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Diagnosis and Treatment of Multiple SclerosisA Review

Educational Objective
To review the clinical management of patients with multiple sclerosis.
1 Credit CME
Abstract

Importance  Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease of the central nervous system characterized by inflammatory demyelination with axonal transection. MS affects an estimated 900 000 people in the US. MS typically presents in young adults (mean age of onset, 20-30 years) and can lead to physical disability, cognitive impairment, and decreased quality of life. This review summarizes current evidence regarding diagnosis and treatment of MS.

Observations  MS typically presents in young adults aged 20 to 30 years with unilateral optic neuritis, partial myelitis, sensory disturbances, or brainstem syndromes such as internuclear ophthalmoplegia developing over several days. The prevalence of MS worldwide ranges from 5 to 300 per 100 000 people and increases at higher latitudes. Overall life expectancy is less than in the general population (75.9 vs 83.4 years), and MS more commonly affects women (female to male sex distribution of nearly 3:1). Diagnosis is made based on a combination of signs and symptoms, radiographic findings (eg, magnetic resonance imaging [MRI] T2 lesions), and laboratory findings (eg, cerebrospinal fluid–specific oligoclonal bands), which are components of the 2017 McDonald Criteria. Nine classes of disease-modifying therapies (DMTs), with varying mechanisms of action and routes of administration, are available for relapsing-remitting MS, defined as relapses at onset with stable neurologic disability between episodes, and secondary progressive MS with activity, defined as steadily increasing neurologic disability following a relapsing course with evidence of ongoing inflammatory activity. These drugs include interferons, glatiramer acetate, teriflunomide, sphingosine 1-phosphate receptor modulators, fumarates, cladribine, and 3 types of monoclonal antibodies. One additional DMT, ocrelizumab, is approved for primary progressive MS. These DMTs reduce clinical relapses and MRI lesions (new T2 lesions, gadolinium-enhancing lesions). Efficacy rates of current DMTs, defined by reduction in annualized relapse rates compared with placebo or active comparators, range from 29%-68%. Adverse effects include infections, bradycardia, heart blocks, macular edema, infusion reactions, injection-site reactions, and secondary autoimmune adverse effects, such as autoimmune thyroid disease.

Conclusions and Relevance  MS is characterized by physical disability, cognitive impairment, and other symptoms that affect quality of life. Treatment with DMT can reduce the annual relapse rate by 29% to 68% compared with placebo or active comparator.

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Article Information

Corresponding Author: Alexander D. Rae-Grant, MD, 10 Estes St, Ipswich, MA 01938 (raegranta@gmail.com).

Accepted for Publication: December 28, 2020.

Correction: This article was corrected on June 1, 2021, for incorrect or incomplete data in Table 3.

Author Contributions: Dr Rae-Grant had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Goldschmidt, Rae-Grant.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: McGinley, Rae-Grant.

Administrative, technical, or material support: McGinley.

Supervision: McGinley, Rae-Grant.

Conflict of Interest Disclosures: Dr McGinley reported serving on scientific advisory boards for Genzyme and Genentech; receiving research support from Novartis; and receiving funding from a KL2 (KL2TR002547) grant from Clinical and Translational Science Collaborative of Cleveland, from the National Center for Advancing Translational Sciences component of the National Institutes of Health. Dr Rae-Grant reported serving as chair of the American Academy of Neurology guideline subcommittee; that he was lead author on the subcommittee’s 2018 guideline on disease-modifying therapy for multiple sclerosis; and working part time as deputy editor for Ebsco industries editing neurology, psychiatry, and palliative care content in Dynamed, a subscription-based online point-of-care tool for clinicians. None of these activities are supported by the pharmaceutical or device industry. No other disclosures were reported.

Additional Contributions: We would like to acknowledge Cleveland Clinic illustrator Amanda Mendelsohn, BS, BFA, for preparing a draft of the figure. Ms Mendelsohn was not compensated for her contributions.

References
1.
