder cases these reductions may only have been evident in the lower extremities. CMT2 can be difficult to distinguish from an idiopathic axonal neuropathy when there is no family history, which was the case in some patients with and without MNF2 mutations. Features that suggested CMT2 in such patients were the absence of known causes of axonal neuropathy, foot abnormalities such as pes cavus, and a history of progression similar to other forms of CMT such as gradual onset and presentation within the first 2 decades of life, or symmetric involvement. At Wayne State University (WSU), the authors evaluated 99 patients diagnosed with CMT2. Evaluations consisted of a neurologic history and examination, completion of a family history, calculation of a CMT Neuropathy Score (CMTNS), and performance of nerve conduction studies (NCS). After determining which patients met CMT2 criteria, those patients were tested for MFN2 mutations. At the National Hospital for Neurology and Neurosurgery in London, the authors evaluated 27 patients diagnosed with CMT2. Evaluations were similar to those at WSU although only those patients with MFN2 mutations received the same detailed evaluation with a prospective CMTNS and examination that was identical to that performed in Detroit.

CMTNS. The severity of the peripheral neuropathy was determined for all evaluated patients by the CMTNS, a validated measurement of disability for patients with CMT.12 The CMTNS is a composite score based on the history of symptoms (total possible points ⫽ 12), the neurologic examination (total possible points ⫽ 16), and clinical neurophysiology (total possible points ⫽ 8); the maximum score is 36 points. Patients with mild, intermediate, and severe disability typically have a CMTNS between 1 and 10, 11 and 20, and 21 or greater.13

Clinical electrophysiology, MRI, and neuro-ophthalmologic evaluations. NCS were performed by standard techniques utilizing either Nicolet Viking or Synergy (Oxford Medical Sys-

tems) EMG systems. Temperature was maintained at 34°C. Surface electrodes were used in all studies. Sensory conduction studies were performed using antidromic techniques (except the median and ulnar nerve studies in London, which were done orthodromically). Nerve conduction velocities were calculated by standard techniques. Standard techniques for MRI and neuro-ophthalmology were utilized.

Genetic testing. Genetic testing was performed for both sites using polymerase chain reaction and DNA sequencing of all exons. Genetic testing through the neurogenetic diagnostic laboratory in the National Hospital for Neurology and Neurosurgery, London, UK, was performed for MFN2 mutations on samples referred from patients with CMT2. In addition, patients at WSU who were personally evaluated by the authors and diagnosed with CMT2 underwent genetic testing performed by Athena Diagnostic Laboratories (Worcester, MA).

Standard protocol approvals, registrations, and patient consents. The Institutional Review Board at Wayne State University and the ethical standards committee at the National Hospital for Neurology and Neurosurgery in London approved the studies performed in this project. All patients signed consent forms. RESULTS

Characterization of patient cohort.

Ninety-nine patients were identified at WSU as having CMT2. The authors evaluated all of these. Fortyfour of the patients had mild clinical impairment (CMTNS ⬍10), 42 had moderate clinical impairment (CMTNS 11–20), and 19 had severe clinical impairment (CMTNS ⬎21). Patient ages ranged from ⬍1 year to 90 years and were equally divided into males and females (42 female, 57 male). MFN2 sequencing was performed in all 99 WSU patients (from 93 families). Twenty-one of the 99 patients (21%) had disease-causing mutations (11 female, 10 male). Separately, MFN2 sequencing was performed on samples from 27 patients in the United Kingdom with a diagnosis of CMT2. Six of these 27 samples (22%) were found to have MFN2 mutations. Combining these results, approximately 21% (21/126) of our patients with CMT2 have CMT2A. Therefore patients evaluated in our clinics have a similar prevalence of MFN2 mutations to what has been published by other centers.2,7,9 The authors evaluated the 21 of the patients identified at WSU with MFN2 mutations and the 6 patients with MFN2 mutations identified in the United Kingdom. Combining these numbers, we personally evaluated 27 patients with CMT2A. The authors evaluated all 78 patients without MFN2 mutations seen in Detroit and all 21 patients without MFN2 mutations seen in London. However, the 21 London patients without MFN2 mutations were not evaluated in the same detail as the 6 with MFN2 mutations. Thus we did not use these 21 London patients without MFN2 in our subsequent clinical evaluaNeurology 76

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Table 1

MFN2 mutations and phenotypes Age, y

Patient ID

At onset

CMTNS

Proprioception

Motor

1

Moderate

Normal

Moderate

1

Severe

Mild

Severe

28

1

Moderate

Normal

Severe

22

4

Severe

Normal

Severe

16

1

Moderate

Normal

Moderate

17

4

Severe

Normal

Severe

a

55

1

Severe

Mild

Severe

T105M

0743-001a

32

1

Mild

Normal

Moderate

L248V

0746-002

16

1

Moderate

Normal

Severe

0746-001a

45

1

Severe

Severe

Severe

R94G

a

14

0149-001a

16

a

0744-001

0745-001 R94Q R94W

Current

L4a 0736-001

a

L5a 0131-001

P251R

0617-002

6

1

Moderate

Normal

Moderate

0617-001a

39

1

Severe

Severe

Severe

a

28

1

Severe

Mild

Moderate

60

2

Severe

Severe

Severe

H361Y

0128-001

R364P

L6a

R364W

0622-001a

6

1

Severe

Normal

Moderate

0741-001a

31

1

Severe

Severe

Severe

0747-001a

41

1

Severe

Moderate

Severe

7

2

Severe

Normal

Severe

8

2

Severe

Mild

Severe

23

1

Severe

Mild

Severe

0747-003 0747-002 C390F

0470-001a

A716T

L1

44

2

Severe

Mild

Severe

W740S

0808-001

53

16

Moderate

Mild

Moderate

0771-001

38

33

Mild

Normal

Normal

0771-002

10

5

Moderate

Normal

Moderate

0771-003

15

15

Mild

Normal

Normal

L3

12

6

Severe

Normal

Moderate

25

14

Severe

Severe

Severe

H750P Y752X

a

L2

Abbreviation: CMTNS ⫽ Charcot-Marie-Tooth Neuropathy Score. a No family history of Charcot-Marie-Tooth disease.

tions. Only the 78 Detroit patients without MFN2 mutations were used in comparison studies of patients with and without CMT2A. Characterization of MFN2 mutations. All disease-

causing mutations were missense mutations, resulting in amino acid substitutions. The individual mutations in the 27 (from 21 different families) patients we evaluated are listed in table 1. Three separate families each had the Arg94Gln, Arg94Trp, and Arg364Trp mutations. Arg364 also had multiple mutations, with an Arg364Pro substitution affecting one family in addition to the Arg364Trp substitutions described above. Six mutations were in the large GTPase domain near the N-terminus (R94G, R94Q, R94W, T105M, L248V, P251R); 3 mutations were located in the 2 coiled-coil domains near the C terminus (W740S, H750P, Y752X), 3 mutations 1692

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were in the highly conserved R3 region (H361Y, R364P, R364W), a single mutation was in a nonconserved cysteine residue at 390 (C390F), and a single mutation was adjacent to the C-terminus coiled-coil domain (A716T). No mutation was identified in the p21Ras domain. The locations of the mutations observed in our families are shown in the figure. Three of the mutations within the GTPase domain (R94G, R94W, T105M), 2 mutations in the R3 region (H361Y, R364W), and one of the mutations in the C-terminus coiled-coil domain (W740S) have previously been reported to cause CMT2A.2,8,9,14-16 The remaining mutations have not been previously identified. Genotype–phenotype correlations. Seventeen out of the 27 patients with MFN2 mutations had severe neuropathies with a CMTNS ⬎21, 7 had moderate neuropathies with a CMTNS between 11 and 20, and 3

Figure

Illustration of MFN2 molecule is shown in which mutations are identified in relation to the functional domains of the molecule

*Mutation that resulted in vision impairment reported by patients.

had mild neuropathies with a CMTNS below 10. Five of the 7 “moderate” patients were ⬍16 years old. Based on their scores, these 5 will likely progress into the severe range by adulthood. The mean CMTNS for patients with MFN2 mutations was 21, in the severe range.11 Seventeen of our 19 patients with severe CMT2 (15 out of 17 families) had MFN2 mutations (90%). Seventeen patients with CMT2A presented sporadically, with no family history. Inheritance was dominant in the remaining 10. In comparison, 55 of the 78 patients (67%) evaluated at Wayne State who tested negative for MFN2 mutations had a dominant family history. Since there was not always male to male transmission we were not able to formally exclude an X-linked dominant inheritance pattern in many of these families. The 78 patients without MFN2 mutations included 41 with a mild neuropathy, 35 with a moderate neuropathy, and only 2 with a severe neuropathy. Only 10 out of 88 total patients (11%) with mild or moderate CMT2 had MFN2 mutations. The average CMTNS for those who tested negative for MFN2 was 11, the lowest level of the moderate range13 (tables 2 and 3). We next compared other features between our patients evaluated with CMT2A and those evaluated at WSU without CMT2A (tables 2 and 3). The average age at onset for patients with MFN2 mutations was 4.4 years, ranging from 7 months of 33 years. Twenty-three of the 27 patients had an onset prior to age 10. For the 15 patients with MFN2 mutations who were over 20 years of age at the time of evalua-

Table 2

tion, only 4 were ambulatory. Two unrelated ambulatory patients had the same Trp740Ser mutation. The average age at onset for the 78 patients without MFN2 mutations was 41.4 years (range 1– 82) with only 2 patients presenting with symptoms prior to age 10. All but one of these patients were ambulatory at age 20 years. Of the 27 severely affected patients, only 2 did not have MFN2 mutations. These 2 patients first noted symptoms at 15 and 30 years of age. One of the 2 was ambulatory after age 20 years. Heterogeneous distribution of abnormalities in patients with CMT2A. Although most of our patients

with CMT2A were severely affected, the distribution of weakness and sensory loss was variable. Eleven patients presented with a pure motor neuropathy, with symptoms and signs of weakness but no sensory loss. Another 5 patients had pronounced weakness but also severe proprioception loss with abnormal position sense at their knees as well as their toes and ankles. A summary of the motor and sensory abnormalities of our patients with CMT2A is provided in table 4. Patients with neuropathy and optic atrophy (CMT6)15 and with pyramidal tract17 and other CNS abnormalities (reviewed in 1) have been described with MFN2 mutations. Neuro-ophthalmologic examinations were performed on all patients with symptoms of visual impairment. Five patients were identified with optic atrophy (figure, asterisk). MRI studies, performed on 10 patients, were normal on 7, though changes in white matter were identified in 3. No brisk deep tendon reflexes or Babinski signs were observed.

Clinical features of CMT2A and non-CMT2A patients CMT2A (n ⴝ 27)

Non-CMT2A (n ⴝ 78)

Age, y, mean ⴞ SD (range)

26.1 ⫾ 15.7 (5–55)

46.5 ⫾ 18.5 (3–90)

M:F

10:11

47:31

Age at onset, y, mean ⴞ SD

4.4 ⫾ 7.1

41.4 ⫾ 22.2

CMTNS, mean ⴞ SD (range)

21.1 ⫾ 8.1 (4–34)

11.3 ⫾ 4.0 (1–25)

Abbreviations: CMT2A ⫽ Charcot-Marie-Tooth disease type 2A; CMTNS ⫽ Charcot-MarieTooth Neuropathy Score.

DISCUSSION We have determined that 21% of our

patients with CMT2 have mutations in the MFN2 gene, a prevalence that is similar to what has been reported.2,7,9,18 However, the clinical heterogeneity of the patients with CMT2A we evaluated was quite different from what has been previously reported.18-20 We did not observe an equal distribution of mild and severely affected patients with CMT2A. Neither did Neurology 76

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Table 3

Neurophysiologic features of CMT2A and non-CMT2A patients, mean ⴞ SD (range)

Median NCV, m/s No. Median CMAP, mV No. Ulnar NCV, m/s No. Ulnar CMAP, mV No.

CMT2A

Non-CMT2A

53.4 ⫾ 5.4 (44.5–63.8)

48.7 ⫾ 8.3 (11.4–59.3)

7 (no response, n ⫽ 13)

78

5.7 ⫾ 1.2 (3.4–7.39)

5.9 ⫾2.8 (0.8–15.7)

7 (no response, n ⫽ 13)

78

54.5 ⫾ 5.2 (45.0–62.6)

51.4 ⫾ 9.2 (9.9–64.0)

10 (no response, n ⫽ 11)

78

5.3 ⫾ 4.2 (0.38–12.06)

6.7 ⫾ 2.6 (0.8–12.2)

10 (no response, n ⫽ 11)

78

Abbreviations: CMAP ⫽ compound muscle action potential; CMT2A ⫽ Charcot-Marie-Tooth disease type 2A; NCS ⫽ nerve conduction studies.

most of our patients with CMT2A present with a “classic phenotype” of mild weakness and sensory loss in the first 2 decades of life with slow progression thereafter. Most of our patients with CMT2A developed very severe axonal neuropathies in childhood. Only 4 of 15 adult patients could ambulate independently by age 20 years. Additionally some of our patients had pure motor neuropathies whereas many others had severe proprioception loss in addition to weakness, suggesting that in some cases clinical involvement of large diameter sensory axons or their perikaryons were spared. Motor-sensory distinctions were not mutation specific as the same mutation caused both motor and sensorimotor phenotypes (table 1). Proximal limb impairment seemed to occur much earlier in our patients than with other forms of CMT such as CMT1A. While this may have been simply a function of the severity of the disease, we were struck by how early and often hip flexor and quadriceps weakness occurred. We identified 4/5 strength or less in 19 of our 27 patients. Similarly, proprioception, when altered in our patients, usually affected the ankle and sometimes the knee as well as toes. Taken together, these results suggest that impairment in CMT2A is less length dependent than in many forms of CMT, suggesting that there may be a neuronopathy component rather than simply an axonal degeneration involved in the pathogenesis. Research into the cell biology of MFN2 suggests that particular domains are essential for the protein to induce mitochondrial fusion or tethering to the ER. Mutated MFN2 constructs bearing 4 of the mutations we evaluated have been shown to be completely unable to induce mitochondrial fusion when introduced by retroviral vectors into mouse embryonic fibroblast (MEF) cell lines lacking Mfn1 and Mfn2 (double Mfn-null cells). Similarly none of these mutations were able to restore mitochondrial tubules, which require fusion, in cell lines.21 The R94Q mutation disrupted ER function and mor1694

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phology. Other mutations affecting our patients have not been tested with respect to their abilities to disrupt mitochondria–ER tethering. However, since this tethering also requires interactions between coiled coil domains in trans between MFN2 from the ER membrane and MFN2 or MFN1 from the mitochondrial outer membrane, as well as GTPase activity,5 it is likely that many of our other mutations disrupt mitochondrial–ER interactions as well. Taken together, these data suggest that most diseasecausing mutations in our patients are in regions of the MFN2 molecule necessary to induce fusion to other mitochondria, similar to what has been suggested in other series,9 as well as in domains necessary to form bridges between mitochondria and the ER. These data therefore suggest that mutations that completely prevent the MFN2-mediated fusion will cause severe neuropathy in patients. We postulate that mutant MFN2 in our patients caused neuropathy by a “dominant-negative” mechanism in which the mutant protein prevents the MFN2 expressed by the normal allele from fusion to other mitochondria or ER. Soluble Mfn2 constructs lacking the GTPase, coiled-coil, or R3 domains prevented mitochondrial fusion mediated by wild-type Mfn2 by similar dominant negative mechanisms in in vitro systems.22 We think it likely that the mutations afflicting our patients that occur in these same domains are also acting as dominant-negatives by binding through their coiled-coil domains with wildtype Mfn2 and preventing both the wild-type and mutant Mfn2 from fusing mitochondria. Consistent with this hypothesis, we are unaware of any amino acid changing mutations acting as benign polymorphisms in these regions. We also hypothesize that mutations in other domains may not act as dominant negatives and would therefore not affect MFN2 expressed from the wild type allele. In these cases mutations would act either as benign polymorphisms or at most cause mild neuropathies. This would explain the relatively large number of missense mutations reported as polymorphisms in MFN2 compared to the low levels of polymorphisms in other autosomal dominant forms of CMT such as CMT1B, CMT1X, or CMT1E, where virtually all amino acid substitutions cause neuropathy (www.molgen.ua.ac.be/ CMTMutations/default.cfm). Why we have seen only isolated cases of milder CMT2A is not clear. We have considered whether this could simply have been an artifact of ascertainment. However we believe that this is an unlikely explanation since both the Detroit and London CMT clinics are large and follow hundreds of patients whose phenotypes for other forms of CMT are representative of those reported in the literature. The

Clinical features of patients with MFN2 mutationsa

Table 4

R94G

Patient ID

Distal weakness LL

Proximal weakness LL

Distal weakness UL

Proximal weakness UL

Proprioception LL

Proprioception UL

Cutaneous LL

Cutaneous UL

0744-001

⫹ (1,4)

⫺ (5,5)

⫹ (3,4,3)

⫺ (5,5,5)

Normal

Normal

Normal

Normal

0149-001

⫹ (0,0)

⫹ (3,0)

⫹ (0,0,0)

⫹ (3,2,2)

Red. toes

Normal

Normal

Normal

0745-001

⫹ (0,0)

⫹ (4,4)

⫹ (2,4,3)

⫺ (5,5,5)

Normal

Normal

Normal

Normal

R94Q

L4

⫹ (0,3)

⫹ (4,4)

⫹ (1,2,1)

⫹ (4,3,5)

Normal

Normal

Normal

Normal

R94W

0736-001

⫹ (0,3)

⫹ (5,4)

⫹ (3,3,3)

⫺ (5,5,5)

Normal

Normal

Normal

Normal

L5

⫹ (0,0)

⫹ (4,1)

⫹ (0,1,0)

⫹ (4,4,5)

Normal

Normal

Abs. toes

Abs. finger

0131-001

⫹ (0,0)

⫹ (4,2)

⫹ (0,0,0)

⫺ (5,5,5)

Abs. toes

Normal

Red. knee

Normal

T105M

0743-001

⫹ (2,4)

⫺ (5,5)

⫹ (4,4,4)

⫺ (5,5,5)

Normal

Normal

Normal

Normal

L248V

0746-002

⫹ (0,0)

⫹ (4,4)

⫹ (1,3,1)

⫺ (5,5,5)

Normal

Normal

Normal

Normal

0746-001

⫹ (0,0)

⫹ (4,1)

⫹ (1,0,1)

⫺ (5,5,5)

Abs. ankle

Normal

Red. toes

Normal

0617-002

⫹ (1,3)

⫺ (5,5)

⫹ (3,2,3)

⫺ (5,5,5)

Normal

Normal

Normal

Normal

0617-001

⫹ (0,0)

⫹ (4,0)

⫹ (0,0,0)

⫹ (4,2,5)

Abs. knee

Red. elbows

Abs. knee

Red. finger

H361Y

0128-001

⫹ (0,0)

⫹ (5,2)

⫹ (0,1,0)

⫺ (5,5,5)

Red. toes

Normal

Red. toes

Red. finger

R364P

L6

⫹ (0,0)

⫹ (4,2)

⫹ (0,0,0)

⫹ (4,2,5)

Abs. knee

Abs. fingers

Abs. knee

Red. finger

R364W

0622-001

⫹ (0,0)

⫹ (2,2)

⫹ (1,1,1)

⫺ (5,5,5)

Normal

Normal

Normal

Normal

0741-001

⫹ (0,0)

⫹ (0,0)

⫹ (0,0,0)

⫹ (5,3,5)

Abs. knee

Normal

Normal

Normal

0747-001

⫹ (0,0)

⫹ (4,2)

⫹ (0,0,0)

⫹ (5,4,4)

Red. ankle

Normal

Red. ankle

Red. wrist

0747-003

⫹ (0,0)

⫹ (4,5)

⫹ (0,0,0)

⫺ (5,5,5)

Normal

Normal

Normal

Normal

P251R

0747-002

⫹ (0,0)

⫹ (4,4)

⫹ (0,0,0)

⫹ (5,4,4)

Abs. toes

Normal

Normal

Normal

C390F

0470-001

⫹ (0,0)

⫹ (2,2)

⫹ (0,1,0)

⫺ (5,5,5)

Abs. toes

Normal

Red. toes

Normal

A716T

L1

⫹ (0,0)

⫹ (2,2)

⫹ (0,0,0)

⫹ (4,2,5)

Abs. toes

Normal

Abs. knee

Abs. elbow

W740S

0808-001

⫹ (3,3)

⫺ (5,5)

⫹ (4,5,4)

⫺ (5,5,5)

Abs. toes

Normal

Red. knee

Normal

0771-001

⫺ (5,5)

⫺ (5,5)

⫺ (5,5,5)

⫺ (5,5,5)

Normal

Normal

Normal

Normal

0771-002

⫹ (3,4)

⫹ (4,5)

⫹ (3,5,4)

⫺ (5,5,5)

Normal

Normal

Normal

Normal

0771-003

⫺ (5,5)

⫺ (5,5)

⫺ (5,5,5)

⫺ (5,5,5)

Normal

Normal

Normal

Normal

H750P

L3

⫹ (3,3)

⫺ (5,5)

⫹ (3,5,4)

⫺ (5,5,5)

Normal

Normal

Normal

Normal

Y752X

L2

⫹ (0,0)

⫹ (2,2)

⫹ (0,0,0)

⫹ (3,2,3)

Abs. knee

Abs. elbow

Abs. knee

Abs. elbow

Abbreviations: Abs. ⫽ absent; LL ⫽ lower limbs; Red. ⫽ reduced; UL ⫽ upper limbs. a Motor weakness based on Medical Research Council scale: LL distal weakness in lower extremities assessed by anterior tibialis and gastrocnemius, LL proximal weakness assessed by iliopsoas and quadriceps; UL distal weakness in upper extremities assessed by first dorsal interosseous, abductor pollicis brevis, and adductor digiti minimi, UL distal weakness assessed by deltoids, biceps brachii, and triceps. ⫹ ⫽ weakness present; ⫺ ⫽ no weakness. Numbers in the table are based on the side that gave the worst score. Proprioception based on joint position sensation and cutaneous sensation based on pinprick examination: normal is no decrease compared to the examiner. Levels given (toes, knees) are the highest level in the lower or upper extremities where a deficit was detected. As with motor testing, the worst side was listed if there were discrepancies between findings on the right or left.

most probable explanation, in our opinion, is that mildly affected patients with CMT2A are unusual, at least in the United States and United Kingdom. Mildly affected patients presumably result from mutations that cause partial loss of MFN2 function or partial dominant negative effects on wild-type MFN2 function, but do not completely block the ability of at least wild-type MFN2 to fuse. Consistent with this hypothesis, the large pedigree with a mild form of CMT2A published by the Utah group had a Val273Gly mutation. Codon 273 is located between the GTPase and R3 domains (7) and thus may not disrupt fusion. It is also possible that the mutations in some milder cases might not be causative but may in fact be benign polymorphisms. As there are many

polymorphisms within MFN2 and many patients that present without a prior family history, it can often be very difficult to be certain that particular mutations are disease causing, particularly if other family members are not analyzed. Several of our patients have had pure motor phenotypes whereas others have also had profound loss of large fiber sensory modalities. In general, patients with normal or mild proprioception loss were younger than those with more severe sensory loss. For 3 of the mutations we have identified, L248V, P251R, and R364W, younger patients had normal or only mildly abnormal proprioception loss, whereas older patients had much more pronounced proprioception deficiencies. Taken together, these data sugNeurology 76

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1695

gest that clinical sensory abnormalities may appear later than motor abnormalities. While that seems to be the case for those 3 mutations, all 7 mutations affecting amino acid 94 had pronounced motor but minimal sensory abnormalities. Thus, certain mutation sites may preferentially affect motor neurons. Some, but not all, of our patients had optic atrophy or CNS abnormalities, which is similar to findings from other studies that found abnormalities outside the PNS in some cases.15,19 Why a subset of patients has CNS phenotypes is not understood, since MFN2 is ubiquitously expressed. One possibility that has been proposed is that MFN1 may compensate for abnormal MFN2. Mammalian cells contain both MFN1 and MFN2, either of which can induce mitochondrial fusion; in fact, Mfn1 tethers mitochondria more efficiently than Mfn223 and OPA1 requires Mfn1 for mitochondrial fusion but will not fuse with Mfn2.24 Some cell types contain more MFN1 than others and in those cell types, such as CNS neurons, the MFN1 might compensate for the abnormal MFN2.24 Alternatively, interactions between mitochondria and the ER may differ between the PNS and CNS. Whether these hypotheses are correct and whether either can also explain why some patients have pure motor and others sensorimotor neuropathies will need to be investigated experimentally.

6.

7.

8.

9.

10.

11.

12. 13.

14.

15.

16.

ACKNOWLEDGMENT The authors thank the patients and families for their participation in this study.

17.

DISCLOSURE S.M.E. Feely, Dr. Laura, C.E. Siskind, S. Sottile, Dr. Davis, and Dr. Gibbons report no disclosures. Dr. Reilly serves on the editorial boards of Brain, Neuromuscular Disorders, and the Journal of the Peripheral Nervous System. Dr. Shy serves on the speakers’ bureau for and has received funding for travel and speaker honoraria from Athena Diagnostics, Inc.; serves on the editorial board of the Journal of Peripheral Nervous System; and receives research support from the NIH/NINDS, the Muscular Dystrophy Association, and the Charcot-Marie-Tooth Association.

Received April 27, 2010. Accepted in final form November 22, 2010. REFERENCES 1. Zuchner S, Vance JM. Molecular genetics of autosomaldominant axonal Charcot-Marie-Tooth disease. Neuromolecul Med 2006;8:63–74. 2. Zuchner S, Mersiyanova IV, Muglia M, et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-MarieTooth neuropathy type 2A. Nat Genet 2004;36:449 – 451. 3. Rojo M, Legros F, Chateau D, Lombes A. Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J Cell Sci 2002;115:1663–1674. 4. Griffin EE, Detmer SA, Chan DC. Molecular mechanism of mitochondrial membrane fusion. Biochim Biophys Acta 2006;1763:482– 489. 5. de Brito OM, Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 2008;456:605– 610. 1696

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Bienfait HM, Baas F, Koelman JH, et al. Phenotype of Charcot-Marie-Tooth disease type 2. Neurology 2007;68: 1658 –1667. Lawson VH, Graham BV, Flanigan KM. Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 2005;65:197–204. Cho HJ, Sung DH, Kim BJ, Ki CS. Mitochondrial GTPase mitofusin 2 mutations in Korean patients with Charcot-Marie-Tooth neuropathy type 2. Clin Genet 2007;71:267–272. Kijima K, Numakura C, Izumino H, et al. Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet 2005;116:23–27. Harding AE, Thomas PK. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 1980;103:259 –280. Harding AE, Thomas PK. Genetic aspects of hereditary motor and sensory neuropathy (types I and II). J Med Genet 1980;17:329 –336. Grandis M, Shy ME. Current therapy for Charcot-MarieTooth disease. Curr Treat Options Neurol 2005;7:23–31. Shy ME, Blake J, Krajewski K, et al. Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology 2005;64:1209 –1214. Verhoeven K, Claeys KG, Zuchner S, et al. MFN2 mutation distribution and genotype/phenotype correlation in CharcotMarie-Tooth type 2. Brain 2006;129:2093–2102. Zuchner S, De Jonghe P, Jordanova A, et al. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol 2006;59:276 –281. Neusch C, Senderek J, Eggermann T, Elolff E, Bahr M, Schneider-Gold C. Mitofusin 2 gene mutation (R94Q) causing severe early-onset axonal polyneuropathy (CMT2A). Eur J Neurol 2007;14:575–577. Zhu D, Kennerson ML, Walizada G, Zuchner S, Vance JM, Nicholson GA. Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations. Neurology 2005;65:496 – 497. Amiott EA, Lott P, Soto J, et al. Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations. Exp Neurol 2008;211: 115–127. Chung KW, Kim SB, Park KD, et al. Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain 2006;129:2103–2118. Calvo J, Funalot B, Ouvrier RA, et al. Genotypephenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations. Arch Neurol 2009;66:1511–1516. Detmer SA, Chan DC. Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J Cell Biol 2007; 176:405– 414. Honda S, Aihara T, Hontani M, Okubo K, Hirose S. Mutational analysis of action of mitochondrial fusion factor mitofusin-2. J Cell Sci 2005;118:3153–3161. Ishihara N, Eura Y, Mihara K. Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J Cell Sci 2004;117:6535– 6546. Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA 2004;101:15927– 15932.

Clinical outcomes of natalizumabassociated progressive multifocal leukoencephalopathy P. Vermersch, MD, PhD L. Kappos, MD R. Gold, MD J.F. Foley, MD T. Olsson, MD, PhD D. Cadavid, MD C. Bozic, MD S. Richman, MD, MPH

Address correspondence and reprint requests to Dr. Sandra Richman, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142 [email protected]

ABSTRACT

Objective: Natalizumab, a therapy for multiple sclerosis (MS), has been associated with progressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the CNS associated with the JC virus. We assessed clinical outcomes and identified variables associated with survival in 35 patients with natalizumab-associated PML.

Methods: Physicians provided Karnofsky scores and narrative descriptions of clinical status. Data were supplemented by the natalizumab global safety database. Results: At the time of analysis, 25 patients (71%) had survived. Survivors were younger (median 40 vs 54 years) and had lower pre-PML Expanded Disability Status Scale scores (median 3.5 vs 5.5) and a shorter time from symptom onset to diagnosis (mean 44 vs 63 days) compared with individuals with fatal cases. Of patients with nonfatal cases, 86% had unilobar or multilobar disease on brain MRI at diagnosis, whereas 70% of those with fatal cases had widespread disease. Gender, MS duration, natalizumab exposure, prior immunosuppressant use, and CSF JC viral load at diagnosis were comparable. Most patients were treated with rapid removal of natalizumab from the circulation. The majority of patients developed immune reconstitution inflammatory syndrome and were treated with corticosteroids. Among survivors with at least 6 months follow-up, disability levels were evenly distributed among mild, moderate, and severe, based on physician-reported Karnofsky scores.

Conclusions: Natalizumab-associated PML has improved survival compared with PML in other populations. Disability in survivors ranged from mild to severe. A shorter time from symptom onset to diagnosis and localized disease on MRI at diagnosis were associated with improved survival. These data suggest that earlier diagnosis through enhanced clinical vigilance and aggressive management may improve outcomes. Neurology® 2011;76:1697–1704 GLOSSARY CI ⫽ confidence interval; EDSS ⫽ Expanded Disability Status Scale; HAART ⫽ highly active antiretroviral therapy; IA ⫽ immunoadsorption; IRIS ⫽ immune reconstitution inflammatory syndrome; JCV ⫽ JC virus; mRDS ⫽ modified Rankin disability scale; MS ⫽ multiple sclerosis; PLEX ⫽ plasma exchange; PML ⫽ progressive multifocal leukoencephalopathy.

Editorial, page 1688

Supplemental data at www.neurology.org

Natalizumab was first approved by the US Food and Drug Administration in 2004 to treat relapsing forms of multiple sclerosis (MS) and is currently approved in more than 50 countries. As of July 2010, more than 71,000 patients have been treated. However, a small number of natalizumab-treated patients develop progressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the CNS. PML probably results from a complex interaction between JC virus (JCV) infection, viral factors, and host factors such as immunosuppression. Two cases of PML were reported in natalizumab MS clinical trials in subjects treated with natalizumab in combination with interferon ␤-1a,1,2 and a third case was later identified in a natalizumab Crohn’s disease clinical trial.3 At that time, the incidence of PML in natalizumab clinical trials was estimated to be 1 case per 1,000 (95% confidence interval [CI] 0.2%–2.8%).4 From the Department of Neurology (P.V.), University of Lille Nord de France, Lille, France; Departments of Neurology and Research (L.K.), University Hospital, Basel, Switzerland; St. Josef-Hospital (R.G.), Ruhr University, Bochum, Germany; Rocky Mountain Multiple Sclerosis Clinic (J.F.F.), Salt Lake City, UT; Center for Molecular Medicine (T.O.), Karolinska Hospital, Stockholm, Sweden; and Biogen Idec, Inc. (D.C., C.B., S.R.), Weston, MA. Disclosure: Author disclosures are provided at the end of the article. Copyright © 2011 by AAN Enterprises, Inc.

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Figure 1

Estimated incidence of progressive multifocal leukoencephalopathy (PML) by natalizumab treatment epoch

Incidence estimates by treatment epoch were calculated based on natalizumab exposure through August 31, 2010, with 68 cases being confirmed as of September 2, 2010. The incidence for each epoch is calculated as the number of PML cases divided by the number of patients exposed to natalizumab (e.g., number of PML cases in patients who received 25–36 infusions is divided by the total number of patients who have ever been exposed to at least 25 infusions and therefore had the risk of developing PML during this time). The 95% confidence interval (CI) is an estimated range that is 95% likely to include the true rate of PML. The width of the CI is an indication of the precision of the estimate. Wider confidence intervals in relation to the point estimate indicate a higher level of uncertainty. Increasing the denominator of treated patients will increase the precision of the estimates and narrow the CI. There are limited data beyond 3 years of treatment.5

The first postmarketing case of natalizumabassociated PML occurred in 2008. As of September 2010, 68 cases of PML have been reported worldwide since market reintroduction. The incidence of PML increases with longer treatment duration (figure 1) but remains within the range observed in clinical trials.4 Data in patients exposed to natalizumab beyond 3 years are limited; all postmarketing cases of PML to date involve patients with MS, none of whom received fewer than 12 natalizumab infusions before diagnosis. A recent publication reviewed the clinical presentation, diagnosis, and management of the first 28 patients with natalizumabassociated PML.5 Our analysis focuses on clinical outcomes and includes a critical evaluation of predictors of survival and assessment of disability status among natalizumabassociated PML survivors. METHODS Between January and March 2010, treating physicians for the first 35 postmarketing cases of natalizumabassociated PML provided clinical status updates on their patients using the Karnofsky Performance Scale,6 a functional outcome 1698

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measure validated in several disease states and patient populations7-11 (table e-1 on the Neurology® Web site at www.neurology.org). Treating physicians also provided descriptions of their patients’ clinical status, with an emphasis on motor function, cognition, and ability to perform daily activities. These outcome data were supplemented with information from the Biogen Idec natalizumab global safety database. The characteristics of patients with nonfatal and fatal cases of PML were compared to identify variables associated with improved survival.

Baseline demographics are shown in table 1. Patients include 10 men and 25 women aged 27–59 years (mean 43.7 years; median 43 years), with a mean MS duration of 12.5 years. Age, gender, and duration of MS in patients with PML were similar to those of the general natalizumab-treated MS population. Eleven patients were from the United States, and 24 patients were from Europe. Natalizumab exposure at the time of PML diagnosis ranged from 12 to 44 infusions (mean 26.6 infusions; median 26 infusions), and 49% of patients received at least one immunosuppressant drug (e.g., mitoxantrone, methotrexate, azathioprine, cyclophosphamide, or mycophenolate) before starting natalizumab. Expanded Disability Status Scale (EDSS) scores before PML diagnosis ranged from 0.0 to 6.5 (mean

RESULTS Patient demographics.

Table 1

Demographics and clinical outcome status of patients with PML

Baseline characteristics

All patients (n ⴝ 35)

Nonfatal cases (n ⴝ 25)

Fatal cases (n ⴝ 10)

Age at diagnosis, y, mean, median (range)

43.7, 43 (27–59)

40.7, 40 (27–52)

51.1, 54 (35–59)

Male

10 (29)

6 (24)

4 (40)

Female

25 (71)

19 (76)

6 (60)

11 (31)

3 (12)

8 (80)

Gender, n (%)

Geography, n (%) United States

24 (69)

22 (88)

2 (20)

Duration of MS at diagnosis, y, mean, median (range)a

Europe

12.5, 12.5 (1.5–21)

11.9, 12.3 (1.5–21)

13.6, 12.5 (6–21)

EDSS score on natalizumab before PML, mean, median (range)

4.2, 4 (0–6.5)

3.9, 3.5 (0–6.5)

4.9, 5.5 (2.0–6.5)

Natalizumab exposure, mean, median (range)

26.6, 26 (12–44)

26.7, 26 (12–44)

26.4, 27 (14–35)

Yes

17 (49)

13 (52)

4 (40)

Mitoxantrone

9

8

1

Methotrexate

4

0

4

Azathioprine

3

3

0

Cyclophosphamide

2

1

1

Mycophenolate

2

2

0

Chemotherapy (NOS)

2

2

0

No

18 (51)

12 (48)

6 (60)

Patients at clinical status, n (%)

35 (100)

25 (71)

10 (29)

Time from PML diagnosis to measurement of clinical status, mo, mean, median (range)

5.8, 5 (0.25–20)

6.8, 5 (0.25–20)

3.1, 1.8 (1–10.5)

Patients at clinical status and <6 mo since PML diagnosis, n (%)

22 (63)

13 (52)

9 (90)

Patients at clinical status and >6 mo since PML diagnosis, n (%)

13 (37)

12 (48)

1 (10)

Prior immunosuppressant use, n (%)

Clinical outcome

Abbreviations: EDSS ⫽ Expanded Disability Status Scale; MS ⫽ multiple sclerosis; NOS ⫽ not otherwise specified; PML ⫽ progressive multifocal leukoencephalopathy. a Onset date of MS missing for 9 patients with PML.

4.2; median 4.0). At the time of the analysis, 25 patients (71%) had survived (3 from the United States and 22 from Europe), with a mean and median follow-up time of 6.8 and 4.5 months, respectively; 10 patients (29%) had died (8 from the United States and 2 from Europe). Predictors of survival in natalizumab-associated PML.

As shown in table 1, patients with nonfatal cases were younger at the time of PML diagnosis compared with those with fatal cases (mean age 40.7 vs 51.1 years) and had less disability before diagnosis, as evidenced by lower EDSS scores while receiving natalizumab (mean 3.9, median 3.5 vs mean 4.9, median 5.5). Gender distribution, duration of MS, natalizumab exposure, and immunosuppressant use before natalizumab were similar among those with nonfatal and fatal cases.

Nonfatal cases had a shorter time between symptom onset and PML diagnosis (mean 44.2 days; median 31 days) compared with fatal cases (mean 62.8 days; median 40.5 days) (figure 2A). Brain MRI results at the time of diagnosis were available for 31 patients and are shown in table 2. The majority of patients with nonfatal cases (86%) had either unilobar or multilobar disease (2 or more contiguous lobes), whereas the majority of those with fatal cases (70%) had widespread disease (2 or more noncontiguous lobes or disease present in both hemispheres). Unilobar PML involved the frontal and occipital lobes in 60% and 40% of patients, respectively. PML involvement of the posterior fossa was very rare, occurring in one patient who presented with widespread disease and had a fatal outcome. Gadolinium enhanceNeurology 76

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Figure 2

Predictors of survival in natalizumab-associated progressive multifocal leukoencephalopathy (PML)

(A) A shorter time interval (mean number of days) between symptom onset and confirmed diagnosis of PML was observed in nonfatal cases than in fatal cases. (B) Median concentrations of JC virus (JCV) DNA in CSF tended to be lower in nonfatal than in fatal cases of natalizumab-associated PML.

ment on MRI was present at diagnosis in 60% of patients with nonfatal cases and 33% of those with fatal cases (Biogen Idec, data on file). This difference was not thought to be clinically meaningful. As shown in figure 2B, JCV concentration in CSF at

Table 2

PML extension by MRI at time of diagnosis

PML extension on MRI at diagnosis (n ⴝ 31)a

Nonfatal cases (n ⴝ 21), n (%)

Fatal cases (n ⴝ 10), n (%)

Unilobar

9 (43)

1 (10)

Multilobar

9 (43)

2 (20)

Widespread

3 (14)

7 (70)

Abbreviation: PML ⫽ progressive multifocal leukoencephalopathy. a MRI results were available for 31 patients. Unilobar indicates that lesions were confined to one lobe, multilobar indicates that lesions were present in 2 or more contiguous lobes, and widespread indicates that lesions were present in 2 or more noncontiguous lobes or present in both hemispheres. 1700

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the time of PML diagnosis was lower in patients with nonfatal cases (mean 121,000 copies/mL; median 626 copies/mL) compared with those with fatal cases (mean 412,000 copies/mL; median 2,350 copies/mL). Twenty-five patients (18 nonfatal and 7 fatal cases) had CSF JCV testing performed by the NIH, which uses an ultrasensitive quantitative real-time PCR. To account for interlaboratory variability, CSF JCV loads for patients tested in the NIH laboratory were reviewed separately; patients with nonfatal cases had lower CSF JCV loads at diagnosis (mean 78,000 copies/mL; median 247 copies/mL) than those with fatal cases (mean 568,000 copies/mL; median 322 copies/mL). However, the difference in median values was small and may not be clinically meaningful. Initial treatment of PML was similar in both groups. Natalizumab treatment was withheld in all patients once PML was suspected. In the majority of patients with nonfatal cases (92%) and in all those with fatal cases, accelerated removal of natalizumab from the circulation was performed using plasma exchange (PLEX) or immunoadsorption (IA). Mefloquine or mirtazapine was prescribed in some patients on the basis of results of in vitro viral replication inhibition studies.12,13 Use of these 2 agents was similar, with 56% of patients with nonfatal cases and 80% of patients with fatal cases receiving mefloquine and 60% of those with nonfatal cases and 70% of those with fatal cases receiving mirtazapine. Almost all patients with PML (32 of 35 [91%]) developed immune reconstitution inflammatory syndrome (IRIS), an enhanced intracerebral inflammatory antiviral reaction associated with restoration of immune surveillance (92% of patients with nonfatal cases and 90% of those with fatal cases). Diagnosis of IRIS was determined by the treating physician. IRIS presented as new or worsening neurologic symptoms, tended to be severe, and usually occurred within days or weeks after accelerated removal of natalizumab. The mean time from initiation of PLEX or IA to onset of IRIS symptoms was similar for patients with nonfatal and fatal cases (35.3 and 32.4 days, respectively). The 3 patients for whom IRIS was not reported included one patient who died 4 weeks after PML diagnosis (before onset of IRIS) and 2 patients in whom PML was diagnosed in January 2010 and for whom physicians had not yet reported the development of IRIS at the time of the analysis. Of the 35 patients, 30 (86%) were treated with corticosteroids. The majority (86% of patients with nonfatal cases and 75% of those with fatal cases) received high-dose corticosteroids (at least 3 g methylprednisolone or the equivalent). Although data are limited, the most common regimens were pulsed IV high-dose cortico-

steroids or IV high-dose corticosteroids followed by oral taper. PML clinical outcomes. Causes and timing of death in

Ten of 35 patients with PML (29%) had died at the time of the analysis. Mean and median times from PML diagnosis to death were 3.1 and 1.8 months, respectively (range 1–10.5 months). Seven of 10 patients died within approximately 2 months of PML diagnosis, and 5 probably died of IRIS. In all 5 possible deaths associated with IRIS, further medical intervention was withheld at the request of the patient or patient’s family because of severe clinical worsening. Other causes of death included aspiration pneumonia (2 patients), hypoventilation syndrome and respiratory failure after residual brainstem injury from PML (1 patient), and progressive clinical worsening, tetraplegia, and coma leading to death 4 months after PML diagnosis (1 patient). In addition, one patient developed seizures/status epilepticus and, in the setting of clinical worsening, requested that further medical intervention and nutrition be withheld; this patient died of dehydration and acute renal failure approximately 11 months after PML diagnosis. Functional outcomes in PML survivors. Disability status measured by Karnofsky scores for the 25 PML survivors is provided in table 3. Four patients (16%) had mild disability (Karnofsky scores 80 –90), 9 patients (36%) had moderate disability (Karnofsky scores 50 –70), and 12 patients (48%) had severe disability (Karnofsky scores 10 – 40). These physicianreported clinical assessments were part of a crosssectional review, and each patient was observed at a different time point in the course of PML. Therefore, the duration between time of PML diagnosis and clinical assessment was evaluated. In general, patients with mild disability seemed to have had more elapsed time since their PML diagnosis (mean 10.4 months; median 8 months) than patients with severe PML.

