Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that leads to demyelination of the nerves in the CNS. Young women are more predominantly affected by this most common demyelinating condition. The etiology of MS is unclear; however, both genetic and environmental factors are believed to play a role. The clinical presentation varies widely depending on the site of lesions, but typically includes neurological symptoms that affect vision, motor functions, sensation, and autonomic function. The diagnosis is made via MRI of the entire CNS (brain and spine) as well as CSF examination. Management involves corticosteroids for acute exacerbations and disease-modifying agents to reduce these exacerbations and slow disease progression. The average life expectancy of individuals with MS is decreased by 5–10 years.

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Definition and Epidemiology


Multiple sclerosis (MS) is an immune-mediated disease resulting in demyelination of the nerves of the CNS.

  • Leads to degeneration of axons in the brain and spinal cord
  • Typically a waxing and waning course with alternating periods of flares and remissions


  • Most common inflammatory disease of the brain and spinal cord
  • One of the most common causes of long-term disability in young patients
  • Seen in all ethnic groups, but most common in Caucasians
  • Prevalence: 50–300 per 100,000 people (depending on region)
  • Female to male ratio: 2–3:1 
  • Age of symptom onset: 20–40 years
Multiple sclerosis risk

Global prevalence of multiple sclerosis

Image: “Multiple sclerosis risk” by Dekoder. License: Public Domain

Etiology and Pathophysiology


The exact etiology of MS is unknown. The disease is thought to be multifactorial with genetic predisposition and environmental factors playing contributive roles.

Genetic factors:

  • No specific inherited gene; likely polygenetic influences 
  • Mutations in MHC class II are associated with 2–4 times higher risk.
  • Interleukin receptor polymorphism also appears to increase the risk.
  • Presence of the HLA-DRB1*15 allele appears to increase risk.
  • Presence of the HLA-A*02 allele appears to decrease risk and confer protective effects. 
  • Female gender and family history of disease appear to increase risk.
  • Concurrence of disease amongst monozygotic twins is approximately 35%.
  • Concurrence of disease amongst 1st-degree relatives is 3%–4%.

Environmental factors:

  • Factors increasing disease risk:
    • Smoking tobacco 
    • Living at higher altitudes
    • History of EBV infections
    • History of HHV-6 infections
    • Obesity in early adolescence
    • Low vitamin D levels
  • Factors decreasing disease risk:
    • Increased exposure to sunlight 
    • High vitamin D levels
  • Geographic distribution suggests that the prevalence increases with an increase in the distance from the equator.


  • Immune system self-attacks oligodendrocytes that form a protective myelin sheath around nerve fibers → inflammatory reaction → damage and oligodendrocyte death → demyelination (loss of the protective myelin sheath) in the CNS (i.e., brain, spinal cord, optic nerves)
  • Axonal damage and degeneration → irreversible decay of nerve fibers → impairment of effective transmission of action potentials
  • Sites that are most likely to undergo demyelination:
    • Periventricular white matter
    • Optic nerve
    • Brain stem
    • Cerebellar peduncles
    • Corpus callosum
    • Spinal cord

Clinical Presentation

Clinical forms

  • Clinically isolated syndrome (CIS):
    • Episode lasting 24 hours and accompanied by neurologic symptoms typically seen in MS
    • In some cases, this is the earliest manifestation of MS. 
    • Affected individuals may or may not develop MS.
  • Relapsing-remitting MS:
    • Most common form
    • Characterized by relapses or recurrences of symptoms followed by periods of remission of symptoms
    • During relapses, existing symptoms worsen and/or new symptoms may occur.
    • Disease is stable between relapses.
  • Secondary progressive MS (SPMS):
    • Develops in about 50% of patients with relapsing-remitting MS
    • Characterized by ongoing relapses and remissions with progressive worsening of disease and development of new CNS lesions between relapses
  • Primary progressive MS (PPMS):
    • Least common form (approximately 15% of cases)
    • Characterized by steady progression and the worsening of disease and symptoms 
    • Acute exacerbations may still occur with worsening of symptoms or the appearance of new symptoms.
Progression types of multiple sclerosis

