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Introduction: Limited data exist on brain MRI enhancement in myelin-oligodendrocyte-glycoprotein (MOG) antibody-associated disease (MOGAD) and differences from aquaporin-4-IgG-positive-neuromyelitis-optica-spectrum-disorder (AQP4+NMOSD), and multiple sclerosis (MS)., Methods: In this retrospective observational study, we identified 122 Mayo Clinic MOGAD patients (1 January 1996-1 July 2020) with cerebral attacks. We explored enhancement patterns using a discovery set (n=41). We assessed enhancement frequency and Expanded Disability Status Scale scores at nadir and follow-up in the remainder (n=81). Two raters assessed T1-weighted-postgadolinium MRIs (1.5T/3T) for enhancement patterns in MOGAD, AQP4+NMOSD (n=14) and MS (n=26). Inter-rater agreement was assessed. Leptomeningeal enhancement clinical correlates were analysed., Results: Enhancement occurred in 59/81 (73%) MOGAD cerebral attacks but did not influence outcome. Enhancement was often patchy/heterogeneous in MOGAD (33/59 (56%)), AQP4+NMOSD (9/14 (64%); p=0.57) and MS (16/26 (62%); p=0.63). Leptomeningeal enhancement favoured MOGAD (27/59 (46%)) over AQP4+NMOSD (1/14 (7%); p=0.01) and MS (1/26 (4%); p<0.001) with headache, fever and seizures frequent clinical correlates. Ring enhancement favoured MS (8/26 (31%); p=0.006) over MOGAD (4/59 (7%)). Linear ependymal enhancement was unique to AQP4+NMOSD (2/14 (14%)) and persistent enhancement (>3 months) was rare (0%-8%) across all groups. Inter-rater agreement for enhancement patterns was moderate., Conclusions: Enhancement is common with MOGAD cerebral attacks and often has a non-specific patchy appearance and rarely persists beyond 3 months. Leptomeningeal enhancement favours MOGAD over AQP4+NMOSD and MS., Competing Interests: Competing interests: PE has no conflicts of interests or financial disclosures to declare regarding this submission. LC received speaker and consultant honoraria from Biomedia, ACCMED, Roche, BMS Celgene and Sanofi. KNK and DG reports no disclosures. JJC has received consulting fees from Roche, UCB and Horizon. ASL-C has served on advisory boards for Genentech and Horizon Therapeutics. ES, VR and PPM reports no disclosures. JLC has received research support from Roche and Genentech for an MS clinical trial, and serves as chair of the DMSC for several migraine clinical trials. DMW has received consulting fees from Alexion, Roche, Genentech, Horizon Therapeutics, Imcyse, Bristol Myers Squibb and Reistone, serves on an attack adjudication committee for a MOGAD clinical trial funded by UCB Pharma and is co-editor in chief of the neurologist. J-MT is associate editor for Journal of Child Neurology. CV-S and ST no disclosures. SJP reports grants, personal fees and non-financial support from Alexion Pharmaceuticals; grants, personal fees, non-financial support and other support from MedImmune, Inc/Viela Bio.; personal fees for consulting from Genentech/Roche. He has a patent, Patent# 8889102 (application#12-678350, Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia)—issued; a patent, Patent# 9891219B2 (application#12-573942, Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive)—issued. EPF has served on advisory boards for Alexion, Genentech, Horizon Therapeutics and UCB. He has received research support from UCB. He has received speaker honoraria from Pharmacy Times. He received royalties from UpToDate. EPF was a site primary investigator in a randomised clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics. EPF has received funding from the NIH (R01NS113828). EPF is a member of the medical advisory board of the MOG project. EPF is an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1-IgG as a biomarker of paraneoplastic autoimmunity., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Diverse acute neurological injuries may cause acute cardiopulmonary events including neurogenic pulmonary edema (NPE) and neurogenic stunned myocardium (NSM). The mechanism is probably mediated by sympathetic nervous system activation. Focal central nervous system (CNS) lesions, such as demyelinating lesions in multiple sclerosis (MS), may also cause cardiopulmonary disturbances. We aim to review the acute cardiopulmonary events associated with MS relapses. We performed a literature search using PubMed, and selected case reports of acute cardiac and/or pulmonary events related to MS exacerbations. We grouped these events into three categories: 1) NPE with normal cardiac function; 2) NSM and Takotsubo cardiomyopathy (TTC); 3) coexisting myocardial dysfunction and pulmonary edema. In some cases, cardiac and pulmonary symptoms preceded the onset of neurological symptoms. The majority of cases were associated with acute demyelinating lesions located in the medulla. Acute brainstem MS relapses, with demyelinating lesions affecting the medulla, may cause acute cardiac and pulmonary events presumably secondary to sympathetic hyperstimulation. Specific regions in the medulla that regulate cardiac function, systemic blood pressure and pulmonary hydrostatic pressure seem to be responsible for these events.