Table 3

Disability status for PML survivors based on Karnofsky scores Disability status for survivors (n ⴝ 25)a

Baseline characteristics

Mild

Moderate

Severe

Patients at clinical status, n (%)

4 (16)

9 (36)

12 (48)

Time from PML diagnosis to current clinical status, mo, mean, median (range)

10.4, 8 (6.5–19)

6.3, 5 (3–14)

6, 4 (0.25–20)

Patients at clinical status and <6 mo since PML diagnosis, n (%)

0

5 (38)

8 (62)

Patients at clinical status and >6 mo since PML diagnosis, n (%)

4 (33)

4 (33)

4 (33)

Abbreviation: PML ⫽ progressive multifocal leukoencephalopathy. a Mild disability, Karnofsky score ⫽ 80–100; moderate disability, Karnofsky score ⫽ 50– 70; severe disability, Karnofsky score ⫽ 10–40.

disability (mean 6 months; median 4 months) (table 3). Evaluation of disability after an acute event is best accomplished once the patient has reached a stable clinical state. In other neurologic conditions, such as acute stroke, the greatest improvements present within the first weeks to months, and neurologic deficits generally stabilize 3– 6 months after the acute event.14 Therefore, clinical outcomes of patients with PML who had at least 6 months follow-up after their PML diagnosis were analyzed separately. Of the 25 PML survivors, 12 had at least 6 months follow-up between PML diagnosis and time of clinical assessment. Four of these 12 patients (33%) had mild disability, 4 (33%) had moderate disability, and 4 (33%) had severe disability. Qualitative assessments of functional outcomes. The range of functional outcomes experienced by natalizumab-associated PML survivors is exemplified by the first 2 cases reported in the postmarketing period.15,16 In a more recent case report, a patient with natalizumab-associated PML was successfully treated and returned to baseline pre-PML EDSS.17 Further examples of PML case outcomes are described in the following. Mild disability. A 45-year-old woman from Europe previously treated with mitoxantrone and with a prePML EDSS of 4.0 while receiving natalizumab was diagnosed with PML after 34 months of natalizumab. CSF JCV load was 760 copies/mL, and MRI demonstrated unilobar PML. Treatment included PLEX. She also received a 3-day course of IV methylprednisolone (1 g daily) followed by a corticosteroid taper over 6 weeks to treat IRIS. At 9 months after the diagnosis of PML, the patient had a Karnofsky score of 90, was ambulatory, and had no cognitive impairment. The only clinical sequela from PML was a bilateral homonymous quadranopsia. Moderate disability. A 35-year-old woman from the United States with no prior immunosuppressant use and with a pre-PML EDSS of 2.0 while receiving natalizumab was diagnosed with PML after 24 doses of natalizumab. CSF JCV load was 1.2 million copies/mL, and MRI demonstrated multilobar PML. Treatment included PLEX, mefloquine, and mirtazapine. She also received a 4-day course of IV methylprednisolone (1 g daily) followed by a corticosteroid taper over 4 weeks to treat IRIS. At 9 months after the diagnosis of PML, the patient had a Karnofsky score of 50. She required assistance with most daily activities and was ambulatory with assistance. Despite marked improvement in her attention and neglect, she continued to have an impaired ability to communicate and plegia in her left arm. Severe disability. A 27-year-old man from Europe with no prior immunosuppressant use and with a preNeurology 76

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PML EDSS of 4.5 while receiving natalizumab was diagnosed with PML after 29 months of natalizumab. CSF JCV load was 325 copies/mL, and MRI demonstrated multilobar PML. Treatment included PLEX, mefloquine, mirtazapine, and IV methylprednisolone before development of IRIS. He subsequently received 3 additional courses of IV corticosteroids over the next 2 months for IRIS. At 8 months after the diagnosis of PML, the patient had a Karnofsky score of 40 and required assistance with all daily activities. His cognitive functions were largely intact, but he had severe rightsided hemiparesis, moderate left leg weakness, and slight expressive dysphasia. DISCUSSION Analysis of the first 35 postmarketing

cases of natalizumab-associated PML revealed 71% survival, with mean and median follow-up times of 6.8 and 4.5 months, respectively. Comparison of patients with nonfatal and fatal cases identified several characteristics that seem to be associated with improved survival in natalizumab-associated PML: younger age at diagnosis, less disability (lower EDSS scores) before PML, more localized disease on MRI, and shorter time from symptom onset to PML diagnosis. There are several possible biologic mechanisms to explain how these characteristics relate to survival after PML. Disability progression (as measured by EDSS) has been shown to correlate with whole-brain atrophy progression,18 and patients with lower levels of disability may therefore have more brain reserve with which to sustain acute injuries such as PML. Conversely, identification of initial PML symptoms in patients with greater levels of disability may be confounded by the presence of severe MS symptoms and delay diagnosis. Earlier PML diagnosis limits irreversible brain damage that can occur before development of IRIS and is therefore likely to influence overall clinical outcome,5 as evidenced by the current analysis. The 71% survival rate for natalizumab-associated PML in this analysis is higher than survival rates reported for PML in other populations such as patients with HIV infection before the era of highly active antiretroviral therapy (HAART) and transplant recipients. A survival rate of 29% has been reported in transplant recipients with PML (17 of 24 died). The median duration of PML in these patients was 2.5 months (range 0.5–15 months).19 In a separate report of renal transplant recipients with PML, survival was 31% (9 of 13 died); 8 patients died within 5 months of PML diagnosis (range 2–13 months). Survivors were more likely to have undergone immunosuppressant reduction or discontinuation.20 In the HIV infection–associated PML population, 1-year survival rates of 10% before the HAART era and 1702

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50% survival rates after the introduction of HAART have been reported.21 A 26% survival rate has been reported among patients with PML within the Danish HIV Cohort Study (35 of 47 died).22 Thirteen patients with PML diagnosed before the HAART era had a median survival of approximately 5 months, whereas 34 patients with PML diagnosed after the introduction of HAART had a median survival of 1.8 years.22 Patients with PML who have immune systems capable of reconstitution have a higher survival rate than patients with immune systems that cannot be reconstituted.5,19,23,24 Therefore, a possible reason for the improved survival seen in natalizumabassociated PML is that these patients have intact, functional immune systems that can be reconstituted. Removal of natalizumab from the circulation by withholding of treatment, PLEX, or IA results in restoration of immune surveillance to the CNS.25 Another factor possibly contributing to improved survival in natalizumab-associated PML is earlier detection of PML. The extensive education on PML that is provided to prescribers, patients, and relatives as part of global risk-management programs for natalizumab has probably resulted in earlier detection of PML, and prompt restoration of immune surveillance has contributed to better clinical outcomes.26 Natalizumab-associated PML survivors exhibit various levels of disability, ranging from mild to severe. Limited information describing the clinical status of PML survivors in other populations is available in the literature. One study evaluated clinical outcomes in 118 patients with HIV infection treated with HAART and PML.27 Of the 118 patients, 75 (63.6%) survived for a median of 114 weeks (2.2 years). For the 73 survivors with available follow-up, neurologic function was “cured” (resolution of symptoms and signs of PML) or “improved” (reduction of symptoms and signs of PML) in 33 patients (44%) and “stabilized” (no change in symptoms and signs of PML) or “worsened” (progression of symptoms and signs of PML) in 40 patients (53%).27 The assessment tool used by investigators in that study differed from the Karnofsky Performance Scale used in our analysis, making a direct comparison of clinical outcomes between natalizumab-associated PML survivors and this particular group of PML survivors with HIV infection difficult. A more recent report of 24 long-term (⬎5 years) PML survivors (23 HIVpositive and one HIV-negative with non-Hodgkin lymphoma)28 used the modified Rankin disability scale (mRDS).29 This validated, quantitative measure of functional status may be more comparable to the Karnofsky Performance Scale. After an average observation period of 94.2 months, 8 of 24 patients (33%) had no significant disability despite persistent symp-

toms (mRDS score ⫽ 1), 6 of 24 patients (25%) were living independently with slight disability (mRDS score ⫽ 2), 5 of 24 patients (21%) were moderately disabled, requiring some help with activities of daily living (mRDS score ⫽ 3), and 5 of 24 patients (21%) had moderately severe disability, requiring constant help or institutionalization (mRDS score ⫽ 4).28 One of the limitations of our analysis is the lack of long-term follow-up of PML survivors. From the time that the first postmarketing case of natalizumab-associated PML was reported in 2008 to the time of the current analysis, the proportion of patients who survive has remained near 70%. Because most deaths of PML occurred within 2 months of diagnosis, it appears likely that this survival rate will be maintained. However, the number of patients with long-term follow-up is still limited; only 12 of 25 PML survivors had follow-up beyond 6 months at the time of this analysis. More detailed and standardized long-term data collection on PML survivors is needed to better characterize functional status and to reassess predictors of disability. Obtaining these long-term data will require a collaborative effort among treating physicians, Biogen Idec, and Elan. Another limitation of the current analysis is that our attempt to characterize the clinical status of PML survivors was probably confounded by disability attributable to underlying MS. Therefore, interpretation of residual disability after PML should be made cautiously. Although PML has traditionally been considered a fatal disease, current data for natalizumab-associated PML challenge this belief. Improved survival is probably the result of earlier diagnosis through enhanced clinical vigilance and aggressive treatment of both the primary PML process and secondary IRIS in the setting of underlying normal immune function. PML remains a serious and sometimes fatal complication of natalizumab therapy, but the majority of patients with natalizumab-associated PML have survived with various levels of disability. Delineation of premorbid risk factors, better understanding of the natural history and epidemiology of natalizumab-associated PML, earlier diagnosis, and further refinement and development of therapeutic modalities for treatment of both PML and IRIS should continue to improve clinical outcomes. AUTHOR CONTRIBUTIONS Statistical analysis was conducted by Dr. Sandra Richman. Dr. Vermersch, Dr. Kappos, Dr. Gold, Dr. Foley, and Dr. Olsson are representatives of the PML Outcomes Working Group.

ACKNOWLEDGMENT The authors thank the following contributors and members of the PML Outcomes Working Group who provided patient information (in alphabetical order): Dr. Zdenek Ambler, Professor Gabriele Arendt, Professor

Bruno Brochet, Professor Renaud Du Pasquier, Dr. John Foley, Professor Ralf Gold, Dr. Kerstin Hellwig, Dr. Karin Hoehn, Professor Michael Hutchinson, Dr. Mark Janicki, Dr. Ilijas Jelcic, Professor Ludwig Kappos, Dr. Klimentini Karageorgiou, Dr. Charles Kaufman, Professor Bernd Kieseier, Dr. Christoph Klawe, Dr. Ingo Kleiter, Dr. Roderick Kriekaart, Dr. Lauren Krupp, Dr. Jens Kuhle, Dr. Chris Laganke, Dr. Hans Linda, Professor Alfred Lindner, Professor Michael Linnebank, Dr. K. Alvin Lloyd, Dr. Jochen Machetanz, Dr. Blair Marsteller, Dr. Claes Martin, Dr. Michael Marvi, Professor Mathias Maschke, Professor Erich Mauch, Dr. Roy Meckler, Dr. Martin-Andreas Mu¨ller, Dr. Erik van Munster, Dr. Kevin Murphy, Professor Tomas Olsson, Dr. Agustín Oterino, Dr. Jean-Christophe Ouallet, Dr. Olivier Outteryck, Dr. Fredrik Piehl, Professor Ernst-Wilhelm Radue, Dr. Alexandra Schro¨der, Professor Klaus V. Toyka, Professor Patrick Vermersch, Professor Sandra Vukusic, Dr. Randall Webb, Dr. Anna Weidlich, Dr. Bianca Weinstock-Guttman, Dr. Gary Weiss, Dr. Werner Wenning, Professor Heinz Wiendl, Dr. He´le`ne Zephir, and Professor Uwe Zettl. Members of the PML Outcomes Working Group participated in the Biogen Idec/Elan–sponsored PML Outcomes Meeting held in London, UK, on February 27–28, 2010, and completed a PML Standardized Data Collection Form with clinical outcome data for their PML patients. The authors thank the following groups of people for their contribution to this manuscript: Biogen Idec Drug Safety and Risk Management (United States and International) for collecting and processing all natalizumab PML cases globally; Biogen Idec Affiliate Medical Directors, Staff, and Distributors for help in contacting PML physicians in their regions and assisting with the collection of PML Standardized Data Collection Forms/Clinical Outcome Data; Biogen Idec US Medical Affairs Representatives/Medical Science Liaisons for help in contacting US PML physicians and assisting with the collection of PML Standardized Data Collection Forms/Clinical Outcome Data; Eugene O. Major, PhD, and the NIH laboratory for performing ultrasensitive quantitative real-time PCR testing for JCV DNA on many of the CSF samples from patients included in this analysis; and Dr. Frederick Munschauer, Dr. Tuan Dong-Si, Dr. Glyn Belcher, Dr. Mariska Kooijmans, Dr. Christophe Hotermans, Dr. Grainne Quinn, and Susan Goelz, PhD, from Biogen Idec and Elan who participated in the PML Outcomes Meeting in London, UK. The authors also thank Dr. Petra Duda for her input to the content of the PML Data Collection Tool and Bill Aschenbach, PhD, for reviewing, copyediting, and providing graphic assistance with this manuscript.

DISCLOSURE Prof. Vermersch serves on scientific advisory boards for Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Teva Pharmaceutical Industries Ltd., and sanofi-aventis; has received funding for travel and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Novartis, Teva Pharmaceutical Industries Ltd., sanofi-aventis, and Merck Serono; and receives research support from Biogen Idec, Merck Serono, sanofiaventis, Teva Pharmaceutical Industries Ltd., and Bayer Schering Pharma. Prof. Kappos serves on the editorial board of the International MS Journal and Multiple Sclerosis Journal; receives research support from the Swiss National Research Foundation, the Swiss MS Society, and the Gianni Rubatto Foundation (Zurich); his department at the University Hospital Basel has received research support from Actelion, Advancell, Allozyne, BaroFold, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, CLC Behring, Elan, Genmab, Genmark, GeNeuro SA, GlaxoSmithKline, Lilly, Merck Serono, MediciNova, Novartis, Novonordisk, Peptimmune, Sanofi-aventis, Santhera, Roche, Teva, UCB, and Wyeth. LK has been principal investigator, member, or chair of steering committees or advisory boards in multiple sclerosis clinical trials sponsored by these companies, and has received lecture fees from one or more of these companies. Payments and consultancy fees were exclusively used for the support of research activities. Prof. Gold serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of American Journal of Pathology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Neurology 76

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Pharma, Merck Serono, and Novartis. Dr. Foley serves on scientific advisory boards for Biogen Idec and Genzyme Corporation; has received funding for travel and speaker honoraria from Biogen Idec and Teva Pharmaceutical Industries Ltd.; serves as a consultant for Novartis, Biogen Idec, Teva Pharmaceutical Industries Ltd., and Genzyme Corporation; and serves on the speakers’ bureau for Novartis, Biogen Idec, and Teva Pharmaceutical Industries Ltd. Prof. Olsson has served on scientific advisory boards for Merck Serono, Biogen Idec, sanofi-aventis, and Novartis; serves as Co-Editor for Current Opinion in Immunology; has received speaker honoraria from Novartis, Biogen Idec, sanofi-aventis, and Merck Serono; and receives research support from Merck Serono, Biogen Idec, sanofi-aventis, Bayer Schering Pharma, Novartis, The Swedish Research Council (07488), the European Union, EURATools, the So¨derbergs Foundation, Bibbi and Nils Jensens Foundation, the Montel Williams Foundation, and the Swedish Brain Foundation. Dr. Cadavid is a full-time employee of and owns stock and stock options in Biogen Idec and has received research support from the NIH. Dr. Bozic is a full-time employee of and owns stock in Biogen Idec. Dr. Richman is a full-time employee of and owns stock in Biogen Idec.

Received August 10, 2010. Accepted in final form November 23, 2010.

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JC virus in vitro. Antimicrob Agents Chemother 2009;53: 1840 –1849. 13. Elphick GF, Querbes W, Jordan JA, et al. The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science 2004;306:1380 –1383. 14. Kelley RE, Borazanci AP. Stroke rehabilitation. Neurol Res 2009;31:832– 840. 15. Lindå H, von Heijne A, Major EO, et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med 2009;361:1081–1087. 16. Wenning W, Haghikia A, Laubenberger J, et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N Engl J Med 2009;361: 1075–1080. 17. Schro¨der A, Lee DH, Hellwig K, Lukas C, Linker RA, Gold R. Successful management of natalizumab-associated progressive multifocal leukoencephalopathy and immune reconstitution syndrome in a patient with multiple sclerosis. Arch Neurol 2010;67:1391–1394. 18. Rudick RA, Fisher E, Lee JC, Duda JT, Simon J. Brain atrophy in relapsing multiple sclerosis: relationship to relapses, EDSS, and treatment with interferon beta-1a. Mult Scler 2000;6:365–372. 19. Shitrit D, Lev N, Bar-Gil-Shitrit A, Kramer MR. Progressive multifocal leukoencephalopathy in transplant recipients. Transpl Int 2005;17:658 – 665. 20. 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. 21. Koralnik IJ. New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol 2004;17:365– 370. 22. Engsig FN, Hansen ABE, Omland LH, et al. Incidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nationwide cohort study. J Infect Dis 2009;199:77– 83. 23. Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003;9(suppl 1):25–31. 24. Miralles P, Berenguer J, Garcia de Viedma D, et al. Treatment of AIDS-associated progressive multifocal leukoencephalopathy with highly active antiretroviral therapy. AIDS 1998;12:2467–2472. 25. Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009;72:402– 409. 26. 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. 27. Berenguer J, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003;36:1047– 1052. 28. Lima MA, Bernal-Cano F, Clifford DB, Gandhi RT, Koralnik IJ. Clinical outcome of long-term survivors of progressive multifocal leukoencephalopathy. J Neurol Neurosurg Psychiatry 2010;81:1288 –1291. 29. Bamford JM, Sandercock PA, Warlow CP, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1989;20:828.

A case of multiple sclerosis presenting with inflammatory cortical demyelination

B.F.Gh. Popescu, MD, PhD R.F. Bunyan, MD J.E. Parisi, MD R.M. Ransohoff, MD C.F. Lucchinetti, MD

Address correspondence and reprint requests to Dr. Claudia F. Lucchinetti, Neurology, Mayo Clinic, College of Medicine, 200 First St. SW, Rochester, MN 55905 [email protected]

ABSTRACT

Objective: To describe a patient presenting with a clinically silent, incidentally found, and pathologically confirmed active demyelinating solitary cortical lesion showing MRI gadolinium contrast enhancement, in whom biopsy was performed before the radiographic appearance of disseminated white matter lesions.

Methods: Neurologic examination, MRI, CSF and serologic analyses, and brain biopsy were performed. Sections of formalin-fixed paraffin-embedded biopsied brain tissue were stained with histologic and immunohistochemical stains.

Results: Biopsy revealed an inflammatory subpial lesion containing lymphocytes and myelin-laden macrophages. Recurrent relapses with dissemination of MRI-typical white matter lesions characterized the subsequent course.

Conclusions: Our findings highlight that cortical demyelination occurs on a background of inflammation and suggest that the noninflammatory character of chronic cortical demyelination may relate to long intervals between lesion formation and autopsy. This case provides pathologic evidence of relapsing-remitting MS presenting with inflammatory cortical demyelination and emphasizes the importance of considering demyelinating disease in the differential diagnosis of patients presenting with a solitary cortical enhancing lesion. Neurology® 2011;76:1705–1710 GLOSSARY EAE ⫽ experimental autoimmune encephalomyelitis; MS ⫽ multiple sclerosis.

Traditionally, multiple sclerosis (MS) has been considered a disease primarily affecting the CNS white matter. Nevertheless, gray matter involvement has been recognized for a long time.1 Recent pathologic studies have revealed that cortical demyelination is more extensive than previously appreciated,2,3 is characteristic of progressive MS,4 and is devoid of lymphocytes and macrophages.3 However, these studies have relied on postmortem tissue analysis from patients with longstanding disease. Therefore, the pathology of early cortical demyelinating MS lesions is virtually unknown. Interestingly, pathologic findings in a focal cortical experimental autoimmune encephalomyelitis (EAE) animal model have challenged the concept that cortical lesions are noninflammatory.5 Recent histopathologic studies have shown that cortical demyelination may occur spatially removed from white matter pathology, without obvious anatomic relationships.6 Therefore, it is plausible that cortical demyelination could represent the earliest pathologic event in some patients with MS and, indeed, MRI evidence of MS cortical onset has been previously reported.7 We describe a patient presenting with a clinically silent, incidentally found, and pathologically confirmed active demyelinating cortical lesion showing MRI gadolinium contrast enhancement, in whom biopsy was performed before the radiographic appearance of disseminated white matter lesions. The patient subsequently fulfilled diagnostic criteria for From the Departments of Neurology (B.F.Gh.P., R.F.B., C.F.L.) and Laboratory Medicine and Pathology (J.E.P.), Mayo Clinic, Rochester, MN; and Neuroinflammation Research Center and Department of Neurosciences (M.R.), Lerner Research Institute, and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH. Study funding: Supported by the NIH (RO1-NS049577-01-A2 to C.F.L. and P50-NS38667 to R.M.R. and C.F.L.) and by the National Multiple Sclerosis Society (NMSS RG 3185-B-3 to C.F.L.). Disclosure: Author disclosures are provided at the end of the article. Copyright © 2011 by AAN Enterprises, Inc.

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Figure 1

Brain MRI prior to biopsy (A–C) and 69 months after biopsy (D–F)

(A) Axial fluid-attenuated inversion recovery (FLAIR) image of left occipital cortical lesion (arrow). (B) Axial T1-weighted image with contrast showing enhancement of the cortical lesion (arrow); inset shows that contrast enhancement is within the cortical gray matter (arrowheads indicate the gray/white matter junction). (C) Axial T2-weighted image showing no periventricular lesions. (D) Sagittal FLAIR image showing the appearance of multiple new white matter lesions, with 2 of the lesions involving the corpus callosum. (E) Axial FLAIR image with the appearance of new periventricular lesions. (F) Axial T2-weighted image at nearly corresponding level of image C showing the appearance of new periventricular white matter lesions.

relapsing-remitting MS. This study provides compelling radiographic and pathologic evidence of relapsing-remitting MS presenting with inflammatory cortical demyelination. METHODS The biopsied brain tissue was fixed in 10%–15% formalin and embedded in paraffin. Sections were stained with hematoxylin & eosin and Luxol fast blue/periodic acid–Schiff. Immunohistochemistry was performed using an avidin– biotin technique and primary antibodies specific for proteolipid protein, 2⬘3⬘-cyclic-nucleotide 3⬘-phosphodiesterase (CNPase), neurofilament, macrophages/microglia (KiM1P), CD3⫹ T (CD3), CD8⫹ T (CD8), and B lymphocytes (CD20), and plasma cells (CD138) as described previously.8

Case report. A 33-year-old Caucasian woman with a history of migraine and 4 months postpartum complained of sudden onset headache and right periorbital pain. She had an upper respiratory tract infection 1 week prior to symptom onset. Neurologic examination was normal. Brain MRI revealed a high signal intensity lesion on T2-weighted imaging involving the left visual association occipital cortex (figure 1, A– C) that enhanced with gadolinium (figure 1B, inset). No other lesions were noted. An open brain biopsy was performed 1 month after symptom onset to exclude neoplasm. 1706

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The biopsy revealed the presence of a hypercellular, focally destructive, cortical demyelinated lesion extending from the pial surface through all cortical layers, with extension into the cortex laterally and partially involving the subcortical white matter (figure 2, A and B). The lesion was infiltrated by phagocytic macrophages containing both early and late intracytoplasmic myelin degradation products, consistent with early-active ongoing cortical demyelination (figure 2, C–F).9 Marked parenchymal and perivascular (⬎3 cell cuffs around at least one blood vessel) cortical inflammatory infiltrates were present and composed of macrophages, microglia, CD3⫹ and CD8⫹ T cells, B lymphocytes, and plasma cells (figure 3, A–I). Perivascular and parenchymal lymphocytic infiltrates in the “pure” cortical part of this subpial lesion (figure 3, A–D), although highly inflammatory, were less cellular than infiltrates located at the gray/white matter junction or in the cavitated area (figure 3, F–I). Plasma cells were largely present in the destructive regions of the cortical plaque (figure 3E). Neuronal injury was evidenced by the presence of scattered pyknotic neurons (figure 3J). Macrophages, microglia, and T lymphocytes were often seen in close apposition to neurons (figure 2H and figure 3, K–N). Foamy macrophages were also concentrated subpially in the cortical molecular layer and subarachnoid space (figure 2G). The destructive region was cavitated, affecting mainly the cortex, with only

Figure 2

Biopsy of the initial MRI enhancing lesion shown in figure 1 revealed a highly inflammatory subpial lesion with predominance of macrophages involved in active demyelination

(A) Subpial lesion showing loss of myelin and an area (arrowheads) of cavitary changes (Luxol fast blue [LFB]/periodic acid-Schiff [PAS]). (B) Subpial lesion showing loss of immunoreactivity for myelin specific proteins (proteolipid protein [PLP]). (C) Actively demyelinating macrophages (arrows); arrowheads indicate neurons (LFB/PAS). (D) Actively demyelinating macrophages (arrows) (PLP). (E) Foamy macrophages (KiM1P). (F) Actively demyelinating macrophages (arrows) (2⬘3⬘cyclic-nucleotide 3⬘-phosphodiesterase [CNPase]). (G) Subpial and CSF foamy macrophages (KiM1P). (H) Macrophages/ microglia (arrows) in close apposition to neurons and neurites (KiM1P).

limited involvement of the gray/white matter junction (figure 2A and figure 3, O and P). The remainder of the lesion showed relative axonal preservation. Acute axonal injury, evi-

denced by axonal swellings, extended beyond the lesion borders into the adjacent normal-appearing white matter and cortex (figure 3, P and Q). Oligodendrocyte density was reNeurology 76

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Figure 3

Cortical and meningeal lymphocytic infiltration, axonal and neuronal injury, loss of oligodendrocytes, and reactive astrocytosis are other neuropathologic findings in this biopsy

(A) Perivascular CD3⫹ T cells (CD3). (B) Perivascular CD8⫹ T cells (CD8, white arrowhead shows a normal-appearing neuron). (C) Perivascular B cells (CD20). (D) Perivascular macrophages (KiM1P). (E) Parenchymal plasma cells (CD138). (F) Junctional perivascular CD3⫹ T cells (CD3). (G) Junctional perivascular CD8⫹ T cells (CD8). (H) Junctional parenchymal CD3⫹ T cells (CD3). (I) Junctional parenchymal CD8⫹ T cells (CD8). (J) Pyknotic neurons (black arrowheads) and reactive astrocytes (arrows) scattered among healthy neurons (white arrowheads) (hematoxylin & eosin [H&E]). (K, L) Macrophages in close apposition to neurons (KiM1P). (M) CD3⫹ T cells (CD3) and (N) CD8⫹ T cells (CD8) in close apposition to neurons. (O) Good axonal preservation, except in the cavitated area (arrowheads) (neurofilament [NF]). (P) Axonal swellings in the cavitated area (black arrowheads); segmental axonal swellings are seen along neurites (white arrowheads) (NF). (Q) Axonal swellings in normal-appearing gray matter (black arrowheads); white arrowheads follow a neurite with segmental axonal swellings (NF). (R1) Oligodendrocytes in normal-appearing cortex (2⬘3⬘-cyclic-nucleotide 3⬘-phosphodiesterase [CNPase]). (R2) Loss of oligodendrocytes in the subpial lesion (CNPase). (S) Gemistocytes (H&E). (T) Mitotic astrocytes (H&E). (U) Creutzfeldt cells (H&E). (V) Cortical reactive astrocytosis (arrows) extending beyond the lesion borders; healthy neuron (white arrowhead) (H&E). (W) Meningeal CD3⫹ T cells (CD3). (X) Meningeal CD8⫹ T cells (CD8). (Y) Meningeal B cells (CD20). (Z) Meningeal plasma cells (CD138).

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duced in the cortical plaque (figure 3R2) when compared to the adjacent nondemyelinated cortex (figure 3R1). A profound reactive astrogliosis was present throughout this subpial lesion (figure 3, J and S–U) extending beyond the lesion edges into the normal-appearing cortex (figure 3V). Reactive astrocytes showed a variety of morphologic changes (figure 3, J and S–U) including mitotic figures (figure 3T) and Creutzfeldt cells (figure 3U). Mild meningeal inflammation was also present and consisted of CD3⫹ T, CD8⫹ T, and B lymphocytes, and plasma cells (figure 3, W–Z). Following biopsy, the patient developed an incongruous right homonymous hemianopia that slowly resolved over several months. Due to persistent headaches, a CSF analysis was performed 4 months postbiopsy and demonstrated an elevated CSF immunoglobulin G synthesis rate with normal protein, glucose, cell count, and one oligoclonal band. Lyme serology was negative. Six months after biopsy, she complained of left-sided chest numbness. Spine MRI showed 2 subtle T2-weighted lesions at C4 –5 and C6 levels. Eleven months after biopsy, she developed burning dysesthesias in the lower extremities. Brain MRI revealed new periventricular T2-weighted white matter lesions. She fulfilled diagnostic criteria for relapsing-remitting MS. At last follow-up (69 months postbiopsy), brain MRI demonstrated an interval increase in the number of white matter lesions (figure 1, D–F), and she was started on glatiramer acetate.

This study provides pathologic evidence of inflammatory cortical demyelination at clinical onset of MS that preceded radiographic evidence of disseminated white matter demyelination typical of MS relapses. A recently developed cortical demyelination rodent EAE model demonstrated that cortical inflammation is early, transient, and rapidly resolving.5 Notably, this case report is based on a brain biopsy obtained early in the disease, whereas previous studies describing noninflammatory MS cortical pathology have relied on autopsy brain sections from patients who died with chronic progressive disease.3 The rapid resolution of cortical inflammation may in part explain these apparent discordant findings with respect to the presence of inflammation in early vs chronic cortical demyelinating lesions. The presence of an inflammatory subpial cortical lesion associated with MRI gadolinium contrast enhancement that preceded the classic dissemination of white matter lesions suggests that inflammation-induced cortical blood– brain barrier damage and demyelination may be early pathogenic events in MS. Whereas double inversion recovery MRI techniques may enhance detectability of cortical lesions,10 it is also possible that there is a very short window of opportunity for detecting such cortical lesions early in MS. The transient and rapidly reversible nature of cortical inflammation and demyelination in early MS5 may preclude the development of larger, more confluent demyelinated lesions, thereby making their clinical or radiographic detection more challeng-

ing, even among symptomatic patients. These atypical presentations may result in diagnostic confusion and potentially lead to unnecessary interventions. This case emphasizes the importance of considering demyelinating disease in the differential diagnosis of patients presenting with a solitary cortical enhancing lesion. The present case report, coupled with previously published MRI data,7 suggests that inflammatory cortical lesions at MS onset may precede the appearance of classic white matter plaques in some patients with MS. Furthermore, cortical onset MS raises interesting questions regarding the potential role of meningeal inflammation and cortical pathology in initiating and perpetuating the MS disease process. Most therapeutic, diagnostic, and research efforts have concentrated on the white matter pathology in MS. However, a better understanding of the specific factors within the cortical microenvironment that favor rapid resolution of cortical inflammation and demyelination5 may lead to new therapeutic approaches aimed at targeting early MS cortical pathology.

DISCUSSION

ACKNOWLEDGMENT The authors thank Patricia Ziemer for technical assistance.

DISCLOSURE Dr. Popescu and Dr. Bunyan report no disclosures. Dr. Parisi serves on scientific advisory boards for the US Government Defense Health Board and the Subcommittee for Laboratory Services and Pathology; serves as a Section Editor for Neurology®; receives royalties from the publication of Principles & Practice of Neuropathology, 2nd ed. (Oxford University Press, 2003); and receives research support from the NIH. Dr. Ransohoff serves on scientific advisory boards for ChemoCentryx, Inc., Vertex Pharmaceuticals, Merck Serono, and GlaxoSmithKline; serves as an Associate Editor for Neurology®; and receives research support from the NIH and the Nancy Davis Center Without Walls (NDCWW). Dr. Lucchinetti is listed as author and receives royalties for patent re: Aquaporin-4 associated antibodies for diagnosis of neuromyelitis optica; receives royalties from the publication of Blue Books of Neurology: Multiple Sclerosis 3 (Saunders Elsevier, 2010); and receives research support from the NIH, the Guthy Jackson Charitable Foundation, and the National MS Society.

Received November 30, 2010. Accepted in final form February 7, 2011. REFERENCES 1. Brownell B, Hughes JT. The distribution of plaques in the cerebrum in multiple sclerosis. J Neurol Neurosurg Psychiatry 1962;25:315–320. 2. Kidd D, Barkhof F, McConnell R, Algra PR, Allen IV, Revesz T. Cortical lesions in multiple sclerosis. Brain 1999;122:17–26. 3. Peterson JW, Bo L, Mork S, Chang A, Trapp BD. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001;50:389 – 400. 4. Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005;128:2705–2712. Neurology 76

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Merkler D, Ernsting T, Kerschensteiner M, Bruck W, Stadelmann C. A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination. Brain 2006; 129:1972–1983. Bo L, Geurts JJ, van der Valk P, Polman C, Barkhof F. Lack of correlation between cortical demyelination and white matter pathologic changes in multiple sclerosis. Arch Neurol 2007;64:76 – 80. Calabrese M, Gallo P. Magnetic resonance evidence of cortical onset of multiple sclerosis. Mult Scler 2009;15:933–941.

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Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47:707–717. Bruck W, Porada P, Poser S, et al. Monocyte/macrophage differentiation in early multiple sclerosis lesions. Ann Neurol 1995;38:788 –796. Calabrese M, Agosta F, Rinaldi F, et al. Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. Arch Neurol 2009; 66:1144 –1150.

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 2009;72:8 –10.

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Diffusion-weighted MRI hyperintensity patterns differentiate CJD from other rapid dementias P. Vitali, MD E. Maccagnano, MD E. Caverzasi, MD R.G. Henry, PhD A. Haman, MD C. Torres-Chae, MPP D.Y. Johnson, BS B.L. Miller, MD M.D. Geschwind, MD, PhD

Address correspondence and reprint requests to Dr. Michael D. Geschwind, UCSF Memory & Aging Center, Department of Neurology, University of California, San Francisco (UCSF), Box 107, San Francisco, CA 94143-1207 [email protected]

ABSTRACT

Background: Diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI have high sensitivity and specificity for Creutzfeldt-Jakob disease (CJD). No studies, however, have demonstrated how MRI can distinguish CJD from nonprion causes of rapidly progressive dementia (npRPD). We sought to determine the diagnostic accuracy of MRI for CJD compared to a cohort of npRPD subjects. Methods: Two neuroradiologists blinded to diagnosis assessed DWI and FLAIR images in 90 patients with npRPD (n ⫽ 29) or prion disease (sporadic CJD [sCJD], n ⫽ 48, or genetic prion disease [familial CJD, n ⫽ 6, and Gerstmann-Stra ¨ussler-Scheinker, n ⫽ 7]). Thirty-one gray matter regions per hemisphere were assessed for abnormal hyperintensities. The likelihood of CJD was assessed using our previously published criteria. Results: Gray matter hyperintensities (DWI ⬎ FLAIR) were found in all sCJD cases, with certain regions preferentially involved, but never only in limbic regions, and rarely in the precentral gyrus. In all sCJD cases with basal ganglia or thalamic DWI hyperintensities, there was associated restricted diffusion (apparent diffusion coefficient [ADC] map). This restricted diffusion, however, was not seen in any npRPD cases, in whom isolated limbic hyperintensities (FLAIR ⬎ DWI) were common. One reader’s sensitivity and specificity for sCJD was 94% and 100%, respectively, the other’s was 92% and 72%. After consensus review, the readers’ combined MRI sensitivity and specificity for sCJD was 96% and 93%, respectively. Familial CJD had overlapping MRI features with sCJD. Conclusions: The pattern of FLAIR/DWI hyperintensity and restricted diffusion can differentiate sCJD from other RPDs with a high sensitivity and specificity. MRI with DWI and ADC should be included in sCJD diagnostic criteria. New sCJD MRI criteria are proposed. Neurology® 2011;76:1711–1719 GLOSSARY ADC ⫽ apparent diffusion coefficient; CI ⫽ confidence interval; CJD ⫽ Creutzfeldt-Jakob disease; DWI ⫽ diffusion-weighted imaging; fCJD ⫽ familial Creutzfeldt-Jakob disease; FLAIR ⫽ fluid-attenuated inversion recovery; GSS ⫽ GerstmannSträussler-Scheinker; npRPD ⫽ nonprion causes of rapidly progressive dementia; RPD ⫽ rapidly progressive dementia; sCJD ⫽ sporadic Creutzfeldt-Jakob disease; UCSF ⫽ University of California, San Francisco.

Supplemental data at www.neurology.org

Jakob-Creutzfeldt disease, more commonly known as Creutzfeldt-Jakob disease (CJD), typically presents as a rapidly progressive dementia (RPD), but other disorders can present in a similar fashion.1 In more than one-third of suspected CJD cases seen at the University of California, San Francisco (UCSF) CJD clinical program, we found an alternative, nonprion, diagnosis.1 Differentiating npRPD from CJD is critically important, both for infection control purposes and because many npRPDs are readily treatable. The EEG and CSF biomarkers have limited utility in CJD diagnosis.2 Prior research has demonstrated that the MRI pattern of e-Pub ahead of print on April 6, 2011, at www.neurology.org. From the Department of Neurology, Memory & Aging Center (P.V., A.H., D.Y.J., C.T.C., B.L.M., M.D.G.), and Department of Radiology (R.H.), University of California, San Francisco (UCSF), San Francisco; Department of Neuroradiology (E.M.), Istituto Nazionale Neurologico “Carlo Besta,” Milan; and Department of Neuroradiology (P.V. and E.C.), IRCCS, “C. Mondino” Foundation, University of Pavia, Italy (E.V.). Study funding: Supported by NIA/NIH grant R01 AG031189; K23 AG021989, grant P50 AG023501 from NIH National Institute on Aging; the California Alzheimer’s Disease Centers (06 –55318 DHS/ADP/ARCC); NIH/NCRR UCSF-CTSI grant number UL1 RR024131; the Michael J. Homer Family Fund (M.D.G.); the John Douglas French Foundation for Alzheimer’s Research (M.D.G.); the McBean Foundation (M.D.G.); the Fondazione Tronchetti-Provera, Milan, Italy (P.V. and E.M.); and IRCCS, “C. Mondino” Foundation, the University of Pavia (E.C.). Disclosure: Author disclosures are provided at the end of the article. Copyright © 2011 by AAN Enterprises, Inc.

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cortical and subcortical gray matter involvement has high sensitivity and specificity for CJD, but these studies did not use ideal npRPD controls.2-4 We evaluated the sensitivity and specificity of fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) MRI for sCJD among a cohort of subjects with RPD and determined the MRI features that help to identify CJD.

DWI MRI scans performed at our center were included (clinical and demographic data in table e-1). Subjects had extensive clinical evaluations, EEG, CSF, blood, and urine analyses. In many, total body CT was performed to rule out nonprion conditions. Most subjects had PRNP gene analysis (appendix e-1). Prion typing was done by the NPDPSC (Cleveland, OH). Criteria for diagnoses for the 61 patients with prion disease5,6 and the 29 patients with npRPD7-10 are shown respectively in tables e-1 and e-2, as well as appendix e-1.

Standard protocol approvals, registrations, and patient consents. We received approval from our institutional internal review board for conducting this study.

METHODS Subjects. This retrospective study included 90 serial subjects, 61 with sporadic or genetic prion disease, and 29 with a nonprion RPD (npRPD) diagnosis, in whom CJD was considered (see figure e-1 on the Neurology® Web site at www.neurology.org for patient flow). Only subjects evaluated at the UCSF Memory & Aging Center between December 15, 2000, and February 15, 2007, with sufficient quality FLAIR and

Table 1

UCSF 2005 and 2010 proposal of MRI criteria for CJD diagnosis

Diagnosis

UCSF 2005 criteria3

UCSF 2011 proposed modifications/ additions

MRI definitely CJD

FLAIR and DWI (or DWI alone) hyperintensity in:

DWI ⬎ FLAIR hyperintensity in:

1. Cortex (⬎1 gyrus) and striatum

Classic pathognomonic: cingulate, striatum, and ⬎1 neocortical gyrus (often precuneus, angular, superior, or middle frontal gyrus) Supportive for subcortical involvement: ● Striatum with anterior-posterior gradient ● Subcortical ADC hypointensity Supportive for cortical involvement: ● Asymmetric involvement of midline neocortex or cingulate ● Sparing of the precentral gyrus ● ADC cortical ribboning hypointensity

2. Cortex only (⬎3 gyri)

Cortex only (⬎3 gyri); see supportive for cortex (above)

1. Unilateral striatum or cortex ⱕ3 gyri

Unilateral striatum or cortex ⱕ3 gyri; see supportive for subcortical (above); see supportive for cortex (above)

2. Bilateral striatum or posteromesial thalamus

Bilateral striatum or posteromesial thalamus; see supportive for subcortical (above)

3. FLAIR ⬎ DWI hyperintensities

Moved to probably not CJD (see below)

1. Only FLAIR/DWI abnormalities in limbic areas, where hyperintensity can be normal (insula, cingulate)

Only FLAIR/DWI abnormalities in limbic areas, where hyperintensity can be normal (e.g., insula, anterior cingulate, hippocampi) and ADC map does not show restricted diffusion in these areas

2. DWI hyperintensities due to artifact (signal distortion)

DWI hyperintensities due to artifact (signal distortion); see other MRI issues (below)

3. FLAIR ⬎ DWI hyperintensities

FLAIR ⬎ DWI hyperintensities; see other MRI issues (below)

1. Normal

No change from prior criteria

MRI probably CJD

MRI probably not CJD

MRI definitely not CJD

No change from prior criteria

Consensus review. If readers disagreed on a diagnosis, they re-examined the MRI together and made a consensus diagnosis. At this time, readers also noted whether FLAIR or DWI hyperintensities were brighter. Sensitivity, specificity, and 95% confidence intervals were calculated for individual and consensus ratings (SAS, version 9.2, SAS Institute, Cary, NC). Determining patterns of gray matter involvement in sCJD. Each of 31 hemispheric regions on DWI MRI was scored 0, 1, or 2, according to how many readers judged a region as hyperintense. The percentage of subjects with sCJD with involvement of each brain region was determined by averaging the ratings of both readers. Next, subjects with sCJD were categorized into 6 different patterns of gray matter involvement (table e-3).

In prolonged courses of sCJD (⬃⬎1 year) brain MRI might show significant atrophy with loss of DWI hyperintensity, particularly in areas previously with restricted diffusion

MRIs “unblinded” to identify crucial differentiating features. Finally, we modified our sCJD MRI criteria3 based on the results of this analysis, as well as our clinical experience since completing this analysis.

To help distinguish abnormality from artifact, obtain sequences in multiple directions (e.g., axial and coronal)

RESULTS Sensitivity and specificity of the visual

Abbreviations: ADC ⫽ apparent diffusion coefficient; CJD ⫽ Creutzfeldt-Jakob disease; DWI ⫽ diffusion-weighted imaging; FLAIR ⫽ fluid-attenuated inversion recovery; sCJD ⫽ sporadic Creutzfeldt-Jakob disease; UCSF ⫽ University of California, San Francisco. 1712

MRI visual assessment. Two neuroradiologists (reader 1, 4 years experience; reader 2, 20 years experience), blinded to the clinical diagnosis, independently reviewed all MRI sequences from the first UCSF scan. To differentiate true abnormalities from FLAIR hyperintensities due to the normal variations of T2 signal and DWI artifact,3 images were viewed in both axial and coronal planes using MRIcro software (www.mricro.com). The gray matter involvement on FLAIR and DWI images was reported according to 26 cortical and 5 subcortical subdivisions per hemisphere, using minor modifications of the TzourioMazoyer atlas (appendix e-1).11 Based on FLAIR and DWI , each reader classified subjects as definitely, probably, probably not, or definitely not CJD, according to our prior MRI criteria (table 1).3 Apparent diffusion coefficient (ADC) maps were reviewed only if subcortical gray matter DWI abnormalities were found, as ADC hypointense signal in the cortex is usually difficult to detect by visual assessment.12

Unblinded review and identifying differentiating features. After consensus review, the readers re-examined the 2. Abnormalities not consistent with CJD

Other MRI issues

MRI acquisition. Brain MRIs were performed on 2 GE Signa 1.5-T scanners at our center. FLAIR and DWI/DTI in axial planes (slice thickness range: 3–5 mm) were obtained for all patients, and most had FLAIR and DWI in coronal planes. Only the DWI combined image, the average of the multiple diffusion directions, was reviewed. See appendix e-1 for additional details.

