Multiple sclerosis

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.

• Genetic predisposition
  • Presence of HLA-DRB1*15 allele increases the risk of MS. ^[3]
  • Presence of HLA-A*02 allele appears to be protective against MS. ^[3]
  • 35% disease concordance among monozygotic twins ^[4]
  • 3–4% disease concordance among first-degree relatives ^[4]
• Environmental risk factors ^[2][5]
  • Low vitamin D levels (insufficient intake, decreased exposure to UV radiation)
  • Cigarette smoking
  • Pathogens: EBV, HHV 6
  • Obesity early in life

• Pathophysiology of MS is characterized by autoimmune inflammation, demyelination, and axonal degeneration.
• Most commonly accepted theory: Activation of autoreactive T-lymphocytes → inflammatory processes → focal demyelination with partial preservation of axons (acute plaques) → loss of axons and atrophy of oligodendrocytes (chronic plaques) → gliosis → inadequate remyelination
• B-lymphocyte dysfunction: The following suggests that B-lymphocytes play a role in the pathogenesis of MS, although the exact mechanism of their involvement is unclear.
  • Anti-CD20 agents (ocrelizumab, ofatumumab, rituximab) are effective in preventing relapses.
  • Presence of tertiary lymphoid organs in the meninges of individuals with secondary progressive MS ^[6]
  • Intrathecal synthesis of IgG (oligoclonal bands; see “Diagnostics” section for more information)
• Progressive phenotypes (forms) of MS are characterized by ^[7]
  • Chronic inflammation that occurs with an intact blood-brain barrier and is driven by immune cells compartmentalized in the leptomeninges and perivascular spaces
  • Accelerated compared to relapsing-remitting phenotype brain atrophy

• Constitutional symptoms
  • Fatigue
  • Headache
• Optic neuritis ^[8][9][10]
  • Most often the earliest manifestation
  • Typically unilateral
  • Can be painful
  • Impaired vision and color blindness
  • Relative afferent pupillary defect (Marcus Gunn pupil)
• Internuclear ophthalmoplegia (INO) as a result of a lesion in the medial longitudinal fasciculus (MLF)
  • Ipsilateral medial rectus weakness but an intact convergence reflex
  • Disconjugate, lateral gaze nystagmus in the contralateral eye
  • More frequently bilateral than unilateral
• Demyelination of spinal cord tracts
  • Lhermitte sign: a shooting electric sensation that travels down the spine upon flexion of the neck
  • Pyramidal tract lesion: upper motor neuron weakness
    • Spasticity
    • Hyperreflexia
    • Positive Babinski sign
  • Involvement of the dorsal spinal column
    • Loss of vibration and fine-touch sensation
    • Numbness, paresthesias
    • Sensory ataxia usually involving the trunk or one or more limbs
  • Neuropathic pain
  • Absent abdominal reflex ^[11]
• Cerebellar involvement: Charcot neurological triad
  • Scanning speech
  • Nystagmus
  • Intention tremors
• Cranial nerve palsies ^[12]
  • Diplopia
  • Trigeminal sensory neuralgia
  • Facial palsy
• Autonomic dysfunction
  • Bowel and bladder neurogenic disorders
  • Impaired sexual function
• Changes in mental state
  • Depression, emotional changes
  • Memory deficits, impaired concentration
• Uhthoff phenomenon: a reversible exacerbation of neurological symptoms following an increase in body temperature, e.g., physical exertion, a warm bath, or fever

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]

Special forms of MS

• Radiologically isolated syndrome (RIS) ^[13][14]
  • Presence of demyelinating lesions characteristic for multiple sclerosis in an asymptomatic individual
  • Not considered a distinct MS phenotype
  • One-third of individuals with RIS go on to develop RR-MS or PP-MS
• 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

• Plain MRI (brain and spine): investigation of choice
  • Multiple sclerotic plaques (most commonly seen in periventricular white matter) ; with finger-like radial extensions (Dawson fingers) related to demyelination and reactive gliosis
    • In T1: hypo-/isointense; severe demyelination and axonal destruction → black hole lesions
    • In T2 and FLAIR: hyperintense
  • Contrast MRI (with gadolinium): enhancement of active lesion during and up to 6 weeks after the exacerbation
• Visual evoked potentials: slowed optic nerve conduction → increased latency

CSF examination

• Lymphocytic pleocytosis
• Oligoclonal bands (↑ production of IgG subfractions): the presence of multiple oligoclonal bands in CSF and their absence in the blood is highly suggestive of MS.
• ↑ myelin basic protein

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:
  • Two or more exacerbations occurring at least 30 days apart
  • MRI demonstrates the presence of both gadolinium-enhancing and nonenhancing lesions at any time or a new hyperintense T2 or enhancing lesion on follow-up MRI
  • Alternatively to DIT: positive CSF oligoclonal bands with no serum oligoclonal bands (indicate ongoing intrathecal inflammation)
• 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

