16.4 Multiple Sclerosis & Central Demyelinating Diseases

Multiple sclerosis (MS) is the leading non-traumatic cause of permanent neurological disability in young adults. For MRCP(UK) Part 1, candidates must master the genetic and immunopathological basis of demyelination, recognize pathognomonic clinical signs, understand the McDonald diagnostic criteria as revised in 2024, evaluate disease-modifying therapies and their toxicities, and differentiate MS from neuromyelitis optica spectrum disorder (NMOSD).

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1. Epidemiology, Genetics & Immunopathogenesis

Epidemiology & Environmental Risk Factors

• Demographics: Typical age of onset is 20 to 40 years; female-to-male ratio is approximately 3:1. Prevalence follows a latitude gradient, with significantly higher rates in temperate regions further from the equator (e.g. Scotland, Northern Europe, Canada).
• Genetic Susceptibility: Polygenic inheritance with the strongest genetic association mapped to the human leukocyte antigen (HLA) Class II region: HLA-DRB1*1501 allele confers an odds ratio of approximately 3.0.
• Environmental Risk Factors:
  1. Epstein-Barr Virus (EBV): Past infection with EBV is virtually a prerequisite for developing MS; seronegativity carries a near-zero lifetime risk of MS.
  2. Hypovitaminosis D & Sunlight: Low serum 25-hydroxyvitamin D levels and reduced ultraviolet B (UVB) exposure strongly correlate with increased incidence and relapse rates.
  3. Cigarette Smoking: Increases risk of developing MS and accelerates progression from relapsing-remitting to secondary progressive disease.
  4. Adolescent Obesity: Doubles the risk of developing MS via chronic low-grade systemic inflammation.

Immunopathogenesis

• Autoimmune breakdown of immunological tolerance against CNS myelin sheath antigens (myelin basic protein [MBP], proteolipid protein [PLP], and myelin oligodendrocyte glycoprotein [MOG]).
• Autoreactive $\text{CD4}^+$ T helper cells (pro-inflammatory Th1 secreting IFN-$\gamma$ and Th17 secreting IL-17) and B cells undergo activation in peripheral lymphoid tissue. They adhere to brain endothelial cells via $\alpha_4\beta_1$ integrin (VLA-4) interacting with vascular cell adhesion molecule-1 (VCAM-1) and migrate across the blood-brain barrier.
• In the CNS parenchyma, reactivation by local antigen-presenting cells triggers recruitment of macrophages, microglia, and $\text{CD8}^+$ cytotoxic T cells, alongside complement fixation. This causes focal perivenular inflammatory demyelination.
• Although remyelination occurs early via oligodendrocyte precursor cells, persistent inflammation, loss of trophic oligodendrocytic support, and mitochondrial dysfunction ultimately produce axonal transection, cortical grey matter atrophy, and progressive neurodegeneration.

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2. Clinical Presentations & Pathognomonic Neurological Phenomena

Optic Neuritis (ON)

• The presenting manifestation in ~20% of MS patients; ~50% of patients with isolated optic neuritis ultimately convert to MS within 15 years.
• Symptoms: Subacute, monocular visual loss developing over hours to days, peaking at 1–2 weeks, characteristically accompanied by retro-orbital or ocular pain worsened by eye movement (due to traction on the inflamed optic nerve sheath at the annulus of Zinn).
• Signs: Decreased visual acuity, marked dyschromatopsia (loss of color vision, especially red desaturation, disproportionate to acuity reduction), and a Relative Afferent Pupillary Defect (RAPD / Marcus Gunn pupil) in the affected eye.
• Fundoscopy: In two-thirds of cases, the optic disc appears completely normal (retrobulbar neuritis; "the patient sees nothing and the doctor sees nothing"). In one-third, anterior papillitis causes disc swelling and hyperaemia.
• Visual Evoked Potentials (VEP): Shows delayed P100 wave latency with preserved wave amplitude, reflecting demyelinating conduction slowing.

Internuclear Ophthalmoplegia (INO)

• Caused by a demyelinating plaque within the Medial Longitudinal Fasciculus (MLF) in the dorsomedial brainstem (pons or midbrain). The MLF coordinates conjugate horizontal gaze by connecting the abducens (CN VI) nucleus to the contralateral oculomotor (CN III) medial rectus subnucleus.
• Clinical Examination Findings: On attempted conjugate horizontal gaze:
  1. Failure of adduction of the eye ipsilateral to the MLF lesion.
  2. Coarse horizontal jerk nystagmus of the abducting contralateral eye.
  3. Convergence is completely preserved (convergence pathways bypass the MLF and project directly to the midbrain CN III nuclei).
• MRCP Exam Pearl: A bilateral INO in a young adult is virtually pathognomonic of multiple sclerosis (whereas unilateral INO in an older individual is most commonly an ischaemic stroke).

