Description

• An autoimmune disease directed against components of the neural myelin sheath causing demyelination often leading to progressive axonal loss and eventual CNS atrophy affecting primarily white matter but may also damage grey matter and overlying meninges
• Four clinical subtypes of multiple sclerosis (MS):
  • Clinically isolated syndrome (CIS): a patient’s initial symptom characteristic of CNS demyelination that may be due to MS but does not fulfill the criteria of dissemination in time. Approximately 60% of individuals diagnosed with CIS will later relapse and be diagnosed with MS.
  • Relapsing-remitting MS (RRMS): episodic flare-ups occurring over days to weeks between periods of neurologic stability. During attacks, new symptoms may present, whereas previous symptoms may worsen. Complete recovery of residual deficits may ensue following each bout (~90% of patients).
  • Secondary progressive MS (SPMS): a gradual decline in disease status after an initial relapsing-remitting disease course. Progressive phase may be associated with acute exacerbations. SPMS is often diagnosed retrospectively.
  • Primary progressive MS (PPMS): a progressive decline in disease status and accumulation of disability from onset of disease without an initial relapsing-remitting disease course (~10% of patients) (1)

Pregnancy Considerations

• In most cases, MS treatment should be discontinued during pregnancy. If treatment is clinically necessary during pregnancy, preferred treatments include interferon-β and glatiramer acetate (2).
• For patients where there is a high risk of relapse of symptoms, natalizumab may be continued until 34 weeks (2).
• A majority of patients experience reduced disease exacerbations during pregnancy, but frequency of relapse typically increases in the postpartum period.
• MS therapy should be promptly resumed after delivery, particularly for individuals with very active disease prior to conception.
• All drugs licensed for MS treatment are contraindicated during breastfeeding. Patients desiring to breastfeed should carefully consider risk of delaying MS treatment (3).

Epidemiology

MS is a complex condition that is multifactorial, and although advances in genomics and immunology have increased our understanding of the disease process, much is yet to be discovered. It most often affects Caucasian women in their 2nd and 3rd generations of life and is more common in those with first-degree relatives with the disease.

Incidence

• Women (worldwide): 3.6 cases per 100,000 person-years
• Men (worldwide): 2.0 cases per 100,000 person-years

Prevalence

• Americas: 117.49 per 100,000 people
• Worldwide: 35.9 per 100,000 people (4)

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.
• Following demyelination, faster salutatory nerve conduction velocities (impulses jumping between nodes of Ranvier) are replaced with considerably slower continuous nerve velocities. These changes in the acute setting lead to the focal neurologic deficits associated with MS.
• Oligodendrocytes, which have survived, or ones 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. MS was once thought to be a disease of strictly affecting white matter tracts; however, there is increasing evidence of inflammatory damage within the cortical grey matter and overlying meninges (1).

Genetics

• MS is polygenic and does not follow a mendelian inheritance pattern. Those with affected first-degree relatives are 5 to 7 times more likely to be diagnosed.
• 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 cluster. The most common being the HLA-DRB1 locus on chromosome 6. These produce major histocompatibility complexes with high-binding affinity for myelin basic proteins.
• Although not fully understood, variations of natural killer cells and their polymorphic killer-immunoglobulin-like receptors are thought to play a major role in the MS disease process (1).

Risk Factors

• Age: peak incidence ages 15 to 45 years, mean age 28 to 31 years (slightly earlier in women than men)
• Race: Caucasian > Afro-Caribbean > East Asian
• Gender: 2 to 3 times more common in women
• Infectious: prior infections with Epstein-Barr virus and history of infectious mononucleosis
• Substance: tobacco smoking
• Geographic: Historically, proximity to the equator and its correlation with increased vitamin D exposure were inversely proportional to MS incidence. However, recently this association has been less obvious and may be due to lifestyle changes that have led to decreased sun exposure in these locations (1).

Commonly Associated Conditions

• Internuclear ophthalmoplegia: Injury to the medial longitudinal fasciculus causes impaired adduction of the affected eye.
• Optic neuritis: inflammation of optic nerve resulting in loss of vision
• Associated with numerous other autoimmune processes