Multiple Sclerosis


Multiple sclerosis (MS) is an autoimmune disease directed against components of the neural myelin sheath causing demyelination. This leads to progressive axonal loss and CNS atrophy affecting primarily white matter but may also damage grey matter and overlying meninges.


Subtypes of MS (1):

  • Clinically isolated syndrome (CIS): Patient’s initial symptoms are characteristic of CNS demyelination that may be due to MS but does not fulfill the criteria of dissemination in time; ~80% of patients with CIS will later relapse and be diagnosed with MS.
  • Radiologically isolated syndrome (RIS): incidental brain or spinal cord MRI findings highly suggestive of MS in an asymptomatic patient; no evidence of clinical attacks suggestive of MS; ~30–40% of patients with RIS later meet criteria for CIS or MS.
  • Relapsing-remitting MS (RRMS): most common type of disease onset; defined by relapse (attacks or exacerbations) followed by partial or complete improvement; recovery of residual deficits may ensue following each episode.
  • Secondary progressive MS (SPMS): progressive worsening of neurologic function following initial RRMS; may be associated with acute exacerbations; often diagnosed retrospectively
  • Primary progressive MS (PPMS): progressive decline in disease status and accumulation of disability from onset of disease without initial relapsing-remitting disease course (~10% of patients) (2)

Pregnancy Considerations

  • If treatment is clinically necessary during pregnancy, preferred treatments include interferon-β and glatiramer acetate (3).
  • Natalizumab may be continued with reduced infusion regimen for patients with high risk of relapse (3).
  • Majority of patients experience reduced disease exacerbations during pregnancy but relapse in the postpartum period.
  • All drugs licensed for MS treatment are contraindicated during breastfeeding.


Most often affects Caucasian women during their 2nd and 3rd generations of life.

2.1 per 100,000 person-years (1)


  • Differs by latitude, higher rates among those living further from the equator (1)
  • America: 117.49 per 100,000 people
  • Worldwide: 43.95 per 100,000 people

Etiology and Pathophysiology

  • Predominately an autoimmune process driven by T cells and B cells against the myelin sheath. Dysregulation and mistaken antigen identity lead CD4 T cells to cross the blood–brain barrier and recognize proteins on the surface of the myelin sheath. Cytokines, interferon-γ, and tumor necrosis factor-α are subsequently released, and activation of macrophages and B cells leads to oligodendrocyte and myelin destruction, resulting in slower saltatory nerve conduction velocities.
  • Oligodendrocytes, which have survived or formed from precursor cells, are able to partially remyelinate stripped axons, producing scars which overtime can lead to irreversible axonal loss and brain atrophy.
  • The majority of axons are typically lost from the lateral corticospinal (motor) tracts of the spinal cord (2).

Over 100 genetic loci have been associated with MS, suggesting that it is ultimately an antigen-specific autoimmune process. Most commonly, these are mapped to the class II region of the HLA gene clusters. The most common is the HLA-DRB1 locus on chromosome 6, which produces major histocompatibility complexes with high-binding affinity for myelin basic proteins.

Risk Factors

  • Age: peak incidence ages 20 to 40 years, but can present at any age (slightly earlier in women than men)
  • Sex: female > male
  • Race: Caucasian > Afro-Caribbean > East Asian
  • Prior infections: Epstein-Barr virus; mononucleosis
  • Substance: tobacco smoking
  • Historically, proximity to the equator and its correlation with increased vitamin D exposure were inversely proportional to MS incidence. However, this association has been less noted and may be due to lifestyle changes leading to decreased sun exposure in these areas (2).
  • Anti-TNF-α inhibitors like etanercept and infliximab have been associated with developing MS.

Commonly Associated Conditions

Internuclear ophthalmoplegia, optic neuritis, transverse myelitis, association with other autoimmune processes


A person with MS may present with a number of neurologic signs and symptoms depending on the locations of the lesion. The essential means of diagnoses is to demonstrate evidence of CNS lesions that are separated by both time and space that are not due to a separate disease process.


Common symptoms may include but not limited to the following: cognitive dysfunction, fatigue, dizziness, visual disturbances, facial palsy, dysphagia, muscle weakness or spasms, hyperesthesia or paresthesia, pain, bowel or bladder incontinence, urinary frequency or retention, or sexual dysfunction (2).