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assessment for sCJD. Sensitivity and specificity for sCJD (vs npRPD) were higher for reader 2 (sensitivity 94%, 95% confidence interval [CI] 0.83– 0.99;

Figure 1

Frequency of gray matter fluid-attenuated inversion recovery (FLAIR) or diffusion-weighted imaging (DWI) hyperintensities in different disease cohorts

No subject with nonprion causes of rapidly progressive dementia (npRPD) had any neocortical hyperintensity, but about 25% had predominantly limbic involvement. Almost half of Gerstmann-Sträussler-Scheinker (GSS) cases were believed to have DWI or FLAIR limbic hyperintensity. Predominant limbic hyperintensity is therefore not suggestive of sporadic Creutzfeldt-Jakob disease (sCJD), but possibly of GSS or npRPD. Familial CJD (fCJD) has an overlapping pattern of MRI abnormality with sCJD.

specificity 100%, 95% CI 0.88 –1.00) than reader 1 (sensitivity 92%, 95% CI 0.80 – 0.98; specificity 72%, 95% CI 0.52– 0.87). A consensus diagnosis was reached on all but 3 cases (1 sCJD, 2 npRPD); by conservatively classifying these cases as misreads, consensus sensitivity was 96% (95% CI 0.86 –1.00) and specificity was 93% (95% CI 0.77– 0.99) using our criteria.3 Pattern of FLAIR and DWI neocortical, limbic, and subcortical hyperintensities in sCJD vs npRPD. The

region of gray matter involvement was different between the sCJD and npRPD patient groups (figure 1). All but one (see below) patient with sCJD had gray matter hyperintensities in the neocortical, limbic, or subcortical areas— or in combinations of these areas— but none had hyperintensity in limbic areas alone (table e-3). Gray matter abnormalities in sCJD were always more evident on DWI than FLAIR and in some cases noted only on DWI. The common patterns in sCJD were neocortical, limbic, and subcortical (54%) and neocortical and limbic (27%) (figure 2, table e-3). No clear MRI pattern was noted based on molecular classification of sCJD by codon 129 polymorphism or prion type.13 There was no neocortical involvement in 11% percent of sCJD cases, including both VV2 cases, and the single MM2-thalamic case did not show gray matter abnormalities, consistent with other studies.13,14 Only 9 of 29 patients with npRPD (23%) had abnormal gray matter hyperintensities; all were greater on FLAIR than on DWI. All had limbic involvement. Two also had subcortical hyperintensi-

ties. Seven with isolated limbic involvement had autoimmune diagnoses (figures 1 and 3). To determine whether subcortical DWI hyperintensities were related to restricted diffusion or T2 shine-through, readers examined the ADC maps during the blinded assessment. Subcortical regions with DWI hyperintensity had normal intensity on the ADC map in patients with npRPD (T2 shine-through), but were always hypointense (restricted diffusion) on the ADC map in sCJD. MRI features in genetic prion disease. Patterns and frequencies of DWI and FLAIR hyperintensities differed between patients with familial CJD (fCJD) and patients with Gerstmann-Sträussler-Scheinker (GSS) (figures 1 and 3). Five of 6 fCJD MRIs had gray matter hyperintensities and were read as positive; 4 (3 E200K and 1 D178N codon 129VV) had diffuse (neocortical, limbic, and subcortical) involvement, and 1 (V180I) had only neocortical hyperintensities. The sixth subject with fCJD (5-octapeptide repeat) had no hyperintensities. Of 7 GSS MRIs, only one was read positive (F198S), with cortical ribboning (neocortex, limbic, and striatum) on DWI. Two (A117V and another F198S) had only limbic hyperintensities, on both FLAIR and DWI. The remaining 4 (P102L and 3 A117V) had no gray matter abnormalities. Detailed analysis of the pattern of FLAIR and DWI hyperintensities at the gyral-nuclear level in patients with sCJD. Because neocortical hyperintensities were

found in only a few npRPD cases, the percentage of gray matter involvement at detailed anatomic levels Neurology 76

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Figure 2

Three common variations of sporadic Creutzfeldt-Jakob disease presentation on MRI

(A) Neocortical (solid arrow), limbic (dashed arrow), and subcortical gray matter (dotted arrow). (B) Neocortical and limbic cortex. (C) Limbic and subcortical. Note that the diffusion-weighted imaging (DWI) shows the hyperintensities much more than the corresponding fluid-attenuated inversion recovery (FLAIR) sequences, and that DWI hyperintensities often have corresponding apparent diffusion coefficient (ADC) hypointensity. Pattern A was found in 54% of cases, pattern B in 27% of cases, and pattern C in 9% of cases. Note that the abnormalities are more readily seen on DWI than on FLAIR. ADC hypointensity, indicating restricted diffusion, corresponds to most DWI hyperintensities. ADC abnormalities are most easily identified in the basal ganglia.

(31 areas per hemisphere) was calculated only in the sCJD group. DWI and, to a lesser extent, FLAIR hyperintensities in the cingulate, precuneus, angular, parahippocampal, superior and middle frontal gyri, and caudate were present in more than 50% of sCJD cases (figure 4). Asymmetric involvement was found in the majority of sCJD cases and was especially notable in the mesial cortex and cingulate (figure 2). Hemispheres were equally involved in the lateral frontal lobe and subcortical structures, but the left hemisphere was more frequently involved in parietal, temporal, and occipital lobes. There was relative sparing of the precentral gyrus, with DWI hyperintensity in only 3 patients (6%). In sCJD (and fCJD), striatal hyperintensity almost always revealed a gradual anterior-posterior gradient, involving mainly the caudate (more than 50% of cases) with relative sparing of the posterior putamen (figure 2). The posterior putamen, however, also was very hy1714

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perintense in some patients with predominantly subcortical involvement. ADC hypointensity was often seen in the pallidus of the predominantly subcortical sCJD cases, but there was concomitant DWI hyperintensity in only one case (figure 2C). Thalamic DWI involvement was usually bilateral, involving the dorsomedian and posterior (pulvinar) regions, and often coupled with bilateral striatal involvement. This pattern is similar to but less intense than the “double hockey stick” sign pattern seen in many variant CJD cases.15 Interestingly, when the double hockey stick sign was seen on DWI, the ADC maps showed more diffuse thalamic hypointensity. The more specific MRI feature for vCJD, the pulvinar sign (posterior thalamus brighter than anterior putamen),15 was not seen in any study subjects. MRI review after “unblinding.” Unblinded review of

all cases showed the diagnostic value of the ADC

Figure 3

Axial MRI from representative cases of familial Creutzfeldt-Jakob disease (fCJD) (A), Gerstmann-Sträussler-Scheinker (GSS) (B), and nonprion causes of rapidly progressive dementia (npRPD) (C)

(A) A fCJD case (E200K mutation) showing neocortical (solid arrow) involvement more evident in the right hemisphere, especially in the right frontal lobe, limbic involvement (dashed arrow) more evident in the right anterior cingulate and right insula and subcortical (dotted arrow) hyperintensities, greater in diffusion-weighted imaging (DWI) than in fluid-attenuated inversion recovery (FLAIR) images. Note the subcortical apparent diffusion coefficient (ADC) hypointensity in bilateral striatum. The image was read as Creutzfeldt-Jakob disease (CJD). (B) A GSS case (F198S mutation) with bilateral limbic hyperintensity in the anterior cingulate, insula, and subtle involvement in the mesiotemporal cortex, equally evident in DWI and FLAIR images. Image read as not CJD. (C) An npRPD case with limbic encephalopathy due to anti-AMPAR with anti-Sox2 antibodies and small-cell lung cancer. Note significant bilateral hyperintensity in mesiotemporal cortex (including hippocampus and amygdala), insula, and cingulate, greater on FLAIR than on DWI images. Image read as not CJD.

map in the subcortical regions. Furthermore, failure to notice diffuse hyperintense cortical signals in subjects without subcortical abnormalities caused falsenegative readings. False-positive ratings were usually due to misinterpreting artifactual hyperintense signals on DWI as restricted diffusion, particularly on poor-quality scans. Three cases without consensus MRI diagnosis at consensus review. In 2 cases, the cortical DWI and

FLAIR abnormalities in the caudate head, anterior cingulate, and insula were slight. The third case had FLAIR abnormalities in the cerebellar peduncles, unilateral caudate head, and DWI abnormalities in these areas and the cortex. At unblinding, the first case was probable DLB, the second pathology-proven sCJD, and the third pathology-proven sarcoid. In the DLB

and sarcoid cases, the caudate was normo-intense on the ADC map. In the sCJD case, the caudate was slightly hypointense on the ADC map, and DWI cortical ribboning in the frontal cortex was so subtle it was missed by readers at initial reading. Improving MRI criteria for sCJD. Based on the above

review and the authors’ collective experience with prion and npRPD cases, we modified our MRI criteria3 for sCJD (table 1). When these were reapplied to the sCJD and npRPD MRIs, unblinded consensus review found 98% sensitivity (95% CI 0.89 –1.00) and 100% specificity (95% CI 0.88 –1.00). In this study, we show that the pattern of MRI involvement can differentiate sCJD

DISCUSSION

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Figure 4

Frequency of gray matter hyperintensities at gyral and nuclear level in sporadic Creutzfeldt-Jakob disease (sCJD)

(A) Percent of subjects with sCJD with DWI brighter than FLAIR in each of 31 brain regions per right (black) and left (blue) hemisphere. (B) Color-coded overlay of frequency of MRI involvement in 31 brain regions per hemisphere. Light blue represents areas involved in 10%–35% of cases, dark blue 35%–50%, red 50%–65%. Neocortical regions are indicated with numbers (1–21) in the right hemisphere; limbic (22–26) and subcortical (27–31) regions are indicated in the left hemisphere.

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from npRPD. Using FLAIR and DWI MRI, we found that after consensus review, MRI sensitivity and specificity for sCJD were 98% and 93%, respectively, higher than any other diagnostic test.4,16-18 We identified 4 distinguishing MRI features: 1. In sCJD, hyperintensity on DWI was greater than on FLAIR, but in npRPD, hyperintensity on FLAIR was greater than on DWI. 2. In subjects with sCJD with subcortical DWI hyperintensity, ADC in these regions was always hypointense (i.e., restricted diffusion). 3. Isolated limbic involvement was not found in sCJD, but often seen in npRPD. 4. sCJD has characteristic DWI patterns of gray matter involvement. Regarding the first 2 features, the prevalence of DWI over FLAIR hyperintensities suggests diffusion restriction is a crucial feature of MRI in sCJD; diffusion restriction and T2 prolongation both contribute to DWI hyperintensity, but only T2 prolongation causes FLAIR hyperintensity. Only sCJD cases had ADC hypointensity correlating with DWI subcortical hyperintensity and this finding had high specificity for sCJD. The diffusion restriction is probably related to vacuolation.19 This study used the first MRI scan obtained at our institution, but we and others have observed that diffusion restriction might decline in late stages of sCJD, particularly in patients with very prolonged courses and significant atrophy.20,21 Nevertheless, we believe that the prevalence of DWI over T2 abnormalities is one of the most important MRI criteria for diagnosing sCJD, which is supported by other studies.18,21 Furthermore, DWI is often bright very early in CJD when T2-weighted images are not.20,21 Many studies have confirmed the sensitivity of DWI in sCJD, some gPrDs, and vCJD.3,13,18,21 In this study we show the high specificity of diffusion restriction (with DWI and ADC map) in the basal ganglia in sCJD compared to npRPDs. A recent large study examined the sensitivity and specificity of FLAIR, and in some cases DWI, MRI in sCJD compared to subjects initially suspected of CJD, but in whom other diagnoses were found.18 This article proposed new MRI criteria for sCJD, but had several problems. First, the authors did not look at true diffusion restriction (ADC map), which is critical for differentiating CJD from npRPD. Secondly, they do not include cingulate, hippocampal, insular, and frontal cortical involvement because of a high rate of false-positive FLAIR or DWI MRI readings in these regions. These regions, however, are among the most common areas affected in CJD (figure 1) and false positivity due to artifact can be avoided by perform-

ing sequences in multiple planes and examining for restricted diffusion (ADC map). Other npRPD conditions (many of which were not included in this cohort) might present with subcortical or cortical DWI hyperintensity—sometimes with decreased ADC—and might mimic CJD MRI findings. For example, subcortical diffusion restriction can be found in striatum in extrapontine myelinolysis22 and Wilson disease,23 and in the posteromesial thalamus in Wernicke encephalopathy24 and in Bartonella infection.25 Since our study was completed, we have identified 2 patients with npRPD (hyperglycemia with seizures and extrapontine myelinolysis) with some MRI findings overlapping those of CJD, DWI hyperintensity, and ADC hypointensity in the striatum (manuscript in preparation). A few npRPDs, such as anti-CV2 limbic encephalopathy and neurofilament inclusion body disease, have striatal T2/FLAIR hyperintensity similar to CJD; in these conditions, however, DWI/ADC abnormalities are absent. Cortical diffusion restriction can be seen in the acute phase of viral encephalitis26 and focal epileptic status.27 Importantly, status epilepticus occurs in npRPDs, such as limbic encephalopathy, and might mimic CJD clinically.28 “Strategic” stroke dementia can show cortical hyperintensity.29 Acute viral encephalitis, focal epileptic status, and stroke usually present cortical swelling, subcortical abnormalities, and often contrast enhancement.26,27 Although DWI and ADC are the most important sequences for diagnosing sCJD, FLAIR images and, in selected cases, T1 pre- and postcontrast must be carefully evaluated in all patients with rapidly progressive dementia. These conditions must be considered when evaluating a patient with suspected CJD. Isolated limbic involvement might help distinguish sCJD from npRPD, for it was found only in our npRPD group, typically in autoimmune encephalopathy. To our knowledge, ADC decreases have never been reported in these encephalopathies, but this might occur with seizures, although this should disappear after seizures have been controlled. If isolated limbic hyperintensity is greater on FLAIR than DWI, we suggest that this be a criterion for “probably not CJD.” If isolated limbic hyperintensity is greater on DWI, particularly with accompanying ADC hypointensity, encephalitis and seizures should be considered. Another distinguishing feature of sCJD was its pattern of gray matter involvement. Consistent with prior studies,3,4 we found that hyperintensities were more commonly cortical than subcortical (table e-3). We also identified the same most frequently involved cortical regions as another study,30 except we rarely Neurology 76

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found occipital cortical involvement. Although the highest frequencies of any specific area of gray matter involvement in that study were significantly higher than in our cohort (85%–95% compared to 50%– 65%), 13 cases were studied without DWI images and no control group was included. As they knew all cases were CJD, they might have overestimated hyperintensities, possibly explaining the more frequent involvement of the precentral gyrus in their study (40%) compared to ours (5%), and why parahippocampal hyperintensities, involved in 50% of our sCJD cohort, were not reported. Susceptibility artifacts make evaluating the anterior parahippocampal gyrus difficult, but the posterior portion can be evaluated more reliably. Thus, to help determine if the abnormal intensities are real or artifact, we recommend performing (or at least reviewing) the DWI/ ADC sequences in 2 planes, axial and coronal. The areas with less frequent FLAIR/DWI hyperintensity in sCJD were the pallidus and precentral gyrus. This characteristic “precentral sparing” sign was especially notable in subjects with sCJD and subjects with fCJD with diffuse cortical involvement (figure 2). Although motor deficits are common in CJD, the sparing of the motor strip might reflect the absence of frank paralysis in most patients. Conversely, because precentral gyrus and the pallidus accumulate the most age-related iron, they have the most hypointense T2-weighted signal.31,32Although the pallidus can be relatively spared on DWI in sCJD,33 pallidal T1 hyperintensity might be pathologically associated with high levels of prion deposits.34 We suspect that involvement of pallidus and precentral gyrus is underestimated on FLAIR and DWI sequences because the concurrent iron-related hypointensity masks the hyperintense signal from prion disease. This “T2 blackout” effect is significant in FLAIR, T2-weighted, and probably greater in echoplanar DWI images.35 One sCJD study demonstrated ADC decrease, despite normal DWI, in the precentral gyrus.36 Of note, our sCJD MM2thalamic case had a normal MRI, consistent with most cases in the literature.37 The MRI pattern in our patients with fCJD generally resembled those of sCJD, but in most GSS cases this pattern was not found. As subcortical ADC maps were examined only in cases with DWI subcortical hyperintensity, after the study, we noted subcortical ADC hypointensity without DWI hyperintensity in some GSS cases; this may be due to the “T2 blackout” effect. Although the P102L case did not have typical sCJD MRI findings, and nor have subsequent cases seen at our center, at least one case has been reported to have a classic CJD MRI.38 1718

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As we found variability among readers, it seems clear that accurate interpretation of MRIs in subjects with CJD requires knowledge of the findings and experience with CJD. Our new criteria should improve diagnostic accuracy and reduce this variability. It is paramount that neurologists and radiologists familiarize themselves with these findings. Future studies should address issues of inter- and intrarater reliability and also might use postprocessing methods to accurately quantitate mean diffusivity values (ADC map). The patterns of FLAIR and DWI abnormalities can differentiate sCJD from npRPD with high accuracy, whereas only some genetic prion cases have overlapping MRI features with sCJD. We propose modification of our prior sCJD MRI (table 1) criteria to improve the sensitivity and specificity of the MRI findings, based on the anatomic distribution of DWI-FLAIR hyperintensities, the relative DWI to FLAIR signal, and the ADC map in subcortical areas. MRI with DWI and ADC should be included in sCJD diagnostic criteria. ACKNOWLEDGMENT The authors thank Alan Bostrom, MS, for statistical assistance.

DISCLOSURE Dr. Vitali has received research support from the Fondazione TronchettiProvera, Milan, Italy. Dr. Maccagnano and Dr. Caverzasi report no disclosures. Dr. Henry serves as an Associate Editor for Frontiers in Neuroscience and receives research support from the NIH (NINDS, NIBIB, NCI) and the Lupus Research Institute. Dr. Haman, C. TorresChae, and D.Y. Johnson report no disclosures. Dr. Miller serves on a scientific advisory board for the Alzheimer’s Disease Clinical Study, serves as an Editor for Neurocase, and served as an Associate Editor of ADAD; receives royalties from the publication of Behavioral Neurology of Dementia (Cambridge, 2009), Handbook of Neurology (Elsevier, 2009), and The Human Frontal Lobes (Guilford, 2008); serves as a consultant for Lundbeck Inc., Allon Therapeutics, Inc., Novartis, and TauRx Pharmaceuticals; serves on the Board of Directors for the John Douglas French Foundation for Alzheimer’s Research and for The Larry L. Hillblom Foundation; and receives research support from Novartis, the NIH/NIA, and the State of California Alzheimer’s Center. Dr. Geschwind serves on a scientific advisory board for Lundbeck Inc.; serves on the editorial board of Dementia and Behavior; has served as a consultant for MedaCorp Inc, Gerson-Lehman Group, and The Council of Advisors; has served on speakers’ bureaus for Forest Laboratories, Inc., Pfizer Inc, Novartis, and Lundbeck Inc.; and received research support from the NIH/NIA, the Michael J. Homer Family Fund, the John Douglas French Foundation for Alzheimer’s Research, and the McBean Foundation.

Received July 26, 2010. Accepted in final form February 10, 2011. REFERENCES 1. Geschwind MD, Shu H, Haman A, Sejvar JJ, Miller BL. Rapidly progressive dementia. Ann Neurol 2008;64:97– 108. 2. Shiga Y, Miyazawa K, Sato S, et al. Diffusion-weighted MRI abnormalities as an early diagnostic marker for Creutzfeldt-Jakob disease. Neurology 2004;I63:443– 449. 3. Young GS, Geschwind MD, Fischbein NJ, et al. Diffusion-weighted and fluid-attenuated inversion recovery imaging in Creutzfeldt-Jakob disease: high sensitivity

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Clinical features and APOE genotype of pathologically proven early-onset Alzheimer disease M. Balasa, MD E. Gelpi, MD, PhD A. Antonell, PhD M.J. Rey, MD, PhD R. Sa´nchez-Valle, MD, PhD J.L. Molinuevo, MD, PhD A. Llado´, MD, PhD For the Neurological Tissue Bank/University of Barcelona/Hospital Clínic NTB/UB/HC Collaborative Group

Address correspondence and reprint requests to Dr. Albert Llado´, Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clínic, C/Villarroel, 170, 08036 Barcelona, Spain [email protected]

ABSTRACT

Objectives: Early-onset Alzheimer disease (EOAD) diagnosis often represents a challenge because of the high frequency of atypical presentations. Our aim was to describe the clinical features, APOE genotype, and its pathologic correlations of neuropathologic confirmed EOAD. Methods: Retrospective review of clinical data (age at onset, family history, clinical presentation, diagnostic delay, diagnosis) and APOE genotype of patients with neuropathologically confirmed EOAD (⬍60 years). Results: Forty cases were selected. Mean age at onset was 54.5 years (range 46–60). The mean disease duration was 11 years with a mean diagnostic delay of 3.1 years. A total of 37.5% had a nonmemory presentation. Behavioral/executive dysfunction was the most prevalent atypical presentation. Incorrect initial clinical diagnoses were common (53%) in patients with atypical presentations, but rare when anterograde amnesia was the presenting symptom (4%). The incorrect initial clinical diagnoses were 2 behavioral variant frontotemporal lobar degeneration, 2 normal pressure hydrocephalus, 1 semantic dementia, 1 primary progressive aphasia, 1 corticobasal degeneration, 1 pseudodementia with depression, and 1 unclassifiable dementia. APOE genotype was ⑀3/⑀3 in 59%, with no significant differences between typical and atypical presentations. APOE ⑀4 was 3.3 times more frequent in subjects with family history of AD. A total of 97.5% of the cases presented advanced neurofibrillary pathology. A total of 45% of the patients had concomitant Lewy body pathology although localized in most cases and without a significant clinical correlate.

Conclusion: One third of patients with pathologic confirmed EOAD presented with atypical symptoms. Patients with EOAD with nonamnestic presentations often receive incorrect clinical diagnoses. Neurology® 2011;76:1720–1725 GLOSSARY AD ⫽ Alzheimer disease; CBD ⫽ corticobasal degeneration; CBS ⫽ corticobasal syndrome; EOAD ⫽ early-onset Alzheimer disease; FTLD ⫽ frontotemporal lobar degeneration; LB ⫽ Lewy body; LOAD ⫽ late-onset Alzheimer disease; NPH ⫽ normal pressure hydrocephalus; NTB/UB/HC ⫽ Neurological Tissue Bank, University of Barcelona–Hospital Clínic; PCA ⫽ posterior cortical atrophy; PPA ⫽ primary progressive aphasia; SemD ⫽ semantic dementia.

Alzheimer disease (AD) is the most frequent cause of degenerative dementia in developed countries.1,2 The typical clinical pattern starts by episodic memory dysfunction and then progresses to other cognitive domains although atypical presentations, without episodic memory impairment at onset, have also been described.3-6 Although the pathologic changes are similar regardless the age at onset, AD has been divided into 2 clinical forms according to age at onset: early-onset AD (EOAD) and late-onset AD (LOAD). Several clinical series have shown that EOAD presents more frequently with atypical clinical manifestations such as visual, executive, behavioral, or language impairment compared with LOAD.7 One limitation of clinical studies is that the diagnosis is made using clinical criteria, often lacking pathologic confirmation.8 Supplemental data at www.neurology.org From the Alzheimer’s Disease and Other Cognitive Disorders Unit (M.B., A.A., R.S.-V., J.L.M., A.L.), Neurology Service, Hospital Clínic, Institut d’Investigacio´ Biome`dica August Pi i Sunyer (IDIBAPS), Barcelona; and Neurological Tissue Bank University of Barcelona/Hospital Clínic (NTB/ UB/HC) (E.G., M.J.R.), Barcelona, Spain. Study funding: Supported by the Hospital Clinic-Emili Letang postresidency grant (M.B.). Disclosure: Author disclosures are provided at the end of the article. 1720

Copyright © 2011 by AAN Enterprises, Inc.

The aim of our study was to describe the clinical features of a population of confirmed EOAD, investigate the frequency of nonmemory presentations in EOAD, and identify features that lead to misdiagnoses. We also sought the frequency of the different APOE genotypes and its correlation with their clinicopathologic phenotypes. METHODS Standard protocol approvals, registrations, and patient consents. All the brain donors fulfilling neuropathologic criteria of AD with age at onset before 60 years were selected from the Neurological Tissue Bank, University of Barcelona–Hospital Clínic (NTB/UB/HC) (1994 –2009). All individuals or relatives had given their informed consent for research. We selected the age at onset before 60 years in order to assure the selection of early-onset cases. We excluded subjects with insufficient clinical information and carriers of pathogenic mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) genes because our aim was to describe clinical profiles of nongenetic EOAD.

Clinical classification. We reviewed the medical records available at the NTB/UB/HC and also contacted the neurologists who attended the patients during life. They were asked to fill in a form with clinical information: age at onset, personal and family history, clinical presentation, cognitive domains affected at first evaluation, diagnostic delay (disease duration until the first diagnosis), initial clinical diagnosis, and final clinical diagnosis (at the last visit before death). Positive family history of disease was considered when at least one first-degree relative presented a clinical picture suggestive of dementia. An autosomal dominant pattern of inheritance was defined by the presence of at least 3 family members with dementia in 2 generations. The cognitive domains affected at first evaluation were assigned according to the opinion of the attending neurologist or the neuropsychological evaluation. In atypical presentations, mild memory impairment could not be excluded in some cases although it was not the main complaint of the patient. Patients were classified into different clinical subtypes: 1. Typical presentation: episodic memory impairment with progression to other cognitive domains. 2. Atypical presentation (no episodic memory dysfunction at clinical onset): frontal variant (behavioral problems [inappropriate social conduct, impulsivity, disinhibition, apathy, or mood disturbances such as depression], predominant executive dysfunction); posterior variants (posterior cortical atrophy [PCA]: visuospatial problems in a patient with normal insight and no ocular disease that could explain the symptoms, components of Balint or Gerstmann syndromes, or progressive apraxic syndrome; corticobasal syndrome [CBS]: combination of asymmetric parkinsonism and cortical dysfunction signs [alien limb, limb apraxia, cortical sensory loss]); and language variant: aphasia as the first and principal symptom at onset.

Neuropathologic diagnosis. Neuropathologic examination was performed according to standardized protocols at the NTB/ UB/HC. Half brain is usually fresh-frozen and stored at ⫺80°C and the other half is fixed in formaldehyde solution. At least 25 representative brain areas are embedded in paraffin. For histologic evaluation, 5-␮m-thick sections are stained with hematox-

ylin & eosin. Immunohistochemistry is performed using various antibodies including anti-␤A4, anti-ptau, anti-RD3, anti-RD4, anti-␣-synuclein, anti-ubiquitin, anti-␣-internexin, and antiTDP-43. Disease evaluation was performed according to international consensus criteria.9,10 Semiquantitative assessment of tau neuropil threads, neurorofibrillary tangles, and ␤-amyloid deposits (⫹ mild, ⫹⫹ moderate, ⫹⫹⫹ severe) was performed in frontal, temporal, parietal, occipital cortices, insula, and amygdala. The presence of tau inclusions in granular neurons of dentate gyrus, tau-positive grains, as well as of capillary cerebral amyloid angiopathy was recorded.11-13

Genetic analysis. DNA was extracted from cerebellum using the QIAamp DNA Minikit for DNA purification from tissues (QIAGEN Co.) following manufacturer’s instructions. The APOE genotype was determined using PCR amplification and HhaI restriction enzyme. In one patient, the determination of APOE genotype was not possible due to lack of sample. Genetic analysis by direct sequencing of PSEN1 (exons 3–12), PSEN2 (exons 3–12), and APP (exons 16 and 17) genes was performed in patients with a positive family history.

Statistical analysis. For statistical analysis, SPSS version 16.0 was used. We used ␹2 test for categorical data and t tests for continuous data. Statistical significance was set at p ⬍ 0.05. RESULTS Demographic features, clinical classification, and genetics. From the initially 54 cases selected, 11

cases of genetic AD and 3 cases without reliable clinical data were excluded. Therefore, a total of 40 cases (25 male, 15 female) were included. Demographic, clinicopathologic, and APOE characteristics of the patients are summarized in table 1. Twenty-five patients (62.5%) presented with typical episodic memory dysfunction as the first symptom. Their initial diagnosis was AD in 24 cases and normal pressure hydrocephalus (NPH) in the other case. In this group, 8 patients (32%) had clinically significant mood disturbances (depression) at onset. The other 15 patients (37.5%) had an atypical presentation. Their clinical phenotypes were frontal variant (7 patients), 5 posterior variant (2 with predominant visuospatial dysfunction and 3 progressive apraxic syndrome/CBS), and language disturbances in 3 patients. Their initial clinical diagnoses were 2 AD, 2 PCA-AD, 3 AD vs frontotemporal lobar degeneration (FTLD), 2 behavioral variant FTLD, 1 semantic dementia (SemD), 1 primary progressive aphasia (PPA), 1 NPH, 1 corticobasal degeneration (CBD), 1 pseudodementia with depression, and 1 unclassifiable dementia (table e-1 on the Neurology® Web site at www.neurology.org). No significant differences were found between typical and atypical presentations in gender, mean age at onset, diagnostic delay, age at death, or disease duration (table 1). Fourteen patients had a positive family history of dementia (with early onset in 4 cases) but none had an autosomal dominant pattern of inheritance as previously defined. No pathogenic mutations in Neurology 76

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Table 1

Demographics, clinical characteristics, and APOE genotypes of the patients

Total

Typical presentation

Atypical presentation

No. of patients

40

25

15

Male

25

13

12

NS

Mean age at onset, y

54.5

54.7

54.2

NS

Diagnostic delay, y

3.1

p Value

3.2

3

NS

Age at death, y

65.5

66.16

64.4

NS

Total duration of disease, y

11

11.4

10.2

NS

APOE ⑀3/⑀3, %

59

58.3

60

NS

APOE ⑀4/⑀3, %

28.2

25

33.3

NS

APOE ⑀4/⑀4, %

12.8

16.6

6.6

NS

Initial clinical misdiagnosis, %

22.5

4

53

0.0003

Final clinical misdiagnosis, %

20

4

47

0.0011

Presence of Lewy body (all localizations), %

45

40

46.6

NS

Abbreviation: NS ⫽ not significant.

PSEN1, PSEN2, and APP genes were identified. Sixteen out of 39 patients (41%) carried APOE ⑀4 allele. Neuropathology. Fresh brain weight varied from

810 g to 1,410 g (mean of 1,092 g). All cases showed Alzheimer-type pathology. The breakdown by Braak stage was 32 cases with Braak stage VI (80%), 7 stage V (17.5%), and 1 stage IV (2.5%). All cases had a high density of neuritic plaques (score C of Consortium to Establish a Registry for Alzheimer’s Disease criteria), and a high probability that the dementia was caused by Alzheimer pathology according to NIA/Reagan Institute criteria. A total of 87.5% had a phase 4 or 5 of amyloid deposits. A total of 18 patients (45%) showed variable degree of concomitant Lewy body (LB) pathology, with amygdalar LB in 9 patients (22.5%), limbic LB (Braak stage 4) in 5 patients (12.5%), and neocortical LB (Braak stage 5) in 3 patients (7.5%). Vascular lesions were observed in 12.5%, 2 patients had additional hippocampal sclerosis, 1 case combined AD pathology with motor neuron disease (TDP-43 positive), and in 1 case AD changes were accompanied by 4R tauopathy compatible with PSP. The distribution of tau and ␤-amyloid pathology in individual subjects in the different brain areas is shown in table e-2. Description of some illustrative atypical cases (appendix e-1). Clinicopathologic and genetic correlation. Overall,

the percentage of initial clinical misdiagnosis was 22.5%, which was maintained until the patient’s death in 20% of the cases (table 1). Misdiagnosis was significantly higher in the atypical compared with typical clinical presentations, both at initial (53% vs 4%, ␹2 test p ⫽ 0.0003) and at final clinical diagnosis (47% vs 4%, ␹2 test p ⫽ 0.0011). 1722

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In the amnestic presentation subgroup there was a low percentage of clinical misdiagnosis: 1/25 (4%) did not have AD as final clinical diagnosis (one initial NPH diagnosis was changed to AD during follow-up and in one patient the final clinical diagnosis was dementia with Lewy bodies). In contrast, 7/15 (47%) of the nonamnestic presentation patients were not diagnosed with AD before death (2 behavioral FTLD, 2 CBD, 1 SemD, 1 FTLD with motor neuron disease, and 1 unclassifiable dementia). No significant differences were found in APOE genotype between typical and atypical presentations (table 1). The APOE ⑀4 carriers were 3.3-fold more frequent in familial cases (76.9% vs 23.1%, confidence interval 1.5–7.1, ␹2 test p ⫽ 0.001). No significant differences were found between APOE ⑀4 carriers/noncarriers in mean age at onset, diagnostic delay, age at death, or disease duration. No differences in the density of tau-positive neuropil threads, tangles, or ␤-amyloid deposits were found in frontal cortex as compared to other brain areas in the behavioral variant of AD compared to the other variants. We also did not find differences in the frequency of capillary CAA, taupositive grains, or tau inclusions in neurons of dentate gyrus (table e-2). There were no correlations between the presence of LB and clinical presentation, age at onset and death, sex, diagnostic delay, disease duration, or APOE genotype. In this retrospective study of pathologically confirmed patients with EOAD, we observed frequent misdiagnoses among patients with atypical (nonmemory) presentations. APOE ⑀4 was more frequent in familial cases but did not appear to have influenced the clinical phenotype. Although relatively high in absolute numbers, the coexisting pathology (mainly LB) lacked a clinical correlate. Atypical presentations of EOAD represent a problem in everyday clinical practice because of its frequency14 and the higher risk of misdiagnosis. Over half of the patients with EOAD with nonamnestic presentations were given etiologic diagnoses other than AD. The percentage of misdiagnoses was maintained at final clinical diagnosis with little changes. The misdiagnoses were mainly degenerative (FTLD group, CBD), but also nondegenerative pathologies (NPH and mood disorders). It is well known by now that, in some cases, the clinical picture correlates poorly with the pathologic changes. One clear example could be the progranulin gene mutation which causes FTLD tau-negative ubiquitin-positive pathology and clinically had been DISCUSSION

related to frontal variant of FTLD, progressive nonfluent aphasia, CBS, or even AD.15 A diagnostic delay of more than 3 years was observed, with no difference between the typical and atypical presentations. The diagnostic delay in EOAD might have been caused by the young age itself because the family and the attending physicians do not contemplate dementia in the initial differential diagnosis. In the future, when there are more potent therapies for AD, it might be desirable to use AD biomarkers for the clinical diagnosis, such as CSF biomarkers or in vivo amyloid neuroimaging techniques, in routine clinical practice. However, at the present time, data about cost/effectiveness of these interventions is needed.16-18 The frontal variant, characterized by behavioral or dysexecutive problems, was the most frequent nonmemory presentation in our group.19 Only 43% had the final clinical diagnosis of AD, with a similar percentage of FTLD clinical misdiagnoses. When a young patient exhibits a disturbance of personality and interpersonal relationships, the usual diagnosis is FTLD.20 However, AD is a common cause of earlyonset dementia and should always be considered as an alternative diagnosis.1,2 One of our patients with advanced AD changes also had ubiquitin and TDP43-positive cytoplasmic inclusions in pyramidal neurons of frontal and primary motor cortex, motor neurons of hypoglossal nerve, dentate nucleus, and motor neurons of spinal cord. There were no TDP43 inclusions in temporal cortex or limbic system including the hippocampus. The clinical presentation was a frontal syndrome, developing memory impairment 3 years later. Nine years after clinical onset he presented aggressive motor neuron disease which led him to death. Although we cannot rule out mixed pathology, he had widespread AD pathology. The posterior variant of AD comprises the syndromes of PCA and CBS. PCA is a well-recognized syndrome associated with AD pathology in the majority of cases,21-23 with 2 clinical subtypes identified: the visuospatial variant (with prominent visuospatial symptoms) and the apraxic type (the biparietal syndrome, presenting with prominent apraxic symptoms associating also visuospatial problems).24,25 The neuropathologic substrate of CBS is in most cases a 4-repeat tauopathy, although various clinicopathologic series showed that a significant percentage of patients with CBS had AD pathology.26 We identified 5 patients with a posterior onset: 2 with prominent visuospatial disturbances (diagnosed correctly as having AD) and 3 with prominent apraxic syndrome with parkinsonism (in only one of them was AD pathology taken into consideration).

A progressive disturbance of language could be the first symptom of AD or FTLD. Several types of degenerative aphasias have been described. Two of them are classified into the group of FTLD: progressive nonfluent aphasia and semantic dementia.20 A third type, logopenic aphasia, appears to be related with AD pathology. It is characterized by a decreased spontaneous speech production, frequent wordfinding pauses, preservation of motor speech and grammar, and altered repetition.27,28 From the 3 aphasic patients of our series, 2 were diagnosed with AD. Unfortunately, all 3 patients were seen in advanced stages and the neuropsychological evaluation did not help to categorize them more accurately. At a pathologic level, we have found a significant percentage of coexistent pathology, mainly LB. Although the synuclein pathology could be considered as high, half of the LB were amygdalar, without involvement of other cerebral structures. Additionally, this finding did not change the pathologic diagnosis and did not have a statistically significant clinical correlate. We cannot rule out completely the presence of late-life hallucinations and the possible correlations with the presence of LB as we have rather poor clinical information on the last phases of the disease in most patients. APOE ⑀4 is the most prevalent genetic risk factor for AD.29,30 In our series, 41% of the patients were APOE ⑀4 carriers. There was no significant difference between the typical and atypical presentations in APOE genotypes. Other studies found different results in clinical cohorts,31,32 showing that the percentage of ⑀4 carriers is lower in atypical AD cases than in memory-onset patients. This discrepancy could have several explanations: one might be that the previously reported data based on clinical criteria (without neuropathologic confirmation) might have overlooked some ⑀4 carriers in the atypical presentation group. It could also be postulated that the typical amnesic phenotype is strongly associated with the APOE ⑀4 allele, but our sample size was too small to detect a relationship. The APOE ⑀4 allele was 3.3 times more frequent among subjects with a first-degree relative affected, suggesting that APOE ⑀4 could account for the familial aggregation of those cases, taking into account that the usual genetic causes of AD had been excluded from our series. Our study has some limitations. First, the retrospective gathering of data could limit the accuracy of some clinical details, especially at the final clinical stages. Second, a selection bias is possible because the clinicians could be more prone to promote brain donation in atypical cases. Neurology 76

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AUTHOR CONTRIBUTIONS

DISCLOSURE

M. Balasa and A. Llado´ conceived the study. M. Balasa, A. Llado´, J.L. Molinuevo, R. Sanchez-Valle, and all the other members of the NTB/ UB/HC collaborative group listed as coinvestigators contributed to subject recruitment. M. Balasa and A. Llado´ gathered the clinical data. E. Gelpí and M.J. Rey gathered and reviewed the pathologic data. M. Balasa and A. Antonell performed the DNA extraction and APOE determination. A. Antonell performed the genetic study of PSEN1, PSEN2, and APP. M. Balasa and A. Llado´ wrote the first draft of the manuscript. M. Balasa performed the statistical analysis. M. Balasa, A. Antonell, E. Gelpí, M.J. Rey, R. Sanchez-Valle, J.L. Molinuevo, A. Llado´, and the other members of the NTB/UB/HC collaborative group listed as coinvestigators provided critical comments and contributed to the discussions/ A. Llado´ provided overall supervision of the study.

Dr. Balasa, Dr. Gelpi, Dr. Antonell, and Dr. Rey report no disclosures. Dr. Sa´nchez-Valle serves as an Associate Editor for the Journal of Alzheimer’s Disease. Dr. Molinuevo serves on scientific advisory boards for Pfizer Inc, Lundbeck Inc., Roche, Novartis, GE Healthcare, Bayer Schering Pharma, Innogenetics, and Bristol-Myers Squibb; has received funding for travel or speaker honoraria from Pfizer Inc, Lundbeck Inc., Janssen, and Novartis; serves as an Associate Editor for Revista Neurologia; and receives research support from Pfizer Inc. Dr. Llado´ reports no disclosures.

COINVESTIGATORS Members of the Neurological Tissue Bank/University of Barcelona/ Hospital Clínic NTB/UB/HC Collaborative Group: Teresa Ribalta, MD, PhD (Neurological Tissue Bank University of Barcelona/Hospital Clínic; gathered and reviewed the pathologic data); Isabel Herna´ndez, MD (Fundacio´ ACE, Institut Catala` de Neurocie`ncies Aplicades Barcelona; submitted the clinical data, reviewed the final version of the manuscript); Ana Mauleo´n, MD, PhD (Fundacio´ ACE, Institut Catala` de Neurocie`ncies Aplicades Barcelona; submitted the clinical data, reviewed the final version of the manuscript); Rafael Blesa, MD, PhD (Hospital de la Santa Creu i Sant Pau; submitted the clinical data, reviewed the final version of the manuscript); Merce´ Boada, MD, PhD (Fundacio´ ACE, Institut Catala` de Neurocie`ncies Aplicades, Hospital Universitari Vall d’Hebron– Institut de Recerca, Universitat Auto`noma de Barcelona; submitted the clinical data, reviewed the final version of the manuscript); Miguel Aguilar, MD (Hospital Universitari Mu´tua de Terrasa; submitted the clinical data, reviewed the final version of the manuscript); Ana Rojo, MD (Hospital Universitari Mu´tua de Terrasa; submitted the clinical data, reviewed the final version of the manuscript); Ramo´n Ren˜e´, MD, PhD (Hospital Universitari de Bellvitge; submitted the clinical data, reviewed the final version of the manuscript); Pilar Latorre, MD, PhD (Hospital Universitari Germans Trias i Pujol; submitted the clinical data, reviewed the final version of the manuscript); Jordi Pen˜a-Casanova, MD, PhD (Hospital del Mar; submitted the clinical data, reviewed the final version of the manuscript); Pedro Roy, MD (Hospital Mare de De´u de la Merce`; submitted the clinical data, reviewed the final version of the manuscript); Elena Barranco MD, PhD (Hospital General de Granollers; submitted the clinical data, reviewed the final version of the manuscript); Pilar Azpiazu, MD (Area de Psicogeriatria, C.A.S.M. Benito Menni Sant Boi de Llobregat; submitted the clinical data, reviewed the final version of the manuscript); Ernest Balaguer, MD, PhD (Capio Hospital General de Catalunya, Department of Neurology; submitted the clinical data, reviewed the final version of the manuscript); Salvador Pile´s, MD (Hospital de Mollet; submitted the clinical data, reviewed the final version of the manuscript); M. Rosich, MD (Hospital Psiquia`tric Universitari Institut Pere Mata, Tarragona; submitted the clinical data, reviewed the final version of the manuscript); Begon˜a Berlanga, MD (Hospital de Sant Joan Despí, Moises Broggi; submitted the clinical data, reviewed the final version of the manuscript); Secundino Lopez-Pousa, MD, PhD (Unitat de Valoracio´ de la Memo`ria i les Deme`ncies, Centre Sociosanitari La Repu´blica, Institut d’Assiste`ncia Sanita`ria, Salt; submitted the clinical data, reviewed the final version of the manuscript); Antoni Turo´n, MD, PhD (Unitat de Valoracio´ de la Memo`ria i les Deme`ncies, Centre Sociosanitari La Repu´blica, Institut d’Assiste`ncia Sanita`ria, Salt; submitted the clinical data, reviewed the final version of the manuscript).

ACKNOWLEDGMENT The authors and the Neurological Tissue Bank thank the patients and their relatives for brain donation; Teresa Botta; Carina Antiga; and Rosa Rivera, Sara Charif, Vero´nica Santiago, Abel Mun˜oz, and Leire Echarri for laboratory work. 1724

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Received November 10, 2010. Accepted in final form February 10, 2011. REFERENCES 1. Garre-Olmo J, Genis Batlle D, del Mar Fernandez M, et al. Incidence and subtypes of early-onset dementia in a geographically defined general population. Neurology 2010;75:1249 –1255. 2. Harvey RJ, Skelton-Robinson M, Rossor MN. The prevalence and causes of dementia in people under the age of 65 years. J Neurol Neurosurg Psychiatry 2003;74:1206 – 1209. 3. Petersen RC. Clinical subtypes of Alzheimer’s disease. Dement Geriatr Cogn Disord 1998;9(suppl 3):16 –24. 4. Stopford CL, Snowden JS, Thompson JC, Neary D. Variability in cognitive presentation of Alzheimer’s disease. Cortex 2008;44:185–195. 5. Galton CJ, Patterson K, Xuereb JH, Hodges JR. Atypical and typical presentations of Alzheimer’s disease: a clinical, neuropsychological, neuroimaging and pathological study of 13 cases. Brain 2000;123:484 – 498. 6. Alladi S, Xuereb J, Bak T, et al. Focal cortical presentations of Alzheimer’s disease. Brain 2007;130:2636 –2645. 7. Licht EA, McMurtray AM, Saul RE, Mendez MF. Cognitive differences between early- and late-onset Alzheimer’s disease. Am J Alzheimers Dis Other Demen 2007;22: 218 –222. 8. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34: 939 –944. 9. Braak H, Braak E. Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging 1997; 18:S85–S88. 10. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. Neurobiol Aging 1997;18:S1–S2. 11. Alafuzoff I, Arzberger T, Al-Sarraj S, et al. Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe Consortium. Brain Pathol 2008;18: 484 – 496. 12. Alafuzoff I, Thal DR, Arzberger T, et al. Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium. Acta Neuropathol 2009; 117:309 –320. 13. Alafuzoff I, Ince PG, Arzberger T, et al. Staging/typing of Lewy body related alpha-synuclein pathology: a study of the BrainNet Europe Consortium. Acta Neuropathol 2009;117:635– 652. 14. Koedam EL, Lauffer V, van der Vlies AE, van der Flier WM, Scheltens P, Pijnenburg YA. Early-versus late-onset

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Historical Abstract: November 1, 1974 EVALUATING STORAGE, RETENTION AND RETRIEVAL IN DISORDERED MEMORY AND LEARNING Herman Buschke, MD and Paula Altman Fuld, PhD Neurology 1974;24:1019-1025 Two simple methods that are clinically useful for analyzing impaired memory and learning are selective reminding or restricted reminding. These new methods provide simultaneous analysis of storage, retention, and retrieval during verbal learning because they let the patient show learning by spontaneous retrieval without confounding by continual presentation. Because selective reminding and restricted reminding let the patient show consistent retrieval without any further presentation, they also distinguish list learning from item learning, so that impaired memory and learning can be analyzed further in terms of two stages of learning (item and list). Free Access to this article at www.neurology.org/content/24/11/1019 Comment from David S. Knopman, MD, FAAN, Deputy Editor: This paper is important because it introduced a modern view of learning and memory into neurology.

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Are networks for residual language function and recovery consistent across aphasic patients? Peter E. Turkeltaub, MD, PhD Samuel Messing, BS Catherine Norise Roy H. Hamilton, MD, MS

Address correspondence and reprint requests to Dr. Peter E. Turkeltaub, Laboratory for Cognition and Neural Stimulation, Department of Neurology, University of Pennsylvania Health System, 3400 Spruce Street, 3W Gates Building, Philadelphia, PA 19104 [email protected]

ABSTRACT

Objectives: If neuroplastic changes in aphasia are consistent across studies, this would imply relatively stereotyped mechanisms of recovery which could guide the design of more efficient noninvasive brain stimulation treatments. To address this question, we performed a metaanalysis of functional neuroimaging studies of chronic aphasia after stroke.