Frischer  JM , Weigand  SD , Guo  Y ,  et al.  Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque.   Ann Neurol. 2015;78(5):710-721. doi:10.1002/ana.24497PubMedGoogle ScholarCrossref
2.
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(5):278-285. doi:10.1056/NEJM199801293380502PubMedGoogle ScholarCrossref
3.
Wallin  MT , Culpepper  WJ , Campbell  JD ,  et al; US Multiple Sclerosis Prevalence Workgroup.  The prevalence of MS in the United States: a population-based estimate using health claims data.   Neurology. 2019;92(10):e1029-e1040. doi:10.1212/WNL.0000000000007035PubMedGoogle ScholarCrossref
4.
Handel  AE , Williamson  AJ , Disanto  G , Dobson  R , Giovannoni  G , Ramagopalan  SV .  Smoking and multiple sclerosis: an updated meta-analysis.   PLoS One. 2011;6(1):e16149. doi:10.1371/journal.pone.0016149PubMedGoogle Scholar
5.
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(9):e12496. doi:10.1371/journal.pone.0012496PubMedGoogle Scholar
6.
Lucas  RM , Ponsonby  AL , Dear  K ,  et al.  Sun exposure and vitamin D are independent risk factors for CNS demyelination.   Neurology. 2011;76(6):540-548. doi:10.1212/WNL.0b013e31820af93dPubMedGoogle ScholarCrossref
7.
Munger  KL , Bentzen  J , Laursen  B ,  et al.  Childhood body mass index and multiple sclerosis risk: a long-term cohort study.   Mult Scler. 2013;19(10):1323-1329. doi:10.1177/1352458513483889PubMedGoogle ScholarCrossref
8.
Munger  KL , Levin  LI , Hollis  BW , Howard  NS , Ascherio  A .  Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis.   JAMA. 2006;296(23):2832-2838. doi:10.1001/jama.296.23.2832PubMedGoogle ScholarCrossref
9.
Patsopoulos  NA , Barcellos  LF , Hintzen  RQ ,  et al.  Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects.   PLoS Genet. 2013;9(11):e1003926. doi:10.1371/journal.pgen.1003926PubMedGoogle Scholar
10.
Browne  P , Chandraratna  D , Angood  C ,  et al.  Atlas of Multiple Sclerosis 2013: a growing global problem with widespread inequity.   Neurology. 2014;83(11):1022-1024. doi:10.1212/WNL.0000000000000768PubMedGoogle ScholarCrossref
11.
Lucchinetti  CF , Popescu  BF , Bunyan  RF ,  et al.  Inflammatory cortical demyelination in early multiple sclerosis.   N Engl J Med. 2011;365(23):2188-2197. doi:10.1056/NEJMoa1100648PubMedGoogle ScholarCrossref
12.
Frischer  JM , Bramow  S , Dal-Bianco  A ,  et al.  The relation between inflammation and neurodegeneration in multiple sclerosis brains.   Brain. 2009;132(pt 5):1175-1189. doi:10.1093/brain/awp070PubMedGoogle ScholarCrossref
13.
Michel  L , Touil  H , Pikor  NB , Gommerman  JL , Prat  A , Bar-Or  A .  B cells in the multiple sclerosis central nervous system: trafficking and contribution to CNS-compartmentalized inflammation.   Front Immunol. 2015;6:636. doi:10.3389/fimmu.2015.00636PubMedGoogle ScholarCrossref
14.
Thompson  AJ , Banwell  BL , Barkhof  F ,  et al.  Diagnosis of multiple sclerosis: 2017 revisions of the McDonald Criteria.   Lancet Neurol. 2018;17(2):162-173. doi:10.1016/S1474-4422(17)30470-2PubMedGoogle ScholarCrossref
15.
van der Vuurst de Vries  RM , Mescheriakova  JY , Wong  YYM ,  et al.  Application of the 2017 revised McDonald Criteria for multiple sclerosis to patients with a typical clinically isolated syndrome.   JAMA Neurol. 2018;75(11):1392-1398. doi:10.1001/jamaneurol.2018.2160PubMedGoogle ScholarCrossref
16.
