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Multiple sclerosis

Last updated: May 7, 2021

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Multiple sclerosis (MS) is a chronic, degenerative disease of the CNS that is caused by an immune-mediated inflammatory process. This process results in demyelination and axonal degeneration in the brain and spinal cord. MS has a higher prevalence among women and people in temperate regions such as Europe and North America. Impaired vision (due to retrobulbar neuritis) is usually the first manifestation of the disease. Other neurological deficits also appear as the disease progresses. The most common clinical course is characterized by exacerbations (relapses) followed by periods of complete/incomplete remission. MRI, which is the investigation of choice, reveals demyelinated sclerotic plaques primarily in white matter. Differential diagnoses of MS includes other chronic demyelinating diseases and neurological infections (e.g., borreliosis, neurosyphilis). Acute exacerbations of MS are treated with high-dose glucocorticoids. Between relapses, patients may be treated with disease-modifying drugs (e.g., β-interferon, glatiramer acetate). No definitive therapy is available for MS.

  • Sex: > (3:1) [1]
  • Age of onset: 20–40 years of age
  • Ethnicity: prevalence among the white population
  • Prevalence: : 50-300 per 100 000 people (greater among people who live further from the equator)

References: [2]

Epidemiological data refers to the US, unless otherwise specified.

The etiology of multiple sclerosis is unclear; it is believed to develop in genetically predisposed people who have been exposed to certain environmental factors.

Fundoscopy is normal in 60% of cases of optic neuritis. Neither the patient nor the doctor are able to see anything.

Uhthoff phenomenon triggered by a viral infection may mimic an exacerbation of MS.

Clinical course [13]

Clinical phenotypes of multiple sclerosis
Phenotype Characteristics Incidence at the time of diagnosis
Relapsing-remitting MS (RR-MS)
  • Exacerbations occur
  • Symptoms remit almost completely between exacerbations
  • 90% (most common clinical course)
Secondary progressive MS (SP-MS)
  • Exacerbations occur
  • Continuous worsening of symptoms in between exacerbations
  • Arises from RR-MS (as per definition)
Primary progressive MS (PP-MS)
  • Exacerbations occur
  • Continuous worsening of symptoms from the very onset of the disease
  • 10%
Definition of exacerbation : new symptoms or significant worsening of existing symptoms, both of which last at least 24 hours and are preceded by at least 30 days of relative clinical stability.

Special forms of MS

  • Radiologically isolated syndrome (RIS) [13][14]
  • Clinically isolated syndrome (CIS): a constellation of neurological symptoms that, in hindsight, can be interpreted as the first episode of MS [13]
  • Diffuse cerebral sclerosis (Schilder disease)
    • Clinical course: primarily affects children; monophasic course with most patients dying within 1–2 years of disease onset
    • Clinical features: large areas of demyelination leading to various neurological deficits and psychological changes depending on the location of the lesion

For more detailed information about the MS diagnostics, see “Revised McDonald criteria.”

Instrument-based diagnostics

CSF examination

The appearance of oligoclonal bands in the early stages of the disease indicates a poor prognosis!

References:[15][16][17][18]

The McDonald criteria are used to diagnose MS based on the dissemination of the CNS lesions in time and space.

  • Dissemination in time (DIT): defined as the appearance of new lesions over time that can be confirmed by one of the following:
  • Dissemination in space (DIS): defined as the presence of lesions in different regions of the CNS that can be confirmed by one of the following:
    • Presence of two or more lesions with objective clinical evidence
      • Objective clinical evidence of a lesion refers to the correlation between the symptoms reported by a patient and corresponding objective findings (e.g., T2 hyperintensities in the regions corresponding to somatosensory tracts on MRI or abnormal somatosensory evoked potentials in a patient who reports sensory loss)
    • Presence of one or more hyperintense lesions on MRI in T2 sequence in at least 2 of the following regions: periventricular, juxtacortical, infratentorial, spinal
McDonald criteria (2017) for the diagnosis of multiple sclerosis [19]
Dissemination in space (DIS)
Criterion met (≥ 2 lesions with objective clinical evidence) Criterion not met (1 lesion with objective clinical evidence)
Dissemination in time (DIT) Criterion met ≥ 2 exacerbations)
  • Clinical evidence is sufficient for the diagnosis of MS.
  • If there is a clear history of a previous exacerbation with a lesion in a distinct CNS location, no more evidence is needed.
  • If there is no history of a previous exacerbation with a lesion in a distinct CNS location, diagnosis requires confirmation of DIS by one of the following:
    • An additional exacerbation with presence of one more lesion with objective clinical evidence involving a different CNS region
    • Presence on MRI of ≥ 1 T2-hyperintense lesion in at least 2 of the following regions: periventricular, juxtacortical, infratentorial, spinal
Criterion not met (1 exacerbation)
  • Diagnosis requires confirmation of DIT by one of the following
  • Diagnosis requires evidence of both DIT and DIS, which can be confirmed by the following:
    • Demonstration of DIS by another exacerbation with objective evidence involving a different CNS region or by MRI (see the criteria for DIS above)
    • Demonstration of DIT by either another exacerbation, MRI (see the criteria for DIT above) or oligoclonal bands in the CSF