Methods: Functional neuroimaging articles using language tasks in patients with chronic aphasia after stroke (n ⫽ 105) and control subjects (n ⫽ 129) were collected. Activation likelihood estimation meta-analysis determined areas of consistent activity in each group. Functional homology between areas recruited by aphasic patients and controls was assessed by determining whether they activated under the same experimental conditions.

Results: Controls consistently activated a network of left hemisphere language areas. Aphasic patients consistently activated some spared left hemisphere language nodes, new left hemisphere areas, and right hemisphere areas homotopic to the control subjects’ language network. Patients with left inferior frontal lesions recruited right inferior frontal gyrus more reliably than those without. Some areas, including right dorsal pars opercularis, were functionally homologous with corresponding control areas, while others, including right pars triangularis, were not. Conclusions: The network of brain areas aphasic patients recruit for language functions is largely consistent across studies. Several recruitment mechanisms occur, including persistent function in spared nodes, compensatory recruitment of alternate nodes, and recruitment of areas that may hinder recovery. These findings may guide development of brain stimulation protocols that can be applied across populations of aphasic patients who share common attributes. Neurology® 2011;76:1726–1734 GLOSSARY ALE ⫽ activation likelihood estimation; FDR ⫽ false discovery rate; IF ⫽ inferior frontal cortex; IFG ⫽ inferior frontal gyrus; LH ⫽ left hemisphere; pMTG ⫽ posterior middle temporal gyrus; POp ⫽ pars opercularis; POrb ⫽ pars orbitalis; PTr ⫽ pars triangularis; RH ⫽ right hemisphere; TMS ⫽ transcranial magnetic stimulation.

Supplemental data at www.neurology.org

In studies investigating transcranial magnetic stimulation (TMS) or transcranial direct current stimulation as treatments for aphasia, stimulation targets are typically selected by examining each subject individually using fMRI or TMS.1-3 These approaches create barriers to efficient treatment, and may be unnecessary if mechanisms of residual language function and recovery in aphasia are consistent across patients. Aphasic patients activate both hemispheres during language tasks in functional neuroimaging studies. Activity in the left hemisphere (LH) is thought to support residual function and recovery.4-8 The role of the right hemisphere (RH) is less clear. RH activity may support recovery if homotopic areas take over functions of lesioned LH nodes,5,9-12 even if they are computationally less efficient.8,13 Alternatively, the RH may limit recovery if its processing is dysfunctional,14 or if transcallosal projections from the RH inhibit the LH.6,15-17 It is likely that some RH areas support recovery while others interfere,2,18 and others play no causal role. From the Laboratory for Cognition and Neural Stimulation (P.E.T., S.M., R.H.H.), Department of Neurology, University of Pennsylvania Health System, Philadelphia; and Haverford College (C.N.), Haverford, PA. Study funding: Supported by the American Academy of Neurology Foundation (Clinical Research Training Fellowship to P.E.T.) and the NIH (K01NS060995 to R.H.H.). Disclosure: Author disclosures are provided at the end of the article.

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To evaluate the consistency of neuroplastic mechanisms across patients, it is important to localize stable activity across methodologically diverse studies. If aphasic patients activate new brain areas in the same experimental contexts as control subjects activate normal language nodes, this would imply a homologous role in language processing for these new areas. We used activation likelihood estimation (ALE), a validated, quantitative neuroimaging meta-analysis method,19-21 to assess mechanisms of adaptation in aphasia by comparing brain activity of patients with chronic aphasia to that of normal control subjects across a variety of experimental contexts. METHODS Identification and selection of articles. We searched PubMed, PsychINFO, and references of recent articles for fMRI or PET studies employing language tasks in patients with chronic aphasia after stroke and healthy controls. For inclusion, articles must have reported 1) results specifically in stroke-induced chronic aphasia; 2) activity for aphasic subjects and controls separately using the same tasks/analyses; 3) standard 3-dimensional coordinates. The ALE analyses only included direct task-vs-baseline contrasts with the lowest level control condition reported (e.g., verb generation vs rest, rather than verb generation vs repetition). The functional homology analysis included all available contrasts. Coordinates were converted to Montreal Neurological Institute space.22

Datasets. Twelve articles met the inclusion criteria, with 319 activation foci from 105 aphasic patients and 267 foci from 129 control subjects (e-references and table e-1 on the Neurology® Web site at www.neurology.org). A total of 16 unique tasks were used, with 22 unique analyses of these tasks. The ALE analyses included 224 task-vs-baseline foci from aphasic subjects and 197 foci from control subjects. Approximately 70 patients were nonfluent based on heterogeneous classification methods across studies. Severity of aphasia varied, but all subjects were able to participate in language-related imaging tasks. To examine the impact of lesion location on activity, we split the aphasia dataset into a group of patients with lesions involving inferior frontal cortex (IF⫹; n ⫽ 65; approximately 62 nonfluent), and a group with lesions sparing it (IF⫺; n ⫽ 40; approximately 32 fluent). Inferior frontal lesion status was extrapolated from published text, figures, and tables. Case series data were split subject-bysubject. Groups with a majority of inferior frontal lesions were included in the IF⫹ list, and groups with a minority were included in the IF⫺ list. This method assigned 90/105 patients correctly. The small proportion of misassignments should not impact results because significance required agreement across multiple studies. As an illustrative example, study 1 compared 3 patients with nonfluent aphasia due to inferior frontal strokes to 4 agematched controls using fMRI.14 Brain activity when subjects named pictures in the scanner (task) was compared to activity during visual fixation (baseline). Controls activated classic LH language areas. In contrast, aphasic subjects activated perilesional LH areas plus RH equivalents of the lesioned language areas. This activity was included in the main ALE analysis. Correla-

tions between naming activity and item variables (e.g., age at acquisition) were reported for both groups, and included in the functional homology analysis.

ALE analyses. ALE is an objective, quantitative, validated metaanalysis method that identifies brain areas at which colocalization of activity occurs across studies beyond what is predicted by chance.21 Coordinates of peak activity in published articles (“foci”) serve as the data. The uncertainty in localization of foci is modeled as Gaussian probability fields.21 The union of probabilities across studies yields voxel-wise activation likelihoods (ALE values), which indicate the level of agreement in location of activity across studies. Gaussian widths are calculated from sample sizes based on the relationship between N and localization uncertainty.19,23 We used an ALE algorithm unbiased by differences between studies in the number of foci or experiments (GingerALE2.04, BrainMap.org).23 Significance was tested as described by Eickhoff and colleagues19 against the null hypothesis that localization of activity is independent between studies, with a false discovery rate (FDR) of 0.01, and a cluster extent threshold of 100 mm3. Clusters and peaks were considered significant only if 3 or more studies activated them in task-vs-baseline analyses.24 Studies that reported a focus within 2 SD of localization uncertainty from an ALE peak were considered to have activated that location. These 2 SD kernels capture 95% of foci corresponding to each ALE peak. AAL atlas anatomic labels were assigned.25 Functional homology analysis. For each peak in the aphasia ALE maps, we identified corresponding control ALE peaks, which we hypothesized the aphasic areas would function like. For each LH aphasia peak, we chose the nearest control peak with the same anatomic label. If a differently labeled control peak was closer by Euclidean distance, we selected it also. For each RH aphasia peak, homotopic control peaks were identified by left-right reversing coordinates and following the same selection rule as above. Next, we determined which analyses activated each ALE peak location using the kernel method described above. The functional homology assessment compared an aphasic ALE peak to a corresponding control peak, determined the agreement between them in terms of the unique analyses that activated both or failed to activate both, and calculated the probability that the observed agreement occurred by chance. For each control ALE peak, we tallied a list of analyses that activated that location and a list of analyses that did not. For a corresponding aphasia ALE peak, we tallied the agreement in terms of analyses that activated the area and those that did not. The probability of equal or greater agreement between an aphasia list and a control list was calculated as the product of 2 cumulative binomial probabilities, one giving the probability of agreement among the analyses active for controls, and one giving the probability of agreement among analyses not active for controls. To confirm these calculations, we performed 5 simulations, each comparing 5 million random aphasic activation lists to a different control ALE site. The binomial probabilities matched the simulated probabilities to within 0.00025. Probabilities were converted to Z scores. Significance was determined using an FDR q of 0.05 multiple comparisons correction.

The ALE analysis of the control dataset revealed an expected network of LH cortical activation likelihoods associated with various language and motor processes (table e-2; figure 1). Corresponding to the preponderance of speech production tasks, much of the activation likelihood was in the left inferior frontal gyrus (IFG) with peaks in the pars opercularis

RESULTS Controls.

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Figure 1

Activation likelihood estimation (ALE) maps in all aphasic patients and control subjects

Control ALE clusters are in blue-green scale, and show left hemisphere language and motor activity. ALE clusters for the group of all aphasic patients are in red-yellow scale. Significant areas in ALE maps represent locations at which peak activity is highly likely to occur in functional imaging experiments, not functional activity per se. ALE maps are overlaid on the standard Colin brain in Montreal Neurological Institute (MNI) space, using a false discovery rate q ⫽ 0.01 critical threshold, and minimum cluster size of 100 mm3. Slices are in radiologic orientation, with the corresponding MNI Z coordinate.

(POp), triangularis (PTr), and orbitalis (POrb). The left posterior middle temporal gyrus (pMTG) also demonstrated significant activation likelihood. Aphasic subjects. The ALE analysis of all patients with aphasia demonstrated a bilateral distribution of activation likelihoods representing areas of consistent activity across multiple studies. This network included spared areas of the normal LH language network, LH areas outside the normal network, and RH areas that mirrored the LH network in controls (table e-2 and figure 1). Like controls, most activation likelihood was in the IFG, although bilaterally for apha1728

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sic subjects. For this reason, we focus our attention on the IFG below. Subanalyses of the IF⫹ and IF⫺ groups demonstrated that left inferior frontal lesions resulted in greater likelihood of right IFG activation (figure 2). In the LH, ALE clusters that overlapped spatially with clusters in the control map (i.e., normal language nodes spared by lesions) were also functionally homologous to them (PTr, POp, and pMTG). Among clusters that did not overlap spatially with control clusters, and hence represented recruitment of areas outside the normal language network acti-

Figure 2

Activation likelihood estimation (ALE) maps of inferior frontal cortex (IF)ⴙ and IFⴚ groups

IF⫺ ALE clusters are in blue-green scale. IF⫹ ALE clusters are in red-yellow scale. ALE maps are overlaid on the standard Colin brain in Montreal Neurological Institute (MNI) space, using a false discovery rate q ⫽ 0.01 critical threshold, and minimum cluster size of 100 mm3. Slices are in radiologic orientation, with the corresponding MNI Z coordinate.

vated by these tasks, some were functionally homologous to nearby control areas (POrb, anterior insula) and others were not (middle frontal gyrus). RH clusters in the aphasia maps were homotopic to LH control clusters to within 10 mm, except in the insula (12 mm). Different patterns of localization and homology were identified in different subregions of the right IFG. A right ventral POp cluster in the overall group (52, 20, 2) was active regardless of lesion site (3 studies in each group, nonsignificant in each group alone) and was functionally homologous to the control subjects’ left POp. The dorsal right POp and the right POrb were present in the IF⫹

map, but not the IF⫺ map, and were homotopic and homologous with their LH counterparts in the control map. A right PTr cluster in the IF⫹ map was closely homotopic with a LH control site (4.9 mm), but was not functionally homologous to it. The IF⫺ group produced only one small right anterior PTr cluster, which was homotopic to a secondary IF⫺ left PTr peak (6 mm) and coactivated in the same studies. We developed interpretative algorithms to infer putative recruitment mechanisms for areas identified in the aphasia ALE maps (figure 3). Based on these algorithms, different compensatory mechanisms acNeurology 76

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Figure 3

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Algorithms used for interpretation and schematics of main results

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counted for different areas consistently recruited by aphasic subjects. The summary schematics in figure 3 illustrate the main results. DISCUSSION We quantitatively compared the brain activity of aphasic patients to that of controls across a variety of language-related tasks. This method allowed us to infer neuroplastic mechanisms in aphasia recovery, but not to identify specific language processes performed by particular areas. As such, we focus our discussion on general mechanisms of recovery rather than specific language functions. The first main finding is that the network of brain regions recruited by chronic aphasic subjects is consistent across methodologically diverse imaging studies. This network is composed of spared areas of the normal LH language network, new LH nodes, and RH nodes that are homotopic to normal LH nodes. This consistency supports the notion that therapeutic brain stimulation targets might be selected based on group-level evidence. Still, patient-specific factors must result in differential recruitment from individual to individual. We were able to show that the recruitment pattern systematically varies based on lesion location, but further investigation is needed to identify other important patient-specific factors. Second, the response properties of different areas activated by aphasic patients suggested different compensatory mechanisms. Regional differences in connectivity, inhibitory connections between nodes,26 and differences in the degree of lateralization between processes27,28 provide a basis for differences in mechanisms of recovery depending on which part of the network is disrupted. In the LH, we identified consistent activity among aphasic subjects in both anterior and posterior language regions that overlapped spatially with those of controls, representing activity of patients whose lesions spared these sites. Although distant lesions can cause network disruption that alters activity in spared nodes,29,30 the spared sites identified here retained their normal role based on our homology measure. Consistent aphasic activity was also identified in LH areas outside the normal network identified in control subjects. The aphasic POrb and anterior insula sites, which did not overlap spatially with control clusters,

likely represent cortical sites in which activity was augmented to compensate for lesioned nodes. The anterior insula was recruited by patients with left inferior frontal lesions and was activated under the same experimental conditions as the normal POrb. This pattern implies that the anterior insula assumed functions of the POrb when it was lesioned. Note that the right POrb was also homologous to the normal left POrb in IF⫹ patients, suggesting that 2 alternate nodes were needed to compensate for the lost left POrb, possibly due to computational inefficiency of the alternate nodes. In contrast, activity in the left POrb site recruited by aphasic subjects, which was anatomically distinct from the control POrb site, only occurred in the patients without inferior frontal lesions, in whom it functioned like the normal control POrb site. Thus, lesions sparing the IFG entirely resulted in a shift of activity from the typically active part of POrb to an alternate site capable of serving the same role in language processing. This might occur due to deafferentation of the preferred POrb node by distant lesions or due to a subtle change in computational demands as new strategies for language processing are adopted by aphasic patients. Aphasic clusters that did not share functional homology with control areas, like the left dorsolateral prefrontal (middle frontal gyrus) cluster, may reflect an increased reliance on supporting cognitive functions, like executive control of working memory, that are not heavily taxed during simple language tasks in normal control subjects.31 The meta-analytic findings in the RH demonstrate that across a variety of experimental conditions and patient characteristics, RH areas recruited by aphasic subjects are mirror images of LH areas recruited by normal healthy subjects for the same tasks. Although some studies report RH language activity in controls32,33 that may play a causal role in some language processes,34 none was consistent in controls across the studies examined here. Thus, the RH activity found here for aphasic subjects cannot be explained on the basis of normal recruitment of the RH. In general, the right IFG was more reliably recruited when the left inferior frontal cortex was lesioned, but this differed between subregions of the IFG. Two different areas of the right PTr were recruited dependent on lesion location, and the function in both was unlike that

Careful consideration of the response properties of areas identified in the aphasia activation likelihood estimation (ALE) analyses suggested reasonable hypotheses regarding the specific adaptive mechanisms to account for the activity. We interpreted the areas identified in the aphasia ALE maps algorithmically based on localization of activity relative to normal control activity, functional homology to corresponding normal control sites, and relationship of activity to lesion location. (A) The algorithm used for left hemisphere (LH) areas. (B) The algorithm used for right hemisphere (RH) areas. (C) Schematics of the main results. Since the right pre/postcentral gyrus activity occurred only in the inferior frontal cortex (IF)⫹ group, we assumed that the left pre/postcentral gyri were lesioned with the left inferior frontal gyrus (IFG) in most cases (this appeared to be true based on available figures in the papers). If this assumption were false, the correct interpretation would be g. *See Discussion for caveats. MTG ⫽ middle temporal gyrus; POp ⫽ pars opercularis; POrb ⫽ pars orbitalis; PTr ⫽ pars triangularis; MFG ⫽ middle frontal gyrus. Neurology 76

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of the normal left PTr. In contrast, the right dorsal POp was recruited specifically by patients with inferior frontal lesions, and functioned like the normal left POp, implying a possible compensatory takeover of the function of the lesioned node. Overall, these findings suggest that different mechanisms likely account for functional activity in different parts of the RH aphasic language network. The functional role of the right posterior IFG (including POp) in aphasia recovery was initially suggested by Barlow,35 who reported the case of a boy who developed aphasia after a LH stroke, recovered language function, and then had a recurrence of aphasia after a second small stroke to the right posterior IFG. Evidence that inhibitory TMS to the right POp disrupts naming in chronic nonfluent aphasic subjects supports the functional role of the right POp in aphasia recovery.2,18 Dorsal stream phonologic processes, in which the POp are involved,36,37 may be relatively less lateralized compared to word level semantic processes.27,28 Evidence suggests that the right POp plays a causal role in phonologic processing even in normal subjects.34 It may then be well suited to sustain recovery of phonologic language functions when the function of the left POp is impaired. In contrast, inhibition of the right PTr with TMS enhances naming and propositional speech performance in some chronic nonfluent aphasic subjects,2,6,16-18 suggesting the right PTr impairs some language functions in these patients. The lack of a relationship between the function of the right PTr and that of the left in our analysis suggests that the right PTr is truly dysfunctional with respect to language processing14 or that it plays a role in a completely different cognitive process than the left PTr. For example, if injury to the left PTr causes increased activation of the right PTr through a release of interhemispheric inhibition,8,38 the overactive right PTr may impede language production through an exaggeration of its normal role in response inhibition.39 The current analysis is not able to discern the specific role of the right PTr, but confirms that its function is fundamentally different from that of the left in aphasic patients and warrants further investigation. The functional homology analysis allowed us to infer reasonable hypotheses regarding why aphasic patients activated specific areas based on whether they were involved in similar functions to normal language areas. Still, the simple presence of activity for a given task does not necessarily imply normal computational efficiency, so homologous areas discussed above may not function exactly like normal language areas in healthy subjects, even if their basic role in language processing is similar. The interpretation of activity becomes simpler (although not un1732

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ambiguous) if only correct responses are considered, but only one study here did so, resulting in typical bilateral activation patterns in the task-vs-baseline comparison.40 Another study directly compared correct and incorrect responses, finding that most right IFG activity occurred during incorrect trials.14 Other causes of aphasia might result in different adaptive mechanisms, so conclusions here are limited to stroke-induced aphasia. Since neural adaptation in aphasia changes over time,5 these findings also cannot be extrapolated to acute or subacute aphasia. We elected to include any aphasia type or language task, but due to the few studies available we were unable to determine whether activation patterns and adaptive mechanisms vary based on these factors, which they almost certainly do. Some studies were excluded due to restrictions of the ALE method (e.g., standardized coordinates were not reported). We also excluded unpublished data because readers would have no way to verify that these experiments were valid. Including these studies could have reduced the homogeneity between studies and changed our results. The goal of this analysis was to gain a broad perspective on residual and recovered language functions in aphasia by considering the anatomic and functional relationships between brain activity of aphasic subjects and controls across a variety of experimental conditions. Collectively, the results suggest a pattern of adaptation after lesions to LH language networks that involves retention of function where possible, anatomic shifts in LH processors when needed, and regionally specific variation in the mechanisms of RH recruitment that depends on lesion location. Localization and recruitment patterns are consistent across studies, providing support for targeting brain stimulation across populations of aphasic patients who share similar attributes, like lesion location. Further research will be needed to confirm the efficacy of this strategy, and to define the relevant patient-specific factors that impact target selection. AUTHOR CONTRIBUTIONS Dr. Turkeltaub contributed to the study conception and design, statistical analysis and interpretation, and drafting the manuscript. S. Messing contributed to the study conception and design and acquisition of data. C. Norise contributed to the analysis and interpretation and acquisition of data. Dr. Hamilton contributed to the study conception and design and study supervision and coordination.

DISCLOSURE Dr. Turkeltaub is funded by the American Academy of Neurology Foundation (Clinical Research Training Fellowship) and the International Dyslexia Association (General Grant 2009). S. Messing owns stock in MEDITECH, Inc. C. Norise reports no disclosures. Dr. Hamilton receives research support from the NIH/NINDS and the Robert Wood Johnson Foundation/Harold Amos Medical Faculty Development Program.

Received November 2, 2010. Accepted in final form February 10, 2011.

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Historical Abstract: July 1, 1987 TREATMENT OF MULTIPLE SCLEROSIS WITH GAMMA INTERFERON: EXACERBATIONS ASSOCIATED WITH ACTIVATION OF THE IMMUNE SYSTEM Hillel S. Panitch, Robert L. Hirsch, John Schindler, Kenneth P. Johnson Neurology 1987;37;1097–1102 We treated 18 clinically definite relapsing-remitting MS patients with recombinant gamma interferon in a pilot study designed to evaluate toxicity and dosage. Patients received low (1 ␮g), intermediate (30 ␮g), or high (1,000 ␮g) doses of interferon by intravenous infusion twice a week for 4 weeks. Serum levels of gamma interferon were proportional to dose and no interferon was detected in CSF. Seven of the 18 patients had exacerbations during treatment, a significant increase compared with the prestudy exacerbation rate (p ⬍ 0.01). Exacerbations occurred in all three dosage groups and were not precipitated by fever or other dose-dependent side effects. There were significant increases in circulating monocytes bearing class II (HLA-DR) surface antigen, in the proliferative responses of peripheral blood leukocytes, and in natural killer cell activity. These results show that systemic administration of gamma interferon has pronounced effects on cellular immunity in MS and on disease activity within the CNS, suggesting that the attacks induced during treatment were immunologically mediated. Gamma interferon is unsuitable for use as a therapeutic agent in MS. Agents that specifically inhibit gamma interferon production or counteract its effects on immune cells should be investigated as candidates for experimental therapy. Free Access to this article at www.neurology.org/content/37/7/1097 Comment from Richard M. Ransohoff, MD, Associate Editor: A very important and startling clinical trial failure, considered counterintuitive at the time, but which later illuminated MS pathogenesis.

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Outcomes and prognostic factors of intracranial unruptured vertebrobasilar artery dissection B.M. Kim, MD S.H. Kim, MD D.I. Kim, MD Y.S. Shin, MD S.H. Suh, MD D.J. Kim, MD S.I. Park, MD K.Y. Park, MD S.S. Ahn, MD

Address correspondence and reprint requests to Dr. Byung Moon Kim, Department of Radiology, Yonsei University College of Medicine Severance Hospital, 250 Seongsanno, 120752, Seoul, Republic of Korea [email protected]

ABSTRACT

Objective: We aimed to evaluate the long-term clinical outcomes and prognostic factors of symptomatic intracranial unruptured vertebrobasilar artery dissection (siu-VBD). Methods: A total of 191 patients (M:F ⫽ 127:64; median age, 46 years) with siu-VBD were treated between January 2001 and December 2008. Presentations, treatments, outcomes, and prognostic factors were retrospectively analyzed. Results: Clinical manifestations were ischemic symptoms with headache (n ⫽ 97) or without headache (n ⫽ 13) and headache without ischemic symptoms (n ⫽ 81). Forty-six patients (24.1%) underwent endovascular treatment. The remaining 145 patients (75.9%) were medically treated with anticoagulants (n ⫽ 49), antiplatelets (n ⫽ 48), or analgesics alone (n ⫽ 48). Clinical follow-up data were available in 178 patients (102 ischemic and 76 nonischemic) at 15 to 102 months (mean, 46 months). None of the siu-VBD hemorrhaged. All 76 patients without ischemic presentation had favorable outcomes (modified Rankin Scale, 0–1). Of the 102 patients with ischemic presentation, outcomes were favorable in 92 and unfavorable in 10 patients. Four patients died; 3 died of causes unrelated to VBD, and one died as a result of basilar artery (BA) dissection. Old age (odds ratio [OR] 1.099; 95% confidence interval [CI] 1.103–1.204; p ⫽ 0.042) and BA involvement (OR 11.886; 95% CI 1.416–99.794; p ⫽ 0.023) were independent predictors of unfavorable outcomes in siu-VBD with ischemic presentation.

Conclusions: Clinical outcomes for siu-VBD were favorable in all patients without ischemic symptoms and in most patients with ischemic presentation. None of the siu-VBD caused subarachnoid hemorrhage. Old age and BA involvement were independent predictors of unfavorable outcome in siu-VBD with ischemic presentation. Neurology® 2011;76:1735–1741 GLOSSARY BA ⫽ basilar artery; CI ⫽ confidence interval; MR ⫽ magnetic resonance; mRS ⫽ modified Rankin Scale; NIHSS ⫽ National Institutes of Health Stroke Scale; OR ⫽ odds ratio; PICA ⫽ posterior inferior cerebellar artery; SAH ⫽ subarachnoid hemorrhage; siu-VBD ⫽ symptomatic intracranial unruptured vertebrobasilar artery dissection; VA ⫽ vertebral artery; VBD ⫽ vertebrobasilar dissection.

Intracranial artery dissection may present as a ruptured form, causing subarachnoid hemorrhage (SAH), or as an unruptured form associated with ischemia or local symptoms.1,2 In East Asian populations, intracranial vertebrobasilar dissection (VBD) is as common as cervical artery dissection.3,4 The clinical courses of cervical artery dissection and ruptured intracranial VBD have been relatively well elucidated.2,3,5-8 In contrast, the clinical course and prognostic factors of symptomatic intracranial unruptured VBD (siu-VBD) are not well known, and its proper management is controversial. Only a few small case studies have examined the clinical course and outcomes of siu-VBD.9-12 The aim of this study is to investigate presenting clinical and angiographic findings, outcomes, and prognostic factors in a large sample of patients with siu-VBD. From the Department of Radiology (B.M.K., D.I.K., D.J.K., S.I.P., K.Y.P., S.S.A.), Yonsei University College of Medicine, Severance Hospital, Seoul; Department of Neurosurgery (S.H.K.), Ajou University Hospital, Suwon; Department of Neurosurgery (Y.S.S.), Catholic University College of Medicine, St. Mary’s Hospital, Seoul; and Department of Radiology (S.H.S.), Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Republic of Korea. Study funding: Supported by a grant (No. A085136) of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea. Disclosure: Author disclosures are provided at the end of the article. Copyright © 2011 by AAN Enterprises, Inc.

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METHODS Standard protocol approvals, registrations, and patient consents. The institutional review boards of all participating hospitals approved this retrospective study and waived the need for informed consent.

Patients. All patients underwent MRI including DWI, and one or more vascular imaging studies including digital subtraction angiography (n ⫽ 175), magnetic resonance (MR) angiography (n ⫽ 151), and CT angiography (n ⫽ 84). Nonexistence of SAH was confirmed by unenhanced CT, lumbar tap, or both. Inclusion criteria were 1) intramural hematoma on fat-suppression T1-weighted MR or MR angiogram source images, 2) intimal flap, 3) double lumen sign, 4) string sign (smoothly tapered steno-occlusive lesion) or pearl-and-string sign, without any atherosclerotic change of the involved artery, 5) aneurysmal dilatation of the arterial trunk not located at an arterial branching point, but associated with sudden onset of severe pulsatile posterior headache or posterior ischemic symptoms, or 6) a combination of the above in vascular imaging studies. Exclusion criteria were 1) ruptured VBD associated with SAH, 2) extracranial VA dissection extending to intradural V4 portion, 3) incidentally found asymptomatic fusiform dilatations of the vertebrobasilar arteries, 4) traumatic VBD, or 5) laboratory or radiographic findings of angiitis, vasculopathy, or fibromuscular dysplasia. A total of 191 patients with siu-VBD were identified from 4 tertiary referral hospitals between January 2001 and December 2008. The case selection process is illustrated in figure 1. The patients consisted of 127 men and 64 women, with ages ranging from 21 to 78 years (median ⫾ SD, 46 ⫾ 11 years).

Radiologic evaluation. The siu-VBDs were classified according to morphologic lesion type as either steno-occlusive type or aneurysmal dilatation. Steno-occlusive type was diagnosed when vascular imaging revealed smoothly tapered stenosis ⱖ50% or occlusion, regardless of the presence of aneurysmal dilatation in the affected segment. Aneurysmal dilatation was diagnosed when

Figure 1

Flow chart of the patient selection process

vascular imaging showed fusiform or irregular dilatation of the vertebrobasilar arterial trunk without stenosis ⱖ50% in the affected segment. If a patient had bilateral vertebral artery (VA) dissection, the patient was allocated according to the shape of the symptomatic dissection. We also evaluated whether the dissected segment involved the basilar artery (BA), the origin of the posterior inferior cerebellar artery (PICA), or both.

Treatment strategy. In the early period, the majority of the siu-VBD patients with a dissecting aneurysm underwent endovascular treatment for fear that the dissecting aneurysm would rupture. In the later period, however, as clinicians gained experience with siu-VBD, most patients were medically treated and sent for vascular imaging follow-up, generally after 1 to 6 months. Endovascular treatment was performed only when the patient had a recurrence or progression of ischemic symptom or an enlarged dissecting aneurysm on follow-up vascular imaging. Patients with ischemic symptoms received anticoagulation or antiplatelet medication for 1 to 6 months. Patients without ischemic symptoms received analgesics with or without antiplatelet medication at their physicians’ discretion based on the patients’ medical condition and lesion type (aneurysmal dilatation or steno-occlusive). When the patients received endovascular treatment, one of 2 types of endovascular treatment, deconstructive or reconstructive, was given. Deconstructive treatments sacrifice the parent artery, and include proximal occlusion or internal coil trapping of the parent artery. Reconstructive treatments preserve the parent artery patency using one to 3 overlapping stents, with or without coiling. The treatment type was determined on a caseby-case basis at each interventional neuroradiologist’s discretion according to the presenting symptoms, hemodynamic status, lesion type, and anatomic factors of the vertebrobasilar artery. In the early period of the study, a balloon-expandable coronary stent was used for reconstructive treatment. Self-expanding neurovascular stents (Neuroform, Boston Scientifics, or Enterprise, Codman) have been preferably used since their introduction. Patients with stenting have received dual antiplatelet premedication (100 –325 mg of aspirin and 75 mg of clopidogrel) for at least 3 days before treatment except in cases of emergency treatment. Patient who underwent emergency stenting without antiplatelet premedication received a loading dose of dual antiplatelet medication (100 –325 mg of aspirin and 300 mg of clopidogrel) just before or after the procedure. Dual antiplatelet medication was maintained for 12 to 24 weeks and then was changed to aspirin monotherapy indefinitely. Clinical follow-up. Each patient’s functional status was evaluated using the modified Rankin Scale (mRS) score through neurologic examination or a structured telephone interview. Functional status at the most recent clinical follow-up or a structured telephone interview at the time of the study was considered as the final outcome. If the patient’s functional status worsened because of an event definitely unrelated to the siu-VBD, the patient’s clinical outcome at the follow-up just before the deteriorating event was considered as the final outcome.

siu-VBD ⫽ symptomatic intracranial unruptured vertebrobasilar artery dissection. 1736

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Statistical analysis. Statistical analysis was performed using SPSS for Windows (version 13.0; SPSS, Chicago, IL). To compare clinical outcomes, we divided the patients into 2 groups: those with favorable outcomes (mRS, 0 –1) and those with unfavorable outcomes (mRS, 2–5 or death). The ␹2 test or Fisher exact test was performed for categorical variables as appropriate. An unpaired t test or the Mann-Whitney U test was used for continuous variables as appropriate. The following variables

were analyzed: age, sex, presenting symptoms (ischemic vs nonischemic), National Institute of Health Stroke Scale (NIHSS) score, diabetes mellitus, history of hypertension, current smoking, history of cerebrovascular accidents, bilateral VA involvement, lesion type (aneurysmal dilatation or steno-occlusive), BA involvement, involvement of the PICA origin, and type of treatment (intervention, anticoagulants, antiplatelets, or analgesics alone). Univariate analysis was performed to determine the association of clinical outcomes with other factors. Logistic regression analysis with a forward stepwise method was then performed to determine the independent association of clinical outcomes with other factors. The univariate analysis cutoff for

Table 1

Clinical and radiographic characteristics of patients with unruptured VBD

Variables

Ischemic (n ⴝ 110)

Nonischemic (n ⴝ 81)

p

Total (n ⴝ 191)

Age, y, mean ⴞ SD

48 ⫾ 12

49 ⫾ 10

0.309a

49 ⫾ 11

Male

75 (59.1)

52 (40.9)

Female

35 (54.7)

29 (45.3)

Sex, n (%)

0.564

Diabetes, n (%)

127 (66.5) 64 (33.5) 0.479

Yes

13 (65.0)

7 (35.0)

20 (10.5)

No

97 (56.7)

74 (43.3)

171 (89.5)

Yes

27 (55.1)

22 (44.9)

No

83 (58.5)

59 (41.5)

Hypertension, n (%)

0.683

Smoking, n (%)

49 (25.7) 142 (74.3) 0.123

Yes

31 (67.4)

15 (32.6)

46 (24.1)

No

79 (54.5)

66 (45.5)

145 (75.9)

Yes

8 (61.5)

5 (38.5)

No

102 (57.3)

76 (42.7)

Old CVA, n (%)

0.765

Angiographic shape, n (%)

13 (6.8) 178 (93.2) 0.000

Steno-occlusive

52 (77.6)

15 (22.4)

67 (35.1)

Aneurysmal

58 (46.8)

66 (53.2)

124 (64.9)

Yes

10 (66.7)

5 (33.3)

No

100 (56.8)

76 (43.2)

Bilateral involvement, n (%)

0.459

BA involvement, n (%)

15 (7.9) 176 (91.1) 0.003

Yes

17 (89.5)

2 (10.5)

19 (9.9)

No

93 (54.1)

79 (45.9)

172 (90.1)

Yes

26 (51.0)

25 (49.0)

No

84 (60.0)

56 (40.0)

PICA involvement, n (%)

0.264

Treatment, n (%)

51 (26.7) 140 (63.3) 0.000

Intervention

20 (43.5)

26 (56.5)

46 (24.1)

Anticoagulation

49 (100)

0

49 (25.7)

Antiplatelet

41 (85.4)

7 (14.6)

48 (25.1)

Analgesics only

0

48 (100)

48 (25.1)

Abbreviations: BA ⫽ basilar artery; CVA ⫽ cerebrovascular accident; PICA ⫽ posterior inferior cerebellar artery; VBD ⫽ vertebrobasilar dissection. a Mann-Whitney U test.

inclusion in the logistic regression analysis was p ⬍ 0.20. The statistical significance was determined as p ⬍ 0.05 for a 95% CI. RESULTS Clinical and radiologic manifestations. In-

tracranial artery dissections have the clear preponderance over extracranial artery dissections (figure 1). Clinical and radiographic characteristics of sui-VBD with ischemic or nonischemic presentation are summarized in table 1. Clinical manifestations were ischemic symptoms associated with prodromal or coincidental posterior headache in 97 patients (50.8%), ischemic symptom without posterior headache in 13 patients (6.8%), and sudden onset of posterior headache without ischemic symptom in 81 patients (42.4%). One patient had a fusiform dilatation of anterior cerebral artery A2 trunk in addition to bilateral sui-VAD. Three patients had coexisting fusiform dilatations of cervical vertebral arteries (C2 portion) apart from sui-VBD, but no patient had coexisting cervical carotid artery dissection. Treatment and imaging follow-up results. Character-

istics of sui-VBD with endovascular or medical treatment are compared in table 2. Forty-six patients underwent endovascular treatment, 8 of whom were initially treated medically, but subsequently received intervention due to enlargement of the dissecting aneurysm (n ⫽ 5) or progressive ischemia (n ⫽ 3). Of the 46 patients, 25 were treated with single or multiple overlapping stents, 15 with internal coil trapping or proximal occlusion of the parent artery, and 6 with stent-assisted coiling. The remaining 145 patients were medically treated with anticoagulants (n ⫽ 49), antiplatelets (n ⫽ 48), or analgesics alone (n ⫽ 48). Four patients, among whom 2 were receiving anticoagulation and the other 2 were receiving antiplatelet medication, had recurrent ischemic symptoms within 6 months after initial presentation. Three patients had recurrent symptoms once and the other 3 times. Thereafter, there was no recurrent symptom recorded during the follow-up. Treatmentrelated complications occurred in 3 patients. One patient had a procedural rupture of the dissection during an attempt at stent insertion. It was promptly controlled by internal coil trapping, but the patient had a poor outcome (mRS 5). The remaining 2 patients had ischemic complications after proximal occlusion or internal coil trapping of the parent artery. Both patients had ipsilateral lateral medullar infarction but recovered completely (mRS 0 for both). In patients treated with anticoagulants or antiplatelet medications, treatment-related complications were not recorded during the clinical follow-up. Of the 153 patients who were initially treated medically, 3 patients (2 basilar artery dissections and one vertebral artery dissection) received stenting Neurology 76

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Table 2

Comparison of characteristics between intervention and medical treatment

Variables

Intervention (n ⴝ 46)

Medical (n ⴝ 145)

p

Age, y, mean ⴞ SD

49 ⫾ 12

49 ⫾ 11

0.737a

M (n ⴝ 127)

32 (25.2)

95 (74.8)

F (n ⴝ 64)

14 (21.9)

50 (78.1)

Sex, n (%)

0.612

Diabetes, n (%)

0.652

Yes (n ⴝ 20)

4 (20.0)

16 (80.0)

No (n ⴝ 171)

42 (24.6)

129 (75.4)

Yes (n ⴝ 49)

12 (24.5)

37 (75.5)

No (n ⴝ 142)

34 (23.9)

108 (76.1)

Hypertension, n (%)

0.939

Smoking, n (%)

0.715

Yes (n ⴝ 46)

12 (26.1)

34 (73.9)

No (n ⴝ 145)

34 (23.4)

111 (76.6)

Yes (n ⴝ 13)

2 (15.4)

11 (84.6)

No (n ⴝ 178)

44 (24.7)

134 (75.3)

Old CVA, n (%)

0.447

Angiographic shape, n (%)

0.030

Steno-occlusive (n ⴝ 67)

10 (14.9)

57 (85.1)

Aneurysmal (n ⴝ 124)

36 (29.0)

88 (71.0)

Yes (n ⴝ 15)

4 (26.7)

11 (73.3)

No (n ⴝ 176)

43 (24.4)

133 (75.6)

Bilateral involvement, n (%)

0.847

BA involvement, n (%)

0.807

Yes (n ⴝ 15)

4 (26.7)

11 (73.3)

No (n ⴝ 176)

42 (23.9)

134 (76.1)

Yes (n ⴝ 51)

21 (41.2)

30 (58.8)

No (n ⴝ 140)

25 (17.9)

115 (82.1)

PICA involvement, n (%)

0.001

Abbreviations: BA ⫽ basilar artery; CVA ⫽ cerebrovascular accident; PICA ⫽ posterior inferior cerebellar artery. a Mann-Whitney U test.

within 3 days for progressive ischemia. In 123 of the remaining 150 patients, follow-up vascular imaging was available at least once, 1– 48 months after initial event. Of the 123 sui-VBD, 83 were aneurysmal dilatation, 35 were tapered stenosis, and 5 were tapered occlusion. Of the 83 aneurysmal sui-VBD, 8 showed spontaneous healing with normal luminal caliber (figure 2), 70 showed no interval change in size and shape, but 5 revealed a progressively enlarged dissecting aneurysm. Of the 5 patients with enlarged dissecting aneurysms, 4 were asymptomatic, but one had brainstem compression symptoms due to the markedly enlarged dissecting basilar artery aneurysm, 3 years after the initial presentation as a small basilar trunk aneurysm with a pontine infarct.13 All the 5 progressively enlarged dissecting aneurysms were en1738

dovascularly treated, as mentioned above. Of the 35 sui-VBDs with tapered stenosis, 30 restored their normal luminal diameter, 4 improved but were still stenotic, and one showed occlusion. Of the 5 suiVBD with tapered occlusions, 4 were recanalized but one showed persistent occlusion.

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Clinical outcomes and prognostic factors. Clinical follow-up data were available in 178 patients (102 patients with ischemia and 76 patients without ischemia) for a mean of 46 months (range 15–102 months) by means of neurologic examination (n ⫽ 150) or a structured telephone interview (n ⫽ 28). Thirteen patients were lost to follow-up. None of the patients with siu-VBD hemorrhaged during the follow-up period. All 76 patients without ischemic symptoms had favorable outcomes (mRS 0 –1). In the 102 patients with ischemic symptoms, clinical outcomes were favorable in 92 patients (90.2%) and unfavorable (mRS 2–5 or death) in 10 (9.8%). There was no significant difference in the duration of follow-up period between favorable and unfavorable groups (table 3). Four patients died; 3 deaths were due to causes unrelated to the siu-VBD (acute myocardial infarct, n ⫽ 1; malignant brain tumor, n ⫽ 1; and chronic renal failure, n ⫽ 1). Only one patient with a BA dissection died due to the progression of a posterior circulation infarction. Therefore, the overall mortality was 2.2% (4/178), but the causespecific mortality was 0.6% (1/178). Old age and BA involvement were the independent predictors of unfavorable outcome in the logistic regression analysis (table 3). DISCUSSION Intracranial artery dissection has the clear preponderance over extracranial dissection (figure 1). In the recent Japanese multicenter registration study, while extracranial internal carotid and vertebral artery dissections occupied only 7% (n ⫽ 35) of spontaneous cervicocephalic arterial dissections (n ⫽ 454), intracranial vertebrobasilar artery dissection formed 68% (n ⫽ 310).6 Also, in the Chinese single-center study, extracranial artery dissection was 32.9% (n ⫽ 24) and intracranial artery dissection was 67.1% (n ⫽ 49) of 73 spontaneous cervicocerebral arterial dissections.14 Based on the literature and our results, there may be a racial difference in the location of cervicocerebral arterial dissection between East Asian and Caucasian populations. Posterior circulation ischemic symptoms with prodromal or coincidental posterior headache were typical presenting events of siu-VBD. However, posterior headache was the most frequent presenting symptom, associated in 93.2% of the patients. This is concordant with the results of case studies of the patients with unruptured VAD.9,11 Ischemic presen-

Figure 2

Spontaneous resolution of a dissecting aneurysm in a 44-year-old man with ischemic presentation

(A) A recent infarction in the left posterolateral medulla (black arrow). (B) Magnetic resonance angiography shows a fusiform dilatation (white arrow) of left intracranial vertebral artery. (C) A 3-dimensional reconstruction image of left vertebral angiogram shows a fusiform dilatation of left vertebral artery. (D) The 3-month follow-up magnetic resonance angiogram reveals normalized left vertebral artery.

tations unfavorably affected the clinical outcomes. Bilateral VA dissection did not affect the clinical course. This is discordant with the previous report that bilateral involvement was a poor prognostic factor.10 Aneurysmal dilatation was more frequent than steno-occlusive type in the angiographic evaluation of the siu-VBD. This finding differs from those associated with extracranial vertebral artery dissection, in which the steno-occlusive type was predominant.4,8 One possible explanation for such difference in lesion type is the absence of external elastic lamina and the decreased amount of medial elastic tissue in the intradural artery.15,16 Because the elastic tissue is responsible for the integrity of the arterial wall, such histologic differences in the intracranial artery may affect the lesion morphology of VBD. There is currently no consensus on the proper management strategy for acute siu-VBD. It is of particular note that regardless of the lesion type (aneurysmal dilatation or steno-occlusive) or treatment method, none of the acute siu-VBD caused SAH during long-term

follow-up. One possible explanation is that the preventive endovascular treatments may have prevented rupture because they were performed in the patients with siu-VBD whose angiographic results showed increased risk of rupture or an enlarging dissecting aneurysm. An alternative explanation is that this is simply the nature of unruptured VBD. Although literature reports on several cases of siu-VBD that subsequently caused SAH,12,17-19 it seems to occur only rarely. Therefore, given the risk of procedure-related complications, definitive endovascular treatment should be saved for the cases with progressive ischemia or recurrent ischemic symptoms despite medication,13,20 or for those with an enlarged dissecting aneurysm on follow-up vascular imaging.9,21 All patients without ischemic presentation had favorable outcomes. In contrast, 9.8% of patients with ischemic symptoms had unfavorable outcomes. These observations suggest that treatment in the acute phase should be focused more on preventing progression or recurrence of ischemic stroke than on Neurology 76

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Table 3

Predictors of clinical outcome in acute intracranial unruptured vertebrobasilar dissection presenting with ischemic symptoms

Variables

Unfavorablea (n ⴝ 10)

Favorablea (n ⴝ 92)

puni

pregression (OR, 95% CI)

Age, y, mean ⴞ SD

58 ⫾ 16

46 ⫾ 10

0.024b

0.042 (1.099, 1.103–1.204)

Follow-up period, mo

47.8

45.8

0.542b

M (n ⴝ 70)

8 (11.4)

62 (88.6)

F (n ⴝ 32)

2 (6.2)

30 (93.8)

Yes (n ⴝ 11)

3 (27.3)

8 (72.7)

No (n ⴝ 91)

7 (7.7)

84 (92.3)

Sex, n (%)

0.414

Diabetes, n (%)

0.039

Hypertension, n (%)

0.110

Yes (n ⴝ 21)

4 (19.0)

17 (81.0)

No (n ⴝ 81)

6 (7.4)

75 (92.6)

Yes (n ⴝ 30)

4 (13.3)

26 (86.7)

No (n ⴝ 72)

6 (8.3)

66 (91.7)

Smoking, n (%)

0.439

Old CVA, n (%)

0.190

Yes (n ⴝ 9)

2 (22.2)

7 (77.8)

No (n ⴝ 93)

8 (8.6)

85 (91.4)

3.4 ⫾ 1.1

2.1 ⫾ 1.2

Baseline NIHSS, mean ⴞ SD Angiographic shape, n (%)

0.001b 0.096

Aneurysmal (n ⴝ 56)

3 (5.4)

53 (94.6)

Steno-occlusive (n ⴝ 46)

7 (15.1)

39 (84.9)

Bilateral involvement, n (%)

0.254

Yes (n ⴝ 10)

2 (20.0)

8 (80.0)

No (n ⴝ 92)

8 (8.7)

84 (91.3)

Yes (n ⴝ 16)

7 (43.8)

9 (56.2)

No (n ⴝ 86)

3 (3.5)

83 (96.5)

BA involvement, n (%)

0.000

PICA involvement, n (%)

0.023 (11.886, 1.416–99.794)

0.288

Yes (n ⴝ 24)

1 (4.2)

23 (95.8)

No (n ⴝ 78)

9 (11.5)

69 (88.5)

Treatment, n (%)

, 0.221

Intervention (n ⴝ 17)

1 (5.9)

16 (94.1)

Anticoagulation (n ⴝ 45)

7 (15.6)

38 (84.4)

Antiplatelet (n ⴝ 40)

2 (5.0)

48 (95.0)

Tx complications, n (%)

0.164

Yes (n ⴝ 3)

1 (33.3)

2 (66.7)

No (n ⴝ 99)

9 (9.1)

90 (90.9)

Yes (n ⴝ 4)

2 (50.0 )

2 (50.0)

No (n ⴝ 98)

8 (8.2)

90 (91.8)

Recurrence, n (%)

0.006

Abbreviations: BA ⫽ basilar artery; CI ⫽ confidence interval; CVA ⫽ cerebrovascular accident; NIHSS ⫽ NIH Stroke Scale; OR ⫽ odds ratio; PICA ⫽ posterior inferior cerebellar artery; Tx complications ⫽ treatment-related complications; VBD ⫽ vertebrobasilar dissection. a Favorable, modified Rankin Scale score, 0–1; Unfavorable, modified Rankin Scale score, 2–5 or death. b Mann-Whitney U test. 1740

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preventing SAH, especially in patients with ischemic presentations. Until now, there has been no consensus on which treatment of anticoagulation and antiplatelet therapy is better for intracranial arterial dissection. Furthermore, unlike cervical artery dissection, it is more difficult to balance safety with the prevention of recurrent infarct because of a small, but existing risk of rupture in siu-VBD. In this study, anticoagulation and antiplatelet therapies were used in similar proportions. There were no complications associated with antiplatelet or anticoagulation therapy. In addition, there were no statistical differences between incidences of recurrence with anticoagulation (4.4%) and that with antiplatelet medication (5%). BA involvement and old age were independent predictors of unfavorable outcome. The initial severity of ischemic symptoms (higher baseline NIHSS score), bilateral VA involvement of the dissection, and intracranial VA involvement have been suggested as predictors of unfavorable outcomes in unruptured VA dissections.2,10 However, the majority of the cases in those studies consisted of extracranial VA dissection. In siu-VBD, it appears to be of critical importance to the clinical outcome whether the dissection affected the BA. This corresponds well with previously published literature.22-25 Because of its retrospective nature, this study has several limitations. First, because cases were collected from 4 hospitals over a long time period, the treatment methods were diverse, were determined at the physicians’ discretion, and changed over the period of case registration. Nevertheless, the goal of this study was not to compare treatment methods but to assess the outcomes and prognostic factors of the unruptured VBD patients regardless of the types of treatment. A second limitation is that either face-toface assessment or a structured telephone interview was used to determine final outcomes. However, it was reported that structured telephone interviews have good agreement with face-to-face assessments.26 Finally, because endovascular treatments were given to the patient who had progressive ischemic symptoms or large or growing dissecting aneurysms, the results have not entirely reflected the natural course of the siu-VBD, but were partly affected by such interventions. Although these limitations exist, the results of this study may offer some important information for the management and further study of siu-VBD. AUTHOR CONTRIBUTIONS Dr. B.M. Kim contributed drafting/revising the manuscript for content, study concept, analysis of data, acquisition of data, and statistical analysis. Dr. S.H. Kim contributed study concept and acquisition of data. Dr. D.I. Kim contributed study concept and study supervision. Dr. Shin contrib-

uted study concept and acquisition of data. Dr. Suh contributed study concept and acquisition of data. Dr. D.J. Kim contributed study concept and acquisition of data. Dr. S.I. Park contributed manuscript drafting/ revising and acquisition of data. Dr. K.Y. Park contributed analysis and acquisition of data. Dr. Ahn contributed analysis and acquisition of data.

