Download PDF
Semin Neurol 2018; 38(02): 212-225
DOI: 10.1055/s-0038-1649502
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Multiple Sclerosis

Bassem I. Yamout
1   Department of Neurology-Nehmeh and Therese Tohmeh Multiple Sclerosis Center, American University of Beirut, Beirut, Lebanon
,
Raed Alroughani
2   Division of Neurology, Department of Medicine, Al-Amiri Hospital, Kuwait City, Kuwait
› Author Affiliations
Further Information

Publication History

Publication Date:
23 May 2018 (online)

    Permissions and Reprints

Abstract

Multiple sclerosis (MS) is a chronic central nervous system inflammatory disease of autoimmune etiology, mediated by activated T cells with evolving evidence of a significant contribution from B cells and cells of the innate immune system. The disease is thought to be due to a complex interaction between different genetic and environmental factors. The prevalence of MS is rising all over the world, due on one hand to earlier diagnosis and prolonged survival, and on the other to a true increase in incidence of the disease. The diagnosis of MS remains clinical despite recent advances in diagnostics and relies on demonstrating dissemination in space and time while excluding alternative diagnoses. The Mc Donald diagnostic criteria, with their recent 2017 revision, are currently widely accepted in the MS community. Although no cure is yet available, many disease-modifying therapies (DMTs) have shown different levels of efficacy in preventing relapses, accumulation of lesions on magnetic resonance imaging (MRI), and disability progression. Current treatment strategies include gradual escalation based on clinical and radiological criteria that determine treatment response, or initial induction with high efficacy DMTs especially in patients with an early aggressive course.

Keywords

multiple sclerosis - review - treatment guidelines - diagnosis
 

  • References

  • 1 Goodin DS. The epidemiology of multiple sclerosis: insights to disease pathogenesis. Handb Clin Neurol 2014; 122: 231-266
    PubMedGoogle Scholar
  • 2 Trojano M, Paolicelli D, Tortorella C. , et al. Natural history of multiple sclerosis: have available therapies impacted long-term prognosis?. Neurol Clin 2011; 29 (02) 309-321
    CrossrefPubMedGoogle Scholar
  • 3 Selter RC, Hemmer B. Update on immunopathogenesis and immunotherapy in multiple sclerosis. ImmunoTargets Ther 2013; 2: 21-30
    PubMedGoogle Scholar
  • 4 Gran B, Hemmer B, Vergelli M, McFarland HF, Martin R. Molecular mimicry and multiple sclerosis: degenerate T-cell recognition and the induction of autoimmunity. Ann Neurol 1999; 45 (05) 559-567
    CrossrefPubMedGoogle Scholar
  • 5 Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 1995; 80 (05) 695-705
    CrossrefPubMedGoogle Scholar
  • 6 Garg N, Smith TW. An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis. Brain Behav 2015; 5 (09) e00362
    PubMedGoogle Scholar
  • 7 Hemmer B, Archelos JJ, Hartung HP. New concepts in the immunopathogenesis of multiple sclerosis. Nat Rev Neurosci 2002; 3 (04) 291-301
    CrossrefPubMedGoogle Scholar
  • 8 O'Connor KC, Bar-Or A, Hafler DA. The neuroimmunology of multiple sclerosis: possible roles of T and B lymphocytes in immunopathogenesis. J Clin Immunol 2001; 21 (02) 81-92
    CrossrefPubMedGoogle Scholar
  • 9 Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338 (05) 278-285
    CrossrefPubMedGoogle Scholar
  • 10 Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 2004; 14 (02) 164-174
    CrossrefPubMedGoogle Scholar
  • 11 Magliozzi R, Howell OW, Reeves C. , et al. A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 2010; 68 (04) 477-493
    CrossrefPubMedGoogle Scholar
