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Monday, August 11, 2025

Multiple sclerosis


Introduction
Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disorder of the central nervous system (CNS) characterized by inflammation, demyelination, gliosis, and axonal loss. It affects the brain, spinal cord, and optic nerves, leading to a wide variety of neurological symptoms. MS is thought to be triggered by an autoimmune process in genetically susceptible individuals, often influenced by environmental factors.

The disease follows different clinical patterns, most commonly a relapsing-remitting course, and can lead to progressive disability over time.

Epidemiology

  • Global prevalence: ~2.8 million people worldwide.

  • Peak age of onset: 20–40 years.

  • Female-to-male ratio: Approximately 2–3:1 in relapsing forms.

  • More common in individuals of Northern European ancestry.

Etiology and Risk Factors

Genetic Factors

  • Increased risk in first-degree relatives.

  • HLA-DRB1*15:01 allele strongly associated.

Environmental Factors

  • Low vitamin D levels.

  • Epstein-Barr virus (EBV) infection.

  • Smoking.

  • High latitude (reduced sunlight exposure).

  • Childhood obesity.

Pathophysiology

MS is characterized by an abnormal immune response targeting myelin in the CNS. The key mechanisms include:

  • Activation of autoreactive T lymphocytes (especially CD4+ Th1 and Th17 cells).

  • Breakdown of the blood–brain barrier allowing immune cells to infiltrate CNS tissue.

  • Inflammatory demyelination and oligodendrocyte damage.

  • Subsequent axonal degeneration leading to irreversible neurological deficits.

Clinical Types of MS

  1. Relapsing-Remitting MS (RRMS) – ~85% of cases at onset.

    • Distinct relapses (attacks) of neurological dysfunction followed by partial or complete recovery.

  2. Secondary Progressive MS (SPMS)

    • Initially relapsing-remitting, then transitions to steady neurological deterioration with or without relapses.

  3. Primary Progressive MS (PPMS) – ~10–15% of cases.

    • Steady functional decline from onset without relapses.

  4. Progressive-Relapsing MS (PRMS) – Rare.

    • Progressive deterioration from onset with acute relapses.

Clinical Features

Symptoms vary depending on CNS region involved. Common manifestations:

Sensory Symptoms

  • Numbness, tingling, paresthesias.

Motor Symptoms

  • Muscle weakness.

  • Spasticity, hyperreflexia.

Visual Symptoms

  • Optic neuritis (painful vision loss, usually unilateral).

  • Diplopia (double vision) from internuclear ophthalmoplegia.

Coordination and Balance

  • Ataxia, tremor, vertigo.

Bladder and Bowel Dysfunction

  • Urinary urgency, retention, constipation.

Cognitive and Psychiatric

  • Memory impairment, difficulty concentrating, depression.

Fatigue

  • A common and often disabling symptom.

Diagnosis

Diagnosis is clinical and supported by investigations, following the McDonald Criteria (revised 2017):

  • Evidence of CNS lesions disseminated in space (different CNS regions) and time (different episodes).

  • MRI: Hyperintense lesions on T2/FLAIR in periventricular, juxtacortical, infratentorial, or spinal cord regions.

  • CSF analysis: Oligoclonal bands on electrophoresis (indicative of intrathecal IgG synthesis).

  • Evoked potentials: Delayed conduction supporting demyelination.

Management

Goals:

  • Short-term: Treat acute relapses.

  • Long-term: Modify disease course to reduce relapses and progression.

  • Symptom management and rehabilitation.

1. Acute Relapse Management

  • Methylprednisolone (IV): 1 g daily for 3–5 days.

  • Prednisolone (oral taper): 60–80 mg/day for 1 week, then taper over 1–2 weeks.

  • Plasma exchange (plasmapheresis) for severe, steroid-resistant relapses.

2. Disease-Modifying Therapies (DMTs)

First-Line Agents (Relapsing MS)

  • Interferon beta-1a: 30 µg IM once weekly or 22–44 µg SC three times weekly.

  • Interferon beta-1b: 250 µg SC every other day.

  • Glatiramer acetate: 20 mg SC daily or 40 mg SC three times weekly.

  • Dimethyl fumarate: 120 mg orally twice daily for 7 days, then 240 mg twice daily.

  • Teriflunomide: 14 mg orally daily.

High-Efficacy Agents (for aggressive disease or after first-line failure)

  • Natalizumab: 300 mg IV every 4 weeks.

  • Ocrelizumab: 300 mg IV on day 1 and day 15, then 600 mg IV every 6 months.

  • Alemtuzumab: 12 mg IV daily for 5 days (first course), then 12 mg IV daily for 3 days after 12 months.

  • Fingolimod: 0.5 mg orally daily.

  • Cladribine: 3.5 mg/kg total over 2 years, given in 2 yearly courses.

For Primary Progressive MS (PPMS)

  • Ocrelizumab is the only FDA-approved agent: dosing as above.

3. Symptom Management

  • Fatigue: Amantadine 100 mg orally twice daily; modafinil 100–200 mg in the morning.

  • Spasticity: Baclofen 5–10 mg orally three times daily (titrate up), tizanidine 2–4 mg three times daily.

  • Neuropathic pain: Gabapentin 300–900 mg orally three times daily; pregabalin 75–150 mg twice daily.

  • Bladder dysfunction: Oxybutynin 2.5–5 mg orally two to three times daily; tolterodine 2 mg twice daily.

  • Depression: SSRIs (e.g., sertraline 50–100 mg daily).

Prognosis

  • Highly variable: Some maintain normal function for years, while others experience rapid progression.

  • Better prognosis with female sex, younger onset, sensory-only symptoms at presentation, and long interval between first and second relapse.

  • Poorer prognosis with early motor/cerebellar involvement, frequent relapses, and high MRI lesion load.




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