ACKNOWLEDGMENT Statistical analyses were conducted by Dr. J.M. Sung, Department of Research Affairs, Yonsei University College of Medicine.

DISCLOSURE Dr. B.M. Kim, Dr. S.H. Kim, Dr. D.I. Kim, Dr. Shin, and Dr. Suh report no disclosures. Dr. D.J. Kim serves on the editorial board of Neurointervention. Dr. S.I. Park, Dr. K.Y. Park, and Dr. Ahn report no disclosures.

Received October 10, 2010. Accepted in final form February 10, 2011. REFERENCES 1. Caplan LR, Baquis GD, Pessin MS, et al. Dissection of intracranial vertebral artery. Neurology 1988;38:868 – 877. 2. Arnold M, Bousser MG, Fahrni G, et al. Vertebral artery dissection: presenting findings and predictors of outcome. Stroke 2006;37:2499 –2503. 3. Yamaura A, Ono J, Hirai S. Clinical picture of intracranial non-traumatic dissecting aneurysm. Neuropathology 2000;20:85–90. 4. Tsukahara T, Minematsu K. Overview of spontaneous cervicocephalic arterial dissection in Japan. Acta Neurochir Suppl 2010;107:35– 40. 5. Schievink WI. Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med 2001;344:898 –906. 6. Redekop GJ. Extracranial carotid and vertebral artery dissection: a review. Can J Neurol Sci 2008;35:146 –152. 7. Mizutani T, Aruga T, Kirino T, Miki Y, Saito I, Tsuchida T. Recurrent subarachnoid hemorrhage from untreated ruptured vertebrobasilar dissecting aneurysms. Neurosurgery 1995;36:905–911. 8. Arauz A, Marquez JM, Artigas C, Balderrama J, Orrego H. Recanalization of vertebral artery dissection. Stroke 2010; 41:717–721. 9. Yoshimoto Y, Wakai S. Unruptured intracranial vertebral artery dissection; clinical course and serial radiographic imagings. Stroke 1997;28:370 –374. 10. de Bray JM, Penisson-Besnier I, Dubas F, Emile J. Extracranial and intracranial vertebrobasilar dissections: diagnosis and prognosis. J Neurol Neurosurg Psychiatry 1997; 63:46 –51. 11. Hosoya T, Adachi M, Yamaguchi K, Haku T, Kayama T, Kato T. Clinical and neuroradiological features of intracranial vertebrobasilar artery dissection. Stroke 1999;30: 1083–1090.

12.

Naito I, Iwai T, Sasaki T. Management of intracranial vertebral artery dissections initially presenting without subarachnoid hemorrhage. Neurosurgery 2002;51:930 –937. 13. Kim BM, Suh SH, Park SI, et al. Management and clinical outcome of acute basilar artery dissection. AJNR Am J Neuroradiol 2008;29:1937–1941. 14. Huang YC, Chen YF, Wang YH, Tu YK, Jeng JS, Liu HM. Cervicocranial arterial dissection: experience of 73 patients in a single center. Surg Neurol 2009;suppl 2:S20 – S27. 15. Wilkinson IM. The vertebral artery: extracranial and intracranial structure. Arch Neurol 1972;27:392–396. 16. Peltier J, Toussaint P, Deramond H, et al. The dural crossing of the vertebral artery. Surg Radiol Anat 2003;25:305– 310. 17. Kawada S, Meguro T, Mandai S, et al. A case of dissecting aneurysm of the vertebro-basilar artery with brain stem ischemia and subarachnoid hemorrhage. Surg Cereb Stroke 1994;22:485– 489. 18. Inagaki T, Saito K, Hirano A, Kato T, Irie S, Murakami T. Vertebral arterial dissection with subarachnoid hemorrhage after ischemic onset. No Shinkei Geka 2000;28: 997–1002. 19. Yamataki A, Kurashima Y, Ueda S. Dissecting vertebral aneurysm with subarachnoid hemorrhage after ischemic onset on the same day: a case report. No Shinkei Geka 2004;32:723–728. 20. Jeon P, Kim BM, Kim DI, et al. Emergent self-expanding stent placement for acute intracranial or extracranial internal carotid artery dissection with significant hemodynamic insufficiency. AJNR Am J Neuroradiol 2010;31:1529 – 1532. 21. Nakagawa K, Touho H, Morisako T, et al. Long-term follow-up study of unruptured vertebral artery dissection: clinical outcomes and serial angiographic findings. J Neurosurg 2000;93:19 –25. 22. Ruecker M, Furtner M, Knoflach M, et al. Basilar artery dissection: series of 12 consecutive cases and review of the literature. Cerebrovasc Dis 2010;30:267–276. 23. Brihaye J, Retif J, Jeanmart L, Flament-Durand J. Occlusion of the basilar artery in young patients. Acta Neurochir 1971;25:225–229. 24. Bugiani O, Piola P, Tabaton M. Nontraumatic dissecting aneurysm of the basilar artery. Eur Neurol 1983;22:256 – 260. 25. Berkovic SF, Spokes RL, Anderson RM, Bladin PF. Basilar artery dissection. J Neurol Neurosurg Psychiatry 1983;46: 126 –129. 26. Janssen PM, Visser NA, Dorhout Mees SM, Klijn CJ, Algra A, Rinkel GJ. Comparison of telephone and face-toface assessment of the modified Rankin Scale. Cerebrovasc Dis 2010;29:137–139.

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Silent brain infarcts, leukoaraiosis, and long-term prognosis in young ischemic stroke patients J. Putaala, MD, PhD E. Haapaniemi, MD, PhD M. Kurkinen, MD O. Salonen, MD, PhD M. Kaste, MD, PhD T. Tatlisumak, MD, PhD

Address correspondence and reprint requests to Dr. Jukka Putaala, Department of Neurology, Helsinki University Central Hospital, Haartmaninkatu 4, FIN-00290, Helsinki, Finland [email protected]

ABSTRACT

Objective: To investigate prognostic relevance of silent brain infarcts (SBIs) and leukoaraiosis (LA) in young patients with ischemic stroke. Methods: This observational cohort study included consecutive MRI-scanned patients aged 15 to 49 with first-ever ischemic stroke treated at Helsinki University Central Hospital (1994–2007) with long-term follow-up data available. Outcome measures were 1) nonfatal or fatal ischemic stroke, 2) composite vascular endpoint, and 3) death from any cause. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) and Bamford criteria allowed for stroke subtyping. Number of SBIs was categorized into none, single, or multiple. LA fell into groups of none, mild, or moderate to severe (validated visual rating scale). Results: The 655 patients (mean age 40.0 ⫾ 8.0 years) included were followed for a mean 8.7 ⫾ 3.8 years (survivors). Of the 86 (13.1%) patients with SBIs, 46 had single and 40 had multiple SBIs. In the 50 (7.6%) patients with LA, these changes were mild in 21 and moderate to severe in 29. In Cox regression analysis, multiple SBIs independently raised the risk for recurrent ischemic stroke (odds ratio 2.48; 95% confidence interval 1.24–4.94) adjusted for age, gender, risk factors, stroke etiology, and LA. After further adjustment for initial stroke severity, TOAST and Bamford subgroups, and presence of SBIs, moderate to severe LA increased the risk for death (3.43; 1.58–7.42). Neither SBIs nor LA associated with the composite vascular endpoint.

Conclusions: MRI-defined SBIs and LA are prognostically valuable in young adults after their firstever ischemic stroke. Neurology® 2011;76:1742–1749 GLOSSARY CI ⫽ confidence interval; DWI ⫽ diffusion-weighted imaging; FLAIR ⫽ fluid-attenuated inversion recovery; LA ⫽ leukoaraiosis; NIHSS ⫽ NIH Stroke Scale; OR ⫽ odds ratio; SBI ⫽ silent brain infarct; T1D ⫽ diabetes mellitus type 1; T2D ⫽ diabetes mellitus type 2; TOAST ⫽ Trial of ORG 10172 in Acute Stroke Treatment.

Supplemental data at www.neurology.org

Silent brain infarcts (SBIs) and leukoaraiosis (LA), common findings in older individuals free of cerebrovascular disease1-4 and among patients with stroke,5,6 are both mainly associated with small-vessel disease pathology.1,7 The association between SBIs and prognosis after an ischemic stroke remains controversial.8-13 Although CT-based studies found no association between LA and patient outcome,14,15 more recent studies utilizing either CT16 or MRI17,18 show LA to be associated with poor functional outcome and higher risk for recurrent stroke. These studies have not, however, included substantial numbers of young patients with considerable differences in risk factor and etiologic profiles with more favorable outcomes than elderly patients face.19-21 We recently reported that 13% of 1,008 consecutive young adults aged 15 to 49 with first-ever ischemic stroke had one or more SBIs and that in CT or MRI ⬎5% presented with LA.19 In the magnetic resonance–imaged subpopulation of that cohort, the majority had only a single SBI, and LA severity was mostly mild to moderate.22 Both SBIs and LA were primarily From the Department of Neurology (J.P., E.H., M. Kurkinen, M. Kaste, T.T.) and Helsinki Medical Imaging Center (O.S.), Helsinki University Central Hospital, Helsinki, Finland. Study funding: Supported by the Helsinki University Central Hospital (T.T.: TYH2008253, TYH2009236; J.P.: TKK2011003), the Finnish Medical Foundation (J.P.), the Finnish Brain Foundation (J.P.), and the Maire Taponen Foundation (J.P.). The sponsor of the study played no role in study design, data collection, data analysis, interpretation, writing of the manuscript, or the decision to submit the manuscript for publication. Disclosure: Author disclosures are provided at the end of the article.

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Copyright © 2011 by AAN Enterprises, Inc.

associated with an index event attributable to small-vessel disease. In turn, in our patients with small-vessel occlusion, 5-year mortality was low (5%) and recurrence rate of ischemic stroke intermediate (15%).20,21 Whether SBIs or LA indicate any higher risk for vascular events or mortality in young adults after ischemic stroke remains unknown. We aimed to assess whether, in our young patient population, SBIs and LA are associated with increased risk for subsequent ischemic stroke, other vascular events, or death from any cause. METHODS Study setting. This study was conducted at the Department of Neurology, Helsinki University Central Hospital, which has the only neurologic emergency room and stroke unit serving a defined population of 1.5 million. We included patients entered into the Helsinki Young Stroke Registry from 1994 to 2007 who had undergone an initial brain MRI scan at 1.0 T or 1.5 T and who had long-term follow-up data available. The registry organization and inclusion and exclusion criteria are reported elsewhere.19 We defined ischemic stroke as an episode of focal neurologic deficits with acute onset and lasting ⬎24 hours or if lasting ⬍24 hours, with imaging evidence of stroke corresponding with current symptoms. TIA was defined similarly but with symptoms lasting ⬍24 hours and without corresponding imaging evidence of an ischemic lesion. Only patients with first-ever ischemic stroke were included in the registry; those with TIAs were excluded. Diagnosis depended on a clinical definition of ischemic stroke plus a corresponding ischemic lesion on MRI. Diffusionweighted imaging (DWI) has been performed since the mid1990s, routinely since the late 1990s in our hospital, and positive DWI findings, if applicable, were incorporated into our definition of ischemic stroke.

Baseline data. According to a written institutional treatment protocol, our patients routinely underwent laboratory and other diagnostic tests as previously described.19 The definitions of risk factors were based on data available before the onset of the index stroke and on all poststroke diagnostic testing related to the event. Cardiovascular risk factors analyzed here were age, gender, dyslipidemia (treated or total cholesterol level ⱖ5.0 mmol/L, low-density lipoprotein level ⱖ3.0 mmol/L, or high-density lipoprotein level ⬍1.0 mmol/L), current smoking (smoking consistently ⱖ1 cigarettes per day within the year prior to the stroke), hypertension (treated, or a history of hypertension as systolic blood pressure ⱖ140 mm Hg or diastolic blood pressure ⱖ90 mm Hg, or both), obesity (body mass index ⱖ30 or patient clearly described as heavily obese), cardiovascular disease (among coronary heart disease, heart failure, myocardial infarction, peripheral arterial disease), atrial fibrillation, history of TIA, as well as diabetes mellitus type 1 (T1D) and 2 (T2D). T1D was distinguished from T2D by regular use of insulin within 1 year of diagnosis. In addition, we included heavy drinking as it has independently predicted long-term mortality in this patient population,20 and was defined as more than clearly moderate drinking, i.e., estimated intake of ⬎200 g of pure alcohol per week consistently as reported by patient or relative.

Stroke severity was assessed with the NIH Stroke Scale (NIHSS) and classified as mild (0 – 6), moderate (7–14), or severe (ⱖ15). Etiologic subtyping was according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria.23 In addition, we further classified index events according to the Bamford criteria24 to account for possible associations between clinical and neuroanatomic features and outcome events.

Assessment of SBIs and LA. Brain imaging studies, originally interpreted by our neuroradiologists, were reanalyzed and rated for SBIs and LA by stroke neurologists and a senior neuroradiologist (O.S.). An SBI was defined as focal hyperintensity on T2-weighted images, ⱖ3 mm in size, and without a corresponding history of neurologic symptoms or signs. To distinguish infarcts from LA, infarcts had corresponding hypointensity on T1-weighted images. If the SBI was located in the basal ganglia area, the lesion was distinguished from perivascular spaces based on their simultaneous hyperintensity on T2-weighted images and hypointensity on fluidattenuated inversion recovery (FLAIR) images. According to number of SBIs, patients were divided into those having no, single, or multiple SBIs. LA was defined as hyperintense lesions in periventricular or subcortical regions, or in the pons, on FLAIR sequences; in 2 patients, on T2-weighted sequences. LA was evaluated according to a validated visual rating scale with good intraobserver (weighted ␬ ⫽ 0.90 – 0.95) and interobserver agreement (weighted ␬ ⫽ 0.72– 0.84).25,26 Periventricular hyperintensities around the frontal and occipital horns, along the bodies of lateral ventricles, and in regions other than periventricular white matter, as well as pontine LA, were scored based on lesion shape and size. The sumscore of these 4 components was originally categorized into mild (1– 4), moderate (5– 8), and severe (9 –12).22 Due to the low number of patients with severe LA, the moderate and severe groups were pooled for statistical analysis, and LA presence and severity was graded as follows: none, mild, or moderate to severe.

Follow-up. Surviving patients were tracked from November 2009 to January 2010 by a structured telephone interview of patients, their next of kin, or nursing staff, with a letter sent to those not reached by telephone. All patient records available from hospitals and primary care underwent a detailed evaluation. Complete mortality data including cause of death came from Statistics Finland in 200820 and were updated in January 2010. The onset of index stroke symptoms served as the starting point for follow-up.

Outcome measures. Outcome events were 1) nonfatal or fatal recurrent ischemic stroke; 2) composite vascular outcome event of myocardial infarct, any recurrent stroke (ischemic or hemorrhagic), revascularization procedure, or vascular death; and 3) death from any cause. Outcome events were classified by study stroke neurologists (E.H. and J.P.) blinded to other clinical data with consensus agreement when necessary. Statistical analyses. Chi-square and Fisher exact tests allowed comparisons of categorical variables between the groups. Student t and Mann-Whitney U test served for comparing means. Kaplan-Meier analysis served to depict cumulative recurrence risks of outcome events in patients with any number of SBIs and LA of any grade compared to patients free of these findings. Patients who died from other than the defined fatal endpoints were considered censored from analyses of outcome events 1 and 2. Those who died within the first 30 days after the index stroke were excluded from the all-cause mortality analyses. Cox proportional hazards models using a backward stepwise method were Neurology 76

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Table 1

Standard protocol approvals, registrations, and patient consents. The study was approved by the appropriate local au-

Baseline data for the study population (n ⴝ 655)a

thorities and the Ethics Committee.

Demographics Age, y

40.0 (8.0)

Male gender

385 (58.8)

Risk factors Dyslipidemia

368 (56.2)

Cigarette smoking

264 (40.3)

Hypertension

244 (37.3)

Obesity

62 (9.5)

Cardiovascular disease

46 (7.0)

History of transient ischemic attack

60 (9.2)

Diabetes mellitus, type 2

37 (5.6)

Diabetes mellitus, type 1

29 (4.4)

Atrial fibrillation

19 (2.9)

Heavy drinking

67 (10.2)

Stroke severity Mild, NIHSS score 0–6

554 (84.6)

Moderate, NIHSS score 7–14

69 (10.5)

Severe, NIHSS score >15

32 (4.9)

Stroke etiology (TOAST) Large-artery atherosclerosis Cardioembolism Small-vessel disease

37 (5.6) 118 (18.0) 89 (13.6)

Other determined etiology

192 (29.3)

Undetermined etiology

219 (33.4)

Bamford classification Lacunar infarct Total anterior circulation infarct

125 (19.1) 68 (10.4)

Partial anterior circulation infarct

142 (21.7)

Posterior circulation infarct

320 (48.9)

Silent brain infarcts None

565 (86.8)

Single

46 (7.1)

Multiple

40 (6.1)

Leukoaraiosis None

605 (92.4)

Mild

21 (3.2)

Moderate to severe

29 (4.4)

Abbreviations: NA ⫽ not applicable; NIHSS ⫽ National Institutes of Health Stroke Scale; TOAST ⫽ Trial of Org in Acute Stroke Treatment. a Data are mean (⫾SD) or n (%).

constructed to identify independent predictors of the 3 outcome events. In addition to age and gender, all models were adjusted for baseline variables with a p ⬍ 0.10 in univariate Cox proportional analyses. The graded variables of SBIs and LA were used in both univariate and multivariate Cox proportional hazards analyses, those free of SBIs or LA serving as referents. All statistical analyses used PASW 18.0 for Macintosh. Two-sided values of p ⬍ 0.05 were considered significant. 1744

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RESULTS Of the 1,008 patients included in the registry, 671 were initially scanned with MRI and of these, only 2 lacked complete imaging data. In the follow-up of these 669 patients, 3 refused to participate, 7 were lost to follow-up with no other information except that they were alive, and 4 patients were judged to have a false primary diagnosis of ischemic stroke during their later follow-up, leaving 655 patients eligible for the present analysis (baseline data in table 1). Excluded patients were older, more often male, and had more severe index strokes; their risk factors and stroke etiology differed significantly from those of the patients included (table e-1 on the Neurology® Web site at www.neurology.org). Of the study cohort, 86 (13.7%) patients had SBIs, of which 46 had single and 40 multiple SBIs. LA occurred in 50 (7.6%), mild in 21, moderate in 27, and severe in 2. No significant trends emerged in the prevalence of SBIs or LA according to year of inclusion (data not shown). Mean interval between the index event and follow-up timepoint or death was 8.3 ⫾ 4.0 years, amounting to a total of 5,439 years of observation (mean follow-up in survivors 8.7 ⫾ 3.8 years). Follow-up was at least 5 years for 75.1% and at least 10 years for 35.0% of the patients. There were 70 nonfatal and 2 fatal ischemic strokes, 10 hemorrhagic strokes, 27 myocardial infarcts or other arterial events, while overall 119 patients had some vascular event (composite vascular endpoint) and 61 died. Four patients died of the index stroke within the first 30 days and were excluded from mortality analyses. Mean interval between index stroke and first composite vascular endpoint event was shorter in patients with any quantity of SBIs (2.8 ⫾ 2.7 years) vs those without SBIs (4.4 ⫾ 3.5 years; p ⫽ 0.040). No significant differences appeared in the interval between index stroke and outcome event regarding other outcome measures. Cumulative risk for recurrent ischemic stroke was significantly higher in patients with SBIs than in those without (figure 1A). Risk for recurrent ischemic stroke was higher also in those with LA than in those free of LA (figure 2A). Risk for the composite vascular endpoint was higher in patients with SBIs than in without SBIs (figure 1B), but no statistically significant difference emerged between those with and without LA (figure 2B). No difference existed in mortality between patients with or without SBIs (figure 1C), whereas a significantly increased long-term risk of death afflicted those with LA compared to those without LA (figure 2C).

Figure 1

Kaplan-Meier estimates of cumulative event rates stratified by the presence (SBIⴙ) or absence (SBIⴚ) of baseline silent brain infarcts

(A) recurrent nonfatal or fatal ischemic stroke; (B) composite vascular endpoint; and (C) death from any cause.

In the univariate Cox proportional hazards analysis, increasing age, hypertension, both types of diabetes, large-artery atherosclerosis underlying the index stroke, presence of single or multiple SBIs, and moderate to severe LA were all associated with risk for nonfatal or fatal recurrent ischemic stroke. Regarding the composite vascular endpoint, increasing age, male gender, smoking, hypertension, cardiovascular disease, T1D, T2D, large-artery and small-vessel disease underlying the index stroke, lacunar infarct by the Bamford criteria, presence of SBIs, and moderate to severe LA showed univariate associations. Increasing age, hypertension, cardiovascular disease, history of TIA, T1D, heavy drinking, severe index stroke (NIHSS ⱖ 15), large-artery atherosclerosis, multiple SBIs, and LA of any grade were associated with longterm mortality (table 2).

Figure 2

In the multivariate Cox proportional hazards analysis, after adjustment for age, gender, risk factors, and etiology, multiple SBIs, but not LA, was independently associated with risk for recurrent ischemic stroke. However, when adjusted for age, gender, risk factors, stroke severity, etiology, and Bamford subtype, moderate to severe LA was associated with increased risk of death. After adjustment for confounders, no association appeared between SBIs or LA and the composite vascular endpoint (table 3). A substantial proportion of our young patients with first-ever ischemic stroke harbored SBIs or LA in brain MRI, which, in turn, was associated with a considerably higher risk for important adverse outcome events during long-term follow-up than seen in those free of these imaging

DISCUSSION

Kaplan-Meier estimates of cumulative event rates stratified by the presence (LAⴙ) or absence (LAⴚ) of baseline leukoaraiosis of any grade

(A) recurrent nonfatal or fatal ischemic stroke; (B) composite vascular endpoint; and (C) death from any cause. Neurology 76

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Table 2

Baseline variables according to occurrence of 1) nonfatal or fatal ischemic stroke, 2) composite vascular endpoint, and 3) death from any cause (only 30-day survivors included in the mortality analysis)a Recurrent ischemic stroke (n ⴝ 72)

p

Composite vascular endpoint (n ⴝ 119)

Hazard ratio

Hazard ratio

p

Death from any cause (n ⴝ 57)

Hazard ratio

p

42.8 (6.0)

1.06b

0.003

43.3 (5.9)

1.07b

⬍0.001

43.7 (5.2)

1.08b

0.001

28 (38.9)

1.12

0.635

80 (67.2)

1.48

0.044

38 (66.7)

1.41

0.224

Dyslipidemia

44 (61.1)

1.11

0.672

76 (63.9)

1.27

0.211

32 (56.1)

0.87

0.590

Cigarette smoking

33 (45.8)

1.24

0.366

64 (53.8)

1.73

0.003

26 (45.6)

1.22

0.450

34 (59.6)

2.62

⬍0.001

9 (15.8)

1.84

0.093

Demographics Age, y Male gender Risk factors

Hypertension

36 (50.0)

1.80

0.013

68 (57.1)

2.45

⬍0.001

Obesity

10 (13.9)

1.61

0.161

16 (13.4)

1.56

0.097

8 (11.1)

1.85

0.102

20 (16.8)

3.01

⬍0.001

14 (24.6)

4.78

⬍0.001

History of TIA

11 (15.3)

1.73

0.094

16 (13.4)

1.41

0.199

12 (21.1)

2.38

0.008

Cardiovascular disease

Diabetes mellitus, type 2

10 (13.9)

2.67

0.004

18 (15.1)

3.01

⬍0.001

6 (10.5)

1.77

0.189

Diabetes mellitus, type 1

9 (12.5)

3.70

⬍0.001

15 (12.6)

4.33

⬍0.001

6 (10.5)

2.93

0.013

Atrial fibrillation

2 (2.8)

1.30

0.718

5 (4.2)

2.07

0.111

3 (5.3)

2.61

0.107

Heavy drinking

9 (12.5)

1.27

0.498

19 (16.0)

1.61

0.057

16 (28.1)

3.38

⬍0.001

1

NA

99 (83.2)

1

NA

44 (77.2)

1

NA

Stroke severity Mild, NIHSS score 0–6

63 (87.5)

Moderate, NIHSS score 7–14

7 (9.7)

0.91

0.821

16 (13.4)

1.36

0.253

7 (12.3)

1.30

0.520

Severe, NIHSS score >15

2 (2.8)

0.60

0.476

4 (3.4)

0.73

0.529

6 (10.5)

2.64

0.026

9 (12.5)

3.10

0.005

14 (11.8)

3.29

⬍0.001

8 (14.0)

3.76

0.003

Cardioembolism

12 (16.7)

1.28

0.506

18 (15.1)

1.35

0.318

9 (15.8)

1.43

0.401

Small-vessel disease

15 (20.8)

1.86

0.069

30 (25.2)

2.74

⬍0.001

11 (19.3)

1.95

0.099

Other determined etiology

16 (22.2)

0.92

0.812

28 (23.5)

1.11

0.690

15 (26.3)

1.27

0.523

Undetermined etiology

20 (27.8)

1

NA

29 (24.4)

1

NA

14 (24.6)

1

NA

17 (23.6)

1.42

0.350

36 (30.3)

1.87

0.025

14 (24.6)

1.46

0.264

6 (8.3)

0.98

0.974

11 (9.2)

1.04

0.908

9 (15.8)

1.95

0.090

Stroke etiology (TOAST) Large-artery atherosclerosis

Bamford classification Lacunar infarct Total anterior circulation infarct Partial anterior circulation infarct

12 (16.7)

1

NA

20 (16.8)

1

NA

11 (19.3)

1.18

0.654

Posterior circulation infarct

37 (51.4)

1.26

0.482

52 (43.7)

1.04

0.875

23 (40.4)

1

NA

54 (75.0)

44 (78.6)

Silent brain infarcts None

1

NA

95 (80.5)

1

NA

1

NA

8 (11.1)

2.14

0.046

12 (11.0)

2.06

0.015

6 (10.7)

1.93

0.132

10 (13.9)

3.18

0.001

10 (8.5)

1.86

0.062

6 (10.7)

2.23

0.066

None

63 (87.5)

1

NA

1

NA

1

NA

Mild

3 (4.2)

1.48

0.507

5 (4.2)

1.40

0.463

4 (7.0)

3.02

0.035

Moderate to severe

6 (8.3)

2.59

0.026

8 (6.7)

1.84

0.095

9 (15.8)

5.27

⬍0.001

Single Multiple Leukoaraiosis

106 (89.1)

44 (77.2)

Abbreviations: NA ⫽ not applicable; NIHSS ⫽ National Institutes of Health Stroke Scale; TOAST ⫽ Trial of Org in Acute Stroke Treatment. a Hazard ratios were computed by the univariate Cox proportional hazards function. Data are mean (⫾SD) or n (%). b Per year.

findings. After accounting for relevant confounders, presence of multiple SBIs elevated independently the risk for recurrent ischemic stroke. When all vascular 1746

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endpoints were grouped, we found no independent associations between SBIs or LA and these events. However, after cardiovascular disease, moderate to

Table 3

Multivariate Cox proportional hazards models predicting 1) recurrent ischemic stroke, 2) composite vascular endpoint, and 3) death from any causea Recurrent nonfatal or fatal ischemic stroke

Composite vascular endpoint

Adjusted HR (95% CI)b

p

Adjusted HR (95% CI)c

p

Adjusted HR (95% CI)d

p

Age, per year

1.04 (1.01–1.08)

0.025

1.05 (1.02–1.09)

0.002

1.05 (1.00–1.10)

0.062

Male gender

0.99 (0.60–1.62)

0.961

1.13 (0.76–1.69)

0.550

1.00 (0.53–1.89)

0.998

Death from any cause

Demographics

Silent brain infarcts None

1

NA

1

NA

1

NA

Single

1.47 (0.68–3.16)

0.326

1.24 (0.66–2.33)

0.497

1.32 (0.51–3.38)

0.566

Multiple

2.48 (1.24–4.94)

0.010

1.28 (0.64–2.59)

0.486

1.15 (0.43–3.04)

0.778

Leukoaraiosis None

1

NA

1

NA

1

NA

Mild

0.85 (0.25–2.85)

0.791

0.59 (0.23–1.52)

0.275

2.59 (0.90–7.47)

0.077

1.07 (0.40–2.85)

0.900

0.82 (0.38–1.76)

0.604

3.43 (1.58–7.42)

0.002

Moderate to severe

Abbreviations: CI ⫽ confidence interval; HR ⫽ hazard ratio; NA ⫽ not applicable. a All models included age, gender, and both silent brain infarcts and leukoaraiosis as covariates. In addition, models were adjusted for variables with p ⬍ 0.10 in a univariate Cox proportional hazards analysis. Mortality model excluded those dying within the 30 days after the index event (n ⫽ 4). b Adjusted for age, gender, hypertension, history of TIA, diabetes mellitus type 1 and 2, stroke etiology, silent brain infarcts, and leukoaraiosis. c Adjusted for age, gender, cigarette smoking, hypertension, obesity, cardiovascular disease, history of TIA, diabetes mellitus type 1 and 2, heavy drinking, stroke etiology, Bamford subtype, silent brain infarcts, and leukoaraiosis. d Adjusted for age, gender, hypertension, obesity, cardiovascular disease, history of TIA, diabetes mellitus type 1, heavy drinking, stroke severity, stroke etiology, Bamford subtype, silent brain infarcts, and leukoaraiosis.

severe LA had the strongest statistical association with long-term risk for death from all causes. Since SBIs and LA seem to be prognostically relevant, and because they are more sensitively detected with MRI than with CT, MRI should be the primary imaging method of choice in all eligible young patients with stroke. CT or MRI studies including patients with nonrheumatic atrial fibrillation and nondisabling ischemic stroke or TIA,8 lacunar infarct,9,27 or nonselected patients with ischemic or hemorrhagic stroke13 presented conflicting results in regard to the association between SBIs and stroke recurrence. In the present cohort, the association between multiple MRIdefined SBIs and recurrent ischemic stroke appeared independently of prognostically important vascular risk factors such as diabetes and stroke etiology. SBIs may thus reflect a high-risk cerebrovascular condition, not fully explained by any independent risk factor.1 In a young patient population, the pathophysiology underlying SBIs differs at least partially with more variety than in elderly patients, although cerebral small-vessel disease is likely to be the predominant cause.22 Our observation on the relationship between SBIs and recurrent stroke awaits replication in another large MRI-scanned nonselected young ischemic stroke patient cohort.

Two studies utilizing CT found no association between SBIs and mortality after a 1-year10 or 3-year follow-up11 among general-population patients with first-ever stroke. Our young patients with SBIs were at higher long-term risk for any vascular event or death, but these associations appeared only in the univariate analysis or were trend-like. These findings are in accordance with these earlier findings and strengthen the view that SBIs at a young age may merely reflect specific types of cerebrovascular rather than universal and prognostically poor vascular disease. CT studies have produced conflicting results also regarding the association of LA with stroke recurrence or death.14,15,28 A recent MRI study showed an independent association between LA and recurrent stroke and mortality.17 Volume of leukoaraiosis quantified by MRI has correlated with worse outcome at 6 months.18 The prevalence of LA was low in our patients, which reflects our low mean cohort age. MRI-defined moderate to severe LA showed a univariate association with recurrent ischemic stroke, but clearly the strongest association was between LA and long-term mortality. After adjustment for appropriate predictors of mortality, including both causative (TOAST) and clinical (Bamford) stroke subtypes, the association between moderate to severe LA and morNeurology 76

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tality persisted. Our findings correlate with the recent observations in the MRI studies on general stroke populations,17,18 but are surprising because of our patients’ young age. Multiple mechanisms may underlie the relationship between LA and greater long-term mortality after stroke, including initial infarct growth,29 dysfunctional white matter tracts impairing plasticity and inhibiting recovery,30 impaired cognitive functioning,31 and poststroke depression.32 All these factors may result in poor treatment and rehabilitation compliance. The association could also reflect the burden of vascular risk factors and diffuse vascular damage involving not only the arteries supplying the brain but also peripheral and coronary arteries.33 In a young patient population, specific medical conditions that can also cause acute ischemic stroke and in which LA is not uncommon—such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or systemic lupus erythematosus—may additionally carry a higher risk for death. Such conditions were infrequent in our patient cohort22 and can only explain our observations in part, however. Our study has certain limitations. We had to exclude patients not scanned with brain MRI. Significant baseline differences existed between included and excluded patients, which, however, mostly reflected the higher mean age of the excluded group with accumulation of vascular risk factors and etiologic spectrum resembling that seen in elderly patients with stroke.19 Those excluded also had had more severe strokes, thus being noneligible for MRI in the first place. The possible selection bias may actually have weakened the relationships observed between SBIs and LA and the outcomes, because the excluded patients presumably had higher prevalences of both SBIs and LA. Due in particular to the relatively low number of patients with LA, the multivariate results must be interpreted with caution. Finally, because only a small minority of our patient cohort was non-Caucasian, our results may not be directly generalizable to other ethnic groups. AUTHOR CONTRIBUTIONS Manuscript drafting or manuscript revision for important intellectual content: all authors; manuscript final version approval: all authors; Jukka Putaala: study concept and planning, data collection, analysis, literature search, interpretation, and manuscript writing and editing; J.P. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis; Elena Haapaniemi: study concept and planning, data collection, manuscript writing and editing; Minna Kurkinen: data collection; Oili Salonen: study concept and planning, data collection, and interpretation; Markku Kaste: study concept and planning, interpretation, manuscript writing and editing, logistic and administrative support, and funding; Turgut Tatlisumak: study concept and planning, interpretation, manuscript writing and editing, logistic and administrative support, and funding. 1748

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ACKNOWLEDGMENT The authors thank Marja Metso, RN, for technical support and Carolyn Brimley Norris, PhD, for revising language.

DISCLOSURE Dr. Putaala has received funding for travel from Boehringer Ingelheim and Genzyme Corporation and has received research support from the Helsinki University Central Hospital, the Finnish Medical Foundation, the Finnish Brain Foundation, and the Maire Taponen Foundation. Dr. Haapaniemi, Dr. Kurkinen, and Dr. Salonen report no disclosures. Dr. Kaste serves on the editorial boards of the International Journal of Stroke and Avh-Lehti (Journal of Cerebrovascular Disorders). Dr. Tatlisumak serves on scientific advisory boards for Boehringer Ingelheim and Mitsubishi Tanabe Pharma Corporation; has received funding for travel from Boehringer Ingelheim; serves/has served on editorial advisory boards for Stroke, Current Vascular Pharmacology, The Open Pharmacology Journal, Clinics of Turkey, Clinics of Turkey/Neurology, The Open Cardiovascular Medicine Journal, Recent Patents on Biotechnology, Recent Patents on CNS Drug Discovery, Experimental and Translational Stroke Medicine, Stroke Research and Treatment, BMC Journal of Experimental and Translational Stroke Medicine, Frontiers in Stroke, Case Reports in Neurology (founding Editor-in-Chief), and Cerebrovascular Diseases; is listed as author on patents re: Stanniocalcin proteins and nucleic acids and methods based thereon, New therapeutic uses (method to prevent brain edema and reperfusion injury), and Thrombolytic compositions (method to prevent postthrombolytic hemorrhage formation); serves as a consultant for Boehringer Ingelheim, PhotoThera, BrainsGate, Schering-Plough Corp., Lundbeck Inc., sanofi-aventis, and Concentric Medical; and receives research support from Boehringer Ingelheim, the Finnish Academy of Sciences, the European Union, Etela¨-Suomen La¨a¨ninhallitus, Biocentrum Finland, Biocentrum Helsinki, Sigrid Juselius Foundation, Liv och Ha¨lsa, the Maire Taponen Foundation, and the SalusAnsvar Science Award for Excellence in Stroke Research (Sweden).

Received October 11, 2010. Accepted in final form February 10, 2011.

REFERENCES 1. Vermeer SE, Longstreth WT Jr, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol 2007;6:611– 619. 2. de Leeuw FE, de Groot JC, Achten E, et al. Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study: The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry 2001;70: 9 –14. 3. Kohara K, Fujisawa M, Ando F, et al. MTHFR gene polymorphism as a risk factor for silent brain infarcts and white matter lesions in the Japanese general population: The NILS-LSA Study. Stroke 2003;34:1130 –1135. 4. Ylikoski A, Erkinjuntti T, Raininko R, Sarna S, Sulkava R, Tilvis R. White matter hyperintensities on MRI in the neurologically nondiseased elderly: analysis of cohorts of consecutive subjects aged 55 to 85 years living at home. Stroke 1995;26:1171–1177. 5. Adachi T, Kobayashi S, Yamaguchi S. Frequency and pathogenesis of silent subcortical brain infarction in acute first-ever ischemic stroke. Intern Med 2002;41:103–108. 6. Leys D, Englund E, Del Ser T, et al. White matter changes in stroke patients: relationship with stroke subtype and outcome. Eur Neurol 1999;42:67–75. 7. Inzitari D. Leukoaraiosis: an independent risk factor for stroke? Stroke 2003;34:2067–2071. 8. EAFT Study Group. Silent brain infarction in nonrheumatic atrial fibrillation: European Atrial Fibrillation Trial. Neurology 1996;46:159 –165.

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de Jong G, Kessels F, Lodder J. Two types of lacunar infarcts: further arguments from a study on prognosis. Stroke 2002;33:2072–2076. Boon A, Lodder J, Heuts-van Raak L, Kessels F. Silent brain infarcts in 755 consecutive patients with a first-ever supratentorial ischemic stroke: relationship with indexstroke subtype, vascular risk factors, and mortality. Stroke 1994;25:2384 –2390. Brainin M, McShane LM, Steiner M, Dachenhausen A, Seiser A. Silent brain infarcts and transient ischemic attacks: a three-year study of first-ever ischemic stroke patients: the Klosterneuburg Stroke Data Bank. Stroke 1995; 26:1348 –1352. Jorgensen HS, Nakayama H, Raaschou HO, Gam J, Olsen TS. Silent infarction in acute stroke patients: prevalence, localization, risk factors, and clinical significance: the Copenhagen Stroke Study. Stroke 1994;25:97–104. Corea F, Henon H, Pasquier F, Leys D, Lille Stroke/ Dementia Study Group. Silent infarcts in stroke patients: patient characteristics and effect on 2-year outcome. J Neurol 2001;248:271–278. Clavier I, Hommel M, Besson G, Noelle B, Perret JE. Long-term prognosis of symptomatic lacunar infarcts. A hospital-based study. Stroke 1994;25:2005–2009. Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS. Leukoaraiosis in stroke patients: The Copenhagen Stroke Study. Stroke 1995;26:588 –592. Koton S, Schwammenthal Y, Merzeliak O, et al. Cerebral leukoaraiosis in patients with stroke or TIA: clinical correlates and 1-year outcome. Eur J Neurol 2009;16:218 –225. Fu JH, Lu CZ, Hong Z, Dong Q, Luo Y, Wong KS. Extent of white matter lesions is related to acute subcortical infarcts and predicts further stroke risk in patients with first ever ischaemic stroke. J Neurol Neurosurg Psychiatry 2005;76:793–796. Arsava EM, Rahman R, Rosand J, et al. Severity of leukoaraiosis correlates with clinical outcome after ischemic stroke. Neurology 2009;72:1403–1410. Putaala J, Metso AJ, Metso TM, et al. Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke: the Helsinki Young Stroke Registry. Stroke 2009; 40:1195–1203. Putaala J, Curtze S, Hiltunen S, Tolppanen H, Kaste M, Tatlisumak T. Causes of death and predictors of 5-year mortality in young adults after first-ever ischemic stroke: the Helsinki Young Stroke Registry. Stroke 2009;40: 2698 –2703.

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Putaala J, Haapaniemi E, Metso AJ, et al. Recurrent ischemic events in young adults after first-ever ischemic stroke. Ann Neurol 2010;68:661– 671. 22. Putaala J, Kurkinen M, Tarvos V, Salonen O, Kaste M, Tatlisumak T. Silent brain infarcts and leukoaraiosis in young adults with first-ever ischemic stroke. Neurology 2009;72:1823–1829. 23. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial TOAST Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35– 41. 24. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991;337:1521– 1526. 25. Ma¨ntyla R, Aronen HJ, Salonen O, et al. Magnetic resonance imaging white matter hyperintensities and mechanism of ischemic stroke. Stroke 1999;30:2053–2058. 26. Ma¨ntyla R, Aronen HJ, Salonen O, et al. The prevalence and distribution of white-matter changes on different MRI pulse sequences in a post-stroke cohort. Neuroradiology 1999;41:657– 665. 27. Mok VC, Lau AY, Wong A, et al. Long-term prognosis of Chinese patients with a lacunar infarct associated with small vessel disease: a five-year longitudinal study. Int J Stroke 2009;4:81– 88. 28. Henon H, Vroylandt P, Durieu I, Pasquier F, Leys D. Leukoaraiosis more than dementia is a predictor of stroke recurrence. Stroke 2003;34:2935–2940. 29. Ay H, Arsava EM, Rosand J, et al. Severity of leukoaraiosis and susceptibility to infarct growth in acute stroke. Stroke 2008;39:1409 –1413. 30. Nordahl CW, Ranganath C, Yonelinas AP, Decarli C, Fletcher E, Jagust WJ. White matter changes compromise prefrontal cortex function in healthy elderly individuals. J Cogn Neurosci 2006;18:418 – 429. 31. De Groot JC, De Leeuw FE, Oudkerk M, et al. Periventricular cerebral white matter lesions predict rate of cognitive decline. Ann Neurol 2002;52:335–341. 32. Sinyor D, Amato P, Kaloupek DG, Becker R, Goldenberg M, Coopersmith H. Post-stroke depression: relationships to functional impairment, coping strategies, and rehabilitation outcome. Stroke 1986;17:1102–1107. 33. Bots ML, van Swieten JC, Breteler MM, et al. Cerebral white matter lesions and atherosclerosis in the Rotterdam Study. Lancet 1993;341:1232–1237.

