From the publishers of The New England Journal of Medicine July 2008 Vol. 10 No. 7

Amyloid Plaques Are reinforce the notion that amyloid plaques the 40-odor University of Pennsylvania are dynamic, again suggesting that Smell Identification Test (UPSIT) and Surprisingly Dynamic they do not result from an unstoppable an average of 2.9 years later (range, 3 he amyloid hypothesis of Alzheimer march of amyloid accretion but, rather, months to 24 years) with the 40-odor T disease predicts that amyloid plaques from a process wherein plaques may UPSIT or a 12-odor version. (One of the are a precursor of neuronal damage. come and (with manipulation) go. Un- study authors is a shareholder in the However, researchers recently proposed doubtedly, the kinetics are different in company that manufactures the smell that neuronal damage may precede humans, but again, overturning conven- test used.) plaque formation. In this study, the tional wisdom enables the contemplation From baseline to follow-up, 11.3% of authors used a novel imaging technique of therapeutic opportunities that might anosmic and 23.3% of hyposmic patients to provide insights into the chronology heretofore have been discarded out regained their age-adjusted sense of of amyloid deposition in the brains of of hand. smell (although significant improvement transgenic mice bred to overexpress — Sam Gandy, MD, PhD occurred in 56.7% and 42.7%, respec- human amyloid precursor protein. Meyer-Luehmann M et al. Rapid appear- tively). Age, initial severity of smell loss, The authors monitored brain paren- ance and local toxicity of amyloid-β and time from onset to baseline signifi- chyma of these transgenic mice weekly plaques in a mouse model of Alzheimer’s cantly predicted the degree of recovery; disease. Nature 2008 Feb 7; 451:720. and then daily. They observed that fully the cause of initial impairment, elapsed morphologically typical amyloid plaques time between tests, gender, and initial could appear within a single day, and smoking habit did not. The authors em- develop to their final size within 1 week. Predicting Recovery phasize the value of quantitative assess- Evidence of neuritic dystrophy appeared ment of smell loss, as 87 of the study after the plaques appeared. from Smell Loss participants had no smell loss on testing. Comment: his was a longitudinal study of pre- Comment: dictors of recovery in 542 people The development of methods for visual- T Smell identification was undertaken who complained of smell loss due to izing amyloid plaques in vivo has led to by two different methods. The authors various causes, including trauma, infec- ongoing revision of our understanding acknowledge the possibility, but con- tion, surgery, and medical treatments. of the biology of these structures. The sider it unlikely, that the loss of sensitiv- Testing was conducted at baseline (mean first surprise, from 3 years ago, was that ity inherent in comparing the two time since smell loss, 1.08 years) with antibodies against amyloid-β could clear away both deposits and the accompany- ing neuritic dystrophy in mice (Nat Med TABLE OF CONTENTS 2001; 7:369). This was quite unexpected, because experimental solubilization of Amyloid Plaques Are New Brain Tumor Therapies, deposits has required denaturing con- Surprisingly Dynamic ...... 49 New Recurrence Patterns ...... 53 centrations of guanidine. The relevance Predicting Recovery from Smell Loss .... 49 SOX1 Antibodies and Paraneoplastic Lambert-Eaton of rapid plaque turnover in mice to Does the Vitamin D Emperor Have Clothes? ...... 50 Myasthenic Syndrome ...... 53 what is certainly a slower process in Cortical Demyelination in MS Distinguishing Polymyositis humans remains unclear. But upending and Progressive Multifocal from Inclusion Body Myositis ...... 54 the conventional wisdom led many in Leukoencephalopathy ...... 51 Restless Legs Syndrome Is Associated the field to contemplate amyloid clear- Epilepsy and Mental Retardation with Cardiovascular Disease ...... 54 ance as a serious therapeutic possibility. in Females: Unusual Inheritance ...... 51 Diaphragm Shrinkage in Mechanically The current findings indicate that Effects of Vagus Nerve Stimulation Ventilated Patients ...... 55 plaque deposition can occur just as on Cardiovascular Regulation ...... 52 Predicting Outcome in Vestibular Neuritis ...... 55 rapidly as can plaque clearance. This Platelet Aggregometry as a Marker of Risk for Vascular Events: Not Yet ...... 52 Surgery Beneficial study has become an instant classic, Venous Sinus Stenting for Idiopathic for Lumbar Spinal Stenosis ...... 56 nicknamed the “popcorn plaque” paper Intracranial Hypertension ...... 52 among the cognoscenti. The findings

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EDITOR-IN-CHIEF different procedures weakens the over- other clinical chemistry assays in the Martin A. Samuels, MD, FAAN, MACP, DSc (hon) all conclusion; if so, the 12-odor test 23 patients with MS and in 23 healthy Professor of Neurology, Harvard Medical School; should have been used on both occasions. laboratory workers (controls). Neurologist-in-Chief and Chairman, Department of Neurology, Although the analysis suggests that The authors state that half of all par- Brigham and Women’s Hospital, Boston original etiology is unimportant, there ticipants had S-25(OH)D levels at or were just two major initial causes (upper below 37 nmol/L (considered deficient) DEPUTY EDITOR respiratory infection and head trauma). at some point during the year. Levels Galen V. Henderson, MD Neurologist, Division of Cerebrovascular Diseases, Idiopathic cases would be difficult to of 25(OH)D were lower and levels of Department of Neurology, include in an etiology-based analysis. intact parathyroid hormone (iPTH) were Brigham and Women’s Hospital, Boston The findings are still useful, but arguably higher during relapses than during re- EXECUTIVE EDITOR they cannot be applied to all