• Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the brain, spinal cord, and optic nerves resulting in ≥1 episode(s) of neurologic dysfunction with a variable course of recovery and disease progression. 
  • The disease is characterized by episodes of limb weakness, impaired vision, poor coordination, and other neurologic deficits caused by inflammation-induced demyelination, axon loss, and neuronal injury 
  • MS affects about 3 times as many women as men, and most commonly presents between the ages of 20 and 50 years.

Types of MS

  • Clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS)
    • CIS — first CNS demyelinating episode, which improves with or without treatment; CIS can progress to MS in about 50% of patients
    • RIS — demyelination features on brain magnetic resonance imaging (MRI) that fulfill criteria of MS without any clinical features
  • Relapsing-remitting MS (reported in about 85% of patients) 
    • Repeated episodes of neurologic symptoms and disability lasting 24 hours or longer without fever or infection followed by partial or complete recovery
    • Symptoms of relapse usually peak after several days or weeks, followed by a period of recovery lasting weeks or months
    • Typical age of onset is between 25 and 29 years (can present from first to seventh decades)
  • Secondary progressive MS
    • Approximately 80% of patients with relapsing-remitting MS develop secondary progressive MS within 20 years; symptoms progress over time
    • Relapses may or may not be superimposed on progression
  • Primary progressive MS (reported in about 15% of patients)
    • Slow progressive neurologic disability (usually gait impairment) starting at disease onset
    • Typical age of onset is between 39 and 41 years
  • Fulminant MS — rare phenotype with rapidly progressive course, significant disability, or death in short time after disease onset


  • Precise pathogenesis is unclear
  • Environmental exposures may lead to aberrant immune processes involving T-lymphocytes and B-lymphocytes  
  • Pathological events result in demyelination and neuroaxonal degeneration 
  • Pathogenic and neurologic effects may worsen over time due to incomplete repair of immune-mediated damage and activation of innate immunity  

Differential Diagnosis

  • Ischemic cerebrovascular events  
  • Vasculitis
  • Behçet syndrome
  • Sjögren syndrome
  • Systemic lupus erythematosus
  • Antiphospholipid antibody syndrome
  • Deficiencies in vitamin B12, copper, and vitamin E
  • Infections (Lyme disease, neurosyphilis, HIV, human T-cell lymphotropic virus type I/II)
  • Amyotrophic lateral sclerosis
  • Migraine
  • Cervical spine disorders
  • Central nervous system (CNS) neoplasms

History of Present Illness

  • Focal neurologic symptoms related to specific area(s) of affected CNS
    • Spinal cord — limb weakness, altered sensations, Lhermitte phenomenon (electrical sensation down spine upon neck flexion), band-like sensation around torso, bowel or bladder problems
    • Optic nerve — impaired vision and/or pain with eye movement
    • Brainstem — double vision, facial paresis, or numbness
    • Cerebellum — poor coordination, vertigo, or tremors
  • Ask if symptoms occur intermittently and last for 24 hours or longer before resolving completely or partially — suggests relapsing-remitting MS
  • Ask if symptoms have been getting progressively worse since they began:
    • No history of relapses or remission suggests primary progressive MS
    • In the context of prior relapses, suggests secondary progressive MS

Physical Examination

  • Eyes
    • Decreased visual acuity, color differentiation, optic disc pallor, or relative afferent pupillary defect (optic neuritis)
    • Oculomotor nerve examination for dysconjugate gaze or nystagmus (brainstem involvement)
  • Neurologic
    • Muscle weakness, flaccid muscle tone, or abnormal sensation (spinal cord inflammation)
    • Gait dysfunction, dysphagia, or cognitive impairment