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CLINICAL IMPLICATIONS OF NEUROSCIENCE RESEARCH

NMDA receptors Recent insights and clinical correlations

Section Editor Eduardo E. Benarroch, MD

Eduardo E. Benarroch, MD

Address correspondence and reprint requests to Dr. Eduardo E. Benarroch, Department of Neurology, Mayo Clinic, 200 First Street SW, West 8A Mayo Bldg., Rochester, MN 55905 [email protected]

Glutamate is the most abundant excitatory neurotransmitter in the CNS. The excitatory effects of glutamate are mediated by ionotropic and metabotropic receptors. The NMDA receptors (NMDARs) are glutamate-gated cation channels that are highly permeable to calcium (Ca2⫹) and are essential for regulation of synaptogenesis, use-dependent synaptic remodeling, and long-term plastic changes in synaptic strength. Excessive NMDAR activation leads to excitotoxicity, which results in cell loss in a wide range of acute, degenerative, and demyelinating neurologic disorders. NMDAR-mediated synaptic plasticity may contribute to levodopa-induced dyskinesia, drug addiction, and neuropathic pain; impaired NMDAR function may contribute to cognitive impairment in dementia and schizophrenia. Not surprisingly, the NMDARs are a very attractive therapeutic target. A characteristic syndrome resulting from autoantibodies against NMDARs emphasizes the critical role of these receptors in cognition, behavior and motor, respiratory, and autonomic control. Over the past several years, there have been important advances in the understanding of the molecular composition, trafficking, and distribution of these receptors well as the differential effects of NMDAR subtypes on cell survival and plasticity. There have been recent excellent reviews on these subjects.1–10

tinct NR1 isoforms. Separate genes produce 4 types of NR2 (NR2A–D) and 2 types of NR3 (NR3A–B) subunits.12 The typical NMDAR requires consists of 2 NR1 subunits, which bind glycine, and 2 NR2 subunits, which bind glutamate1–5,13 (figure 1). The NR3 subunit can form a complex with NR1 subunits to form a glycine-responsive receptor that does not require L-glutamate.14 The NR1, NR2, and NR3 subunits cotranslationally assemble in the endoplasmic reticulum to form functional channels.4 There is high degree of molecular diversity of NMDARs, which affects their synaptic targeting, physiologic, and pharmacologic properties.1– 6 This molecular heterogeneity is determined by RNA splicing of the NR1 subunits, the subtype of NR2 subunit, and the presence or absence of NR3 subunits. There is a differential distribution of the different NR1, NR2, and NR3 subunit isoforms in human brain12 (table). The expression of NMDAR subunits is differentially regulated during development and in response to synaptic activity.4 NR1/NR2A containing NMDAR receptors predominate at synaptic sites in the adult nervous system whereas NR1/NR2B receptors predominate during development and tend to concentrate at extrasynaptic sites.4,6

STRUCTURAL ORGANIZATION, CHANNEL PROPERTIES, AND MODULATION OF NMDARS Composi-

Structure. Each NMDAR subunit contains a large extracellular amino (N)-terminal domain (ATD), 3 membrane-spanning domains (M1, M3, M4), a reentry, or “hairpin,” loop that forms the pore-lining region (membrane domain 2), and an intracellular carboxy (C)-terminal domain1–5,13 (figure 1). The ATD contains allosteric modulatory sites for hydrogen ions and polyamines in the NR1 subunit, zinc (Zn2⫹) in the NR2A subunits, and ligands such as ifenprodil in the NR2B subunit. The pairing of 2 discrete segments or domains S1 (D1) and S2 (D2)

tion. NMDARs are heteromeric complexes composed

of 4 subunits derived from 3 related families: NR1, NR2, and NR3.1–5 According to the current proposed nomenclature, these subunits are termed GluN1, GluN2, and GluN3, respectively.11 The classic nomenclature will be used in this review. The NR1 is an obligatory subunit that combines with NR2 or NR3 subunits to form a functional receptor. The NR1 subunit gene can be alternatively spliced to produce 8 dis-

GLOSSARY AMPAR ⫽ ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; ATD ⫽ amino (N)-terminal domain; CaMKII ⫽ calcium/calmodulin-dependent kinase II; GABA ⫽ ␥-hydroxybutyric acid; LTD ⫽ long-term depression; LTP ⫽ long-term potentiation; MAPK ⫽ mitogen-activated protein kinase; mtHTT ⫽ mutant huntingtin; NMDAR ⫽ NMDA receptor; PKA ⫽ protein kinase A; PKC ⫽ protein kinase C; PSD ⫽ postsynaptic density. From the Department of Neurology, Mayo Clinic, Rochester, MN. Disclosure: The author reports no disclosures. 1750

Copyright © 2011 by AAN Enterprises, Inc.

Figure 1

Structure, gating, and allosteric modulation of NMDA receptors (NMDARs)

The NMDARs are heteromeric complexes composed of 4 subunits derived from 3 related families: NR1, NR2, and NR3; the NR1 is an obligatory subunit that combines with NR2 or NR3 subunits to form a functional receptor. The typical NMDAR requires 2 NR1 subunits, which bind glycine, and 2 NR2 subunits, which bind glutamate. Each NMDAR subunit contains a large extracellular amino (NH2)-terminal domain (ATD), 3 membrane-spanning domains (M1, M3, M4), a re-entry, or hairpin, loop that forms the pore-lining region (M2), and an intracellular carboxy (COOH)-terminal domain that contains phosphorylation (P) sites. Together, S1 and S2 form a bilobed structure that forms a cavity containing the binding sites for glutamate or glycine. The typical NR1/NR2 receptors are permeable to Ca2⫹ and their activation requires binding of 2 molecules of glutamate to the NR2 and 2 molecules of glycine (or D-serine) to the NR1 subunit. The pore region contains critical asparagine (N) residues that determine ion selectivity. The NMDAR channel is gated in a voltage-dependent manner by extracellular Mg2⫹ located in the channel pore. Several modulatory sites affect the function of the NMDAR channels. These include the polyamine site, Zn2⫹ site, proton-sensitive site, and a redox modulatory site. Nitric oxide (NO) reacts with these critical cysteine residues producing S-nitrosylation (R-SNO). CaMKII ⫽ calcium/calmodulin-dependent kinase II; PKA ⫽ protein kinase A; PKC ⫽ protein kinase C; Src and Fyn ⫽ protein tryosine kinases.

forms the agonist binding domain.13 S1 is a sequence located between the ATD and the first transmembrane domain (M1); S2 is a segment on the extracellular loop between the M3 and M4 domains. Together, S1 and S2 form a bilobed structure; the cavity between the 2 lobes contains the binding sites for glutamate or glycine13 (figure 1). Homologous regions in the S1/S2 segments form the glutamatebinding domain in NR2 and the glycine-binding domain in NR1. The pore-lining region (P-loop) forms the ion channel and contains a critical asparagine (N) residue that constitutes the selectivity filter and is a binding for several NMDAR blockers, such as memantine.2,3,7 The intracellular C-terminus contains phosphorylation sites for protein kinases A and C (PKA, PKC), calcium/calmodulin-dependent kinase II (CaMKII) protein tyrosine kinases.2 NMDAR subunit phosphorylation is critical for activitydependent regulation of NMDAR trafficking and function.4 Gating and channel properties. The NMDAR are cat-

ion channels permeable to Ca2⫹.1–5 Full activation of

the NR1/NR2 receptors requires binding of 2 molecules of glutamate to the NR2 and 2 molecules of glycine to the NR1 subunit. The amino acid D-serine, which is synthesized by astrocytes or neurons, may substitute for glycine at this binding site.7 In NR1/NR2 channels, the P-loop region containing the selectivity filter for divalent cations is formed by an interaction between asparagine (N) residues of NR1 (N-site) and NR2 (N ⫹ 1 site) subunits.1–5 Under normal conditions, the NMDAR channel is opened (or gated) by glutamate, but there is also a voltage-sensitive component to gating. When the neuron is in its resting (polarized) state and the channel is gated open by glutamate, the presence of extracellular Mg2⫹ causes an open channel block by permeating the pore and preventing the passage of other ions. The channel is thereby only passing current for brief periods; when depolarization removes the Mg2⫹ blockade of an open channel, full ion flow is restored. The type of NR2 subunit determines many of the biophysical and pharmacologic properties of NMDARs.1–3 The NR2A subunit confers a Neurology 76

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Table

Function and distribution of NMDAR subunits

Subunit type

NR1 (GluN1)

NR2 (GluN2)

NR3 (GluN3)

Variants

8 splice variants

NR2A–D

NR3A–B

Function in NMDAR

Obligatory

NR2A or NR2B are the most common in NR1/NR2 receptors

Activated by binding or glycine only

Binds glycine

Bind glutamate Determine receptor kinetics

Inhibits Ca2⫹

Binding site

Glycine

Glutamate

Glycine

Modulatory sites

Polyamines

Zn2⫹

?

Protons

Redox site NO (nitrosylation) site

Predominant location

Predominant distribution

Postsynaptic density (PSD) and extrasynaptic

Throughout the CNS (particularly NR1.1)

NR2A: PSD

Dendritic spines during development

NR2B: Extrasynaptic (NR2A/NR2B ratio increases in adult brain)

Oligodendrocytes

Hippocampus (NR2A, NR2B)

Neurons

Neocortex (NR2A, NR2B)

Oligodendrocytes

Cerebellum in Purkinje cell (NR2A, NR2C), molecular (NR2B) and granule cell (NR2C) layers Cortical interneuron (NR2C) Brainstem (NR2C)

Abbreviations: NMDAR ⫽ NMDA receptor; NO ⫽ nitric oxide.

lower affinity for glutamate, faster kinetics, greater channel open probability, and more prominent Ca2⫹-dependent desensitization than the NR2B subunit. During postnatal development of mammalian forebrain, there is an increase in the expression of NR2A compared to NR2B subunits; this subunit conversion has profound effects in synaptic plasticity.1,4 Receptors containing NR2C and NR2D subunits have low conductance openings and reduced sensitivity to Mg2⫹ block.1–3 The NR3 subunits have important properties that distinguish them from other subunits14 and act in a dominant-negative manner to suppress NMDAR activity by reducing Ca2⫹ permeability and surface expression of the receptors.15 Allosteric modulation. The NMDAR also contains

several modulatory sites that affect the function of the channels. These include the polyamine site, Zn2⫹ site, proton-sensitive site, and a redox modulatory site (figure 1).27 Endogenous polyamines, such as spermidine and spermine, produce both stimulation or inhibition on NMDAR currents, depending on the presence of specific NR1 and NR2 subunits. Zinc elicits a voltage-dependent inhibition of NR1/ NR2A receptors. Since Zn2⫹ is released together with glutamate by Ca2⫹-dependent exocytosis in some brain regions, these effects may be physiologically relevant. The NMDARs are inhibited by protons. The redox modulatory site located in the 1752

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extracellular N-terminal domain contains cysteine residues that exists in equilibrium between fully reduced (thiol, R-SH) and oxidized (disulfide, R-SS-R) states. Nitric oxide (NO) reacts with these critical cysteine residues, producing S-nitrosylation (R-SNO), which inhibits the NMDAR.7 MACROMOLECULAR ORGANIZATION AND TRAFFICKING OF NMDA RECEPTORS NMDA

receptors as part of macromolecular complexes. Syn-

aptic NMDARs are localized at postsynaptic densities (PSDs) where they are spatially restricted and organized in a large macromolecular signaling complexes that include synaptic scaffolding and adaptor proteins.4,16,17 These proteins physically link the NMDARs to the cytoskeleton, to downstream signaling proteins, and to group I metabotropic glutamate receptors. At mature synapses, scaffolding proteins such as PSD protein of 95 kDa (PSD-95) link the NR1/NR2 receptors to signaling effector proteins, such as CaM kinase II, PKA, PKC, nitric oxide synthase, and Ras, which are important in the regulation of NMDAR number and function. Trafficking of NMDARs. The number and subunit

composition of NMDARs present at the cell surface represent a balance between insertion and clathrinmediated endocytosis; this balance changes in a celland synapse-specific manner during development and in response to neuronal activity. The molecular

mechanisms involved in NMDAR trafficking have been recently reviewed.4 Assembled NMDARs exit the endoplasmic reticulum and reach synaptic sites via transport along microtubules dependent on the motor protein KIF17 (protein kinesin family member 17). The activity-dependent synaptic targeting, incorporation, retrieval, differential sorting into the endosomal–lysosomal pathway, and lateral diffusion between synaptic and extrasynaptic sites involve trafficking signals intrinsic to NR1 and NR2 subunits, their interactions with adaptor proteins such as PSD95, and activity-regulated phosphorylation of specific C-terminus motifs in NR1 and NR2 subunits. For example, phosphorylation of NR1 by PKA and PKC promotes NMDAR trafficking to the plasma membrane, whereas phosphorylation of NR2 by the protein tyrosine kinase Fyn suppresses clathrinmediated endocytosis. Repeated exposure to glutamate promotes dephosphorylation of this tyrosine residue and induces rapid, use-dependent receptor internalization. This may maintain synaptic homeostasis under conditions of high neuronal firing or excessive accumulation of glutamate in the synapse. The number and subunit composition of synaptic NMDARs are also regulated by activity-dependent protein degradation by the ubiquitin–proteasome system. Synaptic activity accelerates the turnover rate of NR1 and NR2B without significantly affecting that of NR2A or PSD-95; this results in a relative increased NR2A and PSD-95 expression at the PSD in active synapses.4 NMDARS AND SYNAPTIC PLASTICITY, NETWORK OSCILLATION, AND CELL SURVIVAL

NMDAR and synaptic plasticity. Whereas AMPA (␣-

amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPAR) mediate most of the fast excitatory effects of glutamate in the CNS, NMDARs have a critical role in mechanisms of synaptic plasticity18 and network synchronization.19 The NMDAR, due to its voltage-dependent block by Mg2⫹, functions as a coincidence detector of presynaptic and postsynaptic firing and is well-suited for triggering use-dependent changes in synaptic activity, such as long-term potentiation (LTP) or long-term depression (LTD). The NMDAR-mediated increase in postsynaptic Ca2⫹ activates kinases, including CaMKII, PKA, PKC, and mitogen-activated protein kinase (MAPK), as well as protein phosphatases, such as calcineurin. CaMKII-mediated phosphorylation of the GluA1 subunit of the AMPAR promotes its incorporation into the synapses and increases AMPAR channel conductance, resulting in LTP. In contrast, calcineurin-triggered dephosphorylation promotes AMPA receptor internalization and thus LTD.20 Alterations in NMDAR number, subunit composition,

or both also contribute to the expression of LTP; Ca2⫹ influx activates PKC and thus synaptic incorporation of NR2A-containing NMDARs.4 Neuronal activity maintains the weight of synaptic strength and neuronal excitability in an optimal range by concomitantly scaling up or down AMPAR and NMDAR responses, thereby maintaining the NMDAR:AMPAR ratio. This process, referred to as homeostatic plasticity or synaptic scaling, is critical for optimal information transfer in the nervous system. NMDARs in GABAergic neurons and network oscillations. The NMDARs are highly expressed in subsets

of inhibitory ␥-hydroxybutyric acid (GABA)ergic neurons, including fast spiking basket cells that target the soma and axon initial segment of pyramidal cells of the cerebral cortex.21 These GABAergic interneurons are critical for cortical network oscillations at ␥ frequency, which allows the precise timing of spiking of functionally linked pyramidal neurons during a variety of cognitive tasks. These NMDARactivated GABAergic networks also inhibit pyramidal neurons of inactive networks, thus preventing “noise” in cortical circuits, including those in the prefrontal cortex involved in working memory.22 Differential effects of synaptic and extrasynaptic NMDA receptors on cell survival. NMDARs not only

cycle in and out of synaptic sites, but also move laterally between synaptic and extrasynaptic sites in the plasma membrane in an activity-dependent manner.6 Extrasynaptic NMDARs are present at perisynaptic sites distributed on dendrites and in some cases adjacent to glia-like processes or axons. Synaptic and extrasynaptic NMDA receptors differ in their subunit composition, downstream transducing cascades, and effects on cell survival (figure 2). This may explain the so-called “NMDAR paradox”: whereas NMDARs mediate glutamateinduced excitotoxicity and neuronal and glial injury in several experimental models, synaptic NMDAR activity is critical for survival of several types of neurons.8 According to a recent model, synaptic NMDARs are neuroprotective, whereas extrasynaptic NMDARs initiate cell death pathways. Synaptic NMDARdependent neuroprotection involves transduction cascades that elicit induction of survival genes, suppression of death genes, or protection against oxidative stress. Extrasynaptic NMDARdependent neuronal death is mediated by several transduction pathways; many of them antagonize those triggered by synaptic NMDARs8 (figure 2). CLINICAL CORRELATIONS NMDAR-mediated toxicity. NMDAR-mediated Ca2⫹ influx triggers ac-

tivation of phospholipases, NOS, calpain, and nucleases, Ca2⫹ overload to the mitochondria, and Neurology 76

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Figure 2

Transduction pathways involved in cell survival or cell death triggered by synaptic or extrasynaptic NMDA receptors (NMDARs)

According to a recent model, synaptic NMDARs, composed primarily of NR1/NR2A subunits, trigger neuroprotective transduction pathways, whereas extrasynaptic NMDARs, composed predominantly by NR1/NR2B subunits, initiate cell death pathways. Extrasynaptic NMDARs are present at perisynaptic sites distributed on dendrites and in some cases adjacent to glia-like processes or axons. Synaptic NMDAR-dependent neuroprotection involves transduction cascades that elicit induction of survival genes, suppression of death genes, or protection against oxidative stress. Calcium influx via synaptic NMDARs triggers Ca2⫹/calmodulin (CaM) kinase IV and extracellular receptor kinase (ERK)1/2 mediated phosphorylation and activation of CREB (cyclic-AMP response element binding protein) and its coactivator CREB binding protein (CBP); calcineurin elicits dephosphorylation and nuclear translocation of the transducer of regulated CREB-activity (TORC), a key step in CREB activation. CREB promotes transcription of activity-regulated inhibitors of death (AID) and brain-derived neurotrophic factor (BDNF) genes, which provide broad-spectrum neuroprotective effects. Synaptic NMDAR activity also triggers transcriptional suppression of core components of the intrinsic apoptosis cascade, in part via suppressing activity forehead box protein O (FOXO)– dependent expression of proapoptotic genes. This antiapoptotic effect results from Akt-mediated phosphorylation and nuclear export of FOXO. Synaptic NMDAR activation also enhances thioredoxin activity, which elicits antioxidant effects (not shown). In contrast, extrasynaptic NMDARs trigger cell death via several transduction pathways; many of them antagonize those triggered by synaptic NMDARs. These include CREB dephosphorylation by Jacob (juxtasynaptic attractor of caldendrin on dendritic spines) protein, inhibition of the ERK1/2 pathway, promotion of nuclear import of FOXO, and activation of calpain. Bim ⫽ bcl2-interacting mediator of cell death; PI3K ⫽ phosphatidyl inositol 3⬘kinase; Txnp ⫽ thioredoxin interacting protein.

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oxidative stress, leading to disruption of membrane and cytoskeletal proteins, mitochondrial release of proapoptotic factors, and DNA damage.7 These mechanisms may contribute to cell death in a wide range of neurologic disorders, including stroke,23–25 trauma,24,25 epilepsy,26 Huntington disease,27 Alzheimer disease,7,28 Parkinson disease,29 HIV-associated dementia,30 and multiple sclerosis.31,32 These mechanisms and their clinical implications have been extensively reviewed8 and will not be discussed in detail here. Recent evidence points to the importance of NMDAR-mediated plasticity4 and downstream pathways triggered by extrasynaptic NMDARs6 in mechanisms of cell injury in both acute and chronic neurologic disorders. For example, extrasynaptic NMDAR activity may be selectively enhanced in ischemia by recruitment of a death-associated protein kinase to NR2B.33 Studies on the YAC128 transgenic mouse model of Huntington disease show that the balance between synaptic and extrasynaptic NMDAR activity controls the toxicity of mutant huntingtin (mtHTT).34 In the presymptomatic YAC128 transgenic mouse, mHTT selectively increases extrasynaptic NMDAR expression in medium spiny neurons of the striatum; these extrasynaptic NMDARs may promote cell death by several mechanisms, including inhibition of expression of prosurvival genes and increased activity of enzymes that promote mtHTT toxicity.34 NMDAR-mediated plasticity and disease. NMDARmediated synaptic plasticity may contribute to the pathophysiology of several neurologic and psychiatric disorders. For example, NMDAR-mediated plastic changes in excitatory transmission in corticostriate synapses on medium spiny neurons may contribute to levodopa-induced dyskinesias.35 Plasticity at the synapses between nociceptor afferents and spinothalamic dorsal horn neurons contribute to central sensitization and neuropathic pain.36,37 Changes in synaptic expression of NMDAR may contribute to cognitive impairment in neurologic and psychiatric disorders such as Alzheimer disease and schizophrenia. Amyloid-␤ increases internalization of NR1/NR2B receptors by promoting tyrosine dephosphorylation of NR2B subunits.38 APOE4 selectively impairs synaptic plasticity and NMDAR phosphorylation by reelin.39 Schizophrenia is characterized by impaired prefrontal lobe function, which has been attributed to impaired NMDAR-mediated activation of GABAergic interneurons, leading to increased synaptic “noise” in prefrontal circuits.40 – 42 This explains the psychotomimetic effects of NMDAR antagonists such as phencyclidine and ketamine.8 Neuregulin 1, a growth factor genetically linked to schizophrenia,

elicits NR2A dephosphorylation, which promotes NMDAR internalization in the prefrontal cortex.43 NMDA receptor antibody-mediated encephalitis. Dalmau et al.9 described a severe but treatment-responsive encephalitis that associates with autoantibodies to the NMDAR. This disorder is characterized by rapid development of prominent psychiatric and behavioral symptoms, memory loss, seizures, abnormal movements, hypoventilation, and autonomic instability.9,44 – 46 The movement disorder is distinctive and characterized by repetitive semirhythmic ocular, jaw, facial, lingual, limb, and trunk movements, with oculogyric deviation, opisthotonus, and dystonic limb posturing.47 In 2 large series9,48 there was a strong female predominance with median age of 19 years; 40% of cases occurred in children, and in 55% of the adults the disorder was associated with the presence of a tumor, particularly ovarian teratoma. In these cases, the tumor contained nervous system tissue expressing NMDARs. The behavioral, psychiatric, and motor symptoms resemble that observed in models of genetic or pharmacologic attenuation of NMDAR function, including phencyclidine and ketamine overdose.9 Recent studies indicate that the NMDAR antibodies selectively target the extracellular domain of the NR1 subunit, leading to capping and internalization of surface NMDARs and producing a selective and reversible decrease in NMDAR surface density, synaptic localization, and function without a substantial loss of synapses.49 Therapeutic implications. Given the prominent role of NMDARs in mechanisms of neurotoxicity and abnormal plasticity underlying a wide variety of neurologic disorders, there is continuous effort to develop agents that block abnormal NMDAR activity without affecting their normal synaptic function.7,8,50 –54 A number of compounds block NMDAR channels by use- and voltage-dependent mechanisms. Dissociative anesthetics, such as phencyclidine and ketamine, elicit a use- and voltage dependent block of the NMDAR channel, but have psychotomimeticlike, motor, and cognitive side effects that have been linked to their slow kinetics of dissociation from their binding site in the NMDAR channel. In contrast, memantine is a noncompetitive, low-affinity voltage-dependent channel blocker that has fast onand-off kinetics and elicits a preferential blockade of excessive NMDAR activity while sparing normal excitatory synaptic function when administered at low doses.7 Memantine is used for treatment of cognitive deficits in moderate to severe Alzheimer disease.51 Like amantadine, which acts by a similar mechanism, memantine improves motor fluctuations and levodopa-induced dyskinesia in Parkinson disNeurology 76

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ease.52,53 In an experimental model of Huntington disease, low-dose memantine exerted a neuroprotective effect by preferentially blocking extrasynaptic NMDAR; higher doses blocked all NMDARs and caused an exacerbation of both striatal cell loss and motor deficits.34 One modulatory site of potential therapeutic relevance is the S-nitrosylation located in the N-terminal domain of NMDARs.7,50 Other NMDAR-targeted drugs are being tested in clinical trials.8 Low-dose ketamine is investigated for its potential use in various pain states54 and dextromethorphan is registered to be tested in clinical trials in children with Rett syndrome.8 Other potentially promising agents are the antibiotic D-cycloserine, which is a partial glycine agonist, and the open channel blockers neramexane and dimebon.8 The role of NMDARs in synaptic plasticity and excitotoxicity has long been established and is strongly supported by experimental evidence. The recognition that NMDAR antagonists are neuroprotective in animal models has prompted efforts to develop drugs that block excessive NMDAR activity without affecting normal synaptic function.50 Advances in solving the X-ray crystal structures of ligand binding cores of NR1 and NR2 subunits may allow the development of selective agonists and antagonists for individual NR2 subunits3; this may have clinical implications given their differential effects of synaptic and extrasynaptic receptors on cell survival. Furthermore, advances in the understanding of the pharmacology and function of the NR3 subunit and its dominant negative effects on NMDAR function may lead to development of selective NR3 antagonists, to improve NMDAR function, or NR3 agonists to offer neuroprotection against gray and white mater disorders.10,14 However, it should be reemphasized that, despite the fundamental role of NMDARs in normal neural function and pathophysiology of neurologic disease, they provide only one of multiple potential mechanisms of synaptic plasticity and cell injury.

PERSPECTIVE

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Waxman EA, Lynch DR. N-methyl-D-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease. Neuroscientist 2005;11:37– 49. 6. Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 2010;11:682– 696. 7. Chen HS, Lipton SA. The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem 2006;97:1611–1626. 8. Kalia LV, Kalia SK, Salter MW. NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol 2008;7:742–755. 9. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDAreceptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7:1091–1098. 10. Lipton SA. NMDA receptors, glial cells, and clinical medicine. Neuron 2006;50:9 –11. 11. Collingridge GL, Olsen RW, Peters J, Spedding M. A nomenclature for ligand-gated ion channels. Neuropharmacology 2009;56:2–5. 12. Rigby M, Le Bourdelles B, Heavens RP, et al. The messenger RNAs for the N-methyl-D-aspartate receptor subunits show region-specific expression of different subunit composition in the human brain. Neuroscience 1996;73:429 – 447. 13. Mayer ML. Glutamate receptors at atomic resolution. Nature 2006;440:456 – 462. 14. Henson MA, Roberts AC, Perez-Otano I, Philpot BD. Influence of the NR3A subunit on NMDA receptor functions. Prog Neurobiol 2010;91:23–37. 15. Matsuda K, Fletcher M, Kamiya Y, Yuzaki M. Specific assembly with the NMDA receptor 3B subunit controls surface expression and calcium permeability of NMDA receptors. J Neurosci 2003;23:10064 –10073. 16. Gardoni F. MAGUK proteins: new targets for pharmacological intervention in the glutamatergic synapse. Eur J Pharmacol 2008;585:147–152. 17. Collins MO, Husi H, Yu L, et al. Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome. J Neurochem 2006;97(suppl 1):16 –23. 18. Wang H, Hu Y, Tsien JZ. Molecular and systems mechanisms of memory consolidation and storage. Prog Neurobiol 2006;79:123–135. 19. Mann EO, Mody I. Control of hippocampal gamma oscillation frequency by tonic inhibition and excitation of interneurons. Nat Neurosci 2010;13:205–212. 20. Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron 2004;44:5–21. 21. Middleton S, Jalics J, Kispersky T, et al. NMDA receptordependent switching between different gamma rhythmgenerating microcircuits in entorhinal cortex. Proc Natl Acad Sci USA 2008;105:18572–18577. 22. Wang H, Stradtman GG 3rd, Wang XJ, Gao WJ. A specialized NMDA receptor function in layer 5 recurrent microcircuitry of the adult rat prefrontal cortex. Proc Natl Acad Sci USA 2008;105:16791–16796. 23. Taghibiglou C, Martin HG, Lai TW, et al. Role of NMDA receptor-dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries. Nat Med 2009;15: 1399 –1406. 24. Hardingham GE. Coupling of the NMDA receptor to neuroprotective and neurodestructive events. Biochem Soc Trans 2009;37:1147–1160.

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Arundine M, Tymianski M. Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell Mol Life Sci 2004;61:657– 668. 26. Walker M. Neuroprotection in epilepsy. Epilepsia 2007; 48(suppl 8):66 – 68. 27. Fan MM, Raymond LA. N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington’s disease. Prog Neurobiol 2007;81:272–293. 28. Wenk GL, Parsons CG, Danysz W. Potential role of N-methyl-D-aspartate receptors as executors of neurodegeneration resulting from diverse insults: focus on memantine. Behav Pharmacol 2006;17:411– 424. 29. Bagetta V, Ghiglieri V, Sgobio C, Calabresi P, Picconi B. Synaptic dysfunction in Parkinson’s disease. Biochem Soc Trans 2010;38:493– 497. 30. Li W, Huang Y, Reid R, et al. NMDA receptor activation by HIV-Tat protein is clade dependent. J Neurosci 2008; 28:12190 –12198. 31. Matute C. Oligodendrocyte NMDA receptors: a novel therapeutic target. Trends Mol Med 2006;12:289 –292. 32. Stys PK, Lipton SA. White matter NMDA receptors: an unexpected new therapeutic target? Trends Pharmacol Sci 2007;28:561–566. 33. Tu W, Xu X, Peng L, et al. DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell 2010;140:222–234. 34. Milnerwood AJ, Gladding CM, Pouladi MA, et al. Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington’s disease mice. Neuron 2010;65:178 –190. 35. Chase TN. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine. Neurology 1998; 50:S17–S25. 36. Attal N, Bouhassira D. Mechanisms of pain in peripheral neuropathy. Acta Neurol Scand Suppl 1999;173:12–24, discussion 48 –52. 37. Brenner GJ, Ji RR, Shaffer S, Woolf CJ. Peripheral noxious stimulation induces phosphorylation of the NMDA receptor NR1 subunit at the PKC-dependent site, serine896, in spinal cord dorsal horn neurons. Eur J Neurosci 2004;20:375–384. 38. Kurup P, Zhang Y, Xu J, et al. Abeta-mediated NMDA receptor endocytosis in Alzheimer’s disease involves ubiquitination of the tyrosine phosphatase STEP61. J Neurosci 2010;30:5948 –5957. 39. Chen Y, Durakoglugil MS, Xian X, Herz J. ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc Natl Acad Sci USA 2010;107:12011–12016.

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Balu DT, Coyle JT. Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. Neurosci Biobehav Rev 2010;35:848 – 870. 41. Hakami T, Jones NC, Tolmacheva EA, et al. NMDA receptor hypofunction leads to generalized and persistent aberrant gamma oscillations independent of hyperlocomotion and the state of consciousness. PLoS One 2009;4:e6755. 42. Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 2007;27: 11496 –11500. 43. Hahn CG, Wang HY, Cho DS, et al. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 2006;12:824 – 828. 44. Wandinger KP, Saschenbrecker S, Stoecker W, Dalmau J. Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. J Neuroimmunol 2011;231:86 –91. 45. Johnson N, Henry C, Fessler AJ, Dalmau J. Anti-NMDA receptor encephalitis causing prolonged nonconvulsive status epilepticus. Neurology 2010;75:1480 –1482. 46. Gonzalez-Valcarcel J, Rosenfeld MR, Dalmau J. [Differential diagnosis of encephalitis due to anti-NMDA receptor antibodies.] Neurologia 2010;25:409 – 413. 47. Kleinig TJ, Thompson PD, Matar W, et al. The distinctive movement disorder of ovarian teratoma-associated encephalitis. Mov Disord 2008;23:1256 –1261. 48. Florance NR, Davis RL, Lam C, et al. Anti-N-methyl-Daspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol 2009;66:11–18. 49. Hughes EG, Peng X, Gleichman AJ, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 2010;30:5866 –5875. 50. Lipton SA. Pathologically activated therapeutics for neuroprotection. Nat Rev Neurosci 2007;8:803– 808. 51. Thomas SJ, Grossberg GT. Memantine: a review of studies into its safety and efficacy in treating Alzheimer’s disease and other dementias. Clin Interv Aging 2009;4:367–377. 52. Varanese S, Howard J, Di Rocco A. NMDA antagonist memantine improves levodopa-induced dyskinesias and “on-off ” phenomena in Parkinson’s disease. Mov Disord 2010;25:508 –510. 53. Crosby NJ, Deane KH, Clarke CE. Amantadine for dyskinesia in Parkinson’s disease. Cochrane Database Syst Rev 2003:CD003467. 54. Collins S, Sigtermans MJ, Dahan A, Zuurmond WW, Perez RS. NMDA receptor antagonists for the treatment of neuropathic pain. Pain Med 2010;11:1726 –1742.

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SPECIAL ARTICLE

Evidence-based guideline: Treatment of painful diabetic neuropathy Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation V. Bril, MD, FRCP(C) J. England, MD, FAAN G.M. Franklin, MD, MPH, FAAN M. Backonja, MD J. Cohen, MD, FAAN D. Del Toro, MD E. Feldman, MD, PhD, FAAN D.J. Iverson, MD, FAAN B. Perkins, MD, FRCP(C), MPH J.W. Russell, MD, MS, FRPC D. Zochodne, MD

Address correspondence and reprint requests to American Academy of Neurology, 1080 Montreal Avenue, St. Paul, MN 55116 [email protected]

ABSTRACT

Objective: To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). Methods: We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: “What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?” Results and Recommendations: Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL. Neurology® 2011;76:1758–1765 GLOSSARY AAN ⫽ American Academy of Neurology; NNT ⫽ number needed to treat; PDN ⫽ painful diabetic neuropathy; QOL ⫽ quality of life; RCT ⫽ randomized controlled trial; SF-MPQ ⫽ Short Form–McGill Pain Questionnaire; SF-QOL ⫽ Short Form–Quality of Life; VAS ⫽ visual analog pain scale.

Diabetic sensorimotor polyneuropathy represents a diffuse symmetric and length-dependent injury to peripheral nerves that has major implications on quality of life (QOL), morbidity, and costs from a public health perspective.1,2 Painful diabetic neuropathy (PDN) affects 16% of patients with diabetes, and it is frequently unreported (12.5%) and more frequently untreated (39%).3 PDN presents an ongoing management problem for patients, caregivers, and physicians. There are many treat-

ment options available, and a rational approach to treating the patient with PDN requires an understanding of the evidence for each intervention. This guideline addresses the efficacy of pharmacologic and nonpharmacologic treatments to reduce pain and improve physical function and QOL in patients with PDN. The pharmacologic agents reviewed include anticonvulsants, antidepressants, opioids, anti-arrhythmics, cannabinoids, aldose reductase inhibitors, protein kinase

Supplemental data at www.neurology.org e-Pub ahead of print on April 11, 2011, at www.neurology.org. From the University Health Network (V.B., B.P.), University of Toronto, Toronto, Canada; Department of Neurology (J.E.), LSU School of Medicine, New Orleans, LA; University of Washington (G.M.F.), Seattle; University of Wisconsin (M.B.), Madison; Dartmouth Hitchcock Medical Center (J.C.), Lebanon, NH; Department of PM&R (D.D.), Medical College of Wisconsin, Milwaukee; University of Michigan (E.F.), Ann Arbor; Humboldt Neurological Medical Group, Inc. (D.J.I.), Eureka, CA; Department of Neurology (J.W.R.), University of Maryland School of Medicine, Baltimore; and University of Calgary (D.Z.), Calgary, Canada. Appendices e-1– e-5 and References e1– e46 are available on the Neurology威 Web site at www.neurology.org. Approved by the AAN Quality Standards Subcommittee on November 13, 2010; by the AAN Practice Committee on December 15, 2010; by the AAN Board of Directors on February 10, 2011; by the Neuromuscular Guidelines Steering Committee on October 8, 2010; by the AANEM Practice Issues Review Panel on January 15, 2011; by the AANEM Board of Directors on February 15, 2011; by the AAPM&R Quality Practice & Policy Committee on February 6, 2011; and by the AAPM&R Board of Governors on March 11, 2011. Disclosure: Author disclosures are provided at the end of the article. 1758

Copyright © 2011 by AAN Enterprises, Inc.

C beta inhibitors, antioxidants ( ␣ -lipoic acid), transketolase activators (thiamines and allithiamines), topical medications (analgesic patches, anesthetic patches, capsaicin cream, clonidine), and others. The nonpharmacologic modalities include infrared therapy, shoe magnets, exercise, acupuncture, external stimulation (transcutaneous electrical nerve stimulation), spinal cord stimulation, biofeedback and behavioral therapy, surgical decompression, and intrathecal baclofen. DESCRIPTION OF THE ANALYTIC PROCESS

In January 2007, the American Academy of Neurology (AAN), the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation convened an expert panel from the United States and Canada, selected to represent a broad range of relevant expertise. In August 2008, a literature search of MEDLINE and EMBASE was performed in all languages using the MeSH term diabetic neuropathies and its text word synonyms and key words for the therapeutic interventions of interest (see appendix e-1 on the Neurology® Web site at www.neurology.org for a full list of search terms). The search identified 2,234 citations, the titles and abstracts of which were reviewed by at least 2 authors for relevance, resulting in 463 articles. All of these articles were reviewed in their entirety, and of these, the panel identified 79 relevant articles. Each of these articles was rated by at least 2 authors according to the AAN criteria for the classification of therapeutic articles (appendix e-2), and recommendations were linked to the strength of evidence (appendix e-3) and to effect size of the intervention. Disagreements regarding classification were arbitrated by a third reviewer. Articles were included if they dealt with the treatment of PDN, described the intervention clearly, reported the completion rate of the study, and defined the outcome measures clearly. The panel also considered the side effects of the treatment and measures of function and QOL, if any. Case reports and review articles were excluded. We anticipated that studies would use varying measures for quantifying pain reduction. For the purposes of this guideline we preferred the following outcome measures, listed in order of preference: 1. The difference in the proportion of patients reporting a greater than 30% to 50% change from baseline on a Likert or visual analog pain scale (VAS) as compared to no treatment (placebo) or the comparative treatment. The Likert scale is an 11-point linear scale ranging from 0 (no pain) to

10 (maximum pain), and the patient rates his or her pain level on this scale.4 – 6 2. The percent change from baseline on a Likert or VAS as compared to no treatment (placebo) or the comparative treatment.6 3. Any other quantitative measure of pain reduction provided by the investigators. For studies reporting the difference in the proportion of patients reporting a greater than 30% to 50% reduction in pain, we considered a risk difference of ⬎20% a large effect (number needed to treat [NNT] ⬍5), a risk difference of ⬎10% to 20% (NNT ⬎5 to 10) a moderate effect, and a risk difference of ⱕ10% (NNT ⬎10) a small effect, where risk difference is the reduction in pain in the active treatment group minus the reduction in the control group. For studies using a mean reduction from baseline on a Likert scale or VAS as compared to no treatment (placebo) or a comparative treatment, we considered a reduction difference of ⬎30% a large effect, ⬎15% to 30% a moderate effect, and ⱕ15% a small effect. For any other quantitative measure of pain reduction, we considered a reduction of ⬎30% a large effect, ⬎15% to 30% a moderate effect, and ⱕ15% a small effect. The panel recognized that older studies generally lacked measures of QOL and function compared to more recent studies. Furthermore, the panel was aware that a standardized QOL measure for PDN or a standardized assessment of function is not available, and multiple instruments were used to measure QOL, such as the SF-36® Health Survey, subsections of the SF-36, and function (such as sleep interference). Studies with the highest levels of evidence for each intervention are discussed in the text, and data from other studies are shown in the tables. Details of Class I, II, and III studies are presented in the evidence tables. ANALYSIS OF EVIDENCE In patients with PDN, what is the efficacy of pharmacologic agents to reduce pain and improve physical function and QOL? Anticonvulsants.

We identified 20 articles relevant to anticonvulsants graded higher than Class IV (table e-1). Most of the randomized controlled trials (RCTs) rated as Class II instead of Class I had completion rates of less than 80% or the completion rate was not identified. Four studies (3 Class I and 1 Class II) evaluated the efficacy of pregabalin.7–10 All studies found that pregabalin relieved pain, but the effect size was small relative to placebo, reducing pain by 11%–13% on the 11-point Likert scale in the Class I studies. A large dose-dependent effect (24%–50% reduction in Likert pain scores compared to placebo) was obNeurology 76

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served in the Class II study.10 The NNT for a 50% reduction in pain was 4 at 600 g/day.7–10 In the QOL measures, social functioning, mental health, bodily pain, and vitality improved, and sleep interference decreased, all changes with p ⬍ 0.05. Two studies (1 Class I and 1 Class II) evaluated the efficacy of gabapentin.11,12 In the Class I study,11 gabapentin had a small effect of net pain reduction from baseline of 11% on the 11-point Likert scale compared to the change in placebo-treated patients, while a Class II gabapentin study showed no effect.12 Gabapentin had no effect on overall QOL in the single study reporting this measure, but did show an improvement in subsets of mental health and vitality.11 Two Class I trials evaluated the efficacy of lamotrigine.13,14 There was no difference in the primary outcome measures in the lamotrigine and placebo groups. Two studies (both Class II) evaluated the efficacy of sodium valproate.15,16 Both showed a 27%–30% pain reduction (moderate) in the Short Form–McGill Pain Questionnaire (SF-MPQ) with sodium valproate compared to placebo, and QOL was not measured. Both studies were conducted by the same principal investigator at the same center but in separate populations with small numbers of patients; each study was remarkable for the lack of any change in placebo patients and for the lack of side effects typically attributed to sodium valproate. Treatment allocation concealment was not described. One Class II study evaluated the efficacy of topiramate.17 The study reported a small effect compared to placebo, 7% net pain reduction on the VAS, and an NNT of 6.6 for ⬎30% pain reduction. Three Class II studies evaluated the efficacy of oxcarbazepine.18 –20 Two studies showed no benefit,18,20 but a third showed a moderate benefit—17% more patients on oxcarbazepine had a ⬎50% pain reduction compared to placebo, with an NNT of 6.023.19 The study showing a positive response had a slightly higher completion rate (73%19 compared to 67%).20 Short Form–Quality of Life (SF-QOL) scores were not improved. Three Class III studies evaluated the efficacy of lacosamide.21–23 All the studies showed a small reduction in pain with 400 mg/day of lacosamide (3%, 6%, and 6% compared to placebo), but in 2 studies no significant differences compared to placebo were observed with 600 mg/day of lacosamide.22,23 In one study, benefits on general activity and sleep interference QOL measures were observed.21 Conclusions. Based on consistent Class I evidence, pregabalin is established as effective in lessening the pain of PDN. Pregabalin also improves QOL and lessens sleep interference, though the effect size is 1760

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small. Based on one Class I study, gabapentin is probably effective in lessening the pain of PDN. Based on 2 Class II studies, sodium valproate is probably effective in treating PDN. Lamotrigine is probably not effective in treating PDN. Based on Class II evidence, oxcarbazepine is probably not effective in treating PDN. There is conflicting Class III evidence for the effectiveness of topiramate in treating PDN. Based on Class III evidence, lacosamide is possibly not effective in treating PDN. The degree of pain relief afforded by anticonvulsant agents is not associated with improved physical function. Recommendations

1. If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A). 2. Gabapentin and sodium valproate should be considered for the treatment of PDN (Level B). 3. There is insufficient evidence to support or refute the use of topiramate for the treatment of PDN (Level U). 4. Oxcarbazepine, lamotrigine, and lacosamide should probably not be considered for the treatment of PDN (Level B). Clinical context. Although sodium valproate may be effective in treating PDN, it is potentially teratogenic and should be avoided in diabetic women of childbearing age. Due to potential adverse effects such as weight gain and potential worsening of glycemic control, this drug is unlikely to be the first treatment choice for PDN. Antidepressants. We identified 14 articles relevant to antidepressants rated higher than Class IV (table e-2). Seventeen articles were excluded. Most of the RCTs rated as Class II instead of Class I had completion rates of less than 80%. Two studies (1 Class I and 1 Class II) evaluated the efficacy of venlafaxine.24,25 The Class I study reported a moderate effect of venlafaxine, with 23% more pain relief than with placebo on the VAS-PI (0 –100) scale and an NNT of 5.24 In the Class II study, venlafaxine plus gabapentin showed a moderate effect in relieving pain on the 11-point Likert scale in PDN, with 18% more relief than with placebo plus gabapentin.25 The QOL measures of bodily pain, mental health, and vitality improved on the SF-36. Three studies (1 Class I and 2 Class II) evaluated the efficacy of duloxetine in PDN.26 –28 The Class I study showed that duloxetine had a small effect compared to placebo, reducing pain by 8% on the 11point Likert scale26; QOL was not assessed. In 2 Class II studies, duloxetine reduced pain (measured by VAS) 13% more than placebo,27,28 but in one study, a moderate effect was shown in responder analysis, with 26% more responders on duloxetine

120 mg/day (total 52%) than placebo (26%) (responders defined as those patients having 50% reduction in their 24-hour average pain score).27 The completion rate in both studies was about 75%.27,28 Duloxetine reduced interference with general activity and improved SF-36 and EQ-5D™ scores.27,28 Three studies (1 Class I and 2 Class II) evaluated the efficacy of amitriptyline.29 –31 The Class I study showed a large responder effect with amitriptyline, with 43% more responders with amitriptyline than with placebo (requiring at least 20% pain reduction for responder status). A third group in this study that was treated with maprotiline had 18% more responders than the placebo group.29 In 2 Class II studies, amitriptyline had a large effect, reducing pain by 63% and 58% more than placebo on a verbal 13item descriptor list converted to a numeric 5-point scale.30,31 In one of these Class II studies, an active placebo was used.30 Two Class III trials evaluated other tricyclic antidepressants (imipramine and nortriptyline).32,33 One Class III study showed that 47% more subjects on imipramine improved on a global evaluation compared to the placebo group, but there was no difference on a 6-point symptom scale.32 Another Class III study showed a large effect with the combination of nortriptyline plus fluphenazine compared to placebo; 63% more patients had a 50% or greater VAS reduction in the combination group.33 One Class III study compared desipramine, amitriptyline, fluoxetine, and placebo and found a small effect (6% pain reduction) for both amitriptyline and desipramine but not for fluoxetine on a 13-word scale converted to 5 points.34 Conclusions. Based on 3 Class I and 5 Class II studies, the antidepressants amitriptyline, venlafaxine, and duloxetine are probably effective in lessening the pain of PDN. Venlafaxine and duloxetine also improve QOL. Venlafaxine is superior to placebo in relieving pain when added to gabapentin. There is insufficient evidence to determine whether desipramine, imipramine, fluoxetine, or the combination of nortriptyline and fluphenazine are effective for the treatment of PDN. Recommendations

1. Amitriptyline, venlafaxine, and duloxetine should be considered for the treatment of PDN (Level B). Data are insufficient to recommend one of these agents over the others. 2. Venlafaxine may be added to gabapentin for a better response (Level C). 3. There is insufficient evidence to support or refute the use of desipramine, imipramine, fluoxetine, or the combination of nortriptyline and fluphenazine in the treatment of PDN (Level U).