Autoimmune diseases associated with inflammatory demyelination

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

• Definition: immune-mediated, chronic inflammatory disorders of the CNS that primarily affect the optic nerve and spinal cord
• Epidemiology
  • Incidence: 0.3-4.4 per 100,000
  • More prevalent in individuals of African and Asian descent than in white populations
  • Peak onset: 40-60 years
• Pathophysiology
  • Not fully understood but is thought to be an autoimmune process
  • Anti-aquaporin-4 (an autoantibody that targets aquaporin-4 in the membrane of astrocytes) is involved in a humoral immune response
  • Process characterized by demyelination and axonal damage of the optic nerve and spinal cord
• Clinical features
  • Closely resembles the clinical appearance of MS
  • Recurrent acute attacks with rapid stepwise deterioration, but no progression in between the attacks
    • Optic neuritis (often bilateral): impaired vision, retrobulbar pain
    • Transverse myelitis: symmetric paraplegia, sensory loss, bladder dysfunction
• Diagnosis: based on
  • Serological evidence of anti-aquaporin-4 (AQP4)
  • The presence of clinical characteristics
    • Optic neuritis
    • Acute myelitis
    • Area postrema syndrome (episodes of intractable nausea, vomiting, and/or hiccups)
    • Acute brainstem syndrome
    • Narcolepsy or acute diencephalic syndrome with typical MRI lesions
    • Cerebral syndrome with typical brain lesions
  • Typical MRI findings (see clinical criteria for NMOSD with negative AQP4-IgG or unknown status below)

• Treatment
  • First line: high-dose glucocorticoid therapy for 3–5 days followed by a taper for 2–8 weeks
  • Plasmapheresis in severe, refractory cases
  • The following biological agents are approved for use in patients with positive AQP4-IgG
    • Eculizumab: antibody against C5 complement component
    • Inebilizumab: antibody against CD19
    • Satralizumab: antibody against IL-6 receptor
  • Immune modulators used off-label (azathioprine, rituximab) may also reduce the risk of acute attacks
  • Natalizumab and IFN-β (effective MS treatment options) can trigger NMOSD exacerbations

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

• Definition: an immune-mediated, demyelinating CNS disease of parainfectious origin (e.g., measles) or after vaccinations (less common)
• Epidemiology: mostly affects children and young adults
• Clinical features: rapidly progressing, usually monophasic, course with multifocal symptoms
  • Evidence of motor, sensory, cranial nerve, and/or brainstem impairment
  • Altered mental status (loss of consciousness is possible)
  • Optic neuritis: impaired vision, retrobulbar pain
• Diagnosis
  • Lumbar puncture: lymphocytic pleocytosis and elevated protein
  • Spinal and/or brain MRI (with and without contrast): typically multiple, bilateral lesions
• Treatment
  • High-dose IV corticosteroid therapy for 3–5 days
  • IV immune globulin therapy or plasma exchange in patients who do not respond to corticosteroids
  • Acyclovir (empiric therapy until infectious etiology is identified)

Other conditions

• Vasculitis resulting from connective tissue disorders (e.g., SLE, polyarteritis nodosa, granulomatosis with polyangiitis, Behcet disease)
• Infections
  • Neuroborreliosis: diagnosed by CSF examination (intrathecal Borrelia-specific antibodies, lymphocytosis)
  • Neurosyphilis: diagnosed by a TPHA screening test
  • Progressive multifocal leukoencephalopathy (PML): perform an HIV test
  • HIV-encephalopathy: perform an HIV test

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.

Treatment of acute exacerbations

• First line: high-dose glucocorticoid therapy for 3–5 days
  • Prophylaxis against side effects of corticosteroids: proton pump inhibitors to prevent gastritis and LMW heparin for thromboprophylaxis
• Second line: plasmapheresis

Disease-modifying MS therapy

Supportive therapy

• Spasticity: dantrolene, baclofen (centrally acting GABA agonist); , tizanidine; (α₂-receptor agonist), physiotherapy
• Tremors: carbamazepine, primidone, propranolol
• Painful paresthesias: anticonvulsants (e.g., carbamazepine), tricyclic antidepressants (e.g., amitriptyline)
• Urinary retention: intermittent catheterization and parasympathomimetic drugs
• Urinary incontinence: parasympatholytic agents (e.g., oxybutynin)
• Walking impairment: dalfampridine (blockage of potassium channels → increased duration of action potentials)
• Erectile dysfunction: sildenafil
• Depression: antidepressants

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]

• Effect of pregnancy on MS:
  • Decreased relapse rate of MS during pregnancy
  • Increased relapse rate in the postpartum period
  • The long-term clinical course of MS remains unchanged.
• Effect of MS on pregnancy: ↑ rate of caesarean sections and ↓ birth weights when compared to mothers without MS

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