  • 12 Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000; 47 (06) 707-717
    CrossrefPubMedGoogle Scholar
  • 13 Kinzel S, Weber MS. B cell-directed therapeutics in multiple sclerosis: rationale and clinical evidence. CNS Drugs 2016; 30 (12) 1137-1148
    CrossrefPubMedGoogle Scholar
  • 14 Federation MSI. Atlas of MS 2013: Mapping Multiple Sclerosis around the world; 2013. Available at: http://www.atlasofms.org . Accessed April 10, 2017
    PubMedGoogle Scholar
  • 15 Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 2010; 9 (05) 520-532
    CrossrefPubMedGoogle Scholar
  • 16 Heydarpour P, Khoshkish S, Abtahi S, Moradi-Lakeh M, Sahraian MA. Multiple sclerosis epidemiology in Middle East and North Africa: a systematic review and meta-analysis. Neuroepidemiology 2015; 44 (04) 232-244
    CrossrefPubMedGoogle Scholar
  • 17 Ascherio A, Munger KL. Epidemiology of multiple sclerosis: from risk factors to prevention-an update. Semin Neurol 2016; 36 (02) 103-114
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Orton SM, Herrera BM, Yee IM. , et al; Canadian Collaborative Study Group. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 2006; 5 (11) 932-936
    CrossrefPubMedGoogle Scholar
  • 19 Westerlind H, Ramanujam R, Uvehag D. , et al. Modest familial risks for multiple sclerosis: a registry-based study of the population of Sweden. Brain 2014; 137 (Pt 3): 770-778
    CrossrefPubMedGoogle Scholar
  • 20 Sadovnick AD, Armstrong H, Rice GP. , et al. A population-based study of multiple sclerosis in twins: update. Ann Neurol 1993; 33 (03) 281-285
    PubMedGoogle Scholar
  • 21 Miretti MM, Walsh EC, Ke X. , et al. A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. Am J Hum Genet 2005; 76 (04) 634-646
    CrossrefPubMedGoogle Scholar
  • 22 Sawcer S, Hellenthal G, Pirinen M. , et al; International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476 (7359): 214-219
    CrossrefPubMedGoogle Scholar
  • 23 Belbasis L, Bellou V, Evangelou E, Ioannidis JP, Tzoulaki I. Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses. Lancet Neurol 2015; 14 (03) 263-273
    CrossrefPubMedGoogle Scholar
  • 24 Yadav SK, Mindur JE, Ito K, Dhib-Jalbut S. Advances in the immunopathogenesis of multiple sclerosis. Curr Opin Neurol 2015; 28 (03) 206-219
    CrossrefPubMedGoogle Scholar
  • 25 Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: noninfectious factors. Ann Neurol 2007; 61 (06) 504-513
    CrossrefPubMedGoogle Scholar
  • 26 Handel AE, Williamson AJ, Disanto G, Handunnetthi L, Giovannoni G, Ramagopalan SV. An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS One 2010; 5 (09) e12496
    CrossrefPubMedGoogle Scholar
  • 27 Orton SM, Wald L, Confavreux C. , et al. Association of UV radiation with multiple sclerosis prevalence and sex ratio in France. Neurology 2011; 76 (05) 425-431
    CrossrefPubMedGoogle Scholar
  • 28 McDowell TY, Amr S, Culpepper WJ. , et al. Sun exposure, vitamin D and age at disease onset in relapsing multiple sclerosis. Neuroepidemiology 2011; 36 (01) 39-45
    CrossrefPubMedGoogle Scholar
  • 29 Munger KL, Zhang SM, O'Reilly E. , et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004; 62 (01) 60-65
    CrossrefPubMedGoogle Scholar
  • 30 Simpson Jr S, Taylor B, Blizzard L. , et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol 2010; 68 (02) 193-203
    PubMedGoogle Scholar
  • 31 Smolders J, Menheere P, Kessels A, Damoiseaux J, Hupperts R. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler 2008; 14 (09) 1220-1224
    CrossrefPubMedGoogle Scholar
  • 32 James E, Dobson R, Kuhle J, Baker D, Giovannoni G, Ramagopalan SV. The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis. Mult Scler 2013; 19 (12) 1571-1579
