Multiple Sclerosis: Weinshenker BG

Polman CH, Reingold SC, Barkhof F, Calabresi PA, Clanet M, Cohen JA, Cutter GR, Freedman MS, Kappos L, Lublin FD, McFarland HF, Metz LM, Miller AE, Montalban X, O'Connor PW, Panitch H, Richert JR, Petkau J, Schwid SR, Sormani MP, Thompson AJ, Weinshenker BG, Wolinsky JS. · Department of Neurology, Free University Medical Center in Amsterdam, PO Box 4075, 1007 MB Amsterdam, The Netherlands. · Neurology. · Pubmed #18362273 No free full text.

Abstract: The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

Pittock SJ, Weinshenker BG, Noseworthy JH, Lucchinetti CF, Keegan M, Wingerchuk DM, Carter J, Shuster E, Rodriguez M. · Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #16606780 No free full text.

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Weinshenker BG. · No affiliation provided · J Neurol Sci. · Pubmed #11535227 No free full text.

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Weinshenker BG. · No affiliation provided · Ther Apher. · Pubmed #10910016 No free full text.

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Weinshenker BG, Kantarci OH. · No affiliation provided · Neurology. · Pubmed #10680779 No free full text.

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Jacob A, Weinshenker BG. · Division of Neurology, Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom. · Semin Neurol. · Pubmed #18256991 No free full text.

Abstract: The differential diagnosis of acute inflammatory transverse myelitis (ATM) is broad. Therefore, physicians must be aware of the many potential etiologies for acute myelopathy, and should pursue an ordered, efficient, and cost-effective approach to the diagnosis based on the patient's clinical history, examination, and magnetic resonance imaging (MRI) findings. Clinical, immunological, and radiological findings of non-compressive myelopathies are reviewed, as are how these findings can be used to distinguish between demyelinating, infectious, other inflammatory, vascular, neoplastic, and paraneoplastic etiologies. We also review predictors of further episodes of ATM in patients with demyelinating disorders. We discuss the diagnostic clues and pitfalls of the not uncommon clinical scenario of a presumed "myelopathy with normal MRI." Finally, we suggest an algorithm for the diagnosis and management of acute myelopathies.

Young NP, Weinshenker BG, Lucchinetti CF. · Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. · Semin Neurol. · Pubmed #18256989 No free full text.

Abstract: Acute disseminated encephalomyelitis (ADEM) is an uncommon monophasic idiopathic inflammatory demyelinating disease. Available diagnostic criteria do not reliably distinguish it from first presentations of relapsing diseases such as multiple sclerosis (MS) and neuromyelitis optica (NMO). In this article, we review current concepts about ADEM and what distinguishes it from other idiopathic inflammatory demyelinating disease, and we highlight controversial aspects and diagnostic problems. We review pathological differences between ADEM and MS in terms of their utility in the diagnosis of ADEM. Finally, we present a practical approach for management of patients suspected of having ADEM when the diagnosis is uncertain.

Weinshenker BG, Wingerchuk DM. · Department of Neurology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55901, USA. · Curr Top Microbiol Immunol. · Pubmed #18219825 No free full text.

Abstract: Neuromyelitis optica (NMO) is a severe demyelinating disease of the CNS that preferentially affects the optic nerves and spinal cord, tends to relapse, and results in early permanent disability for most affected patients. A new autoantibody marker called neuromyelitis optica immunoglobulin G (NMO-IgG), which targets the water channel protein aquaporin-4, is highly specific for NMO. The marker has demonstrated that the NMO spectrum of disorders is wider than previously known and includes some patients with single-episode or recurrent longitudinally extensive myelitis, recurrent isolated optic neuritis, Asian optic-spinal multiple sclerosis, and patients with co-existing systemic autoimmune diseases such as lupus erythematosus or Sjögren's syndrome. We review the place of NMO within the nosology of CNS demyelinating diseases, the discovery of NMO-IgG and its impact on the definition of NMO and its spectrum, implications for understanding NMO pathogenesis, and informing treatment decisions.

Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. · Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ 85259, USA. · Lancet Neurol. · Pubmed #17706564 No free full text.

Abstract: Neuromyelitis optica (also known as Devic's disease) is an idiopathic, severe, demyelinating disease of the central nervous system that preferentially affects the optic nerve and spinal cord. Neuromyelitis optica has a worldwide distribution, poor prognosis, and has long been thought of as a variant of multiple sclerosis; however, clinical, laboratory, immunological, and pathological characteristics that distinguish it from multiple sclerosis are now recognised. The presence of a highly specific serum autoantibody marker (NMO-IgG) further differentiates neuromyelitis optica from multiple sclerosis and has helped to define a neuromyelitis optica spectrum of disorders. NMO-IgG reacts with the water channel aquaporin 4. Data suggest that autoantibodies to aquaporin 4 derived from peripheral B cells cause the activation of complement, inflammatory demyelination, and necrosis that is seen in neuromyelitis optica. The knowledge gained from further assessment of the exact role of NMO-IgG in the pathogenesis of neuromyelitis optica will provide a foundation for rational therapeutic trials for this rapidly disabling disease.

Weinshenker BG. · Department of Neurology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #17562942 No free full text.

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Jacob A, Matiello M, Wingerchuk DM, Lucchinetti CF, Pittock SJ, Weinshenker BG. · Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · J Neuroimmunol. · Pubmed #17512987 No free full text.

Abstract: Neuromyelitis optica (NMO; Devic's disease) and the NMO spectrum disorders are idiopathic inflammatory demyelinating disorders that affect the central nervous system and have a predilection for optic nerves and spinal cord. The identification of NMO-IgG as a disease-specific marker and aquaporin 4 as the target antigen has renewed interest in NMO. Based on current data, we suspect that autoantibodies arising from peripheral B cells bind to aquaporin 4 expressed on astrocyte foot processes on the abluminal surface of microvessels, activate complement and initiate inflammatory demyelination and necrosis. The development of animal models and further analysis of the association of NMO-IgG with disease severity and treatment response will elucidate the pathobiology of NMO.

Matiello M, Jacob A, Wingerchuk DM, Weinshenker BG. · Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. · Curr Opin Neurol. · Pubmed #17495617 No free full text.

Abstract: PURPOSE OF REVIEW: We review recent advances in neuromyelitis optica, an idiopathic inflammatory demyelinating disease of the central nervous system predominantly affecting optic nerves and spinal cord. We concentrate on a recently identified serum antibody biomarker, neuromyelitis optica immunoglobulin G (NMO-IgG), which distinguishes neuromyelitis optica from multiple sclerosis. RECENT FINDINGS: NMO-IgG is detected by indirect immunofluorescence. Its presence and specificity for neuromyelitis optica was confirmed in diverse populations. Seropositivity is now incorporated into new diagnostic criteria for neuromyelitis optica. Testing for this biomarker has suggested that the neuromyelitis optica spectrum is broader than previously recognized. Recently, the molecular target of NMO-IgG was identified as aquaporin-4. Immunopathologic studies suggest that loss of aquaporin-4 immunostaining is detectable in early lesions of neuromyelitis optica. A B-cell-specific monoclonal antibody, rituximab, may be an effective treatment even in patients not responding to other treatments. SUMMARY: Clinical, radiologic, and immunologic features distinguish neuromyelitis optica from other severe cases of multiple sclerosis. NMO-IgG is the first specific marker for a central nervous system demyelinating disease. The discovery of aquaporin-4 as the putative target of NMO-IgG, and recent data suggesting that aquaporin-4-specific antibodies are pathogenic may enhance our understanding of idiopathic inflammatory demyelinating diseases and their treatment.

Weinshenker BG, Wingerchuk DM, Pittock SJ, Lucchinetti CF, Lennon VA. · Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Dis Markers. · Pubmed #17124341 No free full text.