The American Academy of Neurology has published a comprehensive review and guidelines for the use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) for the first time since 2002. These guidelines represent the work of MS experts, patients, and guideline experts and are based on their review of randomized controlled trials and observational evidence that addresses a set of prespecified questions related to starting, switching, and potentially discontinuing DMTs. Many of the recommendations address decision-making regarding the use of DMTs and incorporate the perspective of patients. Modified Delphi methods were used to establish consensus recommendations that were assigned a level of clinical obligation (actions a clinician must [A], should [B], or may [C] do). Most guideline recommendations are level B. Few reached level A, and several achieved only level C, primarily because of lack of evidence. The guidelines eschew formal treatment algorithms and do not address financial considerations and a variety of other controversies. We identify remaining uncertainties, the most important of which is the choice of available DMTs for the average newly diagnosed patient. We reiterate a number of research needs identified in the guidelines that could affect the use of DMTs, including improved definition of breakthrough disease requiring change in therapy, development of better and universally accepted definitions of both benign and aggressive MS, more and longer-duration comparative effectiveness trials, discovery and validation of biomarkers of disease activity and response to therapy, and development of treatment strategies focused on neuroprotection, remyelination, and neural repair., (© 2018 American Academy of Neurology.)

"No evident disease activity" (NEDA) is a proposed measure of disease activity-free status in multiple sclerosis (MS) that is typically defined as absence of relapses, disability progression, and MRI activity over a defined time period. NEDA is increasingly reported in randomized controlled trials of MS disease modifying therapies where it has some perceived advantages over outcomes such as annualized relapse rate. NEDA has also been proposed as a treatment goal in clinical care. At this point, the long-term implications of early NEDA remain largely unknown. We review current NEDA definitions, use in clinical trials, and its prospects for routine use as an actionable treatment target in clinical practice., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The understanding of neuromyelitis optica spectrum disorder (NMOSD) has evolved substantially since its initial description over a century ago. The discovery in 2004 of a pathogenic autoantibody biomarker targeting aquaporin 4 IgG revolutionized diagnosis and therapeutic development. Although NMOSD resembles multiple sclerosis (MS), differences were identified and articulated in the late 1990s. New diagnostic criteria incorporating the biomarker as well as better understanding of the clinical and radiologic features of NMOSD now permit accurate diagnosis and differentiation from MS. Aquaporin 4 IgG-associated NMOSD is now regarded as an immune astrocytopathy with lytic and nonlytic effects on astrocytes. A second autoantibody, myelin oligodendrocyte glycoprotein IgG, which targets myelin rather than astrocytes, leads to an NMOSD syndrome with clinical and radiologic features that overlap but are distinct from those of aquaporin 4 IgG-associated NMOSD and MS. We review current understanding of the clinical aspects, pathophysiology, and treatment of NMOSD., (Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: To characterize patients misdiagnosed with multiple sclerosis (MS)., Methods: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS., Results: Of 110 misdiagnosed patients, 51 (46%) were classified as "definite" and 59 (54%) "probable" misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms., Conclusions: Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis., (© 2016 American Academy of Neurology.)