Physical Exam

  • Weakness, internuclear ophthalmoplegia, gait disturbance, hyperesthesia or paresthesia, cerebellar dysarthria (scanning speech), and spasticity (especially in lower extremities)
  • Uhthoff phenomenon: Symptoms are worse with exposure to higher than usual temperature.
  • Lhermitte phenomenon (barber chair phenomenon): Electric-like shocks extending down the spine caused by neck movement, especially flexion

Differential Diagnosis

  • Infectious: Lyme disease, syphilis, acute disseminated encephalomyelitis, progressive multifocal leukoencephalopathy (PML), Guillain-Barré syndrome, primary cerebral angiitis, amyotrophic lateral sclerosis, Huntington disease, and HIV
  • Autoimmune: systemic lupus erythematosus, antiphospholipid antibody syndrome, neurosarcoidosis, Behçet disease, vasculitis, and Bell palsy
  • CNS: neuromyelitis optica, neoplasms, stroke, migraine, and normal pressure hydrocephalus
  • Medications and illicit substances: Alcohol, anticholinergic drugs, cocaine, etanercept, infliximab, isoniazid, methanol
  • Other: cobalamin (vitamin B12) deficiency, manganese toxicity, paraneoplastic syndrome, hypothyroidism, psychiatric disease (anxiety disorder, conversion disorder), Charcot-Marie-Tooth disease

Diagnostic Tests & Interpretation

  • Blood tests to rule out alternative diagnosis: antinuclear antibody, antineutrophil cytoplasmic antibody, anti–double-stranded DNA antibody, antiphospholipid antibody, erythrocyte sedimentation rate, immunoglobulin G, immunoglobulin M, rheumatoid factor, HIV screening, rapid plasma reagin, thyroid-stimulating hormone (TSH), vitamin B12 level, complete blood count (CBC), Lyme disease antibody (2)[B]
  • MRI of head/spine: Periventricular and callosal lesions are relatively specific for MS; addition of gadolinium can help identify active lesions.
  • Lumbar puncture: cerebrospinal fluid (CSF) with elevated or normal protein levels; oligoclonal immunoglobulin G bands are seen in approximately 90% of MS but may be absent in early disease process. Positive findings are not diagnostic for MS but may be beneficial if other diagnostic criteria are equivocal.
  • McDonald criteria for diagnosing MS (4): apply primarily when clinical suspicion for MS; not used for ruling out other neurologic conditions; dependent on number of attacks and number of CNS lesions:
    • Two or more clinical attacks and two or more lesions with objective clinical evidence; MS is confirmed; may start treatment or
    • Two or more attacks and one lesion, with dissemination in space on MRI or an additional relapse causing new symptoms that effect another CNS region or
    • One attack and two lesions, with dissemination in time on MRI or another disease relapse or a positive test for oligoclonal bands in the CNC (3) or
    • One attack and one lesion, with dissemination in space and time
    • Formal diagnosis of PPMS can be made if symptoms gradually progress for at least 1 year and two of the following criteria are met:
      • At least one lesion in the brain is detected on MRI.
      • At least two spinal cord lesions are detected on MRI.
      • Oligoclonal bands in CSF

Initial Tests (lab, imaging)
MRI of the brain/spine

Follow-Up Tests & Special Considerations
Lumbar puncture, EMG

Diagnostic Procedures/Other
Evoked potentials: Assess function of visual, auditory, and somatosensory motor CNS pathways; measure CNS electric potentials evoked by neural stimulation. A marked delay, without a clinical manifestation, is suggestive of demyelinating disorder. Visual evoked potentials are delayed in 80–90% of individuals with MS (1).


General Measures

  • Multidisciplinary team approach is paramount, including physical, occupational, and speech therapy; mental health specialist; pharmacists; urologist; neurologist; and dietitian.
  • Three main categories currently exist for treatment: treatment for acute relapses, reducing MS-related activity using disease-modifying agents, and symptomatic therapy.
  • Steroids: treatment for initial presentation and acute episodes of MS (1).
  • Disease-modifying treatments (DMT) early in the disease process are likely to slow overall disease progression; should be managed by MS specialist (2)[C]
  • Smoking cessation is encouraged due to possible decrease in disability progression (1).