Progression types of multiple sclerosis

Image: “Progression types of multiple sclerosis” by GetThePapersGetThePapers. License: Public Domain

Signs and symptoms

  • Acute exacerbations are defined as transient dysfunction lasting for at least 24 hours.
  • Relapses are characterized by symptoms lasting at least 24 hours with remission > 30 days since the last relapse.
  • Uhthoff phenomenon: Exacerbation of symptoms occurs with increased body temperature (fever, exercise, hot baths).
  • Constitutional symptoms:
    • Fatigue
    • Headaches
  • Sensory disturbances: 
    • Dysesthesia (altered, unpleasant, and/or painful sensation to touch)
    • Hypoesthesia (complete or partial loss of sensation)
    • Loss or impaired vibration sense 
    • Neuralgia (burning, stabbing pain) 
    • Lhermitte’s sign: a feeling of sudden electrical impulses shooting through the spine and extremities, which are typically elicited by neck flexion
  • Motor abnormalities:
    • Muscle weakness 
    • Spasticity
    • Hyperreflexia
    • Disrupted fine motor skills
    • Positive Babinski sign (big toe extends up and smaller toes fan out)
    • Absent abdominal reflex (absence of abdominal muscle contraction upon anterior abdominal wall stimulation)
  • Ocular abnormalities:
    • Optic or retrobulbar neuritis (common early manifestation):
      • Often unilateral
      • May present with vision impairment, color blindness, and pain with eye movements
      • Marcus Gunn pupil may be seen: pupil does not react appropriately to light as it should; a type of relative afferent pupil defect 
    • Internuclear ophthalmoplegia:
      • More often bilateral than unilateral
      • Occurs due to lesion in medial longitudinal fasciculus
      • Results in impaired conjugate horizontal movements of the eyes 
      • Weakened medial rectus muscle ipsilateral to the lesion impairs adduction in that eye with nystagmus seen in the contralateral abducting eye with lateral gaze.
    • Hazy vision
    • Central scotoma
    • Painless loss of vision for hours or days
    • Double vision
    • Monocular vision
  • Autonomic dysfunction: 
    • Bowel or bladder incontinence
    • Constipation
    • Residual urine buildup
    • Erectile dysfunction
    • Vaginal dryness 
  • Brain stem/cerebellar symptoms: 
    • Vertigo/dizziness
    • Ataxia/impaired walking
    • Loss of balance or coordination
    • Dysarthria
    • Charcot’s triad:
      • Nystagmus
      • Scanning speech
      • Volitional tremor (can be arrested by an act of will)
  • Psychological symptoms:
    • Depressed mood
    • Emotional changes
    • Memory deficits
    • Concentration deficits
    • Cognitive impairment (late manifestation)
Main symptoms of multiple sclerosis

Symptoms of multiple sclerosis

Image: “Main symptoms of multiple sclerosis” by Mikael Häggström. License: Public Domain


The diagnosis of MS is that of exclusion, meaning that neurological symptoms that cannot be better explained by a condition other than MS are excluded. The diagnosis is obtained with the following:

  • History and physical examination
  • Imaging of the entire CNS with MRI of the brain and spine is the gold standard:
    • Reveals multiple sclerotic plaques most commonly in the periventricular areas related to oligodendrocyte loss/demyelination and reactive gliosis
    • T1 sequence: hypointense lesions (“black holes”) seen (poor prognosis)
    • T2 sequence or fluid-attenuated inversion recovery (FLAIR) sequence: hyperintense (bright) lesions seen
    • MRI with contrast (gadolinium): Contrast enhancement of active lesions is indicative of acute inflammation for up to 6 weeks after an exacerbation.
  • EEG: 
    • Visual evoked potentials have the ability to detect inactive lesions in up to 70% of cases.
    • Shows delayed optic nerve conduction with increased latency (delayed response to stimulation)
  • Lumbar puncture/CSF examination:
    • ↑ Leukocyte count (lymphocytic pleocytosis)
    • ↑ Myelin basic protein
    • Presence of multiple oligoclonal bands is indicative of intrathecal IgG synthesis and is diagnostic (also indicates poor prognosis if seen early in the disease course).
  • McDonald criteria: based on temporal and spatial dissemination of CNS lesions 
    • Considers the presence of new lesions and/or exacerbations over time, AND
    • Objective evidence of lesions in different areas of the CNS


Currently, there is no cure for MS. The goals of management are to improve symptoms, slow disease progression, and maintain the quality of life.