cases of missions. The abstract also states, “All Christine Sadlowski smell loss. Intuitively, it would be re- 21 relapses during the study occurred Massachusetts Medical Society markable if all causes of anosmia had at serum iPTH levels >20 ng/L. . . where- ADVISORY BOARD the same outlook when matched for as 38% of patients in remission had Clive Hawkins, MD, DM initial severity. Given that improvements iPTH levels ≤20 ng/L. . . There is an in- Professor of Clinical Neurology, Keele University Medical School; University Hospital of North in smell can occur in as little as 3 months, verse relationship between serum vita- Staffordshire, Stoke-on-Trent, United Kingdom the long intervals between the initial min D level and MS clinical activity.” smell loss and baseline for most study Bryan M. Kies, MD Comment: Associate Professor, Neurology Division, Faculty of participants might explain the apparent Health Sciences, University of Cape Town; Senior prognostic similarity for the different This simple clinician had some difficulty Specialist, Groote Schuur Hospital, Cape Town, following the authors’ presentation. The South Africa etiologies. The patients who improved after baseline might have been those who supplementary figure published online Jun Kimura, MD plotted vitamin D levels and relapses Professor, Emeritus, Kyoto University, Kyoto, were tested earlier in their condition’s Japan; Professor, Department of Neurology, evolution than those who fared badly. over a 1-year interval for 12 patients. Iowa University Health Care, Iowa City, IA This is the largest study of smell re- Relapses did not occur any more often Edward H. Koo, MD covery so far and provides guidance during the presumed high-risk months Professor, Department of Neurosciences, (8 in December through May, when University of California at San Diego, La Jolla, CA in a hitherto poorly defined area. The findings are clearly valuable in counsel- vitamin D levels are lowest) than during Alberto Portera-Sanchez, MD the other months (11 relapses). Professor of Neurology, Emeritus, ing patients and plaintiffs in lawsuits. Complutense University, Madrid, Spain They counter the widely held belief that Figure 2 of the article is a scatter plot of S-25(OH)D and iPTH levels from Amy A. Pruitt, MD olfactory loss is largely irreversible and Department of Neurology, University of are consistent with the theory that origi- patient specimens drawn during relapse Pennsylvania Medical Center, Philadelphia nal cause determines outlook. These (21) or remission (122). All values for Thomas D. Sabin, MD results are of value in assessing olfactory the relapses fit well within calculable Professor and Vice Chair, confidence intervals for the remission Department of Neurology, Tufts University disturbance due to trauma and infection. School of Medicine, Boston I suspect the prognosis estimate will values: Mean vitamin D levels and standard deviations (SDs) were Thomas R. Swift, MD be less accurate for anosmia related to Professor and former Chair, Department of Neurology, neurosurgical and neurodegenerative 47.4±14.4 nmol/L during relapses and Medical College of Georgia, Augusta, GA conditions. 60.0±21.8 nmol/L during remissions, Jaime Toro, MD — Christopher Hawkes, MD, FRCP giving 95% confidence intervals of Chief, Section of Neurology, 19.2 to 75.6 in relapse and 17.3 to 102.7 London B et al. Predictors of prognosis Fundación Santa Fe de Bogotá; Professor and in remission. For iPTH levels, respec- Director of the Program of Neurology, University of in patients with olfactory disturbance. El Bosque, Santa Fe de Bogotá, Colombia Ann Neurol 2008 Feb; 63:159. tive means and standard errors were 33.1 (2.6) ng/L and 26.4 (1.1) ng/L, giving MASSACHUSETTS MEDICAL SOCIETY SDs of 11.91 and 12.15 respectively, for Betty Barrer, Kristin Odmark, Sharon S. Salinger, Staff Editors 95% CIs of 9.8 to 56.5 for relapses and Randi Kravitz, Copy Editor Does the Vitamin D 2.6 to 50.2 for remissions. Patricia Lupien, Sioux Waks, Layout Emperor Have Clothes? Looking at the authors’ data on mea- Christopher R. Lynch surements by season, the groups did Vice President for Publishing he aim of this study was to exam- not differ in vitamin D levels. The iPTH Alberta L. Fitzpatrick, Publisher T ine whether low vitamin D levels peaks, in winter, did differ (41 ng/L in Matthew O’Rourke, Director, correlate with disease activity in multiple Editorial Operations and Development controls, 29 ng/L in patients), but both Art Wilschek, Christine Miller, Lew Wetzel, sclerosis (MS). Subjects were participants were well within the cited normal Wayne Wickman, Advertising Sales from Turku, Finland, in the PRISMS range (15–65 ng/L). Calcium in winter William Paige, Publishing Services Study of interferon beta-1a; 15 patients was also within the normal range Bette Clancy, Customer Service had received either of the two drug (2.15–2.51 mmol/L): about 2.35 mmol/L Published 12 times a year. Subscription rates — U.S.: $119 per year; Resident/Student/Nurse: $69; Institutions: $179; indi- dosages, and 8 had received placebo. in controls and 2.23 mmol/L in patients. vidual print only: $89. Canada: C$163.81 per year; Resident/ From serum specimens that had been For all of these comparisons, the find- Student/Nurse: C$96.19; Institutions: C$252.38. Intl: US$149 per year; Resident/Student/Nurse: US$75; Institutions: drawn every 3 months and at time of ing of statistical significance seems to US$216. Prices do not include GST, HST, or VAT. Remittance relapse, up to 64 weeks, the authors rely on comparing individual test values to: Journal Watch Neurology, P.O. Box 9085, Waltham, MA 02454-9085 or call 1-800-843-6356. E-mail inquiries or com- measured serum 25-hydroxyvitamin D rather than patients, and even then by ments via the Contact Us page at www.jwatch.org. (S-25[OH]D), parathyroid hormone, and Information on our conflict-of-interest policy can be found at relying