Cree  BA , Gourraud  PA , Oksenberg  JR ,  et al; University of California, San Francisco MS-EPIC Team.  Long-term evolution of multiple sclerosis disability in the treatment era.   Ann Neurol. 2016;80(4):499-510. doi:10.1002/ana.24747PubMedGoogle ScholarCrossref
17.
Confavreux  C , Vukusic  S , Moreau  T , Adeleine  P .  Relapses and progression of disability in multiple sclerosis.   N Engl J Med. 2000;343(20):1430-1438. doi:10.1056/NEJM200011163432001PubMedGoogle ScholarCrossref
18.
Weinshenker  BG , Bass  B , Rice  GP ,  et al.  The natural history of multiple sclerosis: a geographically based study, I: clinical course and disability.   Brain. 1989;112(pt 1):133-146. doi:10.1093/brain/112.1.133PubMedGoogle ScholarCrossref
19.
Scalfari  A , Neuhaus  A , Degenhardt  A ,  et al.  The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability.   Brain. 2010;133(pt 7):1914-1929. doi:10.1093/brain/awq118PubMedGoogle ScholarCrossref
20.
Marrie  RA , Elliott  L , Marriott  J ,  et al.  Effect of comorbidity on mortality in multiple sclerosis.   Neurology. 2015;85(3):240-247. doi:10.1212/WNL.0000000000001718PubMedGoogle ScholarCrossref
21.
Fischer  JS , Rudick  RA , Cutter  GR , Reingold  SC ; National MS Society Clinical Outcomes Assessment Task Force.  The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment.   Mult Scler. 1999;5(4):244-250. doi:10.1177/135245859900500409PubMedGoogle ScholarCrossref
22.
Kurtzke  JF .  Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).   Neurology. 1983;33(11):1444-1452. doi:10.1212/WNL.33.11.1444PubMedGoogle ScholarCrossref
23.
Sormani  MP , Bruzzi  P .  MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials.   Lancet Neurol. 2013;12(7):669-676. doi:10.1016/S1474-4422(13)70103-0PubMedGoogle ScholarCrossref
24.
Howell  OW , Reeves  CA , Nicholas  R ,  et al.  Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis.   Brain. 2011;134(pt 9):2755-2771. doi:10.1093/brain/awr182PubMedGoogle ScholarCrossref
25.
Okwuokenye  M , Zhang  A , Pace  A , Peace  KE .  Number needed to treat in multiple sclerosis clinical trials.   Neurol Ther. 2017;6(1):1-9. doi:10.1007/s40120-017-0063-yPubMedGoogle ScholarCrossref
26.
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(4):655-661. doi:10.1212/WNL.43.4.655PubMedGoogle ScholarCrossref
27.
PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group.  Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis.   Lancet. 1998;352(9139):1498-1504. doi:10.1016/S0140-6736(98)03334-0PubMedGoogle ScholarCrossref
28.
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(7):657-665. doi:10.1016/S1474-4422(14)70068-7PubMedGoogle ScholarCrossref
29.
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. doi:10.1056/NEJM200009283431301PubMedGoogle ScholarCrossref
30.
Jacobs  LD , Cookfair  DL , Rudick  RA ,  et al; Multiple Sclerosis Collaborative Research Group (MSCRG).  Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis.   Ann Neurol. 1996;39(3):285-294. doi:10.1002/ana.410390304PubMedGoogle ScholarCrossref
31.
Johnson  KP , Brooks  BR , Cohen  JA ,  et al; Copolymer 1 Multiple Sclerosis Study Group.  Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial.   Neurology. 1995;45(7):1268-1276. doi:10.1212/WNL.45.7.1268PubMedGoogle ScholarCrossref
32.
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(5):387-401. doi:10.1056/NEJMoa0909494PubMedGoogle ScholarCrossref
33.
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(5):402-415. doi:10.1056/NEJMoa0907839PubMedGoogle ScholarCrossref
34.