Opioids. We identified 9 articles relevant to opioids graded higher than Class IV (table e-3). Most of the RCTs rated as Class II instead of Class I had completion rates of less than 80%. One Class I study showed that dextromethorphan relieved pain moderately by 16% more than placebo on a 20-point Gracely Box scale in PDN and improved SF-36 results.35 In one Class II study, dextromethorphan with benztropine reduced pain by 24% more than placebo on a 6-point scale, a moderate reduction.36 A Class II study showed that morphine sulfate had a small effect and reduced pain from baseline by 15% on the SF-MPQ and improved SF-36 and Beck Depression Inventory results.37 In 2 Class II studies, tramadol relieved pain moderately (16% and 20% more than placebo on a Likert scale) in PDN38,39 and improved physical function.38 In 3 Class II studies, oxycodone controlled-release and Ultracet (tramadol ⫹ acetaminophen) relieved pain in PDN.40,e1,e2 Oxycodone had a small effect, with 9% more pain relief on the Pain Inventory than placebo. It also improved sleep quality by 7% more than placebo, but did not change SF-36 scores.40 Ultracet improved pain relief by 13% on the VAS, a small effect, and also improved SF-36 scores by 10%.e1 Oxycodone controlled-release had a moderate effect on pain (27% reduction in the VAS compared to placebo), improved disability by 10%, and improved most SF-36 subscores.e2 Conclusions. Based on one Class I study, dextromethorphan is probably effective in lessening the pain of PDN and improving QOL. Based on Class II evidence, morphine sulfate, tramadol, and oxycodone controlledrelease are probably effective in lessening the pain of PDN. Dextromethorphan, tramadol, and oxycodone controlled-release have moderate effect sizes, reducing pain by 27% compared with placebo. Recommendations. Dextromethorphan, morphine sulfate, tramadol, and oxycodone should be considered for the treatment of PDN (Level B). Data are insufficient to recommend one agent over the other. Clinical context. The use of opioids for chronic nonmalignant pain has gained credence over the last decade due to the studies reviewed in this article. Both tramadol and dextromethorphan were associated with substantial adverse events (e.g., sedation in 18% on tramadol and 58% on dextromethorphan, nausea in 23% on tramadol, and constipation in 21% on tramadol). The use of opioids can be associated with the development of novel pain syndromes such as rebound headache. Chronic use of opioids leads to tolerance and frequent escalation of dose. Neurology 76

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Other pharmacologic agents. We identified 18 articles relevant to other pharmacologic agents rated higher than Class IV (table e-4). Thirteen other articles were excluded. Most of the RCTs rated Class II instead of Class I had completion rates of less than 80%, and those rated Class III often lacked predefined endpoints. One Class I study of 0.075% capsaicin showed a large effect, with 40% more pain reduction on the VAS compared to vehicle cream.e3 One Class II study showed that 0.075% capsaicin reduced pain in PDN with a small effect size of 13% in VAS compared to vehicle cream.e4 One Class I study of isosorbide dinitrate spray showed a moderate effect, with 18% more pain reduction on the VAS relative to placebo.e5 One Class I study of clonidine and pentoxifylline compared to placebo did not show an effect of these drugs on PDN.e6 One Class I study of mexiletine did not show an effect on PDN.e7 Two Class II studies both showed pain reduction with mexiletine, one with a large effect (37% more pain reduction than placebo)e8 and one with a small effect (5% difference compared to placebo).e9 Sleep disturbance was reduced in the first Class II studye8 but not in the second.e9 In a single Class I study of sorbinil, pain relief was not observed.e10 One Class I and 2 Class II studies showed benefit from ␣-lipoic acid in reducing pain in PDN, but pain was not a predefined endpoint in these studies.e11-e13 The effect size in pain reduction was moderate (20%–24% superior to placebo). In 2 Class III studies, IV lidocaine decreased pain relative to placebo infusion.e14,e15 In one study, a transient decrease of 75% was observed in a 5-point symptom scale, compared to a decrease of 50% with placebo infusion.e14 In the other study, the McGill Pain Questionnaire improved by a small amount (9% reduction in present pain intensity) with lignocaine, and the differences with placebo were significant due to worsening in the placebo group.e15 The baseline values were not provided. In 2 Class III studies, the Lidoderm patch improved pain scores with a moderate to large effect (20%–30% reduction in pain scores from baseline and 70% of patients experienced more than a 30% decrease in pain).e16,e17 Conclusions. Based on Class I and Class II evidence, capsaicin cream is probably effective in lessening the pain of PDN. Based on Class III studies, there is insufficient evidence to determine if IV lidocaine is effective in lessening the pain of PDN. Based on Class III evidence, the Lidoderm patch is possibly effective in lessening the pain of PDN. Based on 1762

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Class I evidence, clonidine and pentoxifylline are probably not effective for the treatment of PDN. The evidence for the effectiveness of mexiletine is contradictory; however, the only Class I study of this agent indicates that mexiletine is probably ineffective for the treatment of PDN. There is insufficient evidence to determine whether vitamins and ␣-lipoic acid are effective for the treatment of PDN. Based on Class I evidence, isosorbide dinitrate spray is probably effective for the treatment of PDN. Recommendations

1. Capsaicin and isosorbide dinitrate spray should be considered for the treatment of PDN (Level B). 2. Clonidine, pentoxifylline, and mexiletine should probably not be considered for the treatment of PDN (Level B). 3. The Lidoderm patch may be considered for the treatment of PDN (Level C). 4. There is insufficient evidence to support or refute the usefulness of vitamins and ␣-lipoic acid in the treatment of PDN (Level U). Clinical context. Although capsaicin has been effective in reducing pain in PDN clinical trials, many patients are intolerant of the side effects, mainly burning pain on contact with warm/hot water or in hot weather.

In patients with PDN, what is the efficacy of nonpharmacologic modalities to reduce pain and improve physical function and QOL? We identified 11 articles

relevant to nonpharmacologic treatment of PDN graded higher than Class IV (table e-5). Only articles on electrical stimulation, Reiki therapy, lowintensity laser therapy, and magnetized shoe insoles reached evidence levels sufficient for discussion in the text. Surgical decompression was addressed in a previous AAN practice advisorye18 and will not be considered further in this article. Electrical stimulation. One Class I study reported that percutaneous electrical nerve stimulation reduced pain in PDN by a large magnitude (42% on the VAS) compared with the reduction observed with sham treatment, and also improved sleep.e19 One Class II study reported no effect with electrical stimulation,e20 and one Class II study of frequencymodulated electromagnetic neural stimulation showed a small degree of pain relief (11% on the VAS) in a crossover design, but with no improvement in the placebo group.e21 One Class III study showed the addition of electrotherapy to amitriptyline was more effective than amitriptyline alone.e22 Magnetic field treatment. One Class I study using pulsed electromagnetic fields compared with a sham

device failed to demonstrate an effect in patients with PDN.e23 One Class II study of the use of magnetized shoe insoles in patients with PDN showed a small effect (14% VAS decrease) at 4 months compared with that from nonmagnetized insoles, but the endpoint of burning pain was not predetermined.e24 Other interventions. One Class I study on the use of low-intensity laser treatment compared to sham treatment did not show an effect on pain.e25 Reiki therapy is defined as the transfer of energy from the practitioner to the patient to enable the body to heal itself through balancing energy. One Class I study of Reiki therapy did not show any effect on PDN.e26 Other interventions such as exercise and acupuncture do not have any evidence for efficacy in treating PDN. Conclusion. Based on a Class I study, electrical stimulation is probably effective in lessening the pain of PDN and improving QOL. Based on single Class I studies, electromagnetic field treatment, lowintensity laser treatment, and Reiki therapy are probably not effective for the treatment of PDN. There is not enough evidence to support or exclude a benefit of amitriptyline plus electrotherapy in treating PDN. Recommendations

1. Percutaneous electrical nerve stimulation should be considered for the treatment of PDN (Level B). 2. Electromagnetic field treatment, low-intensity laser treatment, and Reiki therapy should probably not be considered for the treatment of PDN (Level B). 3. Evidence is insufficient to support or refute the use of amitriptyline plus electrotherapy for treatment of PDN (Level U).

Table 1

Summary of recommendations Recommended drug and dose

Not recommended

Level A

Pregabalin, 300–600 mg/d

Level B

Gabapentin, 900–3,600 mg/d

Oxcarbazepine

Sodium valproate, 500–1,200 mg/d

Lamotrigine

Venlafaxine, 75–225 mg/d

Lacosamide

Duloxetine, 60–120 mg/d

Clonidine

Amitriptyline, 25–100 mg/d

Pentoxifylline

Dextromethorphan, 400 mg/d

Mexiletine

Morphine sulphate, titrated to 120 mg/d

Magnetic field treatment

Tramadol, 210 mg/d

Low-intensity laser therapy

Oxycodone, mean 37 mg/d, max 120 mg/d

Reiki therapy

Comparison studies. Studies with 2 active treatment arms and without a placebo arm were considered separately and graded using active control equivalence criteria (appendix e-2; table e-6). We identified 6 comparison studies of agents but did not find sufficient evidence to recommend one over the other.e27-e32 The comparisons were gabapentin to amitriptyline,2 venlafaxine to carbamazepine, nortriptyline ⫹ fluphenazine to carbamazepine, capsaicin to amitriptyline, and benfothiamine ⫹ cyanocobalamin with conventional vitamin B. None of the studies defined the threshold for equivalence or noninferiority. CLINICAL CONTEXT SUMMARY FOR ALL EVIDENCE It is notable that the placebo effect varied

from 0% to 50% pain reduction in these studies. Adjuvant analgesic agents are drugs primarily developed for an indication other than treatment of PDN (e.g., anticonvulsants and antidepressants) that have been found to lessen pain when given to patients with PDN. Their use in the treatment of PDN is common.e33 The panel recognizes that PDN is a chronic disease and that there are no data on the efficacy of the chronic use of any treatment, as most trials have durations of 2–20 weeks. It is important to note that the evidence is limited, the degree of effectiveness can be minor, the side effects can be intolerable, the impact on improving physical function is limited, and the cost is high, particularly for novel agents. A summary of Level A and B recommendations for the treatment of PDN is provided in table 1. RECOMMENDATIONS FOR FUTURE RESEARCH

1. A formalized process for rating pain scales for use in all clinical trials should be developed. 2. Clinical trials should be expanded to include effects on QOL and physical function when evaluating efficacy of new interventions for PDN; the measures should be standardized. 3. Future clinical trials should include head-to-head comparisons of different medications and combinations of medications. 4. Because PDN is a chronic disease, trials of longer duration should be done. 5. Standard metrics for side effects to qualify effect sizes of interventions need to be developed. 6. Cost-effectiveness studies of different treatments should be done. 7. The mechanism of action of electrical stimulation is unknown; a better understanding of its role, mode of application, and other aspects of its use should be studied.

Capsaicin, 0.075% QID Isosorbide dinitrate spray Electrical stimulation, percutaneous nerve stimulation ⫻3–4 weeks

DISCLOSURE Dr. Bril has received research support from Talecris Biotherapeutics, Eisai Inc., Pfizer Inc, Eli Lilly and Company, and Johnson & Johnson. Dr. England serves on the speakers’ bureau for and has received funding for Neurology 76

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travel or speaker honoraria from Talecris Biotherapeutics and Teva Pharmaceutical Industries Ltd.; served as an Associate Editor for Current Treatment Options in Neurology; receives research support from the NIH/ NINDS, Wyeth, Astra Zeneca, and Pfizer Inc; holds stock/stock options in Wyeth and Talecris Biotherapeutics; and has served as an expert witness in a medico-legal case. Dr. Franklin serves on the editorial board of Neuroepidemiology; serves as a consultant for the New Zealand Accident Fund; and serves as a consultant for the Workers Compensation Research Institute. Dr. Backonja served on a Safety Monitoring Board for Medtronic, Inc.; serves on the editorial boards of Clinical Journal of Pain, European Journal of Pain, Journal of Pain, Pain, and Pain Medicine; is listed as author on a patent re: A hand-held probe for suprathreshold thermal testing in patients with neuropathic pain and other neurological sensory disorders; serves as a consultant for Allergan, Inc., Astellas Pharma Inc., Eli Lilly and Company, Medtronic, Inc., Merck Serono, NeurogesX, Pfizer Inc, and SK Laboratories, Inc.; and receives research support from NeurogesX. Dr. Cohen serves on an FDA Peripheral and Central Nervous System Drugs Advisory Committee; receives publishing royalties for What Would You Do Now? Neuromuscular Disease (Oxford University Press, 2009); estimates that he performs clinical neurophysiology testing as 50% of his clinical practice; and has given expert testimony, prepared an affidavit, and acted as a witness in a legal proceeding with regard to vaccinerelated injuries and peripheral nerve injuries. Dr. Del Toro receives research support from the NIH. Dr. Feldman serves on a Data Safety and Monitoring Board for Novartis; serves on the editorial boards of Annals of Neurology and the Journal of the Peripheral Nervous System; receives publishing royalties from UpToDate; and receives research support from the NIH, the Taubman Research Institute, and the American Diabetes Association. Dr. Iverson serves as editor of NeuroPI and has been a treating expert witness with regard to a legal proceeding. Dr. Perkins has received research support from Medtronic, Inc., the Canadian Institutes of Health Research, the Juvenile Diabetes Research Foundation, and the Canadian Diabetes Association. Dr. Russell has received honoraria from Exelixis Inc. and Baxter International Inc.; and receives research support from Baxter International Inc., the NIH, the US Veterans Administration, the American Diabetes Association, and the Juvenile Diabetes Foundation. Dr. Zochodne serves on a scientific advisory board for and holds stock options in Aegera Therapeutics Inc.; has received honoraria from Ono Pharmaceutical Co. Ltd.; receives publishing royalties for Neurobiology of Peripheral Nerve Regeneration (Cambridge University Press, 2008); has received research support from the Canadian Institutes of Health Research, the Canadian Diabetes Association, the Juvenile Diabetes Research Foundation, the National Science and Engineering Research Council, the NIH, and the Alberta Heritage Foundation for Medical Research, Baxter International Inc., and Aegera Therapeutics Inc.; and has served as a co-PI on industry trials with Valeant Pharmaceuticals International and Pfizer Inc.

DISCLAIMER This statement is provided as an educational service of the American Academy of Neurology. It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved. The clinical context section is made available in order to place the evidence-based guideline(s) into perspective with current practice habits and challenges. No formal practice recommendations should be inferred.

CONFLICT OF INTEREST The American Academy of Neurology is committed to producing independent, critical and truthful clinical practice guidelines (CPGs). Significant efforts are made to minimize the potential for conflicts of interest to influence the recommendations of this CPG. To the extent possible, the AAN keeps separate those who have a financial stake in the success or failure of the products appraised in the CPGs and the developers of the guidelines. Conflict of interest forms were obtained from all authors and reviewed by an oversight committee prior to project initiation. AAN lim1764

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its the participation of authors with substantial conflicts of interest. The AAN forbids commercial participation in, or funding of, guideline projects. Drafts of the guidelines have been reviewed by at least three AAN committees, a network of neurologists, Neurology® peer reviewers, and representatives from related fields. The AAN Guideline Author Conflict of Interest Policy can be viewed at www.aan.com.

Received December 15, 2010. Accepted in final form February 15, 2011.

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Clinical/Scientific Notes

R. Kawasaki, PhD M.Z. Che Azemin, MSBE D.K. Kumar, PhD A.G. Tan, MPH G. Liew, PhD T.Y. Wong, PhD P. Mitchell, PhD J.J. Wang, PhD

Supplemental data at www.neurology.org

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FRACTAL DIMENSION OF THE RETINAL VASCULATURE AND RISK OF STROKE: A NESTED CASE-CONTROL STUDY

Recent studies show associations between retinal vascular changes and small infarcts detected on brain imaging, or clinical stroke.1 Fractal dimension has been used as a global measure of the geometric pattern of the retinal vasculature2,3 potentially representing the complex branching pattern of the microvasculature, including the cerebral microvasculature. We have developed an automatic method to assess spectrum fractal dimension (SFD) of the retinal microvasculature using Fouriertransformed images.4,5 Two previous studies have reported crosssectional associations between retinal fractal dimension and lacunar stroke.6,7 In this study, we aimed to examine the association between baseline SFD and stroke incidence using a case-control sample nested in the Blue Mountains Eye Study (BMES). Methods. The BMES is a population-based cohort study of an urban population aged 49 years or older (n ⫽ 3,654), representing 82.4% of eligible population in a defined area of the Blue Mountains region, Australia.1 Stroke cases were defined among participants with no past history of stroke at baseline (1992–1994) but who developed stroke during the subsequent 5 years (1997–1999), or who died from stroke or stroke-related causes by late 2005. Detailed definitions of stroke events and mortality are shown in table e-1 on the Neurology® Web site at www. neurology.org. We identified 130 cases with either a stroke event or stroke-related mortality, and excluded 26 cases who had missing photographs or clinical information, leaving 104 cases for inclusion in this report (21 with stroke event, 86 with strokerelated mortality, and 3 overlapped). Two controls per case were selected and matched for age, gender, diabetes, and hypertension status. Of these, 97.1% (101/104) cases and 88.5% (184/208) controls had baseline retinal photographs of sufficient quality to enable SFD assessment. An area covering 2.5 disc radii from the optic disc center was digitally cropped and enhanced using the Gabor-wavelet transform6,7 (figure e-1). The SFD, a mono-fractal in the vessel image spectrum, represents a slope of linear associaNeurology 76

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tion between the natural log-scaled image intensity and the natural log-scaled pixel density frequency distribution.6,7 This system is fully automated. We performed a Monte Carlo type simulation to assess the reproducibility of image cropping, and found estimates of SFD to be highly correlated on 100 simulated crops (r ⫽ 0.93).7 Standard protocol approvals, registrations, and patient consents. Written informed consent was obtained from

all participants at enrollment for this study.1 Statistical analysis. We used SFD measures from left eye, given the high correlation between 2 eyes (r ⫽ 0.63). We constructed conditional logistic regression models to determine odds ratio (OR) and 95% confidence intervals (CI) for risks associated with each SD decrease or quartile differences in SFD: unadjusted (model 1) or adjusted for stroke risk factors (model 2: body mass index [BMI], smoking, total cholesterol, high-density lipoprotein [HDL] cholesterol, and triglycerides; model 3: plus systolic blood pressure [SBP] and glucose level). Finally, a stepwise-selection method was applied to the variables in model 3. Results. Overall, mean age was 73.8 (SD 8.2) years, 58% were female, 49.5% were hypertensive, and 4.6% had diabetes. There were no significant differences in matched or other unmatched characteristics between cases and controls (table e-2). The mean SFD was 1.509 (SD 0.026). Cases had significantly smaller SFD (1.504) compared to controls (1.511; p ⫽ 0.04). Each SD decrease in baseline SFD was associated with 40% greater risk of stroke events (OR 1.39, 95% CI 1.06 –1.83). Persons in the smallest quartile of SFD (⬍1.494) were twice as likely to have a subsequent stroke than those in the largest quartile (⬎1.527) (stroke incidence 42.3% vs 27.8%; OR 2.30, 95% CI 1.06 – 4.97) (table 1). This association remained significant after adjusting for BMI, smoking, total cholesterol, HDL cholesterol, and triglycerides (model 2: OR 2.42, 95% CI 1.04 –5.62), or further adjusting for SBP and glucose (model 3: OR 2.43, 95% CI 1.04 –5.68). Using a stepwise backward selection method, per SD decrease in the SFD was the only factor that retained statistical significance.

Table 1

Association of the spectrum fractal dimensions of the retinal image (SFD) and cumulative indent stroke event and mortality Cumulative incident stroke (%)

Model 1,a OR (95% CI)

Model 2,b OR (95% CI)

Model 3,c OR (95% CI)

Per 1 SD decrease (ⴚ0.02) in SFD

—

1.39 (1.06–1.83)

1.41 (1.05–1.90)

1.42 (1.05–1.92)

SFD in the largest quartile (Q4; SFD >1.527)

20/72 (27.8)

1.0 (Reference)

1.0 (Reference)

1.0 (Reference)

SFD in the 3rd quartile (Q3; SFD ⴝ 1.511–1.526)

25/71 (35.2)

1.67 (0.77–3.64)

1.66 (0.72–3.79)

1.65 (0.72–3.78)

SFD in the 2nd quartile (Q2; SFD ⴝ 1.494–1.510)

26/71 (36.6)

1.66 (0.80–3.44)

1.58 (0.72–3.46)

1.58 (0.72–3.47)

SFD in the smallest quartile (Q1; SFD <1.494)

30/71 (42.3)

2.30 (1.06–4.97)

2.42 (1.04–5.62)

2.43 (1.04–5.68)

Abbreviations: CI ⫽ confidence interval; OR ⫽ odds ratio; SFD ⫽ spectrum fractal dimension of the retinal vascuature. a Model 1: Conditional simple logistic regression. b Model 2: Conditional multiple logistic regression model adjusting for body mass index, smoking, total cholesterol, highdensity lipoprotein cholesterol, and triglycerides. c Model 3: Conditional multiple logistic regression model adjusting for variables in model 2 plus systolic blood pressure and glucose level.

Discussion. We found that low SFD of retinal vasculature was associated with 2-fold higher risk of incident stroke events compared to persons with high SFD, independent of stroke risk factors. Limitations of our study include potential selection bias from excluding cases with poor quality images, and the lack of stroke subtype information. While our study supports the concept that structural change in the retinal microvasculature may represent a subclinical biomarker of risk for stroke, what the specific changes indicate in the context of stroke pathogenesis remains unclear. We speculate that reduced SFD indicates reduced complexity in the branching pattern of the microvasculature, leading to reduced perfusion and limited ability to form collaterals, which could increase vulnerability to hypoxia. From the Centre for Eye Research Australia (R.K., T.Y.W., J.J.W.), University of Melbourne, Victoria; Royal Victorian Eye and Ear Hospital (R.K.), Victoria; School of Electrical and Computer Engineering (M.Z.C.A., D.K.K.), RMIT University, Victoria; Centre for Vision Research (A.G.T., G.L., P.M., J.J.W.), University of Sydney, NSW, Australia; and Singapore Eye Research Institute (T.Y.W.), Singapore National Eye Centre, Singapore. Disclosure: Dr. Kawasaki receives research support from the NHMRC, Grant-in-Aid for scientific research, Japan Society for the Promotion of Science Projects, and Foundation for Total Health Promotion Project grant, Japan. M.Z. Che Azemin receives scholarship support from the Ministry of Higher Education, Putrajaya, Malaysia. Dr. Kumar serves on editorial advisory boards for IEEE Transactions of Neural Systems and Rehabilitation and the Engineering Journal of Medical and Biological Engineering; serves as a consultant for Intelligent Sensing Pty Ltd, Victoria, Australia; and has received fellowship support from Brazil CNPq. A.G. Tan and Dr. Liew report no disclosures. Dr. Wong has served on scientific advisory boards for Pfizer Inc, Novartis, and Allergan, Inc. Prof. Mitchell serves on the editorial board of British Journal of Ophthalmology and Eye, and has served on advisory boards for No-

vartis, Allergan, Solvay, and Pfizer, receiving consultancy fees and travel support from these companies. Dr. Wang serves on the editorial boards of Clinical & Experimental Ophthalmology and the Journal of Ophthalmology; receives publishing royalties for Epidemiology of Age-related Macular Degeneration Early in the 21st Century, in Retinal Degenerations, Biology, Diagnostics, and Therapeutics (Humana Press, 2007); and receives research support from the NHMRC, the Heart Foundation, and the American Health Assistance Foundation. Received August 7, 2010. Accepted in final form December 22, 2010. Address correspondence and reprint requests to Dr. Jie Jin Wang, Centre for Eye Research Australia, University of Melbourne, 32 Gisborne Street, Victoria 3002 Australia; [email protected] Copyright © 2011 by AAN Enterprises, Inc. 1.

2.

3.

4.

5.

6.

7.

Mitchell P, Wang JJ, Wong TY, Smith W, Klein R, Leeder SR. Retinal microvascular signs and risk of stroke and stroke mortality. Neurology 2005;65:1005–1009. Liew G, Wang JJ, Cheung N, et al. The retinal vasculature as a fractal: methodology, reliability, and relationship to blood pressure. Ophthalmology 2008;115:1951–1956. Grauslund J, Green A, Kawasaki R, Hodgson L, Sjolie AK, Wong TY. Retinal vascular fractals and microvascular and macrovascular complications in type 1 diabetes. Ophthalmology 2010;117:1400 –1405. Azemin MZ, Kumar DK, Wong TY, et al. Age-related rarefaction in the fractal dimension of retinal vessel. Neurobiol Aging Epub 2010 May 14. Che Azemin MZ, Kumar DK, Wong TY, Kawasaki R, Mitchell P, Wang JJ. Robust methodology for fractal analysis of the retinal vasculature. IEEE Trans Med Imaging 2011;30:243–250. Doubal FN, MacGillivray TJ, Patton N, Dhillon B, Dennis MS, Wardlaw JM. Fractal analysis of retinal vessels suggests that a distinct vasculopathy causes lacunar stroke. Neurology 2010;74:1102–1107. Cheung N, Liew G, Lindley RI, et al. Retinal fractals and acute lacunar stroke. Ann Neurol 2010;68:107–111.

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1767

David Dick, MD Rita Horvath, MD, PhD Patrick F. Chinnery, FMedSci

AMACR MUTATIONS CAUSE LATE-ONSET AUTOSOMAL RECESSIVE CEREBELLAR ATAXIA

Progressive cerebellar disorders presenting in late middle age often have a structural, toxic, inflammatory, or endocrine basis. Having excluded these causes, many patients are given a clinical diagnosis of multiple systems atrophy type C, or idiopathic lateonset cerebellar ataxia, and not investigated further. Here we describe a sporadic cerebellar syndrome leading to the diagnosis of a rare metabolic disorder with important implications for treatment. Case report. A 58-year-old man presented with an 8-year history of gait unsteadiness, slurred speech, a few tonic/clonic seizures, and a decline in short-term memory. There was no relevant family history or consanguinity. On examination, he had a cerebellar dysarthria with appendicular and gait ataxia. Deep tendon reflexes were preserved, and plantar responses flexor. His Mini-Mental State Examination test score was 19/23 at 51 years of age, and 21/30 at age 58, with an Addenbrooke cognitive assessment of 61/100. Routine hematology, thyroid function, vitamin E, B12, and copper studies were normal. CSF examination revealed normal protein content, cell count, and no oligoclonal bands. Urinary amino and organic acids, hexosaminidase, and acylcarnitines were normal. Echocardiography was normal. An EEG showed a mild generalized increase in slow wave activity and occasional sharply contoured theta waves in the right frontotemporal region. Nerve conduction studies revealed a mild, length-dependent sensorimotor polyneuropathy. Genetic studies were negative for Friedreich ataxia, spinocerebellar ataxia 1, 2, 3, 6, 7, and 17, dentatorubropallidoluysian atrophy (DRPLA), and the fragile X tremor-ataxia syndrome. Muscle biopsy showed occasional atrophic fibers, but no cytochrome oxidase deficient fibers or ragged red fibers. Long-range PCR detected full-length normal mitochondrial DNA in skeletal muscle. Electron microscopy revealed the presence of occasional subsarcolemmal clusters of enlarged mitochondria containing paracrystalline inclusions. Brain MRI at age 51 (figure) showed high signal on T2-weighted images in the white matter of both hemispheres, thalami, midbrain, and pons with associated brainstem atrophy. There was also extensive cortical thickening in the right frontal lobe with abnormal enhancement after IV contrast. By 51 years of age, the cortical thickening had resolved, leaving frontal atrophy.

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Very long chain fatty acids analysis revealed normal C22:0, C24:0, and C26:0 levels and ratios, but elevated levels of phytanic (14.7 ␮mol/L, normal 0.3–11.5 ␮mol/L) and pristanic (75.9 ␮mol/L, normal 0.0 –1.5 ␮mol/L) acids, suggesting a disorder of peroxisomal fatty acid oxidation. Plasma bile acid analysis revealed normal levels of deoxycholic acid (undetectable, normal ⬍4.4 ␮M), chenodeoxycholic acid (0.27, normal 0.22–12.4 ␮M), cholic acid (undetectable, normal ⬍4.6 ␮M), ursodeoxycholic acid (undetectable, normal ⬍2.1 ␮M), hyocholic acid (undetectable, normal ⬍1.0 ␮M), varanic acid (undetectable), and C29 dicarboxylic acid (undetectable), but elevated levels of dihydroxycoprostanic acid (DHCA, 0.87, normally not detected), and trihydroxycoprostanoic acid (THCA, 0.17, normally not detected). Increased excretion of DHCA and THCA in the presence of an elevated pristanic acid suggested a diagnosis of ␣-methylacyl-CoA racemase (AMACR) deficiency, confirmed by the detection of the homozygous c.154T⬎C (p.S52P) AMACR mutation previously reported in patients with this defect.1 Discussion. AMACR deficiency is a rare cause of relapsing encephalopathy, with only 4 previously published clinical descriptions.1-3 The case described here is unusual because of the predominant cerebellar presentation, with a dysarthria described as a late feature in only one other patient.1 Seizures are unusual in late-onset degenerative ataxias. Potential causes include DRPLA, spinocerebellar ataxia type 10, episodic ataxia type 2, and neurometabolic disorders including mitochondrial diseases. If we include the patient described here, seizures have now been described in 80% of patients of AMACR deficiency. In 2, the first seizure occurred after age 50. Our observations stress the importance of measuring phytanic and pristanic acid levels in patients with unexplained ataxia when there are additional features such as epilepsy, even when there is not an obvious retinopathy or deafness (which would be expected in Refsum disease). It is not clear how elevated phytanic acid levels cause neural cell death, but the mechanism may be mediated through an effect on oxidative phosphorylation, and the supply of ATP.4 This may explain why the clinical presentation and imaging findings in our patient are reminiscent of mitochondrial disorders, which underpin a growing group of recessive cerebellar ataxias.5 It is intriguing that there was no objective cognitive decline in our patient over a 7-year period, despite the progressive ataxia. This contrasts with other cases, where the cognitive decline was prominent and progressive. This emphasizes the importance of di-

Figure

Brain MRI

Images taken at 51 years old (51 y/o ⫽ A–D) and 57 years old (57 y/o ⫽ E–I). All images are axial T2 sequences, with the exception of (I), which is a sagittal fluid-attenuated inversion recovery image: (A) right frontal cortical thickening; (B) bilateral thalamic high signal; (C) bilateral midbrain high signal; (D) bilateral pontine high signal; (E) bilateral frontal cortical high signal; (F) bilateral thalamic high signal; (G) bilateral midbrain high signal; (H) bilateral pontine high signal; (I) atrophy of the posterior fossa structures.

etary modifications aimed at reducing phytanic acid and pristanic acid levels, which may prevent clinical progression.6

Address correspondence and reprint requests to Prof. P.F. Chinnery, Institute of Human Genetics, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK; [email protected]

From the Department of Neurology (D.D.), Norfolk and Norwich University Hospital, Norwich; Institute of Human Genetics (R.H., P.F.C.), Newcastle University, Newcastle, UK. Study funding: Supported by the Wellcome Trust. Disclosure: Dr. Dick and Dr. Horvath report no disclosures. Dr. Chinnery serves as an Associate Editor for Brain and is a Wellcome Trust Senior Fellow in Clinical Science and a UK NIHR Senior Investigator who also receives funding from the Medical Research Council (UK), the UK Parkinson’s Disease Society, Association Franc¸aise contre les Myopathies, and the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust. Received September 17, 2010. Accepted in final form December 22, 2010.

Copyright © 2011 by AAN Enterprises, Inc. ACKNOWLEDGMENT The authors thank Drs. H.R. Waterham and S. Ferdinandusse for providing the AMACR molecular diagnostic service.

1.

2.

Ferdinandusse S, Denis S, Clayton PT, et al. Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet 2000;24:188 –191. Thompson SA, Calvin J, Hogg S, Ferdinandusse S, Wanders RJ, Barker RA. Relapsing encephalopathy in a patient with alpha-methylacyl-CoA racemase deficiency. J Neurol Neurosurg Psychiatry 2008;79:448 – 450.

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3.

4.

McLean BN, Allen J, Ferdinandusse S, Wanders RJ. A new defect of peroxisomal function involving pristanic acid: a case report. J Neurol Neurosurg Psychiatry 2002;72:396 – 399. Ronicke S, Kruska N, Kahlert S, Reiser G. The influence of the branched-chain fatty acids pristanic acid and Refsum disease-associated phytanic acid on mitochondrial functions and calcium regulation of hippocampal neurons,

5.

6.

astrocytes, and oligodendrocytes. Neurobiol Dis 2009;36: 401– 410. Assoum M, Salih MA, Drouot N, et al. Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia. Brain 2010;133:2439–2447. Wierzbicki AS. Peroxisomal disorders affecting phytanic acid alpha-oxidation: a review. Biochem Soc Trans 2007; 35:881– 886.

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Clinical/Scientific Notes

R. Kawasaki, PhD M.Z. Che Azemin, MSBE D.K. Kumar, PhD A.G. Tan, MPH G. Liew, PhD T.Y. Wong, PhD P. Mitchell, PhD J.J. Wang, PhD

Supplemental data at www.neurology.org

1766

FRACTAL DIMENSION OF THE RETINAL VASCULATURE AND RISK OF STROKE: A NESTED CASE-CONTROL STUDY

Recent studies show associations between retinal vascular changes and small infarcts detected on brain imaging, or clinical stroke.1 Fractal dimension has been used as a global measure of the geometric pattern of the retinal vasculature2,3 potentially representing the complex branching pattern of the microvasculature, including the cerebral microvasculature. We have developed an automatic method to assess spectrum fractal dimension (SFD) of the retinal microvasculature using Fouriertransformed images.4,5 Two previous studies have reported crosssectional associations between retinal fractal dimension and lacunar stroke.6,7 In this study, we aimed to examine the association between baseline SFD and stroke incidence using a case-control sample nested in the Blue Mountains Eye Study (BMES). Methods. The BMES is a population-based cohort study of an urban population aged 49 years or older (n ⫽ 3,654), representing 82.4% of eligible population in a defined area of the Blue Mountains region, Australia.1 Stroke cases were defined among participants with no past history of stroke at baseline (1992–1994) but who developed stroke during the subsequent 5 years (1997–1999), or who died from stroke or stroke-related causes by late 2005. Detailed definitions of stroke events and mortality are shown in table e-1 on the Neurology® Web site at www. neurology.org. We identified 130 cases with either a stroke event or stroke-related mortality, and excluded 26 cases who had missing photographs or clinical information, leaving 104 cases for inclusion in this report (21 with stroke event, 86 with strokerelated mortality, and 3 overlapped). Two controls per case were selected and matched for age, gender, diabetes, and hypertension status. Of these, 97.1% (101/104) cases and 88.5% (184/208) controls had baseline retinal photographs of sufficient quality to enable SFD assessment. An area covering 2.5 disc radii from the optic disc center was digitally cropped and enhanced using the Gabor-wavelet transform6,7 (figure e-1). The SFD, a mono-fractal in the vessel image spectrum, represents a slope of linear associaNeurology 76

May 17, 2011

tion between the natural log-scaled image intensity and the natural log-scaled pixel density frequency distribution.6,7 This system is fully automated. We performed a Monte Carlo type simulation to assess the reproducibility of image cropping, and found estimates of SFD to be highly correlated on 100 simulated crops (r ⫽ 0.93).7 Standard protocol approvals, registrations, and patient consents. Written informed consent was obtained from

all participants at enrollment for this study.1 Statistical analysis. We used SFD measures from left eye, given the high correlation between 2 eyes (r ⫽ 0.63). We constructed conditional logistic regression models to determine odds ratio (OR) and 95% confidence intervals (CI) for risks associated with each SD decrease or quartile differences in SFD: unadjusted (model 1) or adjusted for stroke risk factors (model 2: body mass index [BMI], smoking, total cholesterol, high-density lipoprotein [HDL] cholesterol, and triglycerides; model 3: plus systolic blood pressure [SBP] and glucose level). Finally, a stepwise-selection method was applied to the variables in model 3. Results. Overall, mean age was 73.8 (SD 8.2) years, 58% were female, 49.5% were hypertensive, and 4.6% had diabetes. There were no significant differences in matched or other unmatched characteristics between cases and controls (table e-2). The mean SFD was 1.509 (SD 0.026). Cases had significantly smaller SFD (1.504) compared to controls (1.511; p ⫽ 0.04). Each SD decrease in baseline SFD was associated with 40% greater risk of stroke events (OR 1.39, 95% CI 1.06 –1.83). Persons in the smallest quartile of SFD (⬍1.494) were twice as likely to have a subsequent stroke than those in the largest quartile (⬎1.527) (stroke incidence 42.3% vs 27.8%; OR 2.30, 95% CI 1.06 – 4.97) (table 1). This association remained significant after adjusting for BMI, smoking, total cholesterol, HDL cholesterol, and triglycerides (model 2: OR 2.42, 95% CI 1.04 –5.62), or further adjusting for SBP and glucose (model 3: OR 2.43, 95% CI 1.04 –5.68). Using a stepwise backward selection method, per SD decrease in the SFD was the only factor that retained statistical significance.

Table 1

Association of the spectrum fractal dimensions of the retinal image (SFD) and cumulative indent stroke event and mortality Cumulative incident stroke (%)

Model 1,a OR (95% CI)

Model 2,b OR (95% CI)

Model 3,c OR (95% CI)

Per 1 SD decrease (ⴚ0.02) in SFD

—

1.39 (1.06–1.83)

1.41 (1.05–1.90)

1.42 (1.05–1.92)

SFD in the largest quartile (Q4; SFD >1.527)

20/72 (27.8)

1.0 (Reference)

1.0 (Reference)

1.0 (Reference)

SFD in the 3rd quartile (Q3; SFD ⴝ 1.511–1.526)

25/71 (35.2)

1.67 (0.77–3.64)

1.66 (0.72–3.79)

1.65 (0.72–3.78)

SFD in the 2nd quartile (Q2; SFD ⴝ 1.494–1.510)

26/71 (36.6)

1.66 (0.80–3.44)

1.58 (0.72–3.46)

1.58 (0.72–3.47)

SFD in the smallest quartile (Q1; SFD <1.494)

30/71 (42.3)

2.30 (1.06–4.97)

2.42 (1.04–5.62)

2.43 (1.04–5.68)

Abbreviations: CI ⫽ confidence interval; OR ⫽ odds ratio; SFD ⫽ spectrum fractal dimension of the retinal vascuature. a Model 1: Conditional simple logistic regression. b Model 2: Conditional multiple logistic regression model adjusting for body mass index, smoking, total cholesterol, highdensity lipoprotein cholesterol, and triglycerides. c Model 3: Conditional multiple logistic regression model adjusting for variables in model 2 plus systolic blood pressure and glucose level.

Discussion. We found that low SFD of retinal vasculature was associated with 2-fold higher risk of incident stroke events compared to persons with high SFD, independent of stroke risk factors. Limitations of our study include potential selection bias from excluding cases with poor quality images, and the lack of stroke subtype information. While our study supports the concept that structural change in the retinal microvasculature may represent a subclinical biomarker of risk for stroke, what the specific changes indicate in the context of stroke pathogenesis remains unclear. We speculate that reduced SFD indicates reduced complexity in the branching pattern of the microvasculature, leading to reduced perfusion and limited ability to form collaterals, which could increase vulnerability to hypoxia. From the Centre for Eye Research Australia (R.K., T.Y.W., J.J.W.), University of Melbourne, Victoria; Royal Victorian Eye and Ear Hospital (R.K.), Victoria; School of Electrical and Computer Engineering (M.Z.C.A., D.K.K.), RMIT University, Victoria; Centre for Vision Research (A.G.T., G.L., P.M., J.J.W.), University of Sydney, NSW, Australia; and Singapore Eye Research Institute (T.Y.W.), Singapore National Eye Centre, Singapore. Disclosure: Dr. Kawasaki receives research support from the NHMRC, Grant-in-Aid for scientific research, Japan Society for the Promotion of Science Projects, and Foundation for Total Health Promotion Project grant, Japan. M.Z. Che Azemin receives scholarship support from the Ministry of Higher Education, Putrajaya, Malaysia. Dr. Kumar serves on editorial advisory boards for IEEE Transactions of Neural Systems and Rehabilitation and the Engineering Journal of Medical and Biological Engineering; serves as a consultant for Intelligent Sensing Pty Ltd, Victoria, Australia; and has received fellowship support from Brazil CNPq. A.G. Tan and Dr. Liew report no disclosures. Dr. Wong has served on scientific advisory boards for Pfizer Inc, Novartis, and Allergan, Inc. Prof. Mitchell serves on the editorial board of British Journal of Ophthalmology and Eye, and has served on advisory boards for No-

vartis, Allergan, Solvay, and Pfizer, receiving consultancy fees and travel support from these companies. Dr. Wang serves on the editorial boards of Clinical & Experimental Ophthalmology and the Journal of Ophthalmology; receives publishing royalties for Epidemiology of Age-related Macular Degeneration Early in the 21st Century, in Retinal Degenerations, Biology, Diagnostics, and Therapeutics (Humana Press, 2007); and receives research support from the NHMRC, the Heart Foundation, and the American Health Assistance Foundation. Received August 7, 2010. Accepted in final form December 22, 2010. Address correspondence and reprint requests to Dr. Jie Jin Wang, Centre for Eye Research Australia, University of Melbourne, 32 Gisborne Street, Victoria 3002 Australia; [email protected] Copyright © 2011 by AAN Enterprises, Inc. 1.

2.

3.

4.

5.

6.

7.

Mitchell P, Wang JJ, Wong TY, Smith W, Klein R, Leeder SR. Retinal microvascular signs and risk of stroke and stroke mortality. Neurology 2005;65:1005–1009. Liew G, Wang JJ, Cheung N, et al. The retinal vasculature as a fractal: methodology, reliability, and relationship to blood pressure. Ophthalmology 2008;115:1951–1956. Grauslund J, Green A, Kawasaki R, Hodgson L, Sjolie AK, Wong TY. Retinal vascular fractals and microvascular and macrovascular complications in type 1 diabetes. Ophthalmology 2010;117:1400 –1405. Azemin MZ, Kumar DK, Wong TY, et al. Age-related rarefaction in the fractal dimension of retinal vessel. Neurobiol Aging Epub 2010 May 14. Che Azemin MZ, Kumar DK, Wong TY, Kawasaki R, Mitchell P, Wang JJ. Robust methodology for fractal analysis of the retinal vasculature. IEEE Trans Med Imaging 2011;30:243–250. Doubal FN, MacGillivray TJ, Patton N, Dhillon B, Dennis MS, Wardlaw JM. Fractal analysis of retinal vessels suggests that a distinct vasculopathy causes lacunar stroke. Neurology 2010;74:1102–1107. Cheung N, Liew G, Lindley RI, et al. Retinal fractals and acute lacunar stroke. Ann Neurol 2010;68:107–111.