    CrossrefPubMedGoogle Scholar
  • 33 Hedström AK, Hillert J, Olsson T, Alfredsson L. Smoking and multiple sclerosis susceptibility. Eur J Epidemiol 2013; 28 (11) 867-874
    CrossrefPubMedGoogle Scholar
  • 34 Zhang P, Wang R, Li Z. , et al. The risk of smoking on multiple sclerosis: a meta-analysis based on 20,626 cases from case-control and cohort studies. Peer J 2016; 4: e1797
    CrossrefPubMedGoogle Scholar
  • 35 Dobson R, Giovannoni G, Ramagopalan S. The month of birth effect in multiple sclerosis: systematic review, meta-analysis and effect of latitude. J Neurol Neurosurg Psychiatry 2013; 84 (04) 427-432
    CrossrefPubMedGoogle Scholar
  • 36 Glenn JD, Mowry EM. Emerging concepts on the gut microbiome and multiple sclerosis. J Interferon Cytokine Res 2016; 36 (06) 347-357
    CrossrefPubMedGoogle Scholar
  • 37 Kotzamani D, Panou T, Mastorodemos V. , et al. Rising incidence of multiple sclerosis in females associated with urbanization. Neurology 2012; 78 (22) 1728-1735
    CrossrefPubMedGoogle Scholar
  • 38 Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 2005; 4 (05) 281-288
    CrossrefPubMedGoogle Scholar
  • 39 Fisniku LK, Brex PA, Altmann DR. , et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008; 131 (Pt 3): 808-817
    CrossrefPubMedGoogle Scholar
  • 40 Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003; 126 (Pt 4): 770-782
    CrossrefPubMedGoogle Scholar
  • 41 Tintoré M, Rovira A, Río J. , et al. Baseline MRI predicts future attacks and disability in clinically isolated syndromes. Neurology 2006; 67 (06) 968-972
    CrossrefPubMedGoogle Scholar
  • 42 Swanton JK, Fernando KT, Dalton CM. , et al. Early MRI in optic neuritis: the risk for clinically definite multiple sclerosis. Mult Scler 2010; 16 (02) 156-165
    CrossrefPubMedGoogle Scholar
  • 43 Barkhof F, Filippi M, Miller DH. , et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997; 120 (Pt 11): 2059-2069
    CrossrefPubMedGoogle Scholar
  • 44 Swanton JK, Fernando K, Dalton CM. , et al. Is the frequency of abnormalities on magnetic resonance imaging in isolated optic neuritis related to the prevalence of multiple sclerosis? A global comparison. J Neurol Neurosurg Psychiatry 2006; 77 (09) 1070-1072
    CrossrefPubMedGoogle Scholar
  • 45 Mowry EM, Deen S, Malikova I, Pelletier J, Bacchetti P, Waubant E. The onset location of multiple sclerosis predicts the location of subsequent relapses. J Neurol Neurosurg Psychiatry 2009; 80 (04) 400-403
    PubMedGoogle Scholar
  • 46 Villar LM, García-Barragán N, Sádaba MC. , et al. Accuracy of CSF and MRI criteria for dissemination in space in the diagnosis of multiple sclerosis. J Neurol Sci 2008; 266 (1-2): 34-37
    CrossrefPubMedGoogle Scholar
  • 47 Fahrbach K, Huelin R, Martin AL. , et al. Relating relapse and T2 lesion changes to disability progression in multiple sclerosis: a systematic literature review and regression analysis. BMC Neurol 2013; 13: 180
    CrossrefPubMedGoogle Scholar
  • 48 Scalfari A, Neuhaus A, Daumer M, Deluca GC, Muraro PA, Ebers GC. Early relapses, onset of progression, and late outcome in multiple sclerosis. JAMA Neurol 2013; 70 (02) 214-222
    CrossrefPubMedGoogle Scholar
  • 49 Lublin FD, Reingold SC. ; National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996; 46 (04) 907-911
    CrossrefPubMedGoogle Scholar
  • 50 Lublin FD, Reingold SC, Cohen JA. , et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 83 (03) 278-286
    CrossrefPubMedGoogle Scholar
  • 51 Okuda DT, Mowry EM, Beheshtian A. , et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology 2009; 72 (09) 800-805
    CrossrefPubMedGoogle Scholar