Abstract: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that principally targets the optic nerves and spinal cord and often leads to severe disability and occasionally life threatening respiratory failure. Although its clinical manifestations overlap with those of multiple sclerosis (MS), in established cases these two conditions can be distinguished on the basis of clinical, radiological, and routine spinal fluid studies. The diagnosis in early cases or limited forms of NMO is difficult. We recently discovered a unique IgG autoantibody (NMO-IgG) that is highly specific to patients with NMO and thus a valuable diagnostic aid. Its antigen, aquaporin-4 (AQP4), is the central nervous system's predominant water channel protein. This antibody has not yet been proven to be pathogenic, but several facts suggest that it might be, including the similarity of the immunohistochemical pattern of NMO-(AQP4) IgG binding to mouse CNS tissues to the pattern of immune complex deposition in autopsied patients' spinal cord tissue. The spectrum of diseases identified by NMO-IgG is broader than has previously been recognized clinically and includes incomplete forms of NMO, such as recurrent transverse myelitis without optic neuritis and recurrent optic neuritis without myelitis.

Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O'Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS. · VU Medical Center Amsterdam, Free University, PO Box 7057, 1007 MB Amsterdam, the Netherlands. · Ann Neurol. · Pubmed #16283615 No free full text.

Abstract: New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.

Kantarci OH, Weinshenker BG. · Department of Neurology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. · Neurol Clin. · Pubmed #15661086 No free full text.

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Kantarci OH, de Andrade M, Weinshenker BG. · Department of Neurology, Mayo Clinic and Foundation, 200 First Street, SW, Rochester, MN 55905, USA. · J Neuroimmunol. · Pubmed #11880159 No free full text.

Abstract: Evidence is mounting that genetic variation influences not only susceptibility to multiple sclerosis (MS), but also its course and severity. Identification of disease modifying genes, however, poses unique challenges, especially on how to classify the course and outcome of the disease in ways that may be relevant to analysis of biological factors that might be influenced by genes. The power of the statistical approaches to detect small effects of individual genes in complex disorders such as MS is problematic, and approaches to estimate power must be appropriate for the data. Nonetheless, using contemporary schemes of classification, genetic variants that influence disease course have been found; in fact, a small number have been confirmed to influence disease course in two or more independent studies. This review addresses strategies relevant to identification of disease modifying genes in MS, and summarizes and critically evaluates the current state of knowledge in this area.

Wingerchuk DM, Weinshenker BG. · Mayo Medical School, Rochester, Minnesota, USA. · Neuroimaging Clin N Am. · Pubmed #11359715 No free full text.

Abstract: Advances in MR imaging and randomized controlled-trial methodology have fundamentally altered the diagnosis and investigation of multiple sclerosis (MS). Further progress in epidemiology and classification will provide clues toward identification of the genetic and environmental factors that predispose to MS and dictate its course. More detailed understanding of the descriptive natural (untreated) history of the disease and development of intermediate and surrogate outcome measures, with better validity and reliability, will increase the likelihood that future clinical trials will identify beneficial treatments to reduce disability. This article reviews the current state of knowledge of MS epidemiology, genetics, disease classification, natural history, and outcome measures.

Weinshenker BG. · Department of Neurology, Mayo Clinic/Mayo Foundation, Rochester, Minnesota 55905, USA. · J Clin Apher. · Pubmed #11309833 No free full text.

Abstract: Plasma exchange has not been widely accepted as a treatment for multiple sclerosis. However, several uncontrolled studies have suggested that patients with severe attacks of MS and other inflammatory demyelinating disease may improve rapidly after plasma exchange treatment. We recently completed a randomized, sham-controlled, crossover clinical trial of plasma exchange in 22 patients with idiopathic inflammatory demyelinating diseases of the central nervous system. Twelve had MS and ten had other inflammatory demyelinating disease syndromes. Forty-two percent of patients experienced moderate or greater recovery over 2 weeks of active treatment administered every other day while only 6% of patients experienced similar improvement while receiving sham treatment. Three patients who failed the sham treatment subsequently improved rapidly after crossover to active treatment; no patient who failed active treatment improved after crossover to sham. This study illustrates the importance of designing randomized clinical trials based on the treatment regimen and patient population studied in the uncontrolled reports that suggested treatment efficacy. Plasma exchange should be considered for patients with idiopathic inflammatory demyelinating disease syndromes when they have failed corticosteroid therapy.

Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. · Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, Minn 55905, USA. · N Engl J Med. · Pubmed #11006371 No free full text.

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Weinshenker BG. · Department of Neurology, Mayo Clinic/Mayo Foundation, Rochester, Minnesota 55902, USA. · J Clin Apher. · Pubmed #10540370 No free full text.

Abstract: Idiopathic inflammatory demyelinating diseases (IIDDs) of the central nervous system, of which multiple sclerosis is the prototype, represent a family of monophasic, recurrent or progressive diseases with overlapping clinical and pathological manifestations. While most patients recover spontaneously or following a brief course of high-dose corticosteroids, occasional patients, particularly those with fulminant severe IIDDs, such as the Marburg variant, do not respond to corticosteroids and have severe, residual neurological deficits. While it is widely believed that IIDDs are mediated by T lymphocytes, as is experimental allergic encephelomyelitis, additional, possibly humoral, factors may be essential to generate the extensive demyelination seen in these conditions. Anecdotal reports over the past two decades have suggested that patients with acute, severe neurological deficits resulting from IIDDs, who fail to improve after high-dose intravenous corticosteroids, may benefit from plasma exchange. A randomized, sham-controlled, crossover study has recently been completed at the Mayo Clinic, which addresses these observations.

Wingerchuk DM, Weinshenker BG. · Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. · Curr Opin Neurol. · Pubmed #10499179 No free full text.

Abstract: The understanding of the natural history of multiple sclerosis has many implications for the design and interpretation of randomized controlled trials. Selection criteria, patient stratification, outcome measurements, and definitions of treatment failure can influence randomized controlled trial results and limit comparisons among trials. The focus of future studies should shift from short-term determinations of efficacy to definitive evaluations of long-term effectiveness. This will require novel investigative strategies such as the use of historic controls derived from natural history studies.

Weinshenker BG. · Department of Neurology, Mayo Clinic, 200 First Street, SW, Rochester, Minnesota, USA. · Mult Scler. · Pubmed #10467376 No free full text.

Abstract: A database is an organized repository of data. Prospective collection of patient information in a database ('databasing') has been attempted by a few consortia of MS investigators over the past 10 years. This approach promises to facilitate epidemiologic research in MS and investigation of the natural history of the disease and how it might be altered by long-term treatments such as interferon beta. Databasing has some advantages over clinical trials in assessing new therapies, primarily because the focus is on long-term effectiveness in an entire population rather than short-term statistical significance in a highly selected population. The limitations of databasing and strategies to overcome these limitations are addressed.

Miller RC, Lachance DH, Lucchinetti CF, Keegan BM, Gavrilova RH, Brown PD, Weinshenker BG, Rodriguez M. · Department of Radiation Oncology, Mayo Clinic, Rochester, MN55905, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #16965867 No free full text.

Abstract: PURPOSE: The aim of this study was a retrospective assessment of neurotoxicity in patients with multiple sclerosis (MS) receiving external beam radiotherapy (EBRT) to the brain. METHODS AND MATERIALS: We studied 15 consecutively treated patients with MS who received brain EBRT. Neurologic toxicity was assessed with the Common Toxicity Criteria v.3.0. RESULTS: Median follow-up for the 5 living patients was 6.0 years (range, 3.3-27.4 years). No exacerbation of MS occurred in any patient during EBRT. Five patients had Grade 4 neurologic toxicity and 1 had possible Grade 5 toxicity. Kaplan-Meier estimated risk of neurotoxicity greater than Grade 4 at 5 years was 57% (95% confidence interval, 27%-82%). Toxicity occurred at 37.5 to 54.0 Gy at a median of 1.0 year (range, 0.2-4.3 years) after EBRT. Univariate analysis showed an association between opposed-field irradiation of the temporal lobes, central white matter, and brainstem and increased risk of neurotoxicity (p < 0.04). Three of 6 cases of toxicity occurred in patients treated before 1986. CONCLUSIONS: External beam radiotherapy of the brain in patients with MS may be associated with an increased risk of neurotoxicity compared with patients without demyelinating illnesses. However, this risk is associated with treatment techniques that may not be comparable to modern, conformal radiotherapy.