on differences in means rather www.jwatch.org/misc/conflict.dtl calcium levels and performed several than, say, 95% confidence intervals of July 2008 JOURNAL WATCH NEUROLOGY Page 51 the means. Biologic significance could for a greater proportion of cortical de- in these regions also differ. Finally, sub- also be questioned, because all of these myelination. Active PML lesions were pial demyelination is common in MS, differences, regardless of assessment associated with CD68+ macrophages but rare to nonexistent in PML and HIV method, apparently fall within normal and monocytes that were often activated encephalopathy. ranges. The conclusion of an association (major histocompatibility complex class — Kenneth L. Tyler, MD between vitamin D levels and MS relapses II+). T-cell (CD3+) density was highest Moll NM et al. Cortical demyelination in does not seem well substantiated. I am in the white matter of leukocortical PML and MS: Similarities and differences. beginning to wonder how well-clothed lesions. Axon injury (as characterized by Neurology 2008 Jan 29; 70:336. the vitamin D emperor is in MS. interrupted patterns of neurofilament-H Lassmann H and Lucchinetti CF. Corti- — John F. Kurtzke, MD, FACP, FAAN protein staining, variation in neurite cal demyelination in CNS inflammatory demyelinating diseases. Neurology 2008 Soilu-Hänninen M et al. A longitudinal caliber, and presence of neuritic ovoids Jan 29; 70:332. study of serum 25-hydroxyvitamin D and and end bulbs) was more common in intact parathyroid hormone levels indicate white-matter lesions than in cortical the importance of vitamin D and calcium gray-matter lesions. homeostasis regulation in multiple sclero- Subpial lesions were present in none sis. J Neurol Neurosurg Psychiatry 2008 Epilepsy and Mental Feb; 79:152. of the PML samples but in half of the MS samples and accounted for the greatest Retardation in Females: area of demyelinated cortex in MS. Both Unusual Inheritance MS and PML lesions had many activated Cortical Demyelination macrophages and monocytes and a pre- pilepsy and mental retardation lim- + ited to females (EFMR) is a disorder in MS and ponderance of CD3 cells in the white- E matter portion of leukocortical lesions. characterized by convulsions in infancy, Progressive Multifocal mental retardation, and intellectual dis- Comment: Leukoencephalopathy ability. This disorder has a poorly un- There are several important conclusions derstood mode of inheritance, whereby ultiple sclerosis (MS) and progres- to draw from this study, as the editorial- seemingly unaffected males transmit it M sive multifocal leukoencephalopa- ists note. First, the frequency of cortical to their daughters. These authors de- thy (PML) are both demyelinating CNS demyelination in PML had previously scribe the clinical, electrophysiologic, diseases. Prior studies have generally been underappreciated, likely in part and genetic characteristics of four un- focused on the patterns of demyelination because standard MRI does not allow related families with histories suggestive in white matter that are induced by visualization of cortical demyelination. of EFMR. From 58 family members who these diseases. However, there has been These cortical demyelinated lesions provided data, the authors analyzed increasing recognition that demyelina- probably contribute to the “cortical” findings from seizure histories, neuro- tion involving the cerebral cortex likely symptomatology (e.g., altered mental logic examinations, medical records, contributes to the pathogenesis and status, aphasia, and seizures) often seen neuroimaging studies, intelligence as- clinical symptomatology of both PML in PML. Second, both the macrophage/ sessments, and genetic linkage studies. and MS. microglial and T-cell inflammatory Information from 27 affected females In this study the authors provide a responses differ substantially between showed that, on average, seizures began detailed pathological comparison of gray- and white-matter portions of de- at age 14 months and ended at 12 years. cortical demyelination in MS and PML. myelinated lesions in both PML and MS, All had convulsive seizures, and two They examined postmortem brain ma- suggesting that the mechanisms of injury terial from 13 patients with HIV infec- tion and PML, 4 patients with secondary- CONTRIBUTING EDITORS FOR THIS ISSUE progressive MS, 2 patients with HIV Anthony A. Amato, MD, Vice-Chairman, Sunnybrook Health Sciences Centre, Division of encephalopathy, and one control with Department of Neurology, Brigham and Women’s Neurology, Toronto; and Assistant Professor, a non-neurological disease. They classi- Hospital, and Professor of Neurology, Harvard University of Toronto; Amy A. Pruitt, MD, Journal fied cortical demyelination, on the Medical School, Boston; Josep Dalmau, MD, PhD, Watch Neurology Advisory Board Member; Professor of Neurology and Director, Laboratory Michael Ronthal, MD, Professor of Neurology, basis of lesion location, as leukocortical of Neuro-Oncology and Paraneoplastic Disorders, Harvard Medical School and Beth Israel Deaconess (affecting gray and white matter and University of Pennsylvania, Philadelphia; Medical Center, Boston; Steven C. Schachter, MD, crossing the corticomedullary junction), Mitchell S.V. Elkind, MD, MS, Associate Professor Director of Research, Department of Neurology, intracortical (predominantly involving of Neurology, Columbia University, New York Beth Israel Deaconess Medical Center; and City; Sam Gandy, MD, PhD, Mount Sinai Professor Professor of Neurology, Harvard Medical School, layers III through VI), or subpial (ex- of Alzheimer’s Disease Research, Mount Sinai Boston; Ronald J. Tusa, MD, PhD, Professor of tending from the pial surface into the School of Medicine, New York City; Christopher Neurology, Director of the Dizziness and Balance cortex). Hawkes, MD, FRCP, Consultant Neurologist, Center, Emory University, Atlanta; Kenneth