  • 52 Okuda DT, Siva A, Kantarci O. , et al; Radiologically Isolated Syndrome Consortium (RISC); Club Francophone de la Sclérose en Plaques (CFSEP). Radiologically isolated syndrome: 5-year risk for an initial clinical event. PLoS One 2014; 9 (03) e90509
    CrossrefPubMedGoogle Scholar
  • 53 Link H, Huang YM. Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness. J Neuroimmunol 2006; 180 (1-2): 17-28
    CrossrefPubMedGoogle Scholar
  • 54 Polman CH, Reingold SC, Banwell B. , et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69 (02) 292-302
    CrossrefPubMedGoogle Scholar
  • 55 Wingerchuk DM, Hogancamp WF, O'Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic's syndrome). Neurology 1999; 53 (05) 1107-1114
    CrossrefPubMedGoogle Scholar
  • 56 Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006; 66 (10) 1485-1489
    CrossrefPubMedGoogle Scholar
  • 57 Wingerchuk DM, Banwell B, Bennett JL. , et al; International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015; 85 (02) 177-189
    CrossrefPubMedGoogle Scholar
  • 58 Boiko A, Vorobeychik G, Paty D, Devonshire V, Sadovnick D. ; University of British Columbia MS Clinic Neurologists. Early onset multiple sclerosis: a longitudinal study. Neurology 2002; 59 (07) 1006-1010
    CrossrefPubMedGoogle Scholar
  • 59 Banwell B, Krupp L, Kennedy J. , et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 2007; 6 (09) 773-781
    CrossrefPubMedGoogle Scholar
  • 60 Yeh EA, Chitnis T, Krupp L. , et al; US Network of Pediatric Multiple Sclerosis Centers of Excellence. Pediatric multiple sclerosis. Nat Rev Neurol 2009; 5 (11) 621-631
    CrossrefPubMedGoogle Scholar
  • 61 Huppke B, Ellenberger D, Rosewich H, Friede T, Gärtner J, Huppke P. Clinical presentation of pediatric multiple sclerosis before puberty. Eur J Neurol 2014; 21 (03) 441-446
    CrossrefPubMedGoogle Scholar
  • 62 Banwell B, Kennedy J, Sadovnick D. , et al. Incidence of acquired demyelination of the CNS in Canadian children. Neurology 2009; 72 (03) 232-239
    CrossrefPubMedGoogle Scholar
  • 63 Peche SS, Alshekhlee A, Kelly J, Lenox J, Mar S. A long-term follow-up study using IPMSSG criteria in children with CNS demyelination. Pediatr Neurol 2013; 49 (05) 329-334
    CrossrefPubMedGoogle Scholar
  • 64 Callen DJ, Shroff MM, Branson HM. , et al. MRI in the diagnosis of pediatric multiple sclerosis. Neurology 2009; 72 (11) 961-967
    CrossrefPubMedGoogle Scholar
  • 65 Lee CG, Lee B, Lee J, Lee M. The natural course of clinically isolated syndrome in pediatric patients. Brain Dev 2015; 37 (04) 432-438
    CrossrefPubMedGoogle Scholar
  • 66 Renoux C, Vukusic S, Mikaeloff Y. , et al; Adult Neurology Departments KIDMUS Study Group. Natural history of multiple sclerosis with childhood onset. N Engl J Med 2007; 356 (25) 2603-2613
    CrossrefPubMedGoogle Scholar
  • 67 Chitnis T, Krupp L, Yeh A. , et al. Pediatric multiple sclerosis. Neurol Clin 2011; 29 (02) 481-505
    CrossrefPubMedGoogle Scholar
  • 68 Krupp LB, Tardieu M, Amato MP. , et al; International Pediatric Multiple Sclerosis Study Group. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler 2013; 19 (10) 1261-1267
    CrossrefPubMedGoogle Scholar
  • 69 Rubin JP, Kuntz NL. Diagnostic criteria for pediatric multiple sclerosis. Curr Neurol Neurosci Rep 2013; 13 (06) 354
    CrossrefPubMedGoogle Scholar
  • 70 Chitnis T, Tenembaum S, Banwell B. , et al; International Pediatric Multiple Sclerosis Study Group. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler 2012; 18 (01) 116-127
    CrossrefPubMedGoogle Scholar
  • 71 Ghezzi A, Goretti B, Portaccio E, Roscio M, Amato MP. Cognitive impairment in pediatric multiple sclerosis. Neurol Sci 2010; 31 (Suppl. 02) S215-S218
