Stat Consult: Multiple Sclerosis

Background

• 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

Pathogenesis

• 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

Diagnosis

• 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

Management

• 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

Complications

• 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

Prognosis

• 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. 

References

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 concepts. Am J Med. 2018;131(5):464-472. doi:10.1016/j.amjmed.2017.11.044

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

4. Rae-Grant, AD. Unusual symptoms and syndromes in multiple sclerosis. Continuum (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 aspects. Neuroimaging 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. https://www.nice.org.uk/guidance/cg186. 

7. Harrison DM. In the clinic. Multiple sclerosis. Ann 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 Neurology. Neurology. 2018;90(17):777-788. doi:10.1212/WNL.0000000000005347