Kappos  L , Bar-Or  A , Cree  BAC ,  et al; EXPAND Clinical Investigators.  Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study.   Lancet. 2018;391(10127):1263-1273. doi:10.1016/S0140-6736(18)30475-6PubMedGoogle ScholarCrossref
35.
Comi  G , Kappos  L , Selmaj  KW ,  et al; SUNBEAM Study Investigators.  Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial.   Lancet Neurol. 2019;18(11):1009-1020. doi:10.1016/S1474-4422(19)30239-XPubMedGoogle ScholarCrossref
36.
Fox  RJ , Miller  DH , Phillips  JT ,  et al; CONFIRM Study Investigators.  Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.   N Engl J Med. 2012;367(12):1087-1097. doi:10.1056/NEJMoa1206328PubMedGoogle ScholarCrossref
37.
Gold  R , Kappos  L , Arnold  DL ,  et al; DEFINE Study Investigators.  Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.   N Engl J Med. 2012;367(12):1098-1107. doi:10.1056/NEJMoa1114287PubMedGoogle ScholarCrossref
38.
Naismith  RT , Wundes  A , Ziemssen  T ,  et al; EVOLVE-MS-2 Study Group.  Diroximel fumarate demonstrates an improved gastrointestinal tolerability profile compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: results from the randomized, double-blind, phase III EVOLVE-MS-2 study.   CNS Drugs. 2020;34(2):185-196. doi:10.1007/s40263-020-00700-0PubMedGoogle ScholarCrossref
39.
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. doi:10.1056/NEJMoa1014656PubMedGoogle ScholarCrossref
40.
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(3):247-256. doi:10.1016/S1474-4422(13)70308-9PubMedGoogle ScholarCrossref
41.
Giovannoni  G , Comi  G , Cook  S ,  et al; CLARITY Study Group.  A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.   N Engl J Med. 2010;362(5):416-426. doi:10.1056/NEJMoa0902533PubMedGoogle ScholarCrossref
42.
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(9):899-910. doi:10.1056/NEJMoa044397PubMedGoogle ScholarCrossref
43.
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(3):221-234. doi:10.1056/NEJMoa1601277PubMedGoogle ScholarCrossref
44.
Hauser  SL , Bar-Or  A , Cohen  JA ,  et al; ASCLEPIOS I and ASCLEPIOS II Trial Groups.  Ofatumumab versus Teriflunomide in Multiple Sclerosis.   N Engl J Med. 2020;383(6):546-557. doi:10.1056/NEJMoa1917246PubMedGoogle ScholarCrossref
45.
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. doi:10.1016/S0140-6736(12)61769-3PubMedGoogle ScholarCrossref
46.
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. doi:10.1016/S0140-6736(12)61768-1PubMedGoogle ScholarCrossref
47.
Luna  G , Alping  P , Burman  J ,  et al.  Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies.   JAMA Neurol. 2020;77(2):184-191. doi:10.1001/jamaneurol.2019.3365PubMedGoogle ScholarCrossref
48.
Cohen  JA , Comi  G , Selmaj  KW ,  et al; RADIANCE Trial Investigators.  Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial.   Lancet Neurol. 2019;18(11):1021-1033. doi:10.1016/S1474-4422(19)30238-8PubMedGoogle ScholarCrossref
49.
Coles  AJ , Cohen  JA , Fox  EJ ,  et al; CARE-MS II and CAMMS03409 Investigators.  Alemtuzumab CARE-MS II 5-year follow-up: efficacy and safety findings.   Neurology. 2017;89(11):1117-1126. doi:10.1212/WNL.0000000000004354PubMedGoogle ScholarCrossref
50.
Azevedo  CJ , Kutz  C , Dix  A , Boster  A , Sanossian  N , Kaplan  J .  Intracerebral haemorrhage during alemtuzumab administration.   Lancet Neurol. 2019;18(4):329-331. doi:10.1016/S1474-4422(19)30076-6PubMedGoogle ScholarCrossref
51.