    CrossrefPubMedGoogle Scholar
  • 72 Chitnis T, Ghezzi A, Bajer-Kornek B, Boyko A, Giovannoni G, Pohl D. Pediatric multiple sclerosis: escalation and emerging treatments. Neurology 2016; 87 (09) (Suppl. 02) S103-S109
    CrossrefPubMedGoogle Scholar
  • 73 Chitnis T. PARADIGMS: a randomised double-blind study of fingolimod versus interferon beta-1a in paediatric multiple sclerosis. Mult Scler 2017; 23 (S3): 977-978
    PubMedGoogle Scholar
  • 74 Jancic J, Nikolic B, Ivancevic N. , et al. Multiple sclerosis in pediatrics: current concepts and treatment options. Neurol Ther 2016; 5 (02) 131-143
    CrossrefPubMedGoogle Scholar
  • 75 Filippini G, Brusaferri F, Sibley WA. , et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev 2000; (04) CD001331
    PubMedGoogle Scholar
  • 76 Burton JM, O'Connor PW, Hohol M, Beyene J. Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev 2012; 12: CD006921
    PubMedGoogle Scholar
  • 77 Weinshenker BG, O'Brien PC, Petterson TM. , et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 1999; 46 (06) 878-886
    CrossrefPubMedGoogle Scholar
  • 78 Weiner HL, Dau PC, Khatri BO. , et al. Double-blind study of true vs. sham plasma exchange in patients treated with immunosuppression for acute attacks of multiple sclerosis. Neurology 1989; 39 (09) 1143-1149
    CrossrefPubMedGoogle Scholar
  • 79 The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43 (04) 655-661
    CrossrefPubMedGoogle Scholar
  • 80 Jacobs LD, Cookfair DL, Rudick RA. , et al; The Multiple Sclerosis Collaborative Research Group (MSCRG). Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996; 39 (03) 285-294
    CrossrefPubMedGoogle Scholar
  • 81 Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 1998; 352 (9139): 1498-1504
    CrossrefPubMedGoogle Scholar
  • 82 Johnson KP, Brooks BR, Cohen JA. , et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995; 45 (07) 1268-1276
    CrossrefPubMedGoogle Scholar
  • 83 Goodin DS, Reder AT, Ebers GC. , et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology 2012; 78 (17) 1315-1322
    CrossrefPubMedGoogle Scholar
  • 84 Calabresi PA, Kieseier BC, Arnold DL. , et al; ADVANCE Study Investigators. Pegylated interferon β-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol 2014; 13 (07) 657-665
    CrossrefPubMedGoogle Scholar
  • 85 Khan O, Rieckmann P, Boyko A. , et al. Efficacy and safety of a three-times-weekly dosing regimen of glatiramer acetate in relapsing-remitting multiple sclerosis patients: 3-year results of the Glatiramer Acetate Low-Frequency Administration open-label extension study. Mult Scler 2017; 23 (06) 818-829
    CrossrefPubMedGoogle Scholar
  • 86 O'Connor P, Wolinsky JS, Confavreux C. , et al; TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365 (14) 1293-1303
    CrossrefPubMedGoogle Scholar
  • 87 Confavreux C, O'Connor P, Comi G. , et al; TOWER Trial Group. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014; 13 (03) 247-256
    CrossrefPubMedGoogle Scholar
  • 88 Viglietta V, Miller D, Bar-Or A. , et al. Efficacy of delayed-release dimethyl fumarate in relapsing-remitting multiple sclerosis: integrated analysis of the phase 3 trials. Ann Clin Transl Neurol 2015; 2 (02) 103-118
    CrossrefPubMedGoogle Scholar
  • 89 Baharnoori M, Lyons J, Dastagir A, Koralnik I, Stankiewicz JM. Nonfatal PML in a patient with multiple sclerosis treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm 2016; 3 (05) e274
    CrossrefPubMedGoogle Scholar
  • 90 Kappos L, Radue EW, O'Connor P. , et al; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362 (05) 387-401
    CrossrefPubMedGoogle Scholar
  • 91 Cohen JA, Barkhof F, Comi G. , et al; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362 (05) 402-415