Multiple sclerosis (MS) is a common, disabling, putatively autoimmune neurological disease with worldwide distribution. It typically begins as a relapsing disorder that later evolves to a secondary progressive phase. Inflammatory and neurodegenerative mechanisms seem to operate in both phases, but their relative contributions and interactions are incompletely understood. Disease modifying therapies (DMTs) approved for relapsing multiple sclerosis interfere with a variety of immunological mechanisms to reduce rates of relapse, accumulation of disease burden measured by magnetic resonance imaging (MRI), and decline in neurological function over the two to three year duration of typical randomized controlled trials. Benefits of longer duration of therapy on disability are less clear, as data beyond three years are largely limited to observational studies. However, current DMTs do not slow accrual of disability once progressive multiple sclerosis is established. This review summarizes the evidence about the use of approved DMTs and examines how to individualize treatment despite the absence of validated biomarkers to guide drug selection. Methods such as stratifying patients on the basis of estimated risk for future disability, weighing patient specific factors and preferences, and using objective outcomes to adjudicate treatment success are discussed. Emerging drug therapies and strategies are also reviewed., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Nonspecific symptoms such as fatigue and dizziness are common in multiple sclerosis (MS), even in patients with normal exams. Little is known about the relationship of autonomic dysfunction with these symptoms and quality of life., Objective: Assess the association of autonomic symptom burden with fatigue, clinical status and quality of life., Methods: Subjects completed an autonomic symptom (COMPASS-31), quality of life (MSQOL-54) and fatigue (FSS) questionnaire at their routine MS clinic follow-up. Demographic and clinical data were collected from the medical record. Pearson correlations were assessed between autonomic symptoms and fatigue, quality of life, disability and disease duration., Results: One-hundred subjects completed the study (mean age 48 years; 78% female; 84% relapsing-remitting), mean disease duration was 14.7 years and mean EDSS 2.5. MSQOL-54 composite scores were 58 physical and 65 mental. COMPASS-31 correlated with MSQOL-54 (Physical R= -0.60; Mental -0.54; p<0.001) and FSS (R=0.51; p<0.001). There was no relationship between COMPASS-31 and EDSS (R=0, p=0.97) or disease duration (R= -0.02, p=0.84)., Conclusions: Autonomic symptom burden is correlated with decreased quality of life and increased fatigue. Autonomic symptoms are present early in the disease and at low disability and may reflect aspects of disease burden that are not well-captured by current disability measures., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To assess, in a surgical biopsy cohort of active demyelinating lesions, the diagnostic utility of aquaporin-4 (AQP4) immunohistochemistry in identifying neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD) and describe pathologic features that should prompt AQP4 immunohistochemical analysis and AQP4-immunoglobulin G (IgG) serologic testing., Methods: This was a neuropathologic cohort study of 20 surgical biopsies (19 patients; 11 cord/9 brain), performed because of diagnostic uncertainty, interpreted as active demyelinating disease and containing 2 or more of the following additional features: tissue vacuolation, granulocytic infiltrates, or astrocyte injury., Results: AQP4 immunoreactivity was lost in 18 biopsies and increased in 2. Immunopathologic features of the AQP4 loss cohort were myelin vacuolation (18), dystrophic astrocytes and granulocytes (17), vascular hyalinization (16), macrophages containing glial fibrillary acid protein (GFAP)-positive debris (14), and Creutzfeldt-Peters cells (0). All 14 cases with available serum tested positive for AQP4-IgG after biopsy. Diagnosis at last follow-up was NMO/NMOSD (15) and longitudinally extensive transverse myelitis (1 each relapsing and single). Immunopathologic features of the AQP4 increased cohort were macrophages containing GFAP-positive debris and granulocytes (2), myelin vacuolation (1), dystrophic astrocytes (1), Creutzfeldt-Peters cells (1), and vascular hyalinization (1). Diagnosis at last follow-up was multiple sclerosis (MS) and both tested AQP4-IgG seronegative after biopsy., Conclusions: AQP4 immunohistochemistry with subsequent AQP4-IgG testing has diagnostic utility in identifying cases of NMO/NMOSD. This study highlights the importance of considering NMOSD in the differential diagnosis of tumefactive brain or spinal cord lesions. AQP4-IgG testing may avert biopsy and avoid ineffective therapies if these patients are erroneously treated for MS., (© 2014 American Academy of Neurology.)