Bloomgren  G , Richman  S , Hotermans  C ,  et al.  Risk of natalizumab-associated progressive multifocal leukoencephalopathy.   N Engl J Med. 2012;366(20):1870-1880. doi:10.1056/NEJMoa1107829PubMedGoogle ScholarCrossref
52.
Martin  SI , Marty  FM , Fiumara  K , Treon  SP , Gribben  JG , Baden  LR .  Infectious complications associated with alemtuzumab use for lymphoproliferative disorders.   Clin Infect Dis. 2006;43(1):16-24. doi:10.1086/504811PubMedGoogle ScholarCrossref
53.
Brown  JWL , Coles  A , Horakova  D ,  et al; MSBase Study Group.  Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis.   JAMA. 2019;321(2):175-187. doi:10.1001/jama.2018.20588PubMedGoogle ScholarCrossref
54.
Le Page  E , Veillard  D , Laplaud  DA ,  et al; COPOUSEP Investigators; West Network for Excellence in Neuroscience.  Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial.   Lancet. 2015;386(9997):974-981. doi:10.1016/S0140-6736(15)61137-0PubMedGoogle ScholarCrossref
55.
Rolfes  L , Pfeuffer  S , Ruck  T ,  et al.  Therapeutic apheresis in acute relapsing multiple sclerosis: current evidence and unmet needs—a systematic review.   J Clin Med. 2019;8(10):E1623. doi:10.3390/jcm8101623PubMedGoogle Scholar
56.
Kister  I , Spelman  T , Alroughani  R ,  et al; MSBase Study Group.  Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study.   J Neurol Neurosurg Psychiatry. 2016;87(10):1133-1137. doi:10.1136/jnnp-2016-313760PubMedGoogle ScholarCrossref
57.
Kister  I , Spelman  T , Patti  F ,  et al.  Predictors of relapse and disability progression in MS patients who discontinue disease-modifying therapy.   J Neurol Sci. 2018;391:72-76. doi:10.1016/j.jns.2018.06.001PubMedGoogle ScholarCrossref
58.
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(5):285-291. doi:10.1056/NEJM199807303390501PubMedGoogle ScholarCrossref
59.
Vukusic  S , Marignier  R .  Multiple sclerosis and pregnancy in the “treatment era”.   Nat Rev Neurol. 2015;11(5):280-289. doi:10.1038/nrneurol.2015.53PubMedGoogle ScholarCrossref
60.
Dobson  R , Jokubaitis  VG , Giovannoni  G .  Change in pregnancy-associated multiple sclerosis relapse rates over time: a meta-analysis.   Mult Scler Relat Disord. 2020;44:102241. doi:10.1016/j.msard.2020.102241PubMedGoogle Scholar
61.
Skuladottir  H , Wilcox  AJ , Ma  C ,  et al.  Corticosteroid use and risk of orofacial clefts.   Birth Defects Res A Clin Mol Teratol. 2014;100(6):499-506. doi:10.1002/bdra.23248PubMedGoogle ScholarCrossref
62.
Pakpoor  J , Disanto  G , Lacey  MV , Hellwig  K , Giovannoni  G , Ramagopalan  SV .  Breastfeeding and multiple sclerosis relapses: a meta-analysis.   J Neurol. 2012;259(10):2246-2248. doi:10.1007/s00415-012-6553-zPubMedGoogle ScholarCrossref
63.
Almas  S , Vance  J , Baker  T , Hale  T .  Management of multiple sclerosis in the breastfeeding mother.   Mult Scler Int. 2016;2016:6527458. doi:10.1155/2016/6527458PubMedGoogle Scholar
64.
Marrie  RA , Rudick  R , Horwitz  R ,  et al.  Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis.   Neurology. 2010;74(13):1041-1047. doi:10.1212/WNL.0b013e3181d6b125PubMedGoogle ScholarCrossref
65.
Zhu  N , Jacobs  DR  Jr , Schreiner  PJ ,  et al.  Cardiorespiratory fitness and brain volume and white matter integrity: the CARDIA study.   Neurology. 2015;84(23):2347-2353. doi:10.1212/WNL.0000000000001658PubMedGoogle ScholarCrossref
66.