L. Essex Neurosciences Centre, Romford, Essex, Tyler, MD, Reuler-Lewin Family Professor of Cortical demyelination was found in United Kingdom; Autumn Klein, MD, PhD, Neurology and Professor of Medicine, all PML tissue samples. The lesions were Instructor in Neurology, Harvard Medical School, Microbiology, and Immunology, University of intracortical (60%) and leukocortical and Director of the Program in Women’s Colorado Health Sciences Center, and Chief, (40%), never subpial. The intracortical Neurology, Brigham and Women’s Hospital, Neurology Service, Denver Veterans Affairs Boston; John F. Kurtzke, MD, FACP, FAAN, Medical Center; Eelco F.M. Wijdicks, MD, lesions were found predominantly in Professor Emeritus of Neurology, Georgetown Professor of Neurology, Mayo Clinic, Rochester, middle cortical layers (III through VI) University, and Consultant in Neurology and Minnesota; Dileep Yavagal, MD, Director of and were frequently small. Leukocortical Neuroepidemiology, VAMC, Washington, DC; Interventional Neurology and Co-Director of Brian J. Murray, MD, FRCP(C), D, ABSM, Endovascular Neurosurgery, University Of lesions were less numerous than intra- Neurologist and Sleep Medicine Specialist, Miami/Jackson Memorial Hospital, Miami. cortical ones, were larger, and accounted Page 52 JOURNAL WATCH NEUROLOGY Volume 10 Number 7 thirds had febrile seizures. Clinical pre- VNS (on phase) and 5 minutes of no events during the 5-year interval — the sentation, development, and intellect stimulation (off phase) in 21 epilepsy investigators used interviews, question- varied widely. EEGs showed generalized patients at least 9 months after stimulator naires, and chart review. spike-wave discharges, focal abnormali- implantation. (The typical on-off time of There was no association between ties, and diffuse slowing; imaging find- VNS in clinical practice is 30 seconds on the results of aggregometry and recurrent ings were normal. Autism and obsessive- and 5 minutes off.) ischemic events. However, patients with compulsive disorder were prominent. There were no discernible overall recurrent events were older and more The authors note that the male carriers effects on diastolic or systolic BP or RRI. likely to have hypertension than those showed rigid personalities and behaviors However, the low-frequency power of with a single episode. The authors con- on informal assessments. The candidate BP and low- and high-frequency powers clude that traditional risk factors are gene was mapped to Xq22, but no fur- of the RRI were significantly increased more important predictors of recur- ther localization was possible. during the on phase compared with the rence than is platelet function testing. off phase, suggesting VNS-mediated in- Comment: Comment: creases in both sympathetic and para- EFMR exemplifies a disease that does sympathetic cardiovascular modulation. This study provides a counterpoint to not follow typical inheritance patterns. the scant and as-yet unconvincing litera- One could postulate a component of the Comment: ture that suggests that platelet function candidate gene on the X chromosome These intriguing findings add to the evi- tests may be useful for monitoring pa- that is activated only in the presence of dence that VNS has measurable effects tients who take aspirin for vascular pre- another X chromosome, or, conversely, on vagally mediated function, presum- vention. Although the present study has inactivated by a Y chromosome. Although ably via efferent conduction from the important flaws — including its retro- the article focuses on the affected fe- site of stimulation. The clinical conse- spective design, clinic-based population, males, the “unaffected” males, or the quences of these effects — whether and small sample size — it does not rare unaffected female with the disease beneficial, deleterious, or neutral — demonstrate a role for routine testing of locus, may provide better insights into remain uncertain, particularly because platelet function using aggregometry. disease mechanism and transmission. we do not know whether long-term There are problems with all of the — Autumn Klein, MD, PhD VNS affects autonomic tone between existing tests of platelet function, in- Scheffer IE et al. Epilepsy and mental retar- periods of stimulation, and whether or cluding lack of agreement among assay dation limited to females: An under- how VNS might influence cardiovascular results, limited evidence of validity recognized disorder. Brain 2008 Apr; modulation when VNS is applied just compared with aggregometry, and an 131:918. before or during an actual seizure. absence of prospective clinical outcome — Steven C. Schachter, MD data. Larger prospective studies using Stemper B et al. Effects of vagus nerve stim- well-validated measures of platelet func- ulation on cardiovascular regulation in tion are necessary to determine whether Effects of Vagus patients with epilepsy. Acta Neurol Scand laboratory assessment of platelet func- Nerve Stimulation on 2008 Apr; 117:231. tion has a role in stroke prevention. For Cardiovascular Regulation now, the clinician should use standard approved doses of aspirin (50–325 mg he VNS Therapy System (VNS; Platelet Aggregometry daily) and spare the expense of addi- T Cyberonics, Inc.) was approved by tional testing in most patients. the FDA in 1997 as adjunctive therapy as a Marker of Risk for — Mitchell S.V. Elkind, MD, MS for adults and adolescents over 12 years Vascular Events: Not Yet Sztriha LK et al. Optical platelet aggre- of age whose partial-onset seizures gometry does not appear useful as were refractory to antiepileptic drugs, spirin plays an important role in a means of assessing the risk of recurrent thereby becoming the first (and, to A stroke prevention, but many pa- vascular events in aspirin-treated patients. date, only) nonpharmacologic epilepsy tients have recurrent events despite Acta Neurol Scand 2008 Apr; 117:250. treatment