    CrossrefPubMedGoogle Scholar
  • 92 Berger JR. Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord 2017; 12: 59-63
    CrossrefPubMedGoogle Scholar
  • 93 Polman CH, O'Connor PW, Havrdova E. , et al; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354 (09) 899-910
    CrossrefPubMedGoogle Scholar
  • 94 Fernández O, Oreja-Guevara C, Arroyo R, Izquierdo G, Pérez JL, Montalban X. Natalizumab treatment of multiple sclerosis in Spain: results of an extensive observational study. J Neurol 2012; 259 (09) 1814-1823
    CrossrefPubMedGoogle Scholar
  • 95 Butzkueven H, Kappos L, Pellegrini F. , et al; TYSABRI Observational Program (TOP) Investigators. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. J Neurol Neurosurg Psychiatry 2014; 85 (11) 1190-1197
    CrossrefPubMedGoogle Scholar
  • 96 Sørensen PS, Bertolotto A, Edan G. , et al. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler 2012; 18 (02) 143-152
    CrossrefPubMedGoogle Scholar
  • 97 Schwab N, Schneider-Hohendorf T, Pignolet B. , et al. Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values. Neurol Neuroimmunol Neuroinflamm 2016; 3 (01) e195
    CrossrefPubMedGoogle Scholar
  • 98 Alroughani R, Akhtar S, Ahmed SF. , et al. JC virus seroprevalence and seroconversion in multiple sclerosis cohort: a Middle-Eastern study. J Neurol Sci 2016; 360: 61-65
    CrossrefPubMedGoogle Scholar
  • 99 Koendgen H. Chang I, Sperling B, et al. New algorithm to estimate risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML) in antiJCV antibody positive patients: analyses of clinical trial data to provide further temporal precision and inform clinical practice. Mult Scler 2016; 22 (S3): 659
    CrossrefPubMedGoogle Scholar
  • 100 Villar LM, Costa-Frossard L, Masterman T. , et al. Lipid-specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab. Ann Neurol 2015; 77 (03) 447-457
    CrossrefPubMedGoogle Scholar
  • 101 Schwab N, Schneider-Hohendorf T, Pignolet B. , et al. PML risk stratification using anti-JCV antibody index and L-selectin. Mult Scler 2016; 22 (08) 1048-1060
    CrossrefPubMedGoogle Scholar
  • 102 Cohen JA, Coles AJ, Arnold DL. , et al; CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012; 380 (9856): 1819-1828
    CrossrefPubMedGoogle Scholar
  • 103 Coles AJ, Twyman CL, Arnold DL. , et al; CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012; 380 (9856): 1829-1839
    CrossrefPubMedGoogle Scholar
  • 104 Coles AJ, Cohen JA, Arnold DL. , et al. On behalf of the CARE-MS I Investigators. Alemtuzumab provides durable improvements in clinical outcomes in treatment-naive patients with active relapsing remitting multiple sclerosis over 6 years in the absence of continuous treatment (CARE-MS I). Mult Scler 2016; 22 (S3): 75
    PubMedGoogle Scholar
  • 105 Fox EJ, Alroughani R, Brassat D. , et al. On behalf of the CARE-MS II Investigators. Efficacy of alemtuzumab is durable over 6 years in patients with active relapsing-remitting multiple sclerosis and an inadequate response to prior therapy in the absence of continuous treatment (CARE-MS II). Mult Scler 2016; 22 (S3): 596
    PubMedGoogle Scholar
  • 106 Hauser SL, Bar-Or A, Comi G. , et al; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017; 376 (03) 221-234
    CrossrefPubMedGoogle Scholar
  • 107 Jacobs LD, Beck RW, Simon JH. , et al; CHAMPS Study Group. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000; 343 (13) 898-904
    CrossrefPubMedGoogle Scholar
  • 108 Kappos L, Polman CH, Freedman MS. , et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006; 67 (07) 1242-1249
    CrossrefPubMedGoogle Scholar
