Multiple sclerosis

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) c

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Pathophysiology

• Autoreactive T cells cross BBB → attack myelin
• Plaques (sclerotic lesions) form in periventricular white matter, optic nerves, brainstem, spinal cord
• Demyelination → ↓ conduction velocity → neurologic deficits
• Acute: inflammation, demyelination
• Chronic: gliosis, axonal loss (irreversible)

Tip

Only CNS demyelination, no PNS demyelination (unlike GBS) c

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Clinical features

• Core Feature: Multiple neurological deficits disseminated in space and time (CNS demyelinating lesions separated by anatomic location and chronological occurrence). c
• Sensory Disturbances:
  • Paresthesias, numbness, decreased vibration/proprioception.
  • Lhermitte sign: Electric shock-like sensation radiating down the spine and into the limbs upon neck flexion.
• Motor Symptoms:
  • Upper motor neuron (UMN) signs: Spasticity, hyperreflexia, (+) Babinski sign, muscle weakness.
  • Pronator drift: Sensitive physical exam marker for UMN / corticospinal tract lesion (pt extends arms with palms up and eyes closed $\to$ affected arm pronates and drifts downward due to weakness in supinator muscles relative to pronators). c
    • Upper motor neuron lesions cause more weakness in the supinator muscles compared to the pronator muscles of the upper limb.
• Ocular & Visual Symptoms:
  • Optic Neuritis: Acute, unilateral, painful eye movement associated with central vision loss, central scotoma, impaired color vision (dyschromatopsia), and afferent pupillary defect (Marcus Gunn pupil).
  • Internuclear Ophthalmoplegia (INO): Damage to the Medial Longitudinal Fasciculus (MLF). Impaired adduction of the ipsilateral eye with horizontal nystagmus of the contralateral abducting eye during lateral gaze; convergence is preserved. Bilateral INO is highly suggestive of MS.
• Cerebellar & Brainstem Symptoms:
  • Charcot neurologic triad: Scanning speech (dysarthria), Intention tremor, Nystagmus.
  • Ataxia, vertigo, scanning dysarthria.
• Autonomic & Other Features:
  • Uhthoff phenomenon: Transient worsening of neurological symptoms with increased body temperature (e.g., hot shower, exercise, fever).
    • Impulse conduction is dependent on temperature. An increase in body temperature presumably worsens impulse conduction in demyelinated nerves.
  • Neurogenic bladder: Spastic/hyperreflexic bladder causing urge incontinence (detrusor hyperreflexia) or flaccid bladder causing overflow retention.
  • Severe chronic fatigue, depression, cognitive dysfunction.
• Disease Courses:
  • Relapsing-Remitting (RRMS): Most common (~85%); acute attacks with full or partial recovery, stable between attacks.
  • Secondary Progressive (SPMS): Initial RRMS followed by gradual progression with or without relapses.
  • Primary Progressive (PPMS): Continuous progression of disability from onset (~15%).

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

• Initial & Confirmatory / Gold Standard: Brain and Spinal Cord MRI with and without IV Gadolinium. c
  • T2/FLAIR: Hyperintense demyelinating plaques in periventricular regions oriented perpendicular to the lateral ventricles (Dawson fingers), corpus callosum, infratentorial regions, and spinal cord.
  • T1 with Gadolinium: Enhancing lesions indicate acute, active demyelination (provides dissemination in time when combined with non-enhancing older lesions).
• Lumbar Puncture / CSF Analysis (used if MRI is non-diagnostic or atypical):
  • Oligoclonal bands (OCBs) present on CSF electrophoresis (seen in >85–90% of pts; not present in serum).
    • due to increased production of multiple nonspecific IgG sub-fractions in the CSF, which are caused by intrathecal inflammation.
  • Elevated CSF IgG index.
  • Normal glucose, normal or mildly elevated protein, mild lymphocytic pleocytosis (<50 WBCs/µL).
• Evoked Potentials:
  • Visual Evoked Potentials (VEP): Shows delayed P100 latency (indicates subclinical optic nerve demyelination).

