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Key Points

  • Disease summary:

    • Multiple sclerosis (MS) is a genetically complex disorder, involving many susceptibility loci that probably interact with environmental factors to trigger the disease.

    • MS is a chronic, inflammatory demyelinating disorder of the central nervous system (CNS) typically characterized by demyelinating lesions disseminated “in time and space,” meaning that different parts of the CNS are involved and that a patient has had at least two inflammatory events 3 months apart.

    • Demyelinating lesions can occur in the brain, spinal cord, and optic nerves.

    • Clinical presentation includes focal sensory or motor impairment, optic neuritis, transverse myelitis, loss of bowel or bladder function, gait instability, fatigue, depression, cognitive impairment. Vertigo, Uhthoff phenomenon, and Lhermitte sign are common.

    • Disease course is divided into three categories: relapsing remitting MS (RRMS, 85% of first presentations), secondary progressive MS (SPMS, many RRMS patients go on to exhibit a gradual functional and decline reminiscent of neurodegenerative diseases), and primary progressive MS (PPMS, patients who never had a clinical relapse).

    • More rare forms include neuromyelitis optica (NMO), Marburg variant, Schilder disease, Baló concentric sclerosis, and tumefactive MS.

  • Differential diagnosis:

    • Can be organized by site of CNS involvement and includes:

    • Cerebrum and brain stem: acute demyelinating encephalomyelitis (ADEM), lymphoma, infection (Lyme disease, HIV, progressive multifocal leukoencephalopathy [PML], syphilis), small vessel disease (leukoaraiosis), CADASIL, vasculitis, rheumatologic diseases (systemic lupus erythematosus [SLE]), rheumatoid arthritis (RA), Sjögren syndrome), antiphospholipid antibody syndrome (APLAS), spinocerebellar ataxia, and leukodystrophy

    • Optic neuritis: NMO, sarcoidosis, retinal artery occlusion, retinal detachment, acute glaucoma

    • Spinal cord: sarcoidosis, spinal stenosis, syrinx, epidural abscess, spinal arteriovenous malformation (AVM), infectious myelitis (HIV, HTLV-1, Mycoplasma), nutritional (B12, copper or zinc) deficiencies, toxicity, hereditary spastic paraparesis, adrenomyeloneuropathy

  • Monogenic forms:

    • No single gene cause of MS is known to exist.

  • Family history:

    • The lifetime risk of developing MS for a sibling or a child of an MS patient is 2% to 3%, which is about 30 times greater than the risk to the general population.

  • Twin studies:

    • Monozygotic twins have a 30% concordance rate for clinical disease; in one study, concordance was 50% if magnetic resonance imaging (MRI) is performed and clinically silent MS-like lesions are considered as evidence of the disease.

  • Environmental factors:

    • In terms of MS susceptibility, good epidemiologic data support the role of (1) the Epstein-Barr virus (EBV) (particularly in its clinical manifestation as infectious mononucleosis), (2) low vitamin D levels, and (3) smoking. More preliminary evidence supports the role of elevated adolescent body mass index (BMI) and living in Northern latitude during childhood, which may be related to vitamin D. There is some evidence for a gene-environment interaction. For example, individuals who have both the HLA DRB1*1501 allele and high levels of antibodies directed against the EBV protein EBNA-1 (two known risk factors), have a ninefold increase in risk over individuals that have neither risk factor.

  • Genome-wide associations:

    • About 49 well-validated susceptibility loci harboring 54 risk alleles exist. Testing for susceptibility alleles is not yet clinically validated to diagnose ...

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