recognized by the FDA as safe taking it. There is growing interest, and effective. Because stimulation of the therefore, in laboratory tests of effec- vagus nerve in the neck may have physi- tiveness of aspirin that might be used to ologic and potentially clinically relevant target patients for higher doses or for Venous Sinus Stenting effects via both efferent and afferent changing to alternative agents. In this for Idiopathic Intracranial pathways, investigators have studied the study, investigators retrospectively as- Hypertension effects of acute vagus nerve stimulation sessed 241 patients referred for platelet on vagally mediated functions such as aggregometry. All participants had his- ounting evidence has demonstrat- respiration, blood pressure (BP), and tories of at least one clinical vascular M ed the presence of venous sinus heart rate (Epilepsy Res 1999; 35:1, and event (stroke, TIA, myocardial infarction, stenosis in patients with idiopathic in- Respir Physiol 2001; 127:125). In this or unstable angina) within the past 5 tracranial hypertension (IIH). These au- study, the investigators used spectral years and had been taking aspirin for thors report findings from a single-cen- analysis to monitor BP, RR interval (RRI; at least 30 days (about half for at least ter case series of 10 consecutive patients the time interval between two consecu- 1 year). To ascertain the outcome — who underwent venous sinus stenting tive R waves on the ECG), and respira- a clinical history of recurrent vascular for IIH that was refractory to medical tion during 60 seconds of continuous treatment. All 10 patients had a stenosis July 2008 JOURNAL WATCH NEUROLOGY Page 53 at the typical location, the junction of New Brain Tumor of patients, differing steroid doses and the transverse and sigmoid chemotherapy regimens, and lack of sinuses, visualized by three-dimensional Therapies, New definitive differentiation between infil- rotational gadolinium-enhanced magnet- Recurrence Patterns trating tumor, radiation-related gliosis, ic resonance angiography and confirmed and treatment-related leukoencephalop- lthough treatment of malignant by direct retrograde cerebral venography. athy in the bevacizumab-treated patients. gliomas with combination temozo- Eight patients had impaired visual acuity. A Nevertheless, they confirm the safety lomide chemotherapy, irradiation, and The mean prestenting pressure gradient and potential of bevacizumab in glioma surgery has improved survival, prognosis across the stenoses was 19.1 mm Hg. therapy, and they highlight potential remains poor and recurrence inevitable. At 3 months after venous sinus stent- changes in radiographic tumor-recur- Therefore, the search for novel thera- ing, all 10 patients showed normalization rence patterns of which neurologists peutic targets continues. Bevacizumab, of CSF pressures and resolution of papill- must be aware. — Amy A. Pruitt, MD a human monoclonal antibody, targets edema. Headache resolved in six patients, vascular endothelial growth factor Norden AD et al. Bevacizumab for recur- improved in two, and was unchanged in rent malignant gliomas: Efficacy, toxicity, (VEGF), which mediates angiogenesis in two. Relief was maintained for a mean and patterns of recurrence. Neurology gliomas and other cancers. In this study, follow-up of 17 months. Vision was nor- 2008 Mar 4; 70:779. researchers retrospectively assessed malized in four patients, improved in recurrence patterns in 55 patients with three, and unchanged in one. There were recurrent malignant gliomas who re- no perioperative complications. All stents ceived bevacizumab (along with various were patent at 6 months. The authors SOX1 Antibodies and chemotherapy regimens) and in 19 concluded that venous sinus stenting Paraneoplastic Lambert- patients treated with chemotherapy reg- provides an alternative to classic surgi- imens that did not contain bevacizumab. Eaton Myasthenic cal procedures for treatment of IIH. Among the 44 patients with radio- Syndrome Comment: graphic data, the radiographic response n patients with Lambert-Eaton myas- The incidence of idiopathic intracranial rate (i.e., complete or partial tumor re- thenic syndrome (LEMS), researchers hypertension is 1 to 3 cases per 100,000. gression) with bevacizumab was 34.1%. I previously found that 43% of those with The disorder carries high morbidity in One third of all bevacizumab recipients small cell lung cancer (SCLC) also had terms of vision loss and headache. For had reductions in their steroid doses. antiglial nuclear antibodies. The same medically refractory IIH, conventional Judged by blinded imaging review and researchers have now conducted further treatments — lumboperitoneal and by quantitative volumetric analysis of research to identify the antigen of these ventriculoperitoneal shunting — remain recurrence patterns, there was a trend antibodies and to explore its association unsatisfactory, given their high failure toward a higher ratio of infiltrative tumor with paraneoplastic LEMS. rate and need for frequent revision (e.g., to gadolinium-enhancing tumor in beva- First, they used serum from patients Neurology 1997; 49:734). Venous sinus cizumab responders compared with with LEMS, SCLC, and antiglial nuclear stenting has emerged as a “new kid on nonresponders. The authors conclude antibodies to probe a brain cDNA library. the block” for medically refractory IIH. that bevacizumab may help suppress They cloned SOX1, a protein that is in- This study adds to a growing literature enhancing tumor recurrence but not in- volved in neural development and is also showing the effectiveness and safety filtrative tumor growth. expressed in SCLC. Additional studies of this approach, regardless of whether Comment: confirmed that SOX1 was the autoantigen venous sinus stenosis is a primary or Bevacizumab combined with chemo- of the antiglial nuclear antibody. The secondary phenomenon in IIH. The