Tip

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

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Differential diagnostics

Transverse myelitis

• Etiology & Triggers
  • Post-infectious / post-vaccinal immune response (viral URI/GI).
  • Demyelinating disease: Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum Disorder (NMOSD [anti-AQP4]), MOGAD.
  • Systemic autoimmune: SLE, Sjögren syndrome, Sarcoidosis.
• Patho
  • Autoimmune or post-infectious cross-reactivity (molecular mimicry) triggers an inflammatory cascade targeting the spinal cord.
• Clinical Presentation
  • Motor: Bilateral symmetric weakness (paraparesis/tetraparesis); spinal shock (flaccid/areflexic) acutely $\to$ UMN signs (spasticity, hyperreflexia, (+) Babinski) chronically.
  • Sensory: Sharp, discrete sensory level with band-like torso tightness (“corset/belt” sensation); loss of pain, temperature, vibration, and proprioception below lesion. c
  • Autonomic: Urinary retention/overflow incontinence, fecal incontinence/constipation, autonomic dysreflexia (if lesion $\ge$ T6).
• Diagnosis
  • Spinal MRI w/ contrast (Initial & Best): Shows intramedullary T2 hyperintensity + gadolinium enhancement; rules out compressive cord lesion (e.g., abscess, hematoma, metastasis).
  • Brain MRI w/ contrast: Evaluates for demyelinating plaques (MS) or optic nerve lesions (NMOSD).
  • Lumbar Puncture (CSF): Lymphocytic pleocytosis, elevated protein, $\pm$ oligoclonal bands (OCB).
  • Serologies: Anti-AQP4 IgG (rules in NMOSD), Anti-MOG IgG, ANA, HIV, RPR/VDRL.
• Key Differentials
  • Compressive Myelopathy: Extramedullary mass compressing cord on MRI; requires emergent surgical decompression or radiation.
  • Anterior Spinal Artery (ASA) Infarction: Hyperacute onset (<minutes to hours); spares dorsal columns (intact vibration & proprioception).
  • Guillain-Barré Syndrome (GBS): Ascending paralysis, hyporeflexia, no distinct sensory level, normal MRI, CSF showing albuminocytologic dissociation.
  • Multiple Sclerosis (MS): Typically partial/asymmetric cord involvement (<2 vertebral segments), periventricular brain plaques, (+) OCBs.
  • NMOSD: Longitudinally extensive transverse myelitis (LETM) ($\ge$3 vertebral segments), bilateral optic neuritis, (+) anti-AQP4 IgG.
• Management
  • 1st-Line (Acute): High-dose IV Methylprednisolone (1 g/day for 3–5 days). c
  • 2nd-Line (Steroid-refractory / Severe): Plasma Exchange (PLEX) $\times$ 5–7 sessions; IVIG as alternative.
  • Supportive & Prophylaxis:
    • Bladder decompression (Foley catheter / intermittent catheterization).
    • DVT prophylaxis (LMWH + SCDs) due to immobility.
    • Neuropathic pain (Gabapentin/Pregabalin) & spasticity management (Baclofen).
    • Early physical & occupational therapy.

Treatment

• Acute Flares:
  • High-dose IV corticosteroids (e.g., methylprednisolone).
  • Plasma exchange for severe, steroid-refractory flares.
• Chronic/Disease-Modifying Therapy (DMT):
  • Injectables: Interferon-beta, glatiramer acetate.
  • Oral: Dimethyl fumarate, fingolimod.
  • Infusions (highly effective): Natalizumab (risk of PML due to JC virus), Ocrelizumab (anti-CD20).
• Symptomatic Management:
  • Spasticity: Baclofen, tizanidine.
  • Neuropathic pain: Gabapentin, pregabalin, TCAs.
  • Fatigue: Amantadine, modafinil.
  • Urge incontinence: Anticholinergics (e.g., oxybutynin).