• Clinical science

Multiple sclerosis

Summary

Multiple sclerosis (MS) is a chronic, degenerative disease of the CNS that is caused by an immune-mediated inflammatory process. This process results in the demyelination of white matter 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 in white matter. Differential diagnosis 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.

Epidemiology

  • Sex: > (2:1)
  • Age of onset: 20–40 years of age
  • Ethnicity: prevalence among the white population
  • Prevalence is greater among people in temperate zones.

MS is more common in women!

References:[1][2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

  • Unclear
  • Genetic predisposition
  • Environmental triggers
    • UV radiation, insufficient vitamin D consumption, cigarette smoking
    • Pathogens: EBV, HHV 6

References:[1][3][4]

Pathophysiology

  • Immune-mediated damage
    • Exact cause remains unknown
    • Characterized by 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
    • There is evidence for Th1 immune response involving myelin basic proteins
  • Most common sites of demyelination in MS
    1. Periventricular areas
    2. Brainstem
    3. Cerebellum
    4. Spinal cord

References:[2]

Clinical features

In 60% of cases of optic neuritis, fundoscopy is normal. Neither the patient nor doctor are able to see anything!

Uhthoff's phenomenon triggered by a viral infection can be confused with an exacerbation of MS!

References:[1][5][6][7][8][9][10][11]

Stages

Clinical course

Characteristics Incidence at the time of diagnosis
Relapsing-remitting MS (RR-MS)
  • Exacerbations occur
  • Symptoms remit almost completely between exacerbations
  • 90%
Secondary progressive MS (SP-MS)
  • Exacerbations occur
  • Continuous worsening of symptoms in between exacerbations
  • Arises from RR-MS (as per definition)
Primary progressive MS (PP-MS)
  • No exacerbations
  • Continuous worsening of symptoms from the very onset of the disease
  • 10%
Definition of relapse/exacerbation: new symptoms or significant worsening of existing symptoms, both of which last at least 24 hours and are preceded by at least 30 days of relative clinical stability.

References:[1][12][13]

Diagnostics

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's fingers)
    • Contrast MRI (with gadolinium): enhancement of active lesion during and up to 6 weeks after the exacerbation
  • Electrophysiological studies: slowed nerve conduction → increased latency of visually evoked potentials (VEP)
  • For more detailed information, see McDonald's criteria.

Lumbar puncture for CSF examination

The appearance of oligoclonal bands in the early stages of the disease indicates a poor prognosis!

References:[14][15][16][17]

Differential diagnoses

Autoimmune diseases

Infections

References:[18][19]

The differential diagnoses listed here are not exhaustive.

Treatment

Summary of step-wise therapy for multiple sclerosis

  • The goal is to begin treatment as early as possible to treat the primary exacerbation, prevent further exacerbations, and slow down the disease process.
  • Therapeutic strategies include
    • Escalation therapy: Patients who do not respond to first-line therapy with disease-modifying drugs (DMDs), are switched to second-line DMDs.
    • Induction therapy: Patients with severe disease activity at onset, first receive strong immunosuppressant drugs , followed by long-term maintenance therapy with DMDs.
Summary of multiple sclerosis therapy
Indication Relapsing remitting MS (RR-MS) Secondary progressive MS (SP-MS) Primary progressive MS (PP-MS)
Treatment of acute exacerbation
  • No exacerbations present
Prevention of exacerbations
  • There is no established therapy for PP-MS
  • Supportive therapy is essential.

Treatment of acute exacerbations

Disease-modifying MS therapy (prevention of exacerbations)

Disease-modifying drugs (DMDs)
Medication Mechanism of action Indications Side effects

Interferon beta

  • First-line drug in all forms of MS
  • Injection site necrosis
  • Flu-like symptoms
  • Liver dysfunction
  • Thrombotic microangiopathy
  • Depression
Glatiramer acetate (copolymer-1)
Mitoxantrone
  • Third-line drug in RR-MS

Fingolimod
  • First-line drug in RR-MS

Alemtuzumab

  • A monoclonal antibody against the superficial antigen CD52, which is found on the surface of immune cells.(T-cells, B-cells, NKT cells, and monocytes)
  • As a consequence, both B- and T-lymphocytes numbers decrease drastically.
SC/IV
  • Third-line drug in RR-MS
Natalizumab
  • Second-line drug in RR-MS

Supportive therapy

References:[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][1][37][38][39]

Special patient groups

Multiple sclerosis in pregnancy

References:[40]