Autoimmune diseases associated with inflammatory demyelination

Neuromyelitis optica spectrum disorders (NMOSD; previously known as Devic disease or neuromyelitis optica) [20][21]

Diagnostic criteria of NMOSD based on AQP4-IgG status
Serological criteria Clinical criteria Additional criteria
Positive AQP4-IgG
  • Exclusion of other causes (e.g., MS)
Negative AQP4-IgG or unknown status

Acute disseminated encephalomyelitis (ADEM, acute demyelinating encephalomyelitis) [22]

Other conditions

The differential diagnoses listed here are not exhaustive.

Summary of therapy for multiple sclerosis [23]

The goal is to begin treatment as early as possible to treat the primary exacerbation, prevent further exacerbations, and slow down the disease process.

Summary of multiple sclerosis therapy
Indication Clinically isolated syndrome (CIS) Relapsing remitting MS (RR-MS) Secondary progressive MS (SP-MS) Primary progressive MS (PP-MS)
Treatment of acute exacerbation
Prevention of exacerbations

Treatment of acute exacerbations

Disease-modifying MS therapy

Disease-modifying drugs (DMDs)
Medication Mechanism of action Route of application Indications Side effects

Interferon beta

  • SC
  • All forms of MS
Glatiramer acetate (copolymer-1)
Mitoxantrone
  • IV
Dimethyl fumarate
  • An immunomodulator that protects nerve cells through its anti-inflammatory effect
  • PO
Teriflunomide
  • Inhibits pyrimidine synthesis, which has an antiproliferative and anti-inflammatory effect
  • Less activated lymphocytes enter the CNS
Fingolimod
  • PO
Siponimod
Ozanimod

Alemtuzumab

  • SC/IV
Natalizumab
  • IV
Ocrelizumab
  • IV
Ofatumumab
  • SC

Supportive therapy

References:[24][25][26][27][28][29][30][31][32][33][34][35][36][37]

Prognostic factors for disease progression [38][39]

  • Male sex
  • Age at MS onset > 40 years
  • Multiple symptoms with early motor and cerebellar involvement
  • Incomplete recovery after relapses
  • High relapse rate in the first 2 years after MS onset

Multiple sclerosis in pregnancy [40]

