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  Disease summary:

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

    
    
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    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.

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

    
    
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    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.

    
    
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    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).

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

  
  
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  Differential diagnosis:

  
  
  
  
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    Can be organized by site of CNS involvement and includes:

    
    
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    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

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

    
    
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    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

  
  
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  Monogenic forms:

  
  
  
  
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    No single gene cause of MS is known to exist.

  
  
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  Family history:

  
  
  
  
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    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.

  
  
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  Twin studies:

  
  
  
  
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    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.

  
  
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  Environmental factors:

  
  
  
  
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    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.

  
  
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  Genome-wide associations:

  
  
  
  
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    About 49 well-validated susceptibility loci harboring 54 risk alleles exist. Testing for susceptibility alleles is not yet clinically validated to diagnose or guide management of Ms. Genome-wide association studies (GWASs) of disease course and other traits such as resilience and repair are beginning, but there is no variant with a validated role for these traits.

  
  
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  Pharmacogenomics:

  
  
  
  
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    There are no validated associations with response to a given treatment.

Diagnostic Criteria for MS

Diagnostic evaluation should include

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  Neuroimaging of the brain and spinal cord with MRI, with and without gadolinium, to confirm demyelinating lesions in the white and gray matter. Classic findings include acute lesions that enhance with gadolinium; chronic lesions that appear dark on T1 sequence (“black holes”), ovoid-shaped white matter “Dawson fingers” on T2/FLAIR that are perpendicular to the ventricles. In the spinal cord, lesions typically are peripheral and less than one spinal cord segment in length. Imaging also helps to eliminate other elements of the differential diagnosis such as neoplasm and certain infections.

  
  
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  Lumbar puncture to identify oligoclonal bands and calculate an IgG index (CSF IgG/CSF albumin)/(serum IgG/serum albumin), suggestive of demyelination, and to exclude infectious or neoplastic etiologies.

  
  
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  Ophthalmologic examination to assess for optic neuritis or eye movement abnormalities.

  
  
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  Exclusion of rheumatic or granulomatous etiologies with serologic markers (ANA, ESR, ACE) and chest x-ray.

  
  
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  Visual-evoked potentials (VEP) to identify prior demyelination of the optic pathway.

  
  
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  Somatosensory-evoked potentials (SSEP) to identify sensory disturbances.

Diagnostic Criteria for MS (2010 McDonald Criteria)

# clinical attacks (time), # objective lesions (space)→ additional data needed for dx

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  ≥2, ≥2 → None (clinical evidence alone suffices)

  
  
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  ≥2, 1 → Dissemination in space (DIS) by MRI or second clinical attack at new site

  
  
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  1, ≥2 → Dissemination in time by MRI or second clinical attack

  
  
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  1, 1→ DIS by MRI and DIT by MRI; or second clinical attack

  
  
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  0, ≥1→ >1 year progression and two-thirds of (1) DIS on brain MRI (2) DIS on spinal cord MRI (≥2 T2 lesions), (3) +CSF (oligoclonal bands and/or elevated IgG index). Likely PPMS

Criteria for Dissemination in Time or in Space on MRI

Time (DIT):

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   A new T2 and/or gadolinium-enhancing lesion on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI, or

Space (DIS):

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  Greater than or equal to one T2 lesion in greater than or equal to two-fourths CNS areas: periventricular, juxtacortical, infratentorial, spinal cord.

  
  
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  If a subject has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded from the criteria and do not contribute to lesion count.

Clinical Characteristics

The clinical hallmark of MS is demyelinating lesions of the CNS disseminated in time and space.

Specific signs and symptoms can include focal sensory or motor impairment, optic neuritis, transverse myelitis, loss of bowel or bladder function, gait instability. Systemic (fatigue), psychiatric (depression, anxiety), and cognitive symptoms are common. Uhthoff phenomenon (sensitivity to increased body temperature, which causes a transient recrudescence of symptoms) and Lhermitte sign (a sensation described as an electric shock radiating caudally upon neck flexion) are common.

Screening

There is currently no validated role for screening of family members of MS patients or other high-risk individuals. Similarly, there is no role today for screening of the general population. There is also, currently, no validated primary prophylaxis therapy for Ms. Thus, there is no screening tool today.

Counseling

Familial clustering is uncommon. While there is some evidence for the role of rare CYP27B1 variants of strong effects on MS susceptibility, no clearly Mendelian forms of MS have been discovered to date. The use of common variants of modest effect has not entered the clinical setting. Thus, currently, there is no formal counseling. Informally, neurologists discuss the rate of MS in first-degree relatives, which is approximately 2% to 3%.

Acute Attacks are managed with 3 to 5 days of intravenous methylprednisolone (1 g daily), with the goal of halting expansion of the acute inflammatory lesion. Plasmapheresis is considered when symptoms continue to evolve despite the methylprednisolone pulse.

Disease-modifying treatments (DMTs) are approved for reducing the likelihood of relapses. They are also indicated to reduce the risk of or delay the time to a second attack in clinically isolated syndrome. There are nine FDA-approved DMTs.

First-Line Treatments

Beta interferons