Multiple sclerosis (MS) is a chronic inflammatory demyelinating central nervous system disease that typically strikes young adults, especially women. The pathobiology of MS includes inflammatory and neurodegenerative mechanisms that affect both white and gray matter. These mechanisms underlie the relapsing, and often eventually progressive, course of MS, which is heterogeneous; confident prediction of long-term individual prognosis is not yet possible. However, because revised MS diagnostic criteria that incorporate neuroimaging data facilitate early diagnosis, most patients are faced with making important long-term treatment decisions, most notably the use and selection of disease-modifying therapy (DMT). Currently, there are 10 approved MS DMTs with varying degrees of efficacy for reducing relapse risk and preserving neurological function, but their long-term benefits remain unclear. Moreover, available DMTs differ with respect to the route and frequency of administration, tolerability and likelihood of treatment adherence, common adverse effects, risk of major toxicity, and pregnancy-related risks. Thorough understanding of the benefit-risk profiles of these therapies is necessary to establish logical and safe treatment plans for individuals with MS. We review the available evidence supporting risk-benefit profiles for available and emerging DMTs. We also assess the place of individual DMTs within the context of several different MS management strategies, including those currently in use (sequential monotherapy, escalation therapy, and induction and maintenance therapy) and others that may soon become feasible (combination approaches and "personalized medicine"). We conducted this review using a comprehensive search of MEDLINE, PubMed, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials, from January 1, 1990, to August 31, 2013. The following search terms were used: multiple sclerosis, randomized controlled trials, interferon-beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, BG-12, alemtuzumab, rituximab, ocrelizumab, daclizumab, neutralizing antibodies, progressive multifocal leukoencephalopathy., (Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: This review defines current clinical criteria for diagnosis, differential diagnosis, and clinical evaluation of acute disseminated encephalomyelitis, transverse myelitis, and neuromyelitis optica, and summarizes principles of treatment., Recent Findings: Consensus criteria for transverse myelitis and acute disseminated encephalomyelitis have been proposed. A specific biomarker, aquaporin-4 autoantibody, has been discovered for neuromyelitis optica that allows for early and accurate diagnosis even in the absence of cardinal findings of optic neuritis and myelitis. The antibody is pathogenic and is facilitating an understanding of the pathophysiology of neuromyelitis optica and development of antigen-specific treatments., Summary: Clinical and radiologic findings combined with serologic findings may permit classification of syndromes of transverse myelitis and acute disseminated encephalomyelitis in ways that may predict risk of relapse, type of relapse, and prognosis. Treatment, especially to prevent relapse, is dependent on the specific disease context in which syndromes such as transverse myelitis occur.

Background: Cognitive dysfunction affects approximately half of the patients with multiple sclerosis (MS). Cholinesterase inhibitor drugs are approved to treat cognitive dysfunction associated with degenerative dementia., Objective: To critically assess current evidence regarding the efficacy of the cholinesterase inhibitor, donepezil in the treatment of MS-associated cognitive impairment., Methods: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the fields of behavioral neurology and MS., Results: A randomized control trial was selected for critical appraisal. This trial randomized MS patients to receive donepezil 10 mg daily or placebo for treatment of MS-related cognitive dysfunction. There was no significant treatment effect found between the 2 groups on either the primary outcome of memory or any of the secondary cognitive measures. Post hoc analyses suggested a trend favoring donepezil in subjects with greater baseline cognitive dysfunction., Conclusions: Donepezil 10 mg daily for 24 weeks is not superior to placebo in improving MS-related cognitive dysfunction.

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Although its cause is not known, genetic and environmental factors both influence susceptibility to the disease. From the large array of environmental risk factors that have been examined over the past century, infection with Epstein-Barr virus, ultraviolet light exposure/vitamin D status, and cigarette smoking stand out because of the strength of supporting evidence. Epstein-Barr virus infection early in life appears to be necessary permissive step for disease development and probably acts in adolescence and early adulthood. Vitamin D-related mechanisms and cigarette smoking probably modify baseline disease risk and could plausibly do so at several stages of life; smoking appears to negatively affect disease course. This review summarizes current evidence for these 3 putative multiple sclerosis risk factors and early attempts to develop risk models and examine gene-environment interactions for this complex disease., (© 2011 Mount Sinai School of Medicine.)