therapy for recurrent malignant gliomas authors then looked for the SOX1 anti- strength of the study lies in the homo- has produced striking radiographic re- gen in serum from 105 patients with geneous clinical characteristics of pa- sponse rates in previous studies (Clin LEMS (55 with SCLC, 50 idiopathic), tients included in the study. The durable Cancer Res 2007; 13:1253). However, 50 with SCLC and anti-Hu–related syn- resolution of papilledema in all and head- the dramatic radiographic changes dromes, and 50 with SCLC only. They ache in most patients is compelling. may not reflect true antitumor activity. identified SOX1 antibodies in 64% of These promising results are similar to Research suggests that bevacizumab those in previously published case series. may significantly reduce tumor capillary A prospective controlled study is needed permeability and act as a steroid-sparing to define the role of venous sinus stent- agent to decrease peritumoral edema. ing in the management algorithm for The authors refer to preclinical studies medically refractory IIH in wider clinical suggesting that glioma cells co-opt practice. — Dileep Yavagal, MD existing cerebral vasculature as an alter- beta.jwatch.org Donnet A et al. Endovascular treatment native to angiogenesis when VEGF- of idiopathic intracranial hypertension: Clinical and radiologic outcome of 10 mediated tumor angiogenesis is blocked. Participate in the next consecutive patients. Neurology 2008 Feb Thus, the volume of contrast enhance- 19; 70:641. ment may remain stable, but abnormal generation of Journal Watch. FLAIR intensity may increase, reflecting an increase in infiltrating tumor. The valuable observations in this study are limited by the small number Page 54 JOURNAL WATCH NEUROLOGY Volume 10 Number 7 the patients with LEMS and cancer but features, and physicians therefore often clinical examination and consider these in none of the patients with idiopathic ignore distinctive clinical features. To PM mimics before treating patients with LEMS (P<0.0001). By contrast, they examine how histopathologic and clini- possibly harmful immunosuppressive found SOX1 antibodies in only 32% of cal features correlate in patients with medications. the cancer patients with anti-Hu–related myositis, these researchers used their The current findings, from a large syndromes and 22% of those with cancer own combined biopsy and clinical crite- series, support both observations from alone. These findings indicate that the ria to reexamine muscle biopsies and smaller studies and proposed criteria for detection of SOX1 antibodies in patients clinical records of 107 patients who had definite and possible IBM. Using their with LEMS predicts the presence of SCLC. initially been diagnosed with PM or IBM. own criteria, the authors found that PM Of the 107 patients, 64 had IBM, 27 is not extremely rare, but they found it Comment: had PM, and 16 had clinical features of the least common of the idiopathic in- Patients with nonparaneoplastic Lambert- IBM but lacked histologic features nec- flammatory myopathies. Invasion of Eaton myasthenic syndrome are clini- essary for confirmation. Thus, 37% of nonnecrotic muscle fibers is not neces- cally similar to but epidemiologically patients (16 of 43) who would have sary for a clinical diagnosis of PM. We different from patients with small cell been diagnosed as PM on biopsy alone need acceptable consensus criteria for lung cancer and LEMS. In the latter group, actually had IBM. Nonnecrotic muscle PM to achieve better understanding of robust associations have been established fibers invaded by mononuclear cells the pathogenesis and better treatments. with a history of smoking and with the were present in 17 of the 27 patients — Anthony A. Amato, MD absence of human leukocyte antigen B8. with PM, all 64 with IBM, and 13 of the Chahin N and Engel AG. Correlation of The current findings demonstrate that 16 probable-IBM patients. The authors muscle biopsy, clinical course, and out- SOX1 antibodies are a useful biologic suggest that invasion of nonnecrotic come in PM and sporadic IBM. Neurology marker for SCLC. This finding is impor- muscle fibers — advocated by some to 2008 Feb 5; 70:418. tant, because in most patients with LEMS, be necessary for the histopathologic Kissel JT. Polymyositis: Not a unicorn or a the neurologic symptoms precede the diagnosis of PM — should not be a mythological beast...but maybe a duck? diagnosis of SCLC, which can be diffi- required feature. Neurology 2008 Feb 5; 70:414. cult to detect. It is unclear why SCLC patients with LEMS are more likely to Comment: have SOX1 antibodies than are other Histopathologic features of IBM include SCLC patients (those with or without endomysial inflammatory cells, fibers Restless Legs Syndrome other paraneoplastic symptoms). As with rimmed vacuoles, small amyloid Is Associated with discussed in an accompanying editorial, deposits within fibers, and tubulofila- Cardiovascular Disease SOX1 antibodies have also been associ- mentous inclusions in the cytoplasm ated with SCLC in some patients with and myonuclei. However, these features estless legs syndrome (RLS) is a limbic encephalitis and voltage-gated are not present in every biopsy and, R common (5%–10% of the popula- potassium channel antibodies. The im- without a good clinical examination, tion) sensorimotor condition that is plication is that, in SCLC patients, their absence can lead to misdiagnosis diagnosed by evaluating patient history. the immune response to ion channels as PM. Characteristically, the earliest People with RLS experience an urge to (voltage-gated calcium channels in muscles affected in IBM are the quadri- move the limbs (often with uncomfort- LEMS and potassium channels in limbic ceps and the flexor forearm muscles. able sensations) that begins or worsens encephalitis) is linked to the immune This pattern of weakness is not typical with rest, is worse in