Treatment for acute exacerbations of MS

  • Oral or IV corticosteroids (e.g., methylprednisolone) 
  • Plasmapheresis, if unresponsive to steroids

Disease-modifying agents used to prevent relapses and slow disease progression

  • Immunomodulators:
    • Interferon beta: risk of hepatotoxicity
    • Glatiramer acetate: suppresses the Th1 arm of the immune system
  • Immunosuppressants: only used when there is a lack of response or intolerance to immunomodulating agents due to ↑ risk of opportunistic infections 
    • Fingolimod
    • Teriflunomide: FDA warning for hepatotoxicity
    • Dimethyl fumarate
    • Natalizumab: FDA warning for progressive multifocal leukoencephalopathy (often fatal brain infection)
    • Mitoxantrone: FDA warning for cardiotoxicity

Management of related symptoms

  • Spasticity: tizanidine, baclofen, botulinum toxin, cannabis
  • Pain: anticonvulsants (carbamazepine, gabapentin, pregabalin), tricyclic antidepressants (amitriptyline), duloxetine
  • Fatigue: amantadine, modafinil, selective serotonin reuptake inhibitors
  • Gait disorder: fampridine
  • Bladder disorder: 
    • Overactive bladder/detrusor overactivity: anticholinergics (oxybutynin, tolterodine)
    • Voiding disorder: alpha-blockers (phenoxybenzamine, prazosin)
    • Urinary retention: intermittent self-catheterization
  • Erectile dysfunction: tadalafil, sildenafil
  • Constipation: stool softeners, laxatives
  • Depression: selective serotonin reuptake inhibitors (citalopram, sertraline, paroxetine)

Nonpharmacological interventions

  • PT
  • Occupational therapy
  • Speech therapy
  • Prepregnancy counseling

Differential Diagnosis

  • Systemic lupus erythematosus (SLE): an autoimmune condition that can affect virtually any organ system. Patients typically suffer from kidney disease and photosensitivity and can also present with neurological symptoms of numbness, tingling, headaches, and confusion. Patients with SLE commonly test positive for ANA with double-stranded DNA antibodies. Management is with immunosuppressants. 
  • Neurosyphilis: a manifestation of tertiary syphilis caused by the spirochete, Treponema pallidum. Patients with neurosyphilis may present with headaches, mood disturbances, and memory impairment. Demyelination can also occur with neurosyphilis, specifically demyelination of the dorsal column of the spine, which leads to ataxia (referred to as tabes dorsalis). The 1st-line treatment for neurosyphilis is penicillin.
  • Neurosarcoidosis: a condition where sarcoidal granulomas are deposited within the CNS. Neurosarcoidosis most commonly presents with cranial nerve defects or visual disturbances. Diagnosis is made using imaging studies by detecting granulomas and obtaining a tissue diagnosis with biopsy.
  • Vitamin B12 (cobalamin) deficiency: a condition presenting with mild neurological symptoms, such as numbness and tingling of the extremities. As the deficiency becomes more severe, patients can develop mental confusion, psychiatric changes, and ataxia. Vitamin B12 deficiency can be treated using intramuscular vitamin B12 repletion.


  1. National Health Service (NHS). Multiple sclerosis. (Last reviewed December 2018). Retrieved March 22, 2021, from
  2. American Academy of Family Physicians. (2019). Multiple Sclerosis. Retrieved March 11, 2021, from
  3. Le, T., Bhushan, V. (2021). First Aid for the USMLE Step 1. McGraw Hill. p541.
  4. Saguil, A., Kane, S., Farnell, E. (2014). Multiple sclerosis: A primary care perspective. Am Fam Physician. 90(9), 644-652.

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