  • Refer patients with suspected MS for neurologic consult
  • Diagnosis requires involvement of ≥2 areas of the CNS (dissemination in space) at different time points (dissemination in time).
  • Revised McDonald diagnostic criteria
    • Relapse-remitting MS in patients with either:
      • ≥2 monophasic clinical attacks plus either:
        • Evidence of ≥2 lesions
        • Evidence of 1 lesion plus evidence of a previous attack involving lesion in different location
        • Evidence of 1 lesion plus demonstration of dissemination in space (by MRI or an additional attack) implicating different site
      • 1 monophasic clinical attack plus either:
        • Evidence of ≥2 lesions plus either demonstration of dissemination in time (by MRI or additional attack) or presence of CSF-specific oligoclonal bands
        • Evidence of 1 lesion plus both of the following criteria:
          • Demonstration of dissemination in space by MRI or an additional attack implicating a different site
          • Demonstration of dissemination in time (by MRI or additional attack) or presence of CSF-specific oligoclonal bands
    • Primary progressive MS in patients with both:
      • 1 year of steadily increasing objectively documented neurologic disability independent of clinical relapse
      • ≥2 of the following criteria:
        • ≥1 lesion(s) characteristic of MS in periventricular, cortical, juxtacortical, or infratentorial brain regions
        • ≥2 lesions in spinal cord
        • Presence of CSF-specific oligoclonal bands
  • Blood tests to help exclude alternative diagnoses
    • Complete blood count
    • Erythrocyte sedimentation rate
    • C-reactive protein
    • Complete metabolic panel
    • Liver function tests
    • Thyroid function tests
    • Vitamin B12 level
    • HIV serology
  • Magnetic resonance imaging (MRI)
    • Obtain MRI of the brain and spinal cord to assess for characteristic lesions or exclude other diagnoses
    • Lesion characteristics: 
      • Brain lesions throughout white matter
      • Acute lesions demonstrate active gadolinium contrast extravasation 
  • Consider additional testing (including spinal MRI or cerebrospinal fluid) if
    • Insufficient evidence or atypical presentation supporting MS diagnosis 
    • Clinical, imaging, or laboratory features atypical of MS


  • Clinically isolated syndrome
    • Consider methylprednisolone IV to shorten symptom duration
    • If high risk of progression to MS, consider preventative medication (interferon beta-1a, interferon beta-1b, glatiramer acetate, or teriflunomide)
  • Acute relapse of MS
    • Oral methylprednisolone; other options include IV methylprednisolone and intramuscular or subcutaneous adrenocorticotropic hormone
  • Relapsing-remitting MS, offer disease-modifying therapies
    • Injectable therapies — possibly less efficacious, but more favorable safety profile
      • Interferon beta-1a or interferon beta-1b  
      • Glatiramer acetate
    • Oral therapies — easy administration, but unique side-effects  
      • Fingolimod  
      • Dimethyl fumarate  
      • Teriflunomide  
      • Oral cladribine  
      • Siponimod  
    • Infusion therapies — highest efficacy, but may have adverse effects
      • Alemtuzumab
      • Natalizumab
      • Ocrelizumab
      • Rituximab
  • Progressive MS
    • For primary progressive MS, consider ocrelizumab  
    • For active secondary progressive, consider siponimod or oral cladribine 
    • Autologous stem cell transplantation has shown benefit in some patients

Supportive Care and Follow-up

  • Address management of specific impairments in MS with multimodality approach, including rehabilitation programs, counseling, and medications for symptom management
  • Assess for disease activity and progression at least annually with clinical assessment and brain imaging


  • Psychiatric complications — major depressive disorder, bipolar disorder, anxiety disorders, and increased risk of suicide
  • Cognitive impairment
  • Seizures — younger age at multiple sclerosis onset associated with increased risk
  • Stroke and myocardial infarction 
  • Infections


  • Factors associated with increased frequency of relapse in patients with MS include:
    • Systemic infections
    • Self-reported stress
    • Postpartum period in women
  • Approximately 80% of patients with relapsing-remitting MS develop secondary-progressive MS within 20 years 

Kendra Church MS, PA-C, is a physician assistant at Dana-Farber Cancer Institute/Brigham & Women’s Hospital, and is also a senior clinical editor for DynaMed, an evidence-based, point-of-care database. 


1. 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)30470-2

2. Zurawski J, Stankiewicz J. Multiple sclerosis re-examined: essential and emerging clinical conceptsAm J Med. 2018;131(5):464-472. doi:10.1016/j.amjmed.2017.11.044

Continue Reading

3. Nourbakhsh B, Mowry EM. Multiple sclerosis risk factors and pathogenesisContinuum (Minneap Minn). 2019;25(3):596-610. doi:10.1212/CON.000000000000072

4. Rae-Grant, AD. Unusual symptoms and syndromes in multiple sclerosisContinuum (Minneap Minn). 2013;19(4 Multiple Sclerosis):992-1006. doi: 10.1212/01.CON.0000433287.30715.07

5. Vidal-Jordana A, Montalban X. Multiple sclerosis: epidemiologic, clinical, and therapeutic aspectsNeuroimaging Clin N Am. 2017;27(2):195-204. doi:10.1016/j.nic.2016.12.001

6. National Institute for Health and Care Excellence (NICE). Multiple sclerosis in adults: management [CG186]. Updated November 11, 2019. Accessed March 19, 2021.

7. Harrison DM. In the clinic. Multiple sclerosisAnn Intern Med. 2014;160(7):ITC4-2-ITC4-18. doi:10.7326/0003-4819-160-7-201404010-01004

8. Rae-Grant A, Day GS, Marrie RA, 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 NeurologyNeurology. 2018;90(17):777-788. doi:10.1212/WNL.0000000000005347