the evening, and is response against SOX1 (an intranuclear of PM. These observations have led to at least partially relieved by movement. protein). This intriguing possibility criteria for definite and possible IBM To determine whether RLS is associated deserves further study. based on both clinical and histopatho- with cardiovascular disease (CVD), in- — Josep Dalmau, MD, PhD logic criteria (Ann Neurol 1995; 38:705 vestigators conducted a cross-sectional, Sabater L et al. SOX1 antibodies are mark- and 1996; 40:581). observational study of 3433 middle-aged ers of paraneoplastic Lambert-Eaton myas- The prevalence of PM is unknown, and elderly participants in the Sleep thenic syndrome. Neurology 2008 Mar 18; largely because of the lack of universally Heart Health Study — a community- 70:924. acceptable diagnostic criteria. Some based assessment of the cardiovascular Lang B and Evoli A. SOX1 autoantibodies: myopathologists like to see invasion of effects of sleep disorders. Tumor markers in LEMS patients? nonnecrotic muscle fibers to feel more The authors compared the prevalence Neurology 2008 Mar 18; 70:906. secure about a histopathologic diagnosis of CVD in subjects who reported symp- of PM, as endomysial and perivascular toms of RLS and in those who did not inflammation alone is nonspecific and (controls). RLS was present in 6.8% of Distinguishing can be seen in other myopathies, such women and 3.3% of men. After adjust- as dystrophies (Lancet 2003; 362:971). ments for confounding factors, the RLS Polymyositis from In a controversial editorial I coauthored, patients had an odds ratio of 2.07 for Inclusion Body Myositis we suggested that PM exists but is rare presence of CVD. The association of RLS (Neurology 2003; 61:288). Many cases with CVD was stronger in patients with t is not uncommon for inclusion body referred to me as PM are actually misdi- more frequent or more severe symptoms. I myositis (IBM) to be misdiagnosed as agnosed IBM, dystrophy, or another myo- The authors conclude that RLS is associ- polymyositis (PM), largely because the pathic disorder. Our editorial emphasized ated with CVD. diagnoses hinge on histopathologic that physicians must perform a good July 2008 JOURNAL WATCH NEUROLOGY Page 55

Comment: patients with Guillain-Barré syndrome, with involvement of horizontal SCC This well-executed investigation is im- myasthenia gravis, and advanced ALS. based on caloric test but no associated portant. RLS is usually associated with Brief mechanical ventilation is also nec- hearing loss, no previous neuro-otologic periodic limb movements of sleep essary to support any comatose patient disorders, and no tumor or stroke found (PLMS). The association of RLS with with a collapsed upper airway and pa- on MRI. Patients were given symptomatic CVD is consistent with the autonomic tients with refractory seizures who are nonsteroid medication and encouraged stresses associated with PLMS, including placed under full anesthesia. Therefore, to resume daily activities. All patients significant blood pressure increases it is important for neurologists to note had follow-up visits at 1 week and at (Neurology 2007; 68:1213). This new new developments in this area. up to 8 weeks. finding engenders the interesting ques- These findings show that a fully in- There were three significant findings: tion of how to manage PLMS (commonly active, denervated diaphragm shrinks First, all patients initially had horizontal detected in sleep studies) in the absence rapidly. This discovery has major conse- SCC paresis; 82% had ocular torsion of RLS. Are isolated PLMS also associated quences for patients who are on neuro- (based on fundus photos) and 94% had with CVD? Asymptomatic patients would muscular blockers, and it might explain an abnormal subjective visual vertical, tend not to receive treatment, but even why reduced diaphragmatic force can suggesting involvement of the superior PLMS alone may have cardiovascular lead to difficulty in weaning from a vestibular nerve to the utricle; and 49% implications. The CVD association adds ventilator. This study points to a growing of the patients had abnormal vestibular weight to the importance of diagnosing body of evidence that mechanical ven- evoked myogenic potentials (VEMPs), RLS. — Brian J. Murray, MD, tilators can actually harm patients. Cur- indicating involvement of the inferior FRCP(C), D, ABSM rent research is investigating the role of vestibular nerve to the saccule. Second, large tidal volumes in alveolar damage, these otolith abnormalities disappeared Winkelman JW et al. Association of restless legs syndrome and cardiovascular disease and this study suggests that — if neuro- faster than did the horizontal SCC dys- in the Sleep Heart Health Study. Neurology muscular blockage is needed — the re- function based on final follow-up. At 2008 Jan 1; 70:35. spiratory musculature is also at risk. this time, 25% still had ocular torsion Neurologists would be interested to see or tilt; 15% had abnormal VEMPs; and whether the changes in diaphragmatic 45% to 80% still had SCC deficit. Third, function are even worse in patients who at final follow-up, all patients showed Diaphragm Shrinkage already have abnormal neuromuscular marked improvement in symptoms, but in Mechanically transmission. At a practical level, time half still reported episodic (16 of 40) on the mechanical ventilator should be or continuous dizziness (4 of 40). A Ventilated Patients as short as possible, or even avoided in positive head-thrust test at follow-up hether mechanical ventilation favor of noninvasive ventilation. was the single best predictor of persis- W causes disuse atrophy in humans — Eelco F.M. Wijdicks, MD tent dizziness. has been unknown. To explore this issue, Levine S et al. Rapid disuse atrophy of dia- Comment: these authors compared biopsy speci- phragm fibers in mechanically ventilated mens from diaphragms of 14 brain-dead humans. N