  • Acute relapse treatment—high-dose short-term glucocorticoid therapy (2)[A]
    • Methylprednisolone 1 g PO/IV daily for 3 to 5 days; without subsequent tapering; a second course may be given.
      • Side effects (S/E): infection risk, adrenal insufficiency, Cushing syndrome, fluid retention, hypokalemia, GI disturbances, headache, emotional lability, delirium, osteoporosis, hyperglycemia
    • Alternative therapy for those who cannot tolerate high-dose glucocorticoids: ACTH gel 80 to 120 units IM/SC daily for 1 week followed or not followed by taper
    • Plasmapheresis
  • Disease-modifying treatment: initiated to decrease clinical attacks and delay disability progression (1),(2)[B]
    • Platform injection therapies
      • IFN-β1a (Avonex) 30 μg IM weekly or IFN-β1a (Rebif) 22 or 44 μg SC 3 times per week; IFN-β1b (Betaseron/Betaferon/Extavia) 250 μg SC every other day
        • Monitor CBC, LFTs, TSH
        • S/E: flulike symptoms, depression, skin site reactions, thyroid dysfunction, liver enzyme abnormalities
      • Glatiramer acetate (Copaxone) 20 mg SC daily
        • S/E: skin site reactions, postinjection reaction, lipoatrophy
    • Monoclonal antibodies (monitor CBC, LFTs, TSH)
      • Rituximab (Rituxan) 1 g IV once every 2 weeks × 2 doses; repeat 1 g once q6–12mo. Rule out hepatitis B prior to use; S/E: hypogammaglobulinemia, infection, and PML
      • Natalizumab (Tysabri) 300 mg IV q4wk
        • S/E: dizziness, nausea, increased risk of infection, PML
        • Alemtuzumab (Lemtrada) 12 mg/day for 5 days; after 12 months, 12 mg/day for 3 days
          • S/E: infusion reaction, increased risk of infection, thyroid problems, blood clots, immune thrombocytopenia
    • Oral therapies—for those who prefer self-administered oral medication
      • Dimethyl fumarate (Tecfidera) 120 to 240 mg PO BID for 7 days and then 240 mg BID
        • Monitor CBC, LFTs; S/E: diarrhea, cramps, nausea, flushing
      • Teriflunomide (Aubagio) 7 to 14 mg PO daily
        • Monitor CBC, LFTs, UA; S/E: headache, diarrhea, fatigue, arthralgia, hair thinning nausea
        • Fingolimod (Gilenya) 0.5 mg PO daily
          • Monitor ECG, CBC, LFTs, eye exam; S/E: 1st-degree AV block, arrhythmia, infection risk
  • Symptomatic therapies (1),(2)[B]
    • Spasticity: baclofen, dantrolene, tizanidine, cannabis extract (nabiximols), botulinum toxin, benzodiazepines, physiotherapy
    • Pain: amitriptyline, pregabalin, gabapentin, cannabis extract (nabiximols), capsaicin
    • Trigeminal neuralgia: carbamazepine, oxcarbazepine, baclofen, gabapentin
    • Bladder dysfunction: imipramine, muscarinics, cannabis extract, catheterization, intravesical botulinum toxin; avoid spicy, acidic foods, caffeine, and alcohol for detrusor spasm.
    • Fatigue: amantadine, modafinil, SSRI
    • Tremors: diazepam, β-blockers
    • Depression: SSRI, SNRI, TCA
    • Movement disorder: ataxia (baclofen, dantrolene, tizanidine, deep brain stimulation); impaired walking (behavioral change therapy, physiotherapy)

Issues For Referral

  • Neurology: diagnosis and treatment
  • Physical therapy & rehabilitation: physical therapy

Additional Therapies

  • Hematopoietic stem cell transplants are being tested in clinical trials and may alter treatment and prevention of MS in the future (2).
  • Multiple trials are investigating remyelination and neuroprotection to prevent, reverse, or slow the progression of the disease.

Ongoing Care

Follow-up Recommendations

Patient Monitoring
Assessing the severity of neurologic impairment from MS can be done using the Kurtzke Expanded Disability Status Scale (EDSS): The EDSS quantifies severity of disability using eight functional systems (FS): pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, and cerebral. EDSS scoring system is as follows:

  • 1.0: no disability, minimal signs in 1 FS
  • 2.0: minimal disability in 1 FS
  • 3.0: moderate disability in 1 FS; mild disability in 3 to 4 FS but fully ambulatory
  • 4.0: ambulatory without aid or rest for ~500 m
  • 5.0: ambulatory without aid or rest for ~200 m
  • 6.0: intermittent/constant unilateral aid (cane, crutch); must be able to walk 100 m
  • 7.0: unable to walk beyond 5 m even with aid; restricted to wheelchair for ~12 hr/day, wheels self and transfers alone
  • 8.0: essentially restricted to bed, chair, or wheelchair; may be out of bed most of the day; retains self-care functions, generally effective use of arms
  • 9.0: helpless, bedbound; can communicate and eat
  • 10: death due to MS


Average life expectancy is 5 to 10 years less than the unaffected population (2).


Mortality secondary to MS relapse is unusual; death is more commonly associated with a complication of MS such as infection.



  • G35 Multiple sclerosis


  • 24700007 Multiple sclerosis (disorder)
  • 425500002 secondary progressive multiple sclerosis (disorder)
  • 426373005 relapsing remitting multiple sclerosis (disorder)
  • 428700003 Primary progressive multiple sclerosis

Clinical Pearls

  • MS is an immune-mediated inflammatory disease-causing demyelination, neuronal loss, and scarring within the CNS
  • Most common cause of nontraumatic neurologic disability in young adults.
  • Diagnosis is made with the McDonald criteria
  • Treatment is complex and rapidly changing; MS specialist and multiprofessional therapy is necessary.


Afsha Rais Kaisani, MD
Tasaduq Hussain Mir, MD, FAAFP
Sana W. Qureshi, DO


  1. Saguil A, Iv EAF, Jordan TS. Multiple sclerosis: a primary care perspective. Am Fam Physician. 2022;106(2):173–183. [PMID:35977131]
  2. Raffel J, Wakerley B, Nicholas R. Multiple sclerosis. Medicine. 2016;44(9):537–541.
  3. Varytė G, Arlauskienė A, Ramašauskaitė D. Pregnancy and multiple sclerosis: an update. Curr Opin Obstet Gynecol. 2021;33(5):378–383. [PMID:34310364]
  4. 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. [PMID:29275977]

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