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      Defining the clinical course of multiple sclerosis : The 2013 revisions

      review-article
      , MD , , PhD, , MD, , PhD, , MD, DMSc, , MD, , MD, , MD, MSCE, , MD, , MD, PhD, , PhD, , MD, , MD, , MD, , MD, , MD, , MD, , MD, PhD, , MD, , MD, , MD, PhD, , MD, , MD, , MD, , MD, , PhD, , MD, PhD, , MD, , PhD, , MD, PhD, , MD, PhD, , MD, PhD
      Neurology
      Lippincott Williams & Wilkins

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          Abstract

          Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

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          Most cited references31

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          Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria

          New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. Ann Neurol 2011
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            B-cell depletion with rituximab in relapsing-remitting multiple sclerosis.

            There is increasing evidence that B lymphocytes are involved in the pathogenesis of multiple sclerosis, and they may be a therapeutic target. Rituximab, a monoclonal antibody, selectively targets and depletes CD20+ B lymphocytes. In a phase 2, double-blind, 48-week trial involving 104 patients with relapsing-remitting multiple sclerosis, we assigned 69 patients to receive 1000 mg of intravenous rituximab and 35 patients to receive placebo on days 1 and 15. The primary end point was the total count of gadolinium-enhancing lesions detected on magnetic resonance imaging scans of the brain at weeks 12, 16, 20, and 24. Clinical outcomes included safety, the proportion of patients who had relapses, and the annualized rate of relapse. As compared with patients who received placebo, patients who received rituximab had reduced counts of total gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (P<0.001) and of total new gadolinium-enhancing lesions over the same period (P<0.001); these results were sustained for 48 weeks (P<0.001). As compared with patients in the placebo group, the proportion of patients in the rituximab group with relapses was significantly reduced at week 24 (14.5% vs. 34.3%, P=0.02) and week 48 (20.3% vs. 40.0%, P=0.04). More patients in the rituximab group than in the placebo group had adverse events within 24 hours after the first infusion, most of which were mild-to-moderate events; after the second infusion, the numbers of events were similar in the two groups. A single course of rituximab reduced inflammatory brain lesions and clinical relapses for 48 weeks. This trial was not designed to assess long-term safety or to detect uncommon adverse events. The data provide evidence of B-cell involvement in the pathophysiology of relapsing-remitting multiple sclerosis. (ClinicalTrials.gov number, NCT00097188 [ClinicalTrials.gov].). Copyright 2008 Massachusetts Medical Society.
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              Natural history of multiple sclerosis: a unifying concept.

              Multiple sclerosis can follow very different patterns of evolution and variable rates of disability accumulation. This raises the issue whether it represents one or several distinct diseases. We assessed demographic and clinical characteristics in 1844 patients with multiple sclerosis that we categorized according to the classification of Lublin and Reingold (1996) into 1066 (58%) relapsing-remitting, 496 (27%) secondary progressive, 109 (6%) progressive relapsing and 173 (9%) primary progressive cases of multiple sclerosis. Relapsing-remitting and secondary progressive cases shared similar age at disease onset (median = 28.7 versus 29.5 years; P = 0.21), initial symptoms of the relapsing-remitting phase, degree of recovery from the first neurological episode, and time from the first to the second episode. By contrast, disease duration was twice as long in secondary progressive than in relapsing-remitting cases (mean +/- SD = 17.6 +/- 9.6 versus 8.7 +/- 8.6 years; P < 0.001). Progressive relapsing and primary progressive cases were essentially similar in their clinical characteristics. In patients experiencing a progressive course, median age at onset of progressive phase was similar in secondary progressive cases and in cases who were progressive from onset (39.1 versus 40.1 years; P = 0.47). The proportion of cases with superimposed relapses during progression was approximately 40% in both categories. Finally, the 1562 patients with an exacerbating-remitting initial course and the 282 patients with a progressive initial course of the disease were essentially similar with respect to the time course of disability accumulation from assignment to a given disability score, and the age at assignment of disability landmarks. These observational data suggest that the clinical phenotype and course of multiple sclerosis are age dependent. Relapsing-remitting disease can be regarded as multiple sclerosis in which insufficient time has elapsed for the conversion to secondary progression; secondary progressive forms as relapsing-remitting multiple sclerosis that has 'grown older'; and progressive from onset cases as multiple sclerosis 'amputated' from the usual preceding relapsing-remitting phase. Times to reach disability milestones, and ages at which these landmarks are reached, follow a predefined schedule not obviously influenced by relapses, whenever they may occur, or by the initial course of the disease, whatever its phenotype. This leads to a unifying concept of the disease in which primary and secondary progression might be regarded as essentially similar. From the clinical and statistical positions, multiple sclerosis might be considered as one disease with different clinical phenotypes rather than an entity encompassing several distinct diseases-the position of complexity rather than true heterogeneity.
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                Author and article information