Engl J Med 2008 Mar 27; Most of the inner-ear vestibular system organ donors (case patients; on ventila- 358:1327. has not been accessible to vestibular tion for 18 to 69 hours) with biopsy Sieck GC and Mantilla CB. Effect of testing. Caloric and clinical rotary-chair specimens from diaphragms of eight mechanical ventilation on the diaphragm. tests evaluate only the horizontal SCC N Engl J Med 2008 Mar 27; 358:1392. patients undergoing surgery for benign function. During the last several years, conditions or stage 1 lung cancer (con- otolith testing has become clinically trols; on ventilation for 2 to 3 hours). possible and is now standard practice Compared with controls, the cases Predicting Outcome in many centers. had significant diaphragm muscle-fiber Prior studies have evaluated otolith atrophy (57% of slow-twitch fibers and in Vestibular Neuritis function in patients with acute vertigo, but this is the first to use a comprehen- 53% of fast-twitch fibers). The authors estibular neuritis (VN) causes acute estimated that this degree of atrophy sive approach and prospectively follow V vertigo and results from acute loss a large population of individuals with would produce a 50% loss of muscle of function of the superior vestibular strength. In addition, biochemical and vestibular neuritis. There are two key nerve due to viral infection. The best test findings. First, nearly half of the patients gene-expression studies showed evi- for VN, the caloric test, assesses the in- dence that muscle inactivity increased had involvement of the inferior vestibular put for the horizontal semicircular canal nerve. Previous literature has suggested cytosolic calcium concentrations and (SCC). But there are other structures of protease levels, indicating proteolysis. that VN involves only the superior vestib- the inner ear that can now be tested. ular nerve (Brain 1996; 118:755). This Comment: These researchers prospectively eval- discrepancy may relate to the observed uated 51 consecutive patients with Mechanical ventilators have been a faster recovery of otolith function than unilateral VN using a battery of tests blessing for critically ill neurologic pa- of SCC function. Inferior-nerve involve- of otolith and of SCC function to deter- tients. Rescue of patients in respiratory ment may be missed if patients are eval- mine the involvement of the otoliths failure has been possible since the polio uated several weeks from onset. Second, (utricle and saccule) and to identify pre- epidemics engendered widespread use some patients had persistent dizziness dictors of outcome. Patients were seen of endotracheal intubation and artificial even at 2 months. The single best pre- within 7 days of onset of acute vertigo ventilation. Today, ventilation benefits dictor of persistent dizziness was the Except as otherwise set forth herein, no part of this newsletter may be reproduced or otherwise incorporated into any information retrieval system without the written per- mission of the Massachusetts Medical Society. Printed in the USA. ISSN 1524-0207.

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Page 56 JOURNAL WATCH NEUROLOGY Volume 10 Number 7 clinical head thrust, a simple bedside signed to nonsurgical (conservative) had some symptomatic relief after sur- indicator of horizontal SCC function. treatment had had surgery. In the obser- gery for spinal stenosis, 7 to 10 years Whether a persistent head thrust is due vational cohort, 219 patients chose later at least one third reported back to a more severe initial deficit within the surgery, and 96% of these had surgery pain (Spine 2005; 30:936). Less invasive superior vestibular nerve or to a lack of within 2 years. procedures, such as interspinous distrac- central compensation is not clear from The primary outcomes, assessed by tion and minimally invasive surgical the study. questionnaire, were bodily pain on the techniques, are promising and may be — Ronald J. Tusa, MD, PhD Medical Outcomes Study 36-item Short- validated in the future. Kim H-A et al. Otolith dysfunction in Form General Health Survey and physical These results contrast with those of vestibular neuritis: Recovery pattern function on a modified Oswestry Disabil- surgery for lumbar disc herniation, for and a predictor of symptom recovery. ity Index. An as-treated analysis favored which there is little difference in the Neurology 2008 Feb 5; 70:449. surgery over conservative treatment, 1-year outcome for those treated surgi- with significant differences in both pain cally versus conservatively ( JW Neurology and physical-function scores peaking at Sep 2007, p. 70, and N Engl J Med 2007; 6 months and persisting to 2 years. 356:2245). Disk herniations differ Surgery Beneficial for from lumbar spinal stenosis in that Comment: Lumbar Spinal Stenosis herniations often shrink, whereas the Although the authors also provide pathology in lumbar spinal stenosis is hese authors’ goal was to document intention-to-treat results, the crossovers largely bony and therefore unlikely the benefit, or lack thereof, of T in this trial mean that only the as-treated to change spontaneously. surgery for symptomatic lumbar spinal analysis is useful. Taken in conjunction — Michael Ronthal, MD stenosis in an intention-to-treat, random- with two other recent studies (Spine ized trial. They studied two groups of Weinstein JN et al. Surgical versus non- 2007; 32:1, and Spine 2000; 25:556), surgical therapy for lumbar spinal stenosis. patients: 289 who were randomized to these findings suggest that surgery is N Engl J Med 2008 Feb 21; 358:794. surgery or conservative care, and 365 likely a viable option for patients with who were in an observational cohort. spinal stenosis and pain that interferes However, by the final 2-year follow-up, with their daily activities. Although more only 67% of patients assigned to surgery than 80% of patients in cohort studies had been operated on, and 43% of as-