Background: Persistent, high-titer neutralizing antibodies (NAbs) reduce or eliminate the biologic activity of interferon-beta (IFNB) therapies for multiple sclerosis (MS) and are associated with reduction in efficacy. Most patients who develop NAbs have preceding detectable binding antibodies. There is no consensus on prevention or management of NAb-positive patients but switching to noninterferon therapy and use of immunosuppressive strategies, especially corticosteroids, has been proposed., Objective: To evaluate the evidence supporting the efficacy of corticosteroid therapy for (a) reducing the incidence of NAbs; and (b) improving markers of interferon bioavailability, reducing NAbs titers, and improving clinical outcomes in NAb-positive patients with MS receiving IFNB therapy., Methods: The objective was addressed through the development of a structured critically appraised topic. This included a case scenario, structured question, search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the fields of neuroimmunology and multiple sclerosis., Results: We selected 4 papers for detailed review, all of which used pulsed methylprednisolone therapy, either alone or in combination with another immunosuppressive therapy. A randomized open-label trial showed that monthly intravenous methylprednisolone initiated at INFB therapy onset was associated with a lower risk of an ever-positive NAb result but was insufficiently sensitive to detect an effect on more clinically meaningful high-titer NAbs. A randomized controlled trial for patients with active disease despite IFNB therapy showed that baseline NAb titers were reduced by subsequent intravenous methylprednisolone treatment, but the incidence of NAbs was too small to assess clinical relevance. Small open-label observational studies suggest that pulse methylprednisolone, alone or in combination with azathioprine, does not restore the bioavailability of IFNB., Conclusions: Pulse methylprednisolone therapy may reduce the risk of developing NAbs (but possibly not high-titer NAbs of clinical importance) when coadministered with newly initiated IFNB therapy. However, current evidence suggests that methylprednisolone therapy does not restore IFNB biologic response in established NAB-positive MS patients.

In the previous two decades several immunomodulatory and immunosuppressive therapies have been shown to favorably impact the inflammatory activity and course of multiple sclerosis. There are now six approved therapies for the disease. Clinical decision-making has become more complex because of the increasing number of available drugs, the lack of head-to-head comparisons that allow direct comparisons of efficacy, and special factors that may influence efficacy such as neutralizing antibodies against beta-interferon preparations. Furthermore, all current therapies are partially effective; therefore, most patients experience breakthrough disease activity while using them, and there are no validated treatment failure definitions or management algorithms. This review outlines current evidence supporting efficacy of available drugs and scenarios for which more studies are required, and highlights the need for emerging therapies and strategies for multiple sclerosis management, including investigative oral and parenteral agents and combination therapy approaches.