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1767

David Dick, MD Rita Horvath, MD, PhD Patrick F. Chinnery, FMedSci

AMACR MUTATIONS CAUSE LATE-ONSET AUTOSOMAL RECESSIVE CEREBELLAR ATAXIA

Progressive cerebellar disorders presenting in late middle age often have a structural, toxic, inflammatory, or endocrine basis. Having excluded these causes, many patients are given a clinical diagnosis of multiple systems atrophy type C, or idiopathic lateonset cerebellar ataxia, and not investigated further. Here we describe a sporadic cerebellar syndrome leading to the diagnosis of a rare metabolic disorder with important implications for treatment. Case report. A 58-year-old man presented with an 8-year history of gait unsteadiness, slurred speech, a few tonic/clonic seizures, and a decline in short-term memory. There was no relevant family history or consanguinity. On examination, he had a cerebellar dysarthria with appendicular and gait ataxia. Deep tendon reflexes were preserved, and plantar responses flexor. His Mini-Mental State Examination test score was 19/23 at 51 years of age, and 21/30 at age 58, with an Addenbrooke cognitive assessment of 61/100. Routine hematology, thyroid function, vitamin E, B12, and copper studies were normal. CSF examination revealed normal protein content, cell count, and no oligoclonal bands. Urinary amino and organic acids, hexosaminidase, and acylcarnitines were normal. Echocardiography was normal. An EEG showed a mild generalized increase in slow wave activity and occasional sharply contoured theta waves in the right frontotemporal region. Nerve conduction studies revealed a mild, length-dependent sensorimotor polyneuropathy. Genetic studies were negative for Friedreich ataxia, spinocerebellar ataxia 1, 2, 3, 6, 7, and 17, dentatorubropallidoluysian atrophy (DRPLA), and the fragile X tremor-ataxia syndrome. Muscle biopsy showed occasional atrophic fibers, but no cytochrome oxidase deficient fibers or ragged red fibers. Long-range PCR detected full-length normal mitochondrial DNA in skeletal muscle. Electron microscopy revealed the presence of occasional subsarcolemmal clusters of enlarged mitochondria containing paracrystalline inclusions. Brain MRI at age 51 (figure) showed high signal on T2-weighted images in the white matter of both hemispheres, thalami, midbrain, and pons with associated brainstem atrophy. There was also extensive cortical thickening in the right frontal lobe with abnormal enhancement after IV contrast. By 51 years of age, the cortical thickening had resolved, leaving frontal atrophy.

1768

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Very long chain fatty acids analysis revealed normal C22:0, C24:0, and C26:0 levels and ratios, but elevated levels of phytanic (14.7 ␮mol/L, normal 0.3–11.5 ␮mol/L) and pristanic (75.9 ␮mol/L, normal 0.0 –1.5 ␮mol/L) acids, suggesting a disorder of peroxisomal fatty acid oxidation. Plasma bile acid analysis revealed normal levels of deoxycholic acid (undetectable, normal ⬍4.4 ␮M), chenodeoxycholic acid (0.27, normal 0.22–12.4 ␮M), cholic acid (undetectable, normal ⬍4.6 ␮M), ursodeoxycholic acid (undetectable, normal ⬍2.1 ␮M), hyocholic acid (undetectable, normal ⬍1.0 ␮M), varanic acid (undetectable), and C29 dicarboxylic acid (undetectable), but elevated levels of dihydroxycoprostanic acid (DHCA, 0.87, normally not detected), and trihydroxycoprostanoic acid (THCA, 0.17, normally not detected). Increased excretion of DHCA and THCA in the presence of an elevated pristanic acid suggested a diagnosis of ␣-methylacyl-CoA racemase (AMACR) deficiency, confirmed by the detection of the homozygous c.154T⬎C (p.S52P) AMACR mutation previously reported in patients with this defect.1 Discussion. AMACR deficiency is a rare cause of relapsing encephalopathy, with only 4 previously published clinical descriptions.1-3 The case described here is unusual because of the predominant cerebellar presentation, with a dysarthria described as a late feature in only one other patient.1 Seizures are unusual in late-onset degenerative ataxias. Potential causes include DRPLA, spinocerebellar ataxia type 10, episodic ataxia type 2, and neurometabolic disorders including mitochondrial diseases. If we include the patient described here, seizures have now been described in 80% of patients of AMACR deficiency. In 2, the first seizure occurred after age 50. Our observations stress the importance of measuring phytanic and pristanic acid levels in patients with unexplained ataxia when there are additional features such as epilepsy, even when there is not an obvious retinopathy or deafness (which would be expected in Refsum disease). It is not clear how elevated phytanic acid levels cause neural cell death, but the mechanism may be mediated through an effect on oxidative phosphorylation, and the supply of ATP.4 This may explain why the clinical presentation and imaging findings in our patient are reminiscent of mitochondrial disorders, which underpin a growing group of recessive cerebellar ataxias.5 It is intriguing that there was no objective cognitive decline in our patient over a 7-year period, despite the progressive ataxia. This contrasts with other cases, where the cognitive decline was prominent and progressive. This emphasizes the importance of di-

Figure

Brain MRI

Images taken at 51 years old (51 y/o ⫽ A–D) and 57 years old (57 y/o ⫽ E–I). All images are axial T2 sequences, with the exception of (I), which is a sagittal fluid-attenuated inversion recovery image: (A) right frontal cortical thickening; (B) bilateral thalamic high signal; (C) bilateral midbrain high signal; (D) bilateral pontine high signal; (E) bilateral frontal cortical high signal; (F) bilateral thalamic high signal; (G) bilateral midbrain high signal; (H) bilateral pontine high signal; (I) atrophy of the posterior fossa structures.

etary modifications aimed at reducing phytanic acid and pristanic acid levels, which may prevent clinical progression.6

Address correspondence and reprint requests to Prof. P.F. Chinnery, Institute of Human Genetics, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK; [email protected]

From the Department of Neurology (D.D.), Norfolk and Norwich University Hospital, Norwich; Institute of Human Genetics (R.H., P.F.C.), Newcastle University, Newcastle, UK. Study funding: Supported by the Wellcome Trust. Disclosure: Dr. Dick and Dr. Horvath report no disclosures. Dr. Chinnery serves as an Associate Editor for Brain and is a Wellcome Trust Senior Fellow in Clinical Science and a UK NIHR Senior Investigator who also receives funding from the Medical Research Council (UK), the UK Parkinson’s Disease Society, Association Franc¸aise contre les Myopathies, and the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust. Received September 17, 2010. Accepted in final form December 22, 2010.

Copyright © 2011 by AAN Enterprises, Inc. ACKNOWLEDGMENT The authors thank Drs. H.R. Waterham and S. Ferdinandusse for providing the AMACR molecular diagnostic service.

1.

2.

Ferdinandusse S, Denis S, Clayton PT, et al. Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet 2000;24:188 –191. Thompson SA, Calvin J, Hogg S, Ferdinandusse S, Wanders RJ, Barker RA. Relapsing encephalopathy in a patient with alpha-methylacyl-CoA racemase deficiency. J Neurol Neurosurg Psychiatry 2008;79:448 – 450.

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3.

4.

McLean BN, Allen J, Ferdinandusse S, Wanders RJ. A new defect of peroxisomal function involving pristanic acid: a case report. J Neurol Neurosurg Psychiatry 2002;72:396 – 399. Ronicke S, Kruska N, Kahlert S, Reiser G. The influence of the branched-chain fatty acids pristanic acid and Refsum disease-associated phytanic acid on mitochondrial functions and calcium regulation of hippocampal neurons,

5.

6.

astrocytes, and oligodendrocytes. Neurobiol Dis 2009;36: 401– 410. Assoum M, Salih MA, Drouot N, et al. Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia. Brain 2010;133:2439–2447. Wierzbicki AS. Peroxisomal disorders affecting phytanic acid alpha-oxidation: a review. Biochem Soc Trans 2007; 35:881– 886.

Career Moves Begin at Neurology Career Center Job seekers: The AAN’s Neurology Career Center is a one-stop shop for qualified candidates looking to make a career move in neurology. Search for opportunities in your state and area of interest and create a profile that you can share with only those employers in whom you’re interested. Advertising for a position in neurology? Reach more than 22,500 Academy members online, in print, and at special career events. Make your next career connection with the Neurology Career Center! www.aan.com/careers

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NEUROIMAGES

Infantile intraspinal and extensive cutaneous hemangiomas Excellent response to propranolol

Figure 1

Multiple cutaneous hemangiomas on head, face, neck, back, and leg

Figure 2

Cervical and thoracic spine MRI showing hemangioma

(A) T2-weighted prior to steroid treatment; (B) slight reduction in size after steroid treatment; and (C) marked reduction of the hemangioma 8 weeks after starting propranolol.

A 6-week-old girl presented with multiple cutaneous hemangiomas (figure 1). She had brisk lower extremity reflexes without other deficits. Imaging revealed extensive hemangiomas in liver and extrapleural and oropharyngeal areas. Spine MRI showed a C5-T9 intraspinal-extradural hemangioma producing cord compression (figure 2A). There was minimal response of the hemangiomas to steroids but improvement with propranolol (figure 2, B and C). Intraspinal hemangioma is rarely associated with extensive cutaneous hemangiomas.1 Corticosteroids are first-line treatment for extensive infantile hemangiomas. Propranolol’s mechanism of vessel regression involves vasoconstriction, apoptosis of capillary endothelial cells, and decreased expression of vascular-endothelial and basic-fibroblast growth-factor genes.2 Partha S. Ghosh, MD, Debabrata Ghosh, MD, Cleveland, OH Disclosure: The authors report no disclosures. Address correspondence and reprint requests to Dr. Partha S. Ghosh, Pediatric Neurology Center, 9500 Euclid Avenue, Desk S-60, Cleveland, OH 44195; [email protected] 1. 2.

Herna´ndez-Martín A, Torrelo A. Cutaneous and paravertebral infantile hemangioma: report of two cases. Pediatr Dermatol 2008;25:193–195. Le´aute´-Labre`ze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008;358:2649 –2651.

Copyright © 2011 by AAN Enterprises, Inc.

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Historical Abstract: November 1, 1974 EVALUATING STORAGE, RETENTION AND RETRIEVAL IN DISORDERED MEMORY AND LEARNING Herman Buschke, MD and Paula Altman Fuld, PhD Neurology 1974;24:1019-1025 Two simple methods that are clinically useful for analyzing impaired memory and learning are selective reminding or restricted reminding. These new methods provide simultaneous analysis of storage, retention, and retrieval during verbal learning because they let the patient show learning by spontaneous retrieval without confounding by continual presentation. Because selective reminding and restricted reminding let the patient show consistent retrieval without any further presentation, they also distinguish list learning from item learning, so that impaired memory and learning can be analyzed further in terms of two stages of learning (item and list). Free Access to this article at www.neurology.org/content/24/11/1019 Comment from David S. Knopman, MD, FAAN, Deputy Editor: This paper is important because it introduced a modern view of learning and memory into neurology.

Historical Abstract: July 1, 1987 TREATMENT OF MULTIPLE SCLEROSIS WITH GAMMA INTERFERON: EXACERBATIONS ASSOCIATED WITH ACTIVATION OF THE IMMUNE SYSTEM Hillel S. Panitch, Robert L. Hirsch, John Schindler, Kenneth P. Johnson Neurology 1987;37;1097–1102 We treated 18 clinically definite relapsing-remitting MS patients with recombinant gamma interferon in a pilot study designed to evaluate toxicity and dosage. Patients received low (1 ␮g), intermediate (30 ␮g), or high (1,000 ␮g) doses of interferon by intravenous infusion twice a week for 4 weeks. Serum levels of gamma interferon were proportional to dose and no interferon was detected in CSF. Seven of the 18 patients had exacerbations during treatment, a significant increase compared with the prestudy exacerbation rate (p ⬍ 0.01). Exacerbations occurred in all three dosage groups and were not precipitated by fever or other dose-dependent side effects. There were significant increases in circulating monocytes bearing class II (HLA-DR) surface antigen, in the proliferative responses of peripheral blood leukocytes, and in natural killer cell activity. These results show that systemic administration of gamma interferon has pronounced effects on cellular immunity in MS and on disease activity within the CNS, suggesting that the attacks induced during treatment were immunologically mediated. Gamma interferon is unsuitable for use as a therapeutic agent in MS. Agents that specifically inhibit gamma interferon production or counteract its effects on immune cells should be investigated as candidates for experimental therapy. Free Access to this article at www.neurology.org/content/37/7/1097 Comment from Richard M. Ransohoff, MD, Associate Editor: A very important and startling clinical trial failure, considered counterintuitive at the time, but which later illuminated MS pathogenesis.

RESIDENT & FELLOW SECTION

Book Review

Section Editor Mitchell S.V. Elkind, MD, MS

PEDIATRIC EPILEPSY, THIRD EDITION

edited by John M. Pellock, Blaise F.D. Bourgeois, and W. Edwin Dodson, 900 pp., Demos Medical Publishing, 2008, $165 Pediatric Epilepsy is an all-encompassing work that strives to stay current with the publication of the latest edition. Written by leaders in the field of pediatric epilepsy, it is clearly organized, beginning with the basic mechanisms underlying epilepsy, followed by classification (using the 1989 International League Against Epilepsy system), diagnosis, treatment, and, finally, the social and psychological issues specific to children. The third edition improves on the second with the addition of a section on epilepsy syndromes organized by age at onset. It also includes a new chapter on channelopathies written by Dr. Edward Cooper, which was extremely valuable and thorough. In fact, every chapter has been updated or entirely rewritten. I found the section on antiepileptic drugs especially useful. While most texts simply provide a

cursory outline of a medication’s indications, mechanism of action, and other features, this work goes to great lengths in detailing the pivotal trials leading up to approval. Clinical studies and treatment recommendations in the pediatric population are also separated from adult data, making this a valuable reference for child neurologists and residents. While some medication chapters included supplemental tables and figures detailing adverse events and interactions, I would have liked to have seen this for more of the medications. This third edition has many improvements compared to its predecessor. I would highly recommend this work to any trainee or practicing physician caring for children with epilepsy. It is well-written and as concise as a comprehensive reference text can be. Reviewed by Keith R. Ridel, MD Disclosure: Dr. Ridel serves on the editorial board for the Resident & Fellow Section of Neurology®. Copyright © 2011 by AAN Enterprises, Inc.

Note to Book Publishers: Neurology® provides reviews of books of interest to the clinical neurologist. Please send any books for possible review in the journal to: Robert A. Gross, MD, PhD, FAAN, Editor-in-Chief, Neurology, 1080 Montreal Ave, St. Paul, MN 55116. Inquiries can be directed to: [email protected]. Please note that not all books received are chosen for review. We do not return books.

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

Robert K. Shin, MD Andrew G. Cheek, MD

Teaching NeuroImages: Positive apraclonidine test in Horner syndrome

Figure

Apraclonidine reverses anisocoria in Horner syndrome

Address correspondence and reprint requests to Dr. Robert K. Shin, Department of Neurology, 110 South Paca Street, Third Floor, Baltimore, MD 21201 [email protected]

(A) Right ptosis and miosis of the right pupil are present. (B) After instillation of apraclonidine, the right ptosis resolves, and the right pupil dilates, resulting in reversal of anisocoria and confirming the diagnosis of Horner syndrome.

A 36-year-old woman reported right eyelid drooping immediately after anterior cervical discectomy and fusion. Examination 2 weeks later revealed right miosis and right ptosis (figure, A). Instillation of one drop of 0.5% apraclonidine in both eyes resulted in reversal of anisocoria and resolution of ptosis (figure, B). Apraclonidine, a selective ␣2 agonist used to reduce intraocular pressure, has only weak ␣1 action and, therefore, has little to no effect on a normal pupil. Patients with Horner syndrome may develop denervation hypersensitivity of ␣1 receptors on the iris dilator muscle, resulting in mydriasis of the affected pupil in response to apraclonidine. Reversal of ptosis may also occur. This denervation

hypersensitivity may develop as soon as 36 hours after injury.1 Apraclonidine is a US Food and Drug Administration–approved medication, routinely used in glaucoma treatment, and is a readily available alternative to cocaine in the diagnosis of Horner syndrome.2 REFERENCES 1. Lebas M, Seror J, Debroucker T. Positive apraclonidine test 36 hours after acute onset of Horner syndrome in dorsolateral pontomedullary stroke. J Neuroophthalmol 2010;30:12–17. 2. Freedman KA, Brown SM. Topical apraclonidine in the diagnosis of suspected Horner syndrome. J Neuroophthalmol 2005;25:83– 85.

From the Departments of Neurology (R.K.S.) and Ophthalmology and Visual Sciences (R.K.S., A.G.C.), University of Maryland School of Medicine, Baltimore. Disclosure: Dr. Shin has received speaker honoraria from Bayer Schering Pharma and Teva Pharmaceutical Industries Ltd. Dr. Cheek reports no disclosures. e100

Copyright © 2011 by AAN Enterprises, Inc.

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

K.-S. Jang, MD, PhD D.-K. Jang, MD Y.-M. Han, MD, PhD A.H. Lee, MD, PhD Y.S. Park, MD, PhD

Teaching NeuroImages: Dual-phase 3D multislice CT angiography for the detection of intracranial pseudoaneurysm Figure

Dual-phase 3-dimensional multislice CT angiography and pathology of an intracranial pseudoaneurysm

Address correspondence and reprint requests to Dr. Dong-Kyu Jang, Department of Neurosurgery, Incheon St. Mary’s Hospital, 665 Bupyung-Dong, Bupyung-Gu, Incheon, Korea [email protected]

(A) An early-arterial-phase 3-dimensional CT angiogram shows no aneurysm on the right internal carotid artery. (B, C) A dorsal wall aneurysm in the right ICA on a late-arterial-phase 3-dimensional CT angiogram (B, black arrow) and on a coronal maximal intensity projection image (C: arrowhead, pseudoaneurysm; white arrow, fetal-type posterior cerebral artery). (D) Aneurysm wall pathology shows rupture of the internal elastic lamina (double black arrows) (D: elastic stain, ⫻200).

A 45-year-old woman was diagnosed with a subarachnoid hemorrhage. Dual-phase 3-dimensional CT angiography (12 and 23 seconds) showed no aneurysm in the early arterial phase (figure, A), but revealed a dorsal-wall aneurysm in the right internal carotid artery on a 3-dimensional image (figure, B) and a maximal intensity projection image (figure, C) in late arterial phase. This aneurysm was trapped with a bypass surgery, and pathologically confirmed as a pseudoaneurysm (figure, D). Dualphase multislice CT is a valuable tool to confirm an

ongoing bleeding site,1,2 which may be a critical clue for the treatment strategy of an intracranial pseudoaneurysm. REFERENCES 1. Kluner C, Rogalla P, Gralla O, Elgeti T, Hamm B, Kroencke T. Value of dual-phase multislice CT prior to minimally invasive therapy of iatrogenic renal injuries. J Endovasc Ther 2005;12:461– 468. 2. Sadick M, Rohrl B, Schnulle P, Duber C, Diehl SJ. Multislice CT-angiography in percutaneous post-interventional hematuria and kidney bleeding: Influence of diagnostic outcome on therapeutic patient management. Preliminary results Arch Med Res 2007;38:126 –132.

From the Departments of Neurosurgery (K.-S.J., D.-K.J., Y.-M.H., Y.S.P.) and Pathology (A.H.L.), Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea. Disclosure: The authors report no disclosures. Copyright © 2011 by AAN Enterprises, Inc.

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Correspondence

DECREASED SERUM BDNF LEVELS IN PATIENTS WITH EPILEPTIC AND PSYCHOGENIC NONEPILEPTIC SEIZURES Editor’s Note: See erratum published in Neurology威 2011;76: 935, which notes: “For more accurate reporting and for any attempt to replicate the experiment, all references in the article to ‘serum BDNF’ should read: ‘plasma BDNF.’” Please refer to the complete erratum for more information.

To the Editor: LaFrance et al.1 reported lower plasma brain-derived neurotrophic factor (BDNF) levels in patients with epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) than healthy controls (HCs). Reduced BDNF in the plasma may be used to differentiate patients with ES and PNES from HCs, and probably from malingerers. However, the small sample size in this study is concerning. Gender and age differences should be considered. Due to the small sample size, stratified analysis seems unlikely. Plasma levels of BDNF vary between different phases of the menstrual cycle.2 It has also been shown that increasing age was associated with reduced levels of plasma BDNF.3 The gender differences and Beck Depression Inventory II (BDI-II) score may partially explain the differences of plasma BDNF levels between patients with ES or PNES and HCs. Although the authors stated that seizure frequency and temporal proximity did not influence the BDNF levels in either the PNES or ES group, the time point to obtain the blood samples was not consistent. Multiple studies have confirmed increased expression of BDNF after seizures.4 Confounders may have influenced the data interpretation. Determinants in the measurement of plasma BDNF include fasting/nonfasting state of blood draw, earlier/later measurement, and sample storage time.5 Studies on these levels should correct for the time of blood withdrawal and storage. In this study, the HCs were recruited from university staff and student volunteers. It is possible that the samples from the HCs were stored less time than the cohort, which may explain the higher levels of BDNF in the plasma of HCs compared to patients with ES or PNES. Hong-Liang Zhang, Changchun, China Disclosure: The author reports no disclosures. 1772

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To the Editor: LaFrance et al.1 reported decreased plasma BDNF levels in patients with epilepsy or with PNES. The authors concluded that adults with epilepsy appear to have decreased levels of plasma BDNF.1 However, we think that some care should be taken when interpreting the results of this study. The mean age for the controls was 22 years vs 43 years for epileptic patients and 40 years for patients with psychogenic nonepileptic seizures. Although the authors controlled for the effect of age using statistics, the control group may not have been adequate for this study. Even if plasma BDNF levels remain constant in 20- or 40-year-olds, some lifestyle aspects would differ between healthy 20-year-old subjects and patients with epilepsy or neuropsychiatric disease in their 40s. In our view, lifestyle differences might potentially induce considerable systematic bias in studies like this. For example, some studies have shown that plasma BDNF levels might be influenced by daily life activities including watching television, eating fruit, or exercising.6,7 It has also been shown that patients with epilepsy or other chronic conditions might have important lifestyle differences when compared to healthy individuals, including amount of physical activity, sleep disorders, and stress levels.8,9 LaFrance et al.1 did not control for potential biases induced by lifestyle differences. Perhaps the authors should have used their own group of patients with PNES. The group with PNES was age-matched and had a chronic condition that would probably affect lifestyle. When the authors compared these 2 groups, they did not find any statistical differences regarding plasma BDNF levels. It may be premature to draw conclusions about the effects of epilepsy on plasma BDNF levels. Further studies with adequate controls are necessary to assess whether BNDF can be used as a biological marker of epilepsy in adults. M.M. Bianchin, J.A. Bragatti, C.M. Torres, G.L. Nuernberg, C.R. Rieder, Porto Alegre, Brazil Disclosure: Drs. Bianchin and Rieder have a CNPq research fellowship from the Brazilian government. Drs. Bragatti, Machado, and Nuernberg report no disclosures.

Reply from the Authors: We appreciate the comments of Dr. Zhang and Dr. Bianchin et al. on our article.

Dr. Zhang cited the study by Cubeddu et al. on menstruation.1 Studying BDNF levels in larger groups of patients with seizures and analyzing males and females separately could address the potential for menstrual-related levels. Dr. Zhang mentioned that the BDI-II score may partially explain the differences of plasma BDNF levels among patients. We specifically controlled for BDI-II score among all the participants and found no correlation between BDI-II score and decreased BDNF levels in the subjects with ES. Regarding the multiple studies confirming increased expression of BDNF after seizures, the prior studies did not examine plasma BDNF in adult patients with epilepsy. Moreover, we assessed for this potential influence by controlling for the time point between most recent seizure and blood draw. There was no association between most recent seizure or seizure frequency and BDNF level. Regarding the potential for effect of sample storage time, samples from HCs were gathered contemporaneously with samples from subjects. In our article, we listed the limitations mentioned by Bianchin et al. regarding the ages of our sample groups. We acknowledged the limited ability of regression analysis to adequately control for confounding by variables whose distribution is largely nonoverlapping across groups. Regarding the observation by Bianchin et al. on control and symptomatic group differences, the PNES group and the ES groups were alike in many ways, but differed in one significant aspect: psychiatric illness and comorbidities. The PNES group had more psychiatric comorbidities overall, higher BDI-II scores, and PNES itself is classified as a psychiatric illness. However, the ES group was carefully selected to exclude any subject with current or recent psychiatric illness confirmed through BDI-II, physician assessment, past histories, and subject reporting. Given the absence of psychiatric comorbidity in the epilepsy group and multiple reports of decreased plasma BDNF levels in other psychiatric illnesses, the similarly decreased levels of BDNF in a nonpsychiatric ES group is notable. Bianchin also commented on the potential effect of lifestyle differences on plasma BDNF levels. While we did not control

for activity level, we acknowledged the literature showing that BDNF levels may be influenced by obesity. We excluded obese participants from the study, which could be an indirect control for some potential lifestyle effect. Ultimately, the study was a novel finding in BDNF and seizures. In addition, it is a call for more data that could shed light on issues raised by the correspondents. W.C. LaFrance, Jr., K. Leaver, G.D. Papadonatos, E.G. Stopa, A.S. Blum, Providence, RI Disclosure: See original article for full disclosure list. Copyright © 2011 by AAN Enterprises, Inc. 1.

2.

3.

4.

5.

6.

7.

8.

9.

LaFrance WC Jr, Leaver K, Stopa EG, Papandonatos GD, Blum AS. Decreased serum BDNF levels in patients with epileptic and psychogenic nonepileptic seizures. Neurology 2010;75:1285–1291. Cubeddu A, Bucci F, Giannini A, et al. Brain-derived neurotrophic factor plasma variation during the different phases of the menstrual cycle in women with premenstrual syndrome. Psychoneuroendocrinology 2011;36:523–530. Erickson KI, Prakash RS, Voss MW, et al. Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci 2010;30:5368 –5375. Shetty AK, Zaman V, Shetty GA. Hippocampal neurotrophin levels in a kainate model of temporal lobe epilepsy: a lack of correlation between brain-derived neurotrophic factor content and progression of aberrant dentate mossy fiber sprouting. J Neurochem 2003;87:147–159. Bus BA, Molendijk ML, Penninx BJ, et al. Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrinology 2011;36:228 –239. Chan KL, Tong KY, Yip SP. Relationship of serum brainderived neurotrophic factor (BDNF) and health-related lifestyle in healthy human subjects. Neurosci Lett 2008; 447:124 –128. Vaynman S, Gomez-Pinilla F. Revenge of the “sit”: how lifestyle impacts neuronal and cognitive health through molecular systems that interface energy metabolism with neuronal plasticity. J Neurosci Res 2006;84:699 –715. Centers for Disease Control and Prevention (CDC). Health-related quality of life among persons with epilepsy: Texas, 1998. MMWR Morb Mortal Wkly Rep 2001;50: 24 –26. Fisher RS, Vickrey BG, Gibson P, et al. The impact of epilepsy from the patient’s perspective I: descriptions and subjective perceptions. Epilepsy Res 2000;41:39 –51.

CORRECTION Relationship of UV exposure to prevalence of multiple sclerosis in England In the article “Relationship of UV exposure to prevalence of multiple sclerosis in England” by S.V. Ramagopalan et al. (Neurology® 2011;76:1410 –1414), the following information was omitted: “For the study, researchers looked at all hospital admissions to National Health Service hospitals in England over 7 years. Specifically, they identified 56,681 cases of multiple sclerosis and 14,621 cases of infectious mononucleosis.” The authors regret the omission.

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Correspondence

DECREASED SERUM BDNF LEVELS IN PATIENTS WITH EPILEPTIC AND PSYCHOGENIC NONEPILEPTIC SEIZURES Editor’s Note: See erratum published in Neurology威 2011;76: 935, which notes: “For more accurate reporting and for any attempt to replicate the experiment, all references in the article to ‘serum BDNF’ should read: ‘plasma BDNF.’” Please refer to the complete erratum for more information.

To the Editor: LaFrance et al.1 reported lower plasma brain-derived neurotrophic factor (BDNF) levels in patients with epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) than healthy controls (HCs). Reduced BDNF in the plasma may be used to differentiate patients with ES and PNES from HCs, and probably from malingerers. However, the small sample size in this study is concerning. Gender and age differences should be considered. Due to the small sample size, stratified analysis seems unlikely. Plasma levels of BDNF vary between different phases of the menstrual cycle.2 It has also been shown that increasing age was associated with reduced levels of plasma BDNF.3 The gender differences and Beck Depression Inventory II (BDI-II) score may partially explain the differences of plasma BDNF levels between patients with ES or PNES and HCs. Although the authors stated that seizure frequency and temporal proximity did not influence the BDNF levels in either the PNES or ES group, the time point to obtain the blood samples was not consistent. Multiple studies have confirmed increased expression of BDNF after seizures.4 Confounders may have influenced the data interpretation. Determinants in the measurement of plasma BDNF include fasting/nonfasting state of blood draw, earlier/later measurement, and sample storage time.5 Studies on these levels should correct for the time of blood withdrawal and storage. In this study, the HCs were recruited from university staff and student volunteers. It is possible that the samples from the HCs were stored less time than the cohort, which may explain the higher levels of BDNF in the plasma of HCs compared to patients with ES or PNES. Hong-Liang Zhang, Changchun, China Disclosure: The author reports no disclosures. 1772

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To the Editor: LaFrance et al.1 reported decreased plasma BDNF levels in patients with epilepsy or with PNES. The authors concluded that adults with epilepsy appear to have decreased levels of plasma BDNF.1 However, we think that some care should be taken when interpreting the results of this study. The mean age for the controls was 22 years vs 43 years for epileptic patients and 40 years for patients with psychogenic nonepileptic seizures. Although the authors controlled for the effect of age using statistics, the control group may not have been adequate for this study. Even if plasma BDNF levels remain constant in 20- or 40-year-olds, some lifestyle aspects would differ between healthy 20-year-old subjects and patients with epilepsy or neuropsychiatric disease in their 40s. In our view, lifestyle differences might potentially induce considerable systematic bias in studies like this. For example, some studies have shown that plasma BDNF levels might be influenced by daily life activities including watching television, eating fruit, or exercising.6,7 It has also been shown that patients with epilepsy or other chronic conditions might have important lifestyle differences when compared to healthy individuals, including amount of physical activity, sleep disorders, and stress levels.8,9 LaFrance et al.1 did not control for potential biases induced by lifestyle differences. Perhaps the authors should have used their own group of patients with PNES. The group with PNES was age-matched and had a chronic condition that would probably affect lifestyle. When the authors compared these 2 groups, they did not find any statistical differences regarding plasma BDNF levels. It may be premature to draw conclusions about the effects of epilepsy on plasma BDNF levels. Further studies with adequate controls are necessary to assess whether BNDF can be used as a biological marker of epilepsy in adults. M.M. Bianchin, J.A. Bragatti, C.M. Torres, G.L. Nuernberg, C.R. Rieder, Porto Alegre, Brazil Disclosure: Drs. Bianchin and Rieder have a CNPq research fellowship from the Brazilian government. Drs. Bragatti, Machado, and Nuernberg report no disclosures.

Reply from the Authors: We appreciate the comments of Dr. Zhang and Dr. Bianchin et al. on our article.

Dr. Zhang cited the study by Cubeddu et al. on menstruation.1 Studying BDNF levels in larger groups of patients with seizures and analyzing males and females separately could address the potential for menstrual-related levels. Dr. Zhang mentioned that the BDI-II score may partially explain the differences of plasma BDNF levels among patients. We specifically controlled for BDI-II score among all the participants and found no correlation between BDI-II score and decreased BDNF levels in the subjects with ES. Regarding the multiple studies confirming increased expression of BDNF after seizures, the prior studies did not examine plasma BDNF in adult patients with epilepsy. Moreover, we assessed for this potential influence by controlling for the time point between most recent seizure and blood draw. There was no association between most recent seizure or seizure frequency and BDNF level. Regarding the potential for effect of sample storage time, samples from HCs were gathered contemporaneously with samples from subjects. In our article, we listed the limitations mentioned by Bianchin et al. regarding the ages of our sample groups. We acknowledged the limited ability of regression analysis to adequately control for confounding by variables whose distribution is largely nonoverlapping across groups. Regarding the observation by Bianchin et al. on control and symptomatic group differences, the PNES group and the ES groups were alike in many ways, but differed in one significant aspect: psychiatric illness and comorbidities. The PNES group had more psychiatric comorbidities overall, higher BDI-II scores, and PNES itself is classified as a psychiatric illness. However, the ES group was carefully selected to exclude any subject with current or recent psychiatric illness confirmed through BDI-II, physician assessment, past histories, and subject reporting. Given the absence of psychiatric comorbidity in the epilepsy group and multiple reports of decreased plasma BDNF levels in other psychiatric illnesses, the similarly decreased levels of BDNF in a nonpsychiatric ES group is notable. Bianchin also commented on the potential effect of lifestyle differences on plasma BDNF levels. While we did not control

for activity level, we acknowledged the literature showing that BDNF levels may be influenced by obesity. We excluded obese participants from the study, which could be an indirect control for some potential lifestyle effect. Ultimately, the study was a novel finding in BDNF and seizures. In addition, it is a call for more data that could shed light on issues raised by the correspondents. W.C. LaFrance, Jr., K. Leaver, G.D. Papadonatos, E.G. Stopa, A.S. Blum, Providence, RI Disclosure: See original article for full disclosure list. Copyright © 2011 by AAN Enterprises, Inc. 1.

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LaFrance WC Jr, Leaver K, Stopa EG, Papandonatos GD, Blum AS. Decreased serum BDNF levels in patients with epileptic and psychogenic nonepileptic seizures. Neurology 2010;75:1285–1291. Cubeddu A, Bucci F, Giannini A, et al. Brain-derived neurotrophic factor plasma variation during the different phases of the menstrual cycle in women with premenstrual syndrome. Psychoneuroendocrinology 2011;36:523–530. Erickson KI, Prakash RS, Voss MW, et al. Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci 2010;30:5368 –5375. Shetty AK, Zaman V, Shetty GA. Hippocampal neurotrophin levels in a kainate model of temporal lobe epilepsy: a lack of correlation between brain-derived neurotrophic factor content and progression of aberrant dentate mossy fiber sprouting. J Neurochem 2003;87:147–159. Bus BA, Molendijk ML, Penninx BJ, et al. Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrinology 2011;36:228 –239. Chan KL, Tong KY, Yip SP. Relationship of serum brainderived neurotrophic factor (BDNF) and health-related lifestyle in healthy human subjects. Neurosci Lett 2008; 447:124 –128. Vaynman S, Gomez-Pinilla F. Revenge of the “sit”: how lifestyle impacts neuronal and cognitive health through molecular systems that interface energy metabolism with neuronal plasticity. J Neurosci Res 2006;84:699 –715. Centers for Disease Control and Prevention (CDC). Health-related quality of life among persons with epilepsy: Texas, 1998. MMWR Morb Mortal Wkly Rep 2001;50: 24 –26. Fisher RS, Vickrey BG, Gibson P, et al. The impact of epilepsy from the patient’s perspective I: descriptions and subjective perceptions. Epilepsy Res 2000;41:39 –51.

CORRECTION Relationship of UV exposure to prevalence of multiple sclerosis in England In the article “Relationship of UV exposure to prevalence of multiple sclerosis in England” by S.V. Ramagopalan et al. (Neurology® 2011;76:1410 –1414), the following information was omitted: “For the study, researchers looked at all hospital admissions to National Health Service hospitals in England over 7 years. Specifically, they identified 56,681 cases of multiple sclerosis and 14,621 cases of infectious mononucleosis.” The authors regret the omission.

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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®, 1080 Montreal Ave., St. Paul, MN 55116 [email protected]

2011 MAY 16–20 Gamma Knife Radiosurgery Course will be held at the Cleveland Clinic Gamma Knife Center, Cleveland, OH. Info: http://my.clevelandclinic.org/brain_tumor/education/ gamma_knife_radiosurgery/default.aspx. MAY 20 Submission deadline for the NORD Funding for Corticobasal Degeneration Clinical Research Grant, 2011. Info: tel: (800) 999-NORD; e-mail: [email protected]; http:// www.rarediseases.org/research/requests. MAY 21 Current and Emerging Uses of Botulinum Toxins in Neurology and Rehabilitation: A Comprehensive Practical Skills Workshop will be held at the InterContinental Hotel and Bank of America Conference Center, Cleveland, OH. MAY 26–28 7th International Headache Seminar “Focus on Headaches: Update and Upcoming Developments” will be held at the Hotel Regina Palace, Stresa (VB), Italy. Info: e-mail: [email protected]; www.istituto-besta.it. JUN. 5-9 15th International Congress of Parkinson’s Disease and Movement Disorders will be held at the Metro Toronto Convention Centre, Toronto, ON, Canada. Info: http://www. movementdisorders.org/congress/congress11/. JUN. 10–11 Florida Neurosurgical Society Annual Meeting will be held at the Ritz-Carlton, Sarasota, FL. Info: tel: (305) 325-4873; http://www.floridaneurosurgerysociety.com/. JUN. 16–23 International Society for the History of the Neurosciences and Cheiron Joint Meeting in Calgary (June 16–19) and Banff (June 19–23), Alberta, Canada. Info: e-mail: [email protected] or [email protected]; http://www.ishn.org/. JUN. 24 Mellen Center Update in Multiple Sclerosis and Related Disorders will be held at the InterContinental Hotel and Bank of America Conference Center, Cleveland, OH. Info: www.ccfcme.org/ms11. JUN. 24–26 11th Annual TianTan International Stroke Conference in Beijing, China. Info: Dr. Liping Liu, e-mail: [email protected]. JUN. 27–JUL. 1 Neuroradiology Review with the Experts (NRE) Summer Session will be held at Park Hyatt Aviara Resort, Carlsbad, CA. Info: www.nreconference.com. JUL. 6–8 UCLA Transcranial Doppler & Cerebral Blood Flow Monitoring Course will be held at Ronald Reagan UCLA Med. Ctr., Los Angeles, CA. Info: Karen Einstein, e-mail: [email protected], tel: (310) 206-0626, fax: (310) 794-2147; http://neurosurgery.ucla.edu/tcdcourse.

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JUL. 13–19 Cleveland Spine Review Hand-on Course 2011 will be held at Cleveland Clinic Lutheran Hospital, Cleveland, OH. Info: www.ccfcme.org/spinereview11. JUL. 14–17 Headache Update – 2011 will be held at Disney’s Grand Floridian, Lake Buena Vista, FL. Info: tel: (877) 706-6363 (toll free) or (773) 883-2062; e-mail: [email protected]; www.dhc-fdn.org. AUG. 5–7 2011 Neurology Update - Comprehensive Review for the Clinician will be held at the Ritz-Carlton, Washington, DC. Info: www.ccfcme.org/NeuroUpdate11. AUG. 8–12 Gamma Knife Radiosurgery Course will be held at the Cleveland Clinic Gamma Knife Center, Cleveland, OH. Info: http://my.clevelandclinic.org/brain_tumor/education/ gamma_knife_radiosurgery/default.aspx. SEP. 9–10 Neuromuscular Update will be held in Cleveland, OH. Info: tel: (216) 983-1239 or (800) 274-8263; e-mail: [email protected]; http://casemed.case.edu/cme (click on Activities & Events). SEP. 16 3rd Annual Practical Management of Acute Stroke Conference will be held at the Embassy Suites Hotel & Conference Center, Independence, OH. Info: www.ccfcme.org/ acutestroke11. SEP. 16-18 12th biennial Conference of the Indian Society for Stereotactic and Functional Neurosurgery, ISSFN 2011, will be held at The Raintree Hotel, Mount Road, Chennai, Tamil Nadu, India. Info: Dr. M. Balamurugan, e-mail: [email protected]; www.issfn2011.co.in. SEP. 25–28 The American Neurological Association will hold its 136th Annual Meeting at the Manchester Grand Hyatt, San Diego, CA. Info: www.aneuroa.org. OCT. 13–16 5th World Congress on Controversies in Neurology (CONy) will take place in Beijing, China. Info: http:// comtecmed.com/cony/2011/. OCT. 21–22 Neurocritical Care 2011: Across the Universe comprises the 9th Annual Cleveland Neurocritical Care and Stroke Conference, the 4th Annual Critical Care Bioinformatics Workshop, the 3rd Annual Transcranial Doppler Ultrasound Workshop, and the 2nd Annual Cleveland Music and Medicine Symposium. At Case Western Reserve University, Cleveland, OH. Select components also available live via the internet. Info: tel: (216) 983-1239 or (800) 274-8263; e-mail: [email protected]; http:// casemed.case.edu/cme (click on Activities & Events). OCT. 21–23 2011 American Academy of Neurology Fall Conference will be held at Encore Wynn, Las Vegas, NV.

OCT. 24–25 Gamma Knife Radiosurgery Course will be held at the Cleveland Clinic Gamma Knife Center, Cleveland, OH. Info: http://my.clevelandclinic.org/brain_tumor/education/ gamma_knife_radiosurgery/default.aspx. NOV. 2–4 UCLA Transcranial Doppler & Cerebral Blood Flow Monitoring Course will be held at Ronald Reagan UCLA Med. Ctr., Los Angeles, CA. Info: Karen Einstein, e-mail: [email protected], tel: (310) 206-0626, fax: (310) 794-2147; http://neurosurgery.ucla.edu/tcdcourse.

NOV. 3–5 4th Conference Clinical Trials on Alzheimer’s Disease will be held in San Diego, CA. Info: http://www.ctad.fr. NOV. 28–DEC. 2 Gamma Knife Radiosurgery Course will be held at the Cleveland Clinic Gamma Knife Center, Cleveland, OH. Info: http://my.clevelandclinic.org/brain_tumor/ education/gamma_knife_radiosurgery/default.aspx. DEC. 8–11 North American Neuromodulation Society 15th Annual Meeting will be held at the Wynn, Las Vegas, NV.

Retain a Permanent Record of the 2011 AAN Annual Meeting Watch webcasts, read syllabi, and listen to MP3s on the best programming at the 2011 Annual Meeting. Whether you made it to Hawaii or not, you’ll want these valuable products for future reference. Order today at www.aan.com/vam.

Save These Dates for AAN CME Opportunities! Mark these dates on your calendar for exciting continuing education opportunities, where you can catch up on the latest neurology information. Regional Conference ● October 21–23, 2011, Las Vegas, Nevada, Encore Wynn Hotel AAN Annual Meeting ● April 21–28, 2012, New Orleans, Louisiana, Morial Convention Center

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In the next issue of Neurology® Volume 76, Number 21, May 24, 2011 www.neurology.org THE MOST WIDELY READ AND HIGHLY CITED PEER-REVIEWED NEUROLOGY JOURNAL

IN FOCUS

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Spotlight on the May 24 Issue

VIEWS & REVIEWS

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EDITORIALS

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Looking into posterior cortical atrophy: Providing insight into Alzheimer disease David F. Tang-Wai and Neill R. Graff-Radford Are all IV thrombolysis exclusion criteria necessary? Being SMART about evidence-based medicine David Tong

ARTICLES

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CSF biomarkers in posterior cortical atrophy J. Seguin, M. Formaglio, et al.

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Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution M.H. Rosenbloom, A. Alkalay, N. Agarwal, et al.

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Resting bold fMRI differentiates dementia with Lewy bodies vs Alzheimer disease J.E. Galvin, J.L. Price, Z. Yan, J.C. Morris, et al. Progression of language decline and cortical atrophy in subtypes of primary progressive aphasia E. Rogalski, D. Cobia, T.M. Harrison, et al.

Reconsidering recent myocardial infarction as a contraindication for IV stroke thrombolysis D.A. De Silva, J.J.F. Manzano, H.M. Chang, et al.

CLINICAL/SCIENTIFIC NOTES

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Floppy epiglottis as a contraindication of CPAP in patients with multiple system atrophy T. Shimohata, M. Tomita, H. Nakayama, et al.

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No influence of KIF1B on neurodegenerative markers in multiple sclerosis M.H. Sombekke, N. Jafari, K. Bendfeldt, et al.

NEUROIMAGES

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Fenestration of the internal carotid artery mimicking floating thrombus on CT and MR angiography T. Tourdias, J. Berge, P. Menegon, and I. Sibon

HISTORICAL ABSTRACTS

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Familial agenesis of cerebellar vermis: A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation

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Early childhood prolonged febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy: An MRI volumetric study

RESIDENT & FELLOW SECTION

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International Issues: Tropical neurology in Vietnam Sarah I. Sheikh Teaching NeuroImages: Schwannoma of the cauda equina M. Sawires, R. Knapp, and K. Berek

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Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease A.F. Ramlackhansingh, S.K. Bose, I. Ahmed, et al.

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Final results from 18 years of the International Lamotrigine Pregnancy Registry M.C. Cunnington, J.G. Weil, et al.

CORRESPONDENCE

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Vitamin D in African Americans with multiple sclerosis J.M. Gelfand, B.A.C. Cree, J. McElroy, et al. Diabetes mellitus and ischemic stroke in the young: Clinical features and long-term prognosis J. Putaala, R. Liebkind, D. Gordin, L.M. Thorn, et al.

Subject to change

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Open biopsy in acute progressive neurologic decline

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Improving safety for the neurologic patient

DEPARTMENTS

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Book Review Calendar

FUTURE ISSUES

Abstracts In the Next Issue of Neurology®

THE OFFICIAL JOURNAL OF THE AMERICAN ACADEMY OF NEUROLOGY

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