                Contributors
                Journal
                Neurology
                Neurology
                neurology
                neur
                neurology
                NEUROLOGY
                Neurology
                Lippincott Williams & Wilkins (Hagerstown, MD )
                0028-3878
                1526-632X
                15 July 2014
                15 July 2014
                : 83
                : 3
                : 278-286
                Affiliations
                From the Corinne Goldsmith Dickenson Center for Multiple Sclerosis (F.D.L., A.E.M.), Icahn School of Medicine at Mount Sinai, New York, NY; Scientific and Clinical Review Associates, LLC (S.C.R.), Salisbury, CT; The Mellen Center for MS Treatment and Research (J.A.C., R.J.F., R.A.R.), Cleveland Clinic, OH; the Department of Biostatistics (G.R.C.), University of Alabama at Birmingham; the Danish Multiple Sclerosis Center (P.S.S.), Department of Neurology, Copenhagen University Hospital Rigshospitalet, Denmark; University College London Institute of Neurology (A.J.T.), UK; the Department of Neurology (J.S.W., J.A.L.), University of Texas Health Sciences Center, Houston; the Department of Neurology (L.J.B.), New York University Langone Medical Center, New York; the Division of Neurology (B. Banwell), The Children's Hospital of Philadelphia, PA; the Departments of Radiology and Nuclear Medicine (F.B.) and Neurology (C.H.P.), VU Medical Center, Amsterdam, the Netherlands; Research Programs Department (B. Bebo), National Multiple Sclerosis Society, New York, NY; the Department of Neurology (P.A.C.), The Johns Hopkins Hospital, Baltimore, MD; Fédération de Neurologie (M.C.), CHU Hôpital Purpan, Toulouse, France; the Department of Neurology (G.C.), Scientific Institute San Raffaele, University Vita-Salute San Raffaele, Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Canada; the Department of Neurology (A.D.G.), University of Rochester Medical Center, NY; the Departments of Neurology, Radiology and Neuroscience (M.I.), Mount Sinai School of Medicine, New York, NY; the Department of Neurology (L.K.), University Hospital, Basel, Switzerland; the Department of Neurology (B.C.K.), Heinrich-Heine-University, Düsseldorf, Germany; the Department of Neurology (C.L.), Salpêtrière Hospital, UPMC, Paris, France; the Department of Neurology-Neuroimmunology (X.M.), Cemcat, Hospital Universitari Vall d'Hebron, Barcelona, Spain; the Division of Neurology (P.W.O.), St Michael's Hospital, Toronto; the Department of Statistics (J.P.), University of British Columbia, Vancouver, Canada; the Department of Neurology and Psychiatry (C.P.), Sapienza University, Rome; the Unit of Biostatistics (M.P.S.), Health Sciences Department, Genoa, Italy; the Department of Neurology (O.S.), University of Texas Health Sciences Center, Dallas; and the Multiple Sclerosis Center (E.W.), University of California, San Francisco.
                Author notes
                Correspondence to Dr. Lublin: fred.lublin@ 123456mssm.edu

                F.D.L., S.C.R., J.A.C., G.R.C., P.S.S., A.J.T., J.S.W., L.J.B., B. Banwell, F.B., P.A.C., M.C., G.C., M.S.F., A.D.G., L.K., B.C.K., C.L., A.E.M., X.M., P.W.O., J.P., C.P., M.P.S., O.S., and C.H.P. are members of the International Advisory Committee on Clinical Trials in Multiple Sclerosis.

                Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was paid by the International Advisory Committee on Clinical Trials in Multiple Sclerosis with funds provided by the European Committee for Treatment and Research in Multiple Sclerosis and the National Multiple Sclerosis Society (USA).

                Article
                NEUROLOGY2013555623
                10.1212/WNL.0000000000000560
                4117366
                24871874
                25ee6ba5-3ad1-4961-ba60-4d7fd17b5f7e
                © 2014 American Academy of Neurology

                This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivative 3.0 License, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

                History
                : 22 October 2013
                : 26 February 2014
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