Purpose of Review: Advanced immunopathological techniques hold promise for more precise diagnosis of idiopathic demyelinating diseases of the central nervous system. We review recent progress in differentiating and understanding the disease mechanisms of acute disseminated encephalomyelitis, neuromyelitis optica, and classical multiple sclerosis., Recent Findings: Four distinct immunopathological patterns have been described in multiple sclerosis patients, potentially implicating different inflammatory, demyelinating, and apoptotic mechanisms. A specific serum biomarker, neuromyelitis optica immunoglobulin G, is strongly associated with neuromyelitis optica and identifies patients with severe optic nerve and spinal cord lesions with specific pathological features such as eosinophilic and neutrophilic inflammatory infiltrates, necrosis, vascular hyalinization, and extensive vasculocentric immunoglobulin and complement deposition. This biomarker targets the water channel aquaporin-4, which is lost in neuromyelitis optica lesions. Acute disseminated encephalomyelitis still has no validated clinical diagnostic criteria but its perivenous pathological findings distinguish it from multiple sclerosis and neuromyelitis optica., Summary: The clinically heterogeneous group of idiopathic inflammatory demyelinating diseases of the central nervous system is characterized by several immunopathological patterns that suggest the involvement of diverse pathogenic effector mechanisms. Future advances in experimental pathology, immunology, molecular genetics, and neuroimaging, as well as the discovery of specific biomarkers, will more precisely define these disorders and lead to better targeted therapies.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that typically affects optic nerves and spinal cord. Its pathogenic relationship to multiple sclerosis (MS) is uncertain. Unlike MS, NMO lesions are characterized by deposits of IgG and IgM co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. A recently identified specific serum autoantibody biomarker, NMO-IgG, targets aquaporin-4 (AQP4), the most abundant water channel protein in the CNS, which is highly concentrated in astrocytic foot processes. We analysed and compared patterns of AQP4 immunoreactivity in CNS tissues of nine patients with NMO, 13 with MS, nine with infarcts and five normal controls. In normal brain, optic nerve and spinal cord, the distribution of AQP4 expression resembles the vasculocentric pattern of immune complex deposition observed in NMO lesions. In contrast to MS lesions, which exhibit stage-dependent loss of AQP4, all NMO lesions demonstrate a striking loss of AQP4 regardless of the stage of demyelinating activity, extent of tissue necrosis, or site of CNS involvement. We identified a novel NMO lesion in the spinal cord and medullary tegmentum extending into the area postrema, characterized by AQP4 loss in foci that were inflammatory and oedematous, but neither demyelinated nor necrotic. Foci of AQP4 loss coincided with sites of intense vasculocentric immune complex deposition. These findings strongly support a role for a complement activating AQP4-specific autoantibody as the initiator of the NMO lesion, and further distinguish NMO from MS.

Background: The authors previously proposed diagnostic criteria for neuromyelitis optica (NMO) that facilitate its distinction from prototypic multiple sclerosis (MS). However, some patients with otherwise typical NMO have additional symptoms not attributable to optic nerve or spinal cord inflammation or have MS-like brain MRI lesions. Furthermore, some patients are misclassified as NMO by the authors' earlier proposed criteria despite having a subsequent course indistinguishable from prototypic MS. A serum autoantibody marker, NMO-IgG, is highly specific for NMO. The authors propose revised NMO diagnostic criteria that incorporate NMO-IgG status., Methods: Using final clinical diagnosis (NMO or MS) as the reference standard, the authors calculated sensitivity and specificity for each criterion and various combinations using a sample of 96 patients with NMO and 33 with MS. The authors used likelihood ratios and logistic regression analysis to develop the most practical and informative diagnostic model., Results: Fourteen patients with NMO (14.6%) had extra-optic-spinal CNS symptoms. NMO-IgG seropositivity was 76% sensitive and 94% specific for NMO. The best diagnostic combination was 99% sensitive and 90% specific for NMO and consisted of at least two of three elements: longitudinally extensive cord lesion, onset brain MRI nondiagnostic for MS, or NMO-IgG seropositivity., Conclusions: The authors propose revised diagnostic criteria for definite neuromyelitis optica (NMO) that require optic neuritis, myelitis, and at least two of three supportive criteria: MRI evidence of a contiguous spinal cord lesion 3 or more segments in length, onset brain MRI nondiagnostic for multiple sclerosis, or NMO-IgG seropositivity. CNS involvement beyond the optic nerves and spinal cord is compatible with NMO.

There are five approved, partially effective, parenteral disease-modifying therapies for multiple sclerosis (MS), including three interferon-beta preparations, glatiramer acetate and the antineoplastic agent mitoxantrone. A sixth drug, natalizumab, was withdrawn from the market in 2005 but could return with increased safety measures. Careful surveillance for, and management of, the minor and serious adverse effects associated with these therapies in routine practice provides the best opportunity for maintaining compliance and achieving maximal therapeutic efficacy. This review outlines the strategies for the prevention, identification and management of the complications associated with administration and ongoing use of current MS therapies. These skills will become increasingly important to those caring for MS patients as contemporary treatment regimens become increasingly complex.