Marrie  RA , Horwitz  R , Cutter  G , Tyry  T , Campagnolo  D , Vollmer  T .  Comorbidity delays diagnosis and increases disability at diagnosis in MS.   Neurology. 2009;72(2):117-124. doi:10.1212/01.wnl.0000333252.78173.5fPubMedGoogle ScholarCrossref
67.
McKay  KA , Tremlett  H , Fisk  JD ,  et al; CIHR Team in the Epidemiology and Impact of Comorbidity on Multiple Sclerosis.  Psychiatric comorbidity is associated with disability progression in multiple sclerosis.   Neurology. 2018;90(15):e1316-e1323. doi:10.1212/WNL.0000000000005302PubMedGoogle ScholarCrossref
68.
Marrie  RA , Horwitz  R , Cutter  G , Tyry  T , Campagnolo  D , Vollmer  T .  The burden of mental comorbidity in multiple sclerosis: frequent, underdiagnosed, and undertreated.   Mult Scler. 2009;15(3):385-392. doi:10.1177/1352458508099477PubMedGoogle ScholarCrossref
69.
Fragoso  YD , Adoni  T , Anacleto  A ,  et al.  Recommendations on diagnosis and treatment of depression in patients with multiple sclerosis.   Pract Neurol. 2014;14(4):206-209. doi:10.1136/practneurol-2013-000735PubMedGoogle ScholarCrossref
70.
Korostil  M , Feinstein  A .  Anxiety disorders and their clinical correlates in multiple sclerosis patients.   Mult Scler. 2007;13(1):67-72. doi:10.1177/1352458506071161PubMedGoogle ScholarCrossref
71.
Bamer  AM , Johnson  KL , Amtmann  D , Kraft  GH .  Prevalence of sleep problems in individuals with multiple sclerosis.   Mult Scler. 2008;14(8):1127-1130. doi:10.1177/1352458508092807PubMedGoogle ScholarCrossref
72.
Brass  SD , Li  CS , Auerbach  S .  The underdiagnosis of sleep disorders in patients with multiple sclerosis.   J Clin Sleep Med. 2014;10(9):1025-1031. doi:10.5664/jcsm.4044PubMedGoogle ScholarCrossref
73.
Soilu-Hänninen  M , Airas  L , Mononen  I , Heikkilä  A , Viljanen  M , Hänninen  A .  25-Hydroxyvitamin D levels in serum at the onset of multiple sclerosis.   Mult Scler. 2005;11(3):266-271. doi:10.1191/1352458505ms1157oaPubMedGoogle ScholarCrossref
74.
Fitzgerald  KC , Munger  KL , Köchert  K ,  et al.  Association of vitamin D levels with multiple sclerosis activity and progression in patients receiving interferon Beta-1b.   JAMA Neurol. 2015;72(12):1458-1465. doi:10.1001/jamaneurol.2015.2742PubMedGoogle ScholarCrossref
75.
Simon  KC , Schmidt  H , Loud  S , Ascherio  A .  Risk factors for multiple sclerosis, neuromyelitis optica and transverse myelitis.   Mult Scler. 2015;21(6):703-709. doi:10.1177/1352458514551780PubMedGoogle ScholarCrossref
76.
Martinelli Boneschi  F , Colombo  B , Annovazzi  P ,  et al.  Lifetime and actual prevalence of pain and headache in multiple sclerosis.   Mult Scler. 2008;14(4):514-521. doi:10.1177/1352458507085551PubMedGoogle ScholarCrossref
77.
Rizzo  MA , Hadjimichael  OC , Preiningerova  J , Vollmer  TL .  Prevalence and treatment of spasticity reported by multiple sclerosis patients.   Mult Scler. 2004;10(5):589-595. doi:10.1191/1352458504ms1085oaPubMedGoogle ScholarCrossref
78.
Bakshi  R .  Fatigue associated with multiple sclerosis: diagnosis, impact and management.   Mult Scler. 2003;9(3):219-227. doi:10.1191/1352458503ms904oaPubMedGoogle ScholarCrossref
79.