Weinshenker BG, O'Brien PC, Petterson TM, Noseworthy JH, Lucchinetti CF, Dodick DW, Pineda AA, Stevens LN, Rodriguez M. · Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, MN 55902, USA. · Ann Neurol. · Pubmed #10589540 No free full text.

Abstract: There are no established treatments for patients with acute, severe neurological deficits caused by multiple sclerosis or other inflammatory demyelinating diseases of the central nervous system who fail to recover after treatment with high-dose corticosteroids. We conducted a randomized, sham-controlled, double-masked study of plasma exchange without concomitant immunosuppressive treatment in patients with recently acquired, severe neurological deficits resulting from attacks of inflammatory demyelinating disease, who failed to recover after treatment with intravenous corticosteroids. Patients who did not achieve moderate or greater improvement after the first treatment phase crossed over to the opposite treatment. Moderate or greater improvement in neurological disability occurred during 8 of 19 (42.1%) courses of active treatment compared with 1 of 17 (5.9%) courses of sham treatment. The primary analysis was positive. Improvement occurred early in the course of treatment, and was sustained on follow-up. However, 4 of the patients who responded to the active treatment experienced new attacks of demyelinating disease during 6 months of follow-up. Moderate or greater improvement occurred during follow-up in only 2 of 13 patients who failed to improve during the treatment phase. Plasma exchange leads to functionally important neurological recovery in an important proportion of severely disabled patients with acute attacks of idiopathic inflammatory demyelinating disease.

Magaña SM, Matiello M, Pittock SJ, McKeon A, Lennon VA, Rabinstein AA, Shuster E, Kantarci OH, Lucchinetti CF, Weinshenker BG. · Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Neurology. · Pubmed #19237699 No free full text.

Abstract: BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is characterized by vasogenic subcortical edema without infarction. It has been associated with hypertensive crises and with immunosuppressive medications but not with neuromyelitis optica (NMO). METHODS: We reviewed the clinical and neuroimaging features of five NMO-immunoglobulin G (IgG) seropositive white women who experienced an episode of PRES and had a coexisting NMO spectrum disorder (NMOSD). We also tested for the aquaporin-4 (AQP4) water channel autoantibody (NMO-IgG) in 14 patients from an independently ascertained cohort of individuals with PRES. RESULTS: All five patients developed abrupt confusion and depressed consciousness consistent with PRES. The encephalopathy resolved completely within 7 days. Comorbid conditions or interventions recognized to be associated with PRES included orthostatic hypotension with supine hypertension, plasma exchange, IV immunoglobulin treatment, and high-dose IV methylprednisolone. Brain MRI studies revealed bilateral T2-weighted (T2W) hyperintense signal abnormalities, primarily in frontal, parieto-occipital, and cerebellar regions. Three patients had highly symmetric lesions and three had gadolinium-enhancing lesions. Follow-up neuroimaging revealed partial or complete disappearance of T2W hyperintensity or gadolinium-enhancing lesions in all five patients. Patients with PRES without NMOSD were uniformly NMO-IgG seronegative. CONCLUSIONS: Brain lesions in some patients with neuromyelitis optica spectrum disorder (NMOSD) may be accompanied by vasogenic edema and manifest as posterior reversible encephalopathy syndrome (PRES). Water flux impairment due to aquaporin-4 autoimmunity may predispose to PRES in patients with NMOSD who experience blood pressure fluctuations or who are treated with therapies that can cause rapid fluid shifts.