Background: Epidemiological and ecological studies suggest links between vitamin D deficiency and increased multiple sclerosis (MS) prevalence., Objective: To evaluate the safety and tolerability of oral calcitriol therapy in an open label pilot study., Methods: 15 ambulatory patients with relapsing-remitting MS and at least one clinical relapse within the previous 12 months received oral calcitriol (target dose: 2.5 microg/d) for 48 weeks. Dietary calcium was restricted to 800 mg/d. Patients were monitored using frequent clinical and laboratory examinations, the expanded disability status scale (EDSS), and brain magnetic resonance imaging (MRI)., Results: Two patients withdrew because of symptomatic hypercalcaemia (serum calcium >3.35 mmol/l in each case) resulting from persistent dietary indiscretion. Two diet compliant patients required temporary dose adjustments for mild asymptomatic hypercalcaemia. Diet compliant patients experienced mild adverse effects. The on-study exacerbation rate (27%) was less than baseline. Four patients experienced five clinical relapses but only one patient worsened by >1 EDSS point. Brain MRI revealed enhancing lesions in five patients at baseline (33%) and in four (29%) at both 24 and 48 weeks., Conclusions: Oral calcitriol is safe and well tolerated for up to one year by diet compliant relapsing-remitting MS patients. Further study of vitamin D related mechanisms is warranted in MS.

Pharmacotherapeutic options for multiple sclerosis (MS)-related fatigue are limited. Thirty patients were randomly assigned to aspirin (ASA) 1,300 mg/day or placebo in a double-blind crossover study. Results favored ASA for the main clinical outcomes: Modified Fatigue Impact Scale scores (p = 0.043) and treatment preference (p = 0.012). There were no significant adverse effects. The results warrant further study and support a role for ASA-influenced mechanisms, perhaps immunologic, in the generation of MS-related chronic fatigue.

Background: Neuromyelitis optica is an inflammatory demyelinating disease with generally poor prognosis that selectively targets optic nerves and spinal cord. It is commonly misdiagnosed as multiple sclerosis. Neither disease has a distinguishing biomarker, but optimum treatments differ. The relation of neuromyelitis optica to optic-spinal multiple sclerosis in Asia is uncertain. We assessed the capacity of a putative marker for neuromyelitis optica (NMO-IgG) to distinguish neuromyelitis optica and related disorders from multiple sclerosis., Methods: Indirect immunofluorescence with a composite substrate of mouse tissues identified a distinctive NMO-IgG staining pattern, which we characterised further by dual immunostaining. We tested masked serum samples from 102 North American patients with neuromyelitis optica or with syndromes that suggest high risk of the disorder, and 12 Japanese patients with optic-spinal multiple sclerosis. Control patients had multiple sclerosis, other myelopathies, optic neuropathies, and miscellaneous disorders. We also established clinical diagnoses for 14 patients incidentally shown to have NMO-IgG among 85000 tested for suspected paraneoplastic autoimmunity., Findings: NMO-IgG outlines CNS microvessels, pia, subpia, and Virchow-Robin space. It partly colocalises with laminin. Sensitivity and specificity were 73% (95% CI 60-86) and 91% (79-100) for neuromyelitis optica and 58% (30-86) and 100% (66-100) for optic-spinal multiple sclerosis. NMO-IgG was detected in half of patients with high-risk syndromes. Of 14 seropositive cases identified incidentally, 12 had neuromyelitis optica or a high-risk syndrome for the disease., Interpretation: NMO-IgG is a specific marker autoantibody of neuromyelitis optica and binds at or near the blood-brain barrier. It distinguishes neuromyelitis optica from multiple sclerosis. Asian optic-spinal multiple sclerosis seems to be the same as neuromyelitis optica.

People with multiple sclerosis (MS) are increasingly referred for specialty care to tertiary centers, particularly for advice regarding initiation and monitoring of immunomodulatory therapies. However, the generalist must still be able to apply appropriate skills and technology to diagnose the disease and its complications, provide basic counseling of patients, and be aware of potential treatment options at the time of diagnosis and when therapeutic regimens fail. A general approach, supported by evidence where possible, to common and contemporary clinical issues in MS care is provided in a case-based narrative.