Fox  RJ , Bacon  TE , Chamot  E ,  et al.  Prevalence of multiple sclerosis symptoms across lifespan: data from the NARCOMS Registry.   Neurodegener Dis Manag. 2015;5(6)(suppl):3-10.PubMedGoogle Scholar
80.
Caminero  A , Bartolomé  M .  Sleep disturbances in multiple sclerosis.   J Neurol Sci. 2011;309(1-2):86-91. doi:10.1016/j.jns.2011.07.015PubMedGoogle ScholarCrossref
81.
Amato  MP , Portaccio  E .  Management options in multiple sclerosis-associated fatigue.   Expert Opin Pharmacother. 2012;13(2):207-216. doi:10.1517/14656566.2012.647767PubMedGoogle ScholarCrossref
82.
Rao  SM , Leo  GJ , Bernardin  L , Unverzagt  F .  Cognitive dysfunction in multiple sclerosis, I: frequency, patterns, and prediction.   Neurology. 1991;41(5):685-691. doi:10.1212/WNL.41.5.685PubMedGoogle ScholarCrossref
83.
Amato  MP , Ponziani  G , Siracusa  G , Sorbi  S .  Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years.   Arch Neurol. 2001;58(10):1602-1606. doi:10.1001/archneur.58.10.1602PubMedGoogle ScholarCrossref
84.
Litwiller  SE , Frohman  EM , Zimmern  PE .  Multiple sclerosis and the urologist.   J Urol. 1999;161(3):743-757. doi:10.1016/S0022-5347(01)61760-9PubMedGoogle ScholarCrossref
85.
Chia  YW , Fowler  CJ , Kamm  MA , Henry  MM , Lemieux  MC , Swash  M .  Prevalence of bowel dysfunction in patients with multiple sclerosis and bladder dysfunction.   J Neurol. 1995;242(2):105-108. doi:10.1007/BF00887825PubMedGoogle ScholarCrossref
86.
Hinds  JP , Eidelman  BH , Wald  A .  Prevalence of bowel dysfunction in multiple sclerosis: a population survey.   Gastroenterology. 1990;98(6):1538-1542. doi:10.1016/0016-5085(90)91087-MPubMedGoogle ScholarCrossref
87.
Zorzon  M , Zivadinov  R , Monti Bragadin  L ,  et al.  Sexual dysfunction in multiple sclerosis: a 2-year follow-up study.   J Neurol Sci. 2001;187(1-2):1-5. doi:10.1016/S0022-510X(01)00493-2PubMedGoogle ScholarCrossref
88.
Pittock  SJ , McClelland  RL , Mayr  WT , Rodriguez  M , Matsumoto  JY .  Prevalence of tremor in multiple sclerosis and associated disability in the Olmsted County population.   Mov Disord. 2004;19(12):1482-1485. doi:10.1002/mds.20227PubMedGoogle ScholarCrossref
89.
Alusi  SH , Worthington  J , Glickman  S , Bain  PG .  A study of tremor in multiple sclerosis.   Brain. 2001;124(pt 4):720-730. doi:10.1093/brain/124.4.720PubMedGoogle ScholarCrossref
90.
Alali  D , Ballard  K , Bogaardt  H .  The frequency of dysphagia and its impact on adults with multiple sclerosis based on patient-reported questionnaires.   Mult Scler Relat Disord. 2018;25:227-231. doi:10.1016/j.msard.2018.08.003PubMedGoogle ScholarCrossref
91.
Mohr  DC , Goodkin  DE , Likosky  W , Gatto  N , Baumann  KA , Rudick  RA .  Treatment of depression improves adherence to interferon beta-1b therapy for multiple sclerosis.   Arch Neurol. 1997;54(5):531-533. doi:10.1001/archneur.1997.00550170015009PubMedGoogle ScholarCrossref
92.
