Key points

• Multiple sclerosis (MS) is a chronic degenerative disease of the CNS characterized by demyelination and axonal degeneration in the brain and spinal cord, which are caused by an immune-mediated inflammatory process.
• Impaired vision (due to retrobulbar neuritis) is usually the first manifestation of MS; other neurological deficits appear as the disease progresses. The most common clinical course is characterized by exacerbations followed by periods of complete or incomplete remission.

Epidemiology

• Sex: ♀ > ♂ (3:1)
• Age of onset: 20–40 years of age
• Ethnicity: ↑ prevalence among the white and black population
• Prevalence: 50-300 per 100 000 people (greater among people who live further from the equator)

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Etiology

The etiology of multiple sclerosis is unclear; it is believed to develop in genetically predisposed people who have been exposed to certain environmental factors.

• Environmental risk factors
  • Low vitamin D levels (insufficient intake, decreased exposure to UV radiation)

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Pathophysiology

• Pathophysiology of MS is characterized by autoimmune 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
• B-lymphocyte dysfunction: The following suggests that B-lymphocytes play a role in the pathogenesis of MS, although the exact mechanism of their involvement is unclear.
  • Anti-CD20 agents (ocrelizumab, ofatumumab, rituximab) are effective in preventing exacerbations.
  • Presence of tertiary lymphoid organs in the meninges of individuals with secondary progressive MS
  • Intrathecal synthesis of IgG (oligoclonal bands; see “Diagnostics” section for more information)
• Progressive phenotypes (forms) of MS are characterized by
  • Chronic inflammation that occurs with an intact blood-brain barrier and is driven by immune cells compartmentalized in the leptomeninges and perivascular spaces
  • Accelerated compared to relapsing-remitting phenotype brain atrophy

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Clinical features

• Optic neuritis
  • Most often the earliest manifestation
  • Typically unilateral
  • Can be painful
  • Impaired vision and color blindness
  • Relative afferent pupillary defect (Marcus Gunn pupil)
• Internuclear ophthalmoplegia (INO) as a result of a lesion in the medial longitudinal fasciculus (MLF)
  • Ipsilateral medial rectus weakness but an intact convergence reflex
  • Disconjugate, lateral gaze nystagmus in the contralateral eye
  • More frequently bilateral than unilateral
• Demyelination of spinal cord tracts
  • Lhermitte sign: a shooting electric sensation that travels down the spine upon flexion of the neck
  • Pyramidal tract lesion: upper motor neuron weakness, spasticity, hyperreflexia, positive Babinski sign, impaired gait
  • Dorsal spinal column lesion: loss of vibration and fine-touch sensation, numbness, paresthesias, sensory ataxia usually involving the trunk or one or more limbs
  • Neuropathic pain
  • Absent abdominal reflex
• Cerebellar involvement: poor postural control, imbalance, gait dysfunction, Charcot neurological triad of scanning speech, nystagmus, and intention tremors
• Transverse myelitis
  • Asymmetric paraplegia, unilateral sensory loss, bladder dysfunction
  • Partial transverse myelitis is a common early manifestation of MS, causing asymmetric neurologic dysfunction below the lesion.
• Cranial nerve palsies: diplopia, facial palsy, trigeminal neuralgia (can be bilateral)
  • Trigeminal neuralgia (TN) typically manifests unilaterally.
  • Bilateral TN should raise concern for MS, especially in younger patients.
• Autonomic dysfunction: bowel and bladder neurogenic disorders (e.g., urinary incontinence), impaired sexual function
• Changes in mental state: depression, emotional changes, memory deficits, impaired concentration
• Uhthoff phenomenon: a reversible exacerbation of neurological symptoms following an increase in body temperature, e.g., physical exertion, a warm bath, or fever
  • Impulse conduction is dependent on temperature. An increase in body temperature presumably worsens impulse conduction in demyelinated nerves.

Tip

MS is a chronic condition that typically manifests in a relapsing-remitting form characterized by episodic CNS dysfunction (exacerbations) with at least partial recovery between episodes.

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Diagnostics

• Diagnosis of MS depends on a combination of clinical findings (e.g., optic neuritis, Lhermitte sign, sensory abnormalities, cerebellar signs), imaging, and laboratory results.
• The McDonald Criteria for both DIT and DIS must both be met to confirm a diagnosis of MS:
  • Dissemination in time (DIT): the appearance of new CNS lesions over time that can be confirmed clinically, with imaging, or with CSF analysis
  • Dissemination in space (DIS): the presence of lesions in different regions of the CNS that can be confirmed clinically or in MRI

Imaging

• MRI: Multiple sclerotic plaques (most commonly found in the periventricular white matter) with finger-like radial extensions (Dawson fingers) related to demyelination and reactive gliosisThere are extensive demyelinating lesions (plaques) bilaterally, appearing as hyperintensities in the periventricular white matter (green overlay). The finger-like radial extensions of these lesions are called “Dawson fingers.”

Additional studies

• CSF examination
  • Oligoclonal bands
    • Oligoclonal bands manifest due to increased production of multiple nonspecific IgG sub-fractions in the CSF, which are caused by intrathecal inflammation.
  • Other common findings: moderate lymphocytic pleocytosis, increased myelin basic protein

Tip

The presence of multiple oligoclonal bands in CSF and their absence in the blood is highly suggestive of MS.

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Treatment

• Alemtuzumab
  • A monoclonal antibody against the superficial antigen CD52; found on the surface of lymphocytes and monocytes
  • Depletes B and T lymphocytes
  • See 单抗记忆

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