MS poses formidable challenges to clinical investigators. Obstacles to the study of MS therapies include disease chronicity, an unpredictable clinical course, radiologic and pathologic heterogeneity, and limited understanding of the underlying pathophysiology. Randomized controlled trials (RCTs) provide a means to assess therapeutic efficacy while reducing the risks of study bias and confounding factors that influence interpretation of results. RCTs have demonstrated that type 1 interferons and glatiramer acetate alter the short-term natural history of MS and have served as the basis of approval for the marketing of these treatments. Improvements and optimization of trial methodology may hasten the discovery of effective therapies and facilitate better comparisons of the results of individual drug trials. The most urgent need is for improved surrogate end points for clinical outcome with predictive validity for long-term disability. Even if RCT methodology is optimal, however, several limitations inherent to MS trials threaten to impede further progress, including obstacles to long-term studies (e.g., costs), patient withdrawal, and escalating sample size requirements to detect partial therapeutic benefit. There is a crucial need to develop alternative investigative methods, possibly through enhanced collaboration across centers and with industry, and by exploring innovative techniques to use existing RCT and natural history databases to greater advantage.

Multiple sclerosis (MS) is an often disabling disease primarily affecting young adults that exhibits extraordinary clinical, radiological, and pathological heterogeneity. We review the following: (a) known environmental and genetic factors that contribute to MS susceptibility; (b) current knowledge regarding fundamental pathophysiological processes in MS, including immune cell recruitment and entry into the central nervous system (CNS), formation of the plaque, and orchestration of the immune response; (c) descriptive and qualitative distinct pathological patterns in MS and their implications; (d) the evidence supporting the causative role of direct toxins, cell-mediated and humorally mediated immune mechanisms, and the concept of a "primary oligodendrogliopathy" in demyelination and axonal injury; (e) the potential benefits of inflammation; (f) the prospects for remyelination; and (g) therapeutic implications and approaches suggested by putative pathophysiological mechanisms.

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.

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.

We scanned for all genetic variants in functionally important regions of the tumor necrosis factor receptor 1 gene (TNF-R1) in 100 to 111 MS patients from Olmsted County, MN, and analyzed selected variants for an association with disease course and severity. Ten genetic variants were uncovered. Only one variant, a silent substitution, was found in coding sequence. One intronic variant may generate a novel splice-junction sequence. We did not find an association between either this intronic variant or another common promoter variant and the course or severity of MS.

In this review, we analyzed clinical outcome measures used in multiple sclerosis (MS) clinical trials in which the primary goal is to slow or arrest progression of disease. In addition, we examined rating scales that quantify symptomatic complications of MS (for example, spasticity) and the current role of magnetic resonance imaging in MS treatment trials. Each proposed scale has advantages and deficiencies, and none meets all the criteria for an ideal outcome measure. The validity of trial design may be improved by using combinations of selected components of current scales as well as new instruments targeted to specific variables (such as motor strength). Symptom-specific rating scales are most appropriately used in trials of symptomatic therapeutic strategies for MS. Until serial magnetic resonance imaging changes are definitely known to predict long-term impairment and disability in patients with MS, clinical outcome measures will remain the primary means of assessing therapeutic efficacy in phase III clinical trials.

The objective of this study was to determine whether sequence variation in the tumor necrosis factor alpha (TNF alpha) gene is associated with MS course and severity in Olmsted County, MN. The severity and temporal course of MS are heterogeneous. Genetic factors may play a role in determining the course of MS. TNF alpha expression is temporally associated with exacerbations of MS and is increased in individuals with progressive disease. The entire TNF alpha gene was amplified by polymerase chain reaction in 78 MS patients and in 39 patients with schizophrenia. Denaturation finger-printing, a modification of direct sequencing that detects virtually all genetic polymorphisms, was performed for four regions spanning the functionally significant portions of the gene, including the promoter region. Polymorphisms were confirmed by complete sequencing. The severity and temporal course of MS were compared in those with wild-type versus variant alleles. Four sequence changes were detected, three of which occurred in MS patients. None occurred in a protein-encoding sequence. Neither of the two most common sequence variants were associated with disease severity or temporal course. Genetic variation of the TNF alpha gene is not associated with variation in the course or long-term outcome of MS in this population-based sample.