Geraldes  R , Esiri  MM , DeLuca  GC , Palace  J .  Age-related small vessel disease: a potential contributor to neurodegeneration in multiple sclerosis.   Brain Pathol. 2017;27(6):707-722. doi:10.1111/bpa.12460PubMedGoogle ScholarCrossref
93.
Briken  S , Gold  SM , Patra  S ,  et al.  Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial.   Mult Scler. 2014;20(3):382-390. doi:10.1177/1352458513507358PubMedGoogle ScholarCrossref
94.
Sumowski  JF , Rocca  MA , Leavitt  VM ,  et al.  Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS.   Neurology. 2014;82(20):1776-1783. doi:10.1212/WNL.0000000000000433PubMedGoogle ScholarCrossref
95.
Sundström  P , Nyström  L .  Smoking worsens the prognosis in multiple sclerosis.   Mult Scler. 2008;14(8):1031-1035. doi:10.1177/1352458508093615PubMedGoogle ScholarCrossref
96.
Aboud  T , Schuster  NM .  Pain management in multiple sclerosis: a review of available treatment options.   Curr Treat Options Neurol. 2019;21(12):62. doi:10.1007/s11940-019-0601-2PubMedGoogle ScholarCrossref
97.
Lerdal  A , Celius  EG , Krupp  L , Dahl  AA .  A prospective study of patterns of fatigue in multiple sclerosis.   Eur J Neurol. 2007;14(12):1338-1343. doi:10.1111/j.1468-1331.2007.01974.xPubMedGoogle ScholarCrossref
98.
Coyle  PK .  Symptom management and lifestyle modifications in multiple sclerosis.   Continuum (Minneap Minn). 2016;22(3):815-836. doi:10.1212/CON.0000000000000325PubMedGoogle Scholar
99.
Burt  RK , Balabanov  R , Burman  J ,  et al.  Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: a randomized clinical trial.   JAMA. 2019;321(2):165-174. doi:10.1001/jama.2018.18743PubMedGoogle ScholarCrossref
100.
Mancardi  GL , Sormani  MP , Gualandi  F ,  et al; ASTIMS Haemato-Neurological Collaborative Group, on behalf of the Autoimmune Disease Working Party (ADWP) of the European Group for Blood and Marrow Transplantation (EBMT); ASTIMS Haemato-Neurological Collaborative Group on behalf of the Autoimmune Disease Working Party ADWP of the European Group for Blood and Marrow Transplantation EBMT.  Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial.   Neurology. 2015;84(10):981-988. doi:10.1212/WNL.0000000000001329PubMedGoogle ScholarCrossref
101.
Nash  RA , Hutton  GJ , Racke  MK ,  et al.  High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report.   JAMA Neurol. 2015;72(2):159-169. doi:10.1001/jamaneurol.2014.3780PubMedGoogle ScholarCrossref
102.
Sedel  F , Bernard  D , Mock  DM , Tourbah  A .  Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis.   Neuropharmacology. 2016;110(pt B):644-653.Google ScholarCrossref
103.
Green  AJ , Gelfand  JM , Cree  BA ,  et al.  Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial.   Lancet. 2017;390(10111):2481-2489. doi:10.1016/S0140-6736(17)32346-2PubMedGoogle ScholarCrossref
104.
Cadavid  D , Mellion  M , Hupperts  R ,  et al; SYNERGY Study Investigators.  Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial.   Lancet Neurol. 2019;18(9):845-856. doi:10.1016/S1474-4422(19)30137-1PubMedGoogle ScholarCrossref
105.
Harris  VK , Stark  J , Vyshkina  T ,  et al.  Phase I trial of intrathecal mesenchymal stem cell–derived neural progenitors in progressive multiple sclerosis.   EBioMedicine. 2018;29:23-30. doi:10.1016/j.ebiom.2018.02.002PubMedGoogle ScholarCrossref
106.
Cree  BAC , Cutter  G , Wolinsky  JS ,  et al; SPI2 Investigative Teams.  Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial.   Lancet Neurol. 2020;19(12):988-997. doi:10.1016/S1474-4422(20)30347-1PubMedGoogle ScholarCrossref
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