  • 109 Comi G, Martinelli V, Rodegher M. , et al; PreCISe study group. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 2009; 374 (9700): 1503-1511
    CrossrefPubMedGoogle Scholar
  • 110 Comi G, De Stefano N, Freedman MS. , et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol 2012; 11 (01) 33-41
    CrossrefPubMedGoogle Scholar
  • 111 Noyes K, Weinstock-Guttman B. Impact of diagnosis and early treatment on the course of multiple sclerosis. Am J Manag Care 2013; 19 (17, Suppl): s321-s331
    PubMedGoogle Scholar
  • 112 Sormani MP, Rio J, Tintorè M. , et al. Scoring treatment response in patients with relapsing multiple sclerosis. Mult Scler 2013; 19 (05) 605-612
    CrossrefPubMedGoogle Scholar
  • 113 Freedman MS, Selchen D, Arnold DL. , et al; Canadian Multiple Sclerosis Working Group. Treatment optimization in MS: Canadian MS Working Group updated recommendations. Can J Neurol Sci 2013; 40 (03) 307-323
    CrossrefPubMedGoogle Scholar
  • 114 Freedman MS, Forrestal FG. Canadian treatment optimization recommendations (TOR) as a predictor of disease breakthrough in patients with multiple sclerosis treated with interferon beta-1a: analysis of the PRISMS study. Mult Scler 2008; 14 (09) 1234-1241
    CrossrefPubMedGoogle Scholar
  • 115 Yamout B, Alroughani R, Al-Jumah M. , et al. Consensus recommendations for the diagnosis and treatment of multiple sclerosis: the Middle East North Africa Committee for Treatment and Research In Multiple Sclerosis (MENACTRIMS). Curr Med Res Opin 2015; 31 (07) 1349-1361
    CrossrefPubMedGoogle Scholar
  • 116 Montalban X, Hauser SL, Kappos L. , et al; ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017; 376 (03) 209-220
    CrossrefPubMedGoogle Scholar
  • 117 Hawker K, O'Connor P, Freedman MS. , et al; OLYMPUS trial group. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 2009; 66 (04) 460-471
    CrossrefPubMedGoogle Scholar
  • 118 Tourbah A, Lebrun-Frenay C, Edan G. , et al; MS-SPI study group. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, double-blind, placebo-controlled study. Mult Scler 2016; 22 (13) 1719-1731
    CrossrefPubMedGoogle Scholar
  • 119 Kappos L, Bar-Or A, Cree BAC. , et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): A double blind, randomised, phase 3 study. Lancet 2018; 391: 1263-1273
    CrossrefPubMedGoogle Scholar
  • 120 Hartung HP, Gonsette R, König N. , et al; Mitoxantrone in Multiple Sclerosis Study Group (MIMS). Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002; 360 (9350): 2018-2025
    CrossrefPubMedGoogle Scholar
  • 121 Martinelli Boneschi F, Vacchi L, Rovaris M, Capra R, Comi G. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev 2013; (05) CD002127
    PubMedGoogle Scholar
  • 122 Goodkin DE, Rudick RA, VanderBrug Medendorp S. , et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol 1995; 37 (01) 30-40
    CrossrefPubMedGoogle Scholar
  • 123 Zephir H, de Seze J, Duhamel A. , et al. Treatment of progressive forms of multiple sclerosis by cyclophosphamide: a cohort study of 490 patients. J Neurol Sci 2004; 218 (1-2): 73-77
    CrossrefPubMedGoogle Scholar
  • 124 Frohman EM, Brannon K, Racke MK, Hawker K. Mycophenolate mofetil in multiple sclerosis. Clin Neuropharmacol 2004; 27 (02) 80-83
    CrossrefPubMedGoogle Scholar
  • 125 Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. ; Pregnancy in Multiple Sclerosis Group. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998; 339 (05) 285-291
    CrossrefPubMedGoogle Scholar
  • 126 Hughes SE, Spelman T, Gray OM. , et al; MSBase study group. Predictors and dynamics of postpartum relapses in women with multiple sclerosis. Mult Scler 2014; 20 (06) 739-746
    CrossrefPubMedGoogle Scholar