  1. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The Lancet Neurology. 2018; 17 (2): p.162-173. doi: 10.1016/s1474-4422(17)30470-2 . | Open in Read by QxMD
  2. Dobson R, Giovannoni G. Multiple sclerosis – a review. European Journal of Neurology. 2018; 26 (1): p.27-40. doi: 10.1111/ene.13819 . | Open in Read by QxMD
  3. Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O. Multiple sclerosis. The Lancet. 2018; 391 (10130): p.1622-1636. doi: 10.1016/s0140-6736(18)30481-1 . | Open in Read by QxMD
  4. Schmidt H, Williamson D, Ashley-Koch A. HLA-DR15 haplotype and multiple sclerosis: A HuGE review. Am J Epidemiol. 2007; 165 (10): p.1097-1109. doi: 10.1093/aje/kwk118 . | Open in Read by QxMD
  5. Hansen T, Skytthe A, Stenager E, Petersen HC, Brønnum-Hansen H, Kyvik KO. Concordance for multiple sclerosis in Danish twins: an update of a nationwide study. Multiple Sclerosis Journal. 2005; 11 (5): p.504-510. doi: 10.1191/1352458505ms1220oa . | Open in Read by QxMD
  6. O'Gorman C, Lucas R, Taylor B. Environmental risk factors for multiple sclerosis: a review with a focus on molecular mechanisms. Int J Mol Sci. 2012; 13 (9): p.11718-52. doi: 10.3390/ijms130911718 . | Open in Read by QxMD
  7. Mitsdoerffer M, Peters A. Tertiary Lymphoid Organs in Central Nervous System Autoimmunity. Frontiers in Immunology. 2016; 7 . doi: 10.3389/fimmu.2016.00451 . | Open in Read by QxMD
  8. Correale J, Gaitán MI, Ysrraelit MC, Fiol MP. Progressive multiple sclerosis: from pathogenic mechanisms to treatment.. Brain. 2017; 140 (3): p.527-546. doi: 10.1093/brain/aww258 . | Open in Read by QxMD
  9. Voss E, Raab P, Trebst C, Stangel M. Clinical approach to optic neuritis: pitfalls, red flags and differential diagnosis. Ther Adv Neurol Disord. 2011; 4 (2): p.123-134. doi: 10.1177/1756285611398702 . | Open in Read by QxMD
  10. Shaygannejad V, Golabchi K, Dehghani A, Ashtari F, Haghighi S, Mirzendehdel M, Ghasemi M. Color blindness among multiple sclerosis patients in Isfahan. J Res Med Sci. 2012; 17 (3): p.254–257.
  11. Rodriguez M, Siva A, Cross SA, O'Brien PC, Kurland LT. Optic neuritis: A population-based study in Olrnsted County, Minnesota. NEUROLOGY. 1995; 45 : p.244-250.
  12. Dick JPR. The deep tendon and the abdominal reflexes. J Neurol Neurosurg Psychiatry. 2003; 74 : p.150-153.
  13. Zadro I, Barun B, Habek M, Brinar VV. Isolated cranial nerve palsies in multiple sclerosis. Clinical Neurology and Neurosurgery. 2008; 110 (9): p.886-888. doi: 10.1016/j.clineuro.2008.02.009 . | Open in Read by QxMD
  14. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2014; 83 (3): p.278-286. doi: 10.1212/wnl.0000000000000560 . | Open in Read by QxMD
  15. Hosseiny M, Newsome SD, Yousem DM. Radiologically Isolated Syndrome: A Review for Neuroradiologists.. AJNR Am J Neuroradiol. 2020; 41 (9): p.1542-1549. doi: 10.3174/ajnr.A6649 . | Open in Read by QxMD
  16. Olek MJ, González-Scarano F, Dashe JF. Diagnosis of Multiple Sclerosis in Adults. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/diagnosis-of-multiple-sclerosis-in-adults.Last updated: May 4, 2017. Accessed: July 14, 2017.
  17. Biller. Practical Neurology. Lippincott Williams & Wilkins ; 2012
  18. Rammohan KW. Cerebrospinal fluid in multiple sclerosis. Ann Indian Acad Neurol. 2009; 12 (4): p.246–253. doi: 10.4103/0972-2327.58282 . | Open in Read by QxMD
  19. Avasarala JR, Cross AH, Trotter JL. Oligoclonal band number as a marker for prognosis in multiple sclerosis. Arch Neurol. 2001; 58 (12): p.2044-5.
  20. Barnett Y. Conventional and Advanced Imaging in Neuromyelitis Optica. American Journal of Neuroradiology. 2014 .
  21. Wingerchuk D. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. American Academy of Neurology. 2015 .
  22. Marchioni E, Tavazzi E, Minoli L et al. Acute disseminated encephalomyelitis. Curr Infect Dis Rep. 2008; 10 (4): p.307-314. doi: 10.1007/s10072-008-0966-6 . | Open in Read by QxMD