  • 127 Finkelsztejn A, Brooks JB, Paschoal Jr FM, Fragoso YD. What can we really tell women with multiple sclerosis regarding pregnancy? A systematic review and meta-analysis of the literature. BJOG 2011; 118 (07) 790-797
    CrossrefPubMedGoogle Scholar
  • 128 Houtchens MK, Kolb CM. Multiple sclerosis and pregnancy: therapeutic considerations. J Neurol 2013; 260 (05) 1202-1214
    CrossrefPubMedGoogle Scholar
  • 129 Lu E, Wang BW, Guimond C, Synnes A, Sadovnick D, Tremlett H. Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review. Neurology 2012; 79 (11) 1130-1135
    CrossrefPubMedGoogle Scholar
  • 130 Neudorfer O, Sandberg-Wollheim M, Coyle PK. , et al. The Glatiramer acetate pregnancy database. Mult Scler 2015; 21 (S11): 793
    PubMedGoogle Scholar
  • 131 Karlsson G, Francis G, Koren G. , et al. Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis. Neurology 2014; 82 (08) 674-680
    CrossrefPubMedGoogle Scholar
  • 132 Pozzilli C, Pugliatti M. ; ParadigMS Group. An overview of pregnancy-related issues in patients with multiple sclerosis. Eur J Neurol 2015; 22 (Suppl. 02) 34-39
    CrossrefPubMedGoogle Scholar
  • 133 Kieseier BC, Benamor M. Pregnancy outcomes following maternal and paternal exposure to teriflunomide during treatment for relapsing-remitting multiple sclerosis. Neurol Ther 2014; 3 (02) 133-138
    CrossrefPubMedGoogle Scholar
  • 134 Gold R, Phillips JT, Havrdova E. , et al. Delayed-release dimethyl fumarate and pregnancy: preclinical studies and pregnancy outcomes from clinical trials and postmarketing experience. Neurol Ther 2015; 4 (02) 93-104
    CrossrefPubMedGoogle Scholar
  • 135 Friend S, Richman S, Bloomgren G, Cristiano LM, Wenten M. Evaluation of pregnancy outcomes from the Tysabri® (natalizumab) pregnancy exposure registry: a global, observational, follow-up study. BMC Neurol 2016; 16 (01) 150
    CrossrefPubMedGoogle Scholar
  • 136 Haghikia A, Langer-Gould A, Rellensmann G. , et al. Natalizumab use during the third trimester of pregnancy. JAMA Neurol 2014; 71 (07) 891-895
    CrossrefPubMedGoogle Scholar
  • 137 Achiron A, Chambers C, Fox EJ. , et al. Pregnancy outcomes in patients with active RRMS who received alemtuzumab in the clinical development program. Mult Scler 2015; 21 (S11): 581
    PubMedGoogle Scholar
  • 138 Hviid A, Mølgaard-Nielsen D. Corticosteroid use during pregnancy and risk of orofacial clefts. CMAJ 2011; 183 (07) 796-804
    CrossrefPubMedGoogle Scholar
  • 139 Ray JG, Vermeulen MJ, Bharatha A, Montanera WJ, Park AL. Association between MRI exposure during pregnancy and fetal and childhood outcomes. JAMA 2016; 316 (09) 952-961
    CrossrefPubMedGoogle Scholar
  • 140 Langer-Gould A, Huang SM, Gupta R. , et al. Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis. Arch Neurol 2009; 66 (08) 958-963
    CrossrefPubMedGoogle Scholar
  • 141 Portaccio E, Ghezzi A, Hakiki B. , et al; MS Study Group of the Italian Neurological Society. Breastfeeding is not related to postpartum relapses in multiple sclerosis. Neurology 2011; 77 (02) 145-150
    CrossrefPubMedGoogle Scholar
  • 142 Haas J, Hommes OR. A dose comparison study of IVIG in postpartum relapsing-remitting multiple sclerosis. Mult Scler 2007; 13 (07) 900-908
    CrossrefPubMedGoogle Scholar
  • 143 Hellwig K, Beste C, Schimrigk S, Chan A. Immunomodulation and postpartum relapses in patients with multiple sclerosis. Ther Adv Neurol Disorder 2009; 2 (01) 7-11
    PubMedGoogle Scholar
  • 144 de Seze J, Chapelotte M, Delalande S, Ferriby D, Stojkovic T, Vermersch P. Intravenous corticosteroids in the postpartum period for reduction of acute exacerbations in multiple sclerosis. Mult Scler 2004; 10 (05) 596-597
    CrossrefPubMedGoogle Scholar