  23. Rae-Grant A., et al.. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2019; 92 (2): p.112-112. doi: 10.1212/wnl.0000000000006722 . | Open in Read by QxMD
  24. Montero-Melendez T. ACTH: The forgotten therapy. Semin Immunol. 2015; 27 (3): p.216-226. doi: 10.1016/j.smim.2015.02.003 . | Open in Read by QxMD
  25. Walker BR, Colledge NR, Raston SR, Penman ID. Davidson's Principles and Practice of Medicine. Elsevier ; 2013
  26. Dörr J, Paul F. The Transition From First-Line to Second-Line Therapy in Multiple Sclerosis. Curr Treat Options Neurol. 2015; 17 (6): p.354. doi: 10.1007/s11940-015-0354-5 . | Open in Read by QxMD
  27. Olek MJ. Treatment of progressive multiple sclerosis in adults. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/treatment-of-progressive-multiple-sclerosis-in-adults?source=see_link.Last updated: January 4, 2017. Accessed: March 30, 2017.
  28. Gilhus NE, Barnes MP, Brainin M. European Handbook of Neurological Management. Blackwell Publishing ; 2011
  29. Neuhaus O, Farina C, Wekerle H, Hohlfeld R. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology. 2001; 56 (6): p.702-708.
  30. Fox EJ. Mechanism of action of mitoxantrone. Neurology. 2004; 63 (12 Suppl 6): p.S15-S18.
  31. Gajofatto A, Turatti M, Monaco S, Benedetti MD. Clinical efficacy, safety, and tolerability of fingolimod for the treatment of relapsing-remitting multiple sclerosis. Drug Healthc Patient Saf. 2015; 7 : p.157-167. doi: 10.2147/DHPS.S69640 . | Open in Read by QxMD
  32. Abreu P, Peixoto C, Carvalho C, Santos L, Sarmento A, Sá MS. A Case Of Hemophagocytic Lymphohistiocytosis Syndrome In A Patient With Multiple Sclerosis On Fingolimod Therapy. (P2.206). Neurology. 2015; 82 (10 Supplement P2.206).
  33. UpToDate. Natalizumab: Drug information. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/natalizumab-drug-information.Last updated: January 1, 2017. Accessed: March 30, 2017.
  34. Rieckmann P. Concepts of induction and escalation therapy in multiple sclerosis.. J Neurol Sci.. 2009; 277 (Suppl 1): p.42-45. doi: 10.1016/S0022-510X(09)70012-7 . | Open in Read by QxMD
  35. Fenu G, Lorefice L, Frau F, Coghe GC, Marrosu MG, Cocco E. Induction and escalation therapies in multiple sclerosis. Antiinflamm Antiallergy Agents Med Chem. 2015; 14 (1): p.26-34.
  36. Ross AP, Ben-Zacharia A, Harris C, Smrtka J. Multiple sclerosis, relapses, and the mechanism of action of adrenocorticotropic hormone. Front Neurol. 2013; 4 : p.21. doi: 10.3389/fneur.2013.00021 . | Open in Read by QxMD
  37. Berkovich R, Agius MA. Mechanisms of action of ACTH in the management of relapsing forms of multiple sclerosis. Ther Adv Neurol Disord. 2014; 7 (2): p.83-96. doi: 10.1177/1756285613518599 . | Open in Read by QxMD
  38. Gajofatto A, Calabrese M, Benedetti MD, Monaco S. Clinical, MRI, and CSF Markers of Disability Progression in Multiple Sclerosis. Dis Markers. 2013; 35 : p.687-699. doi: 10.1155/2013/484959 . | Open in Read by QxMD
  39. Iaffaldano P, Lucisano G, Patti F, et al. Transition to secondary progression in relapsing-onset multiple sclerosis: Definitions and risk factors. Multiple Sclerosis Journal. 2020 : p.135245852097436. doi: 10.1177/1352458520974366 . | Open in Read by QxMD
  40. Voskuhl R, Momtazee C. Pregnancy: Effect on Multiple Sclerosis, Treatment Considerations, and Breastfeeding. Neurotherapeutics. 2017; 14 (4): p.974-984. doi: 10.1007/s13311-017-0562-7 . | Open in Read by QxMD
  41. Herold G. Internal Medicine. Herold G ; 2014
  42. Spiegel HE, Nowacki G, Hsiao KJ. Advances in Clinical Chemistry. Academic Press ; 2001
  43. McDonald Diagnostic Criteria for Multiple Sclerosis. https://radiopaedia.org/articles/mcdonald-diagnostic-criteria-for-multiple-sclerosis. . Accessed: July 28, 2017.
  44. Feinstein A . The Clinical Neuropsychiatry of Multiple Sclerosis. Cambridge University Press ; 2007