Pathognomonic Clinical Phenomena

• Lhermitte's Sign: An electric shock-like sensation shooting down the spine into the limbs precipitated by neck flexion. Reflects mechanical hyperexcitability of demyelinated axons within the cervical dorsal columns.
• Uhthoff's Phenomenon: Reversible, transient worsening of neurological symptoms or visual blurring occurring with an elevation in core body temperature (e.g. following a hot bath, strenuous exercise, or fever). Caused by heat-induced inactivation of voltage-gated sodium channels, abolishing the already compromised safety factor of conduction in demyelinated nerve fibres.

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3. Clinical Disease Courses

Relapsing-Remitting MS (RRMS, ~85%)
  │ (Acute relapses followed by full/partial remission)
  ▼ (Over 10–20 years in untreated patients)
Secondary Progressive MS (SPMS)
  (Gradual progressive accumulation of irreversible disability ± relapses)

Primary Progressive MS (PPMS, ~10–15%)
  (Steady, insidious neurological decline from onset without distinct attacks;
   typically presents as progressive spastic paraparesis in older patients, equal sex ratio)

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4. Diagnostic Criteria: The McDonald Criteria (2024 Revisions) & CSF Analysis

The McDonald criteria were revised in 2024 by the International Advisory Committee on Clinical Trials in MS, convened by ECTRIMS and the National MS Society, and published in The Lancet Neurology in September 2025. They supersede the 2017 criteria but retain the same core architecture, diagnosing MS by demonstrating Dissemination in Space (DIS) and Dissemination in Time (DIT) while excluding alternative diagnoses:

Cerebrospinal Fluid (CSF) Analysis

• Oligoclonal Bands (OCBs): Evaluated by isoelectric focusing (IEF) of paired CSF and serum samples. Pattern 2 (positive): Two or more distinct IgG oligoclonal bands identified in the CSF that are completely absent in matched serum, indicating intrathecal synthesis of clonal immunoglobulins (present in $> 95%$ of established MS).
• Cell Count & Biochemistry: Mild lymphocytic pleocytosis ($< 50\text{ cells/}\mu\text{L}$); protein is normal or mildly elevated ($< 1.0\text{ g/L}$). Warning: A CSF cell count $> 50\text{ cells/}\mu\text{L}$ or presence of neutrophils strongly argues against MS and suggests NMOSD, sarcoidosis, or CNS infection.

What Changed in the 2024 Revisions

Older revision material still teaches the 2017 criteria verbatim, so the differences are worth holding separately:

The bedrock facts are unchanged and remain the ones most often tested: oligoclonal bands present in cerebrospinal fluid but absent from a paired serum sample indicate intrathecal immunoglobulin synthesis and are found in about 90-95% of people with MS, and matched bands in both compartments simply reflect a systemic inflammatory process rather than MS.

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5. Treatment Strategies: Relapse & Disease-Modifying Therapies (DMTs)

Acute Relapse Management

• Indicated for acute relapses causing significant functional impairment (e.g. optic neuritis, disabling myelitis, ataxia).
• First-Line Regimen: High-dose Oral Methylprednisolone 500 mg once daily for 5 days (or IV Methylprednisolone 1 g daily for 3–5 days). Co-prescribe an oral proton pump inhibitor (e.g. omeprazole 20 mg) for gastroprotection.
• Mechanism & Efficacy: High-dose corticosteroids accelerate the rate of functional recovery from the acute attack by resolving perilesional inflammatory oedema and restoring blood-brain barrier integrity; corticosteroids do NOT alter the long-term progression of neurological disability.
• Refractory Relapse: Plasma exchange (plasmapheresis, 5–7 cycles) for severe relapses failing high-dose corticosteroids.

Disease-Modifying Therapies (DMTs)

Symptomatic Management in Multiple Sclerosis

• Spasticity: First-line: Oral baclofen (GABA-B agonist) or oral tizanidine (central $\alpha_2$-agonist); second-line: gabapentin, dantrolene; severe refractory cases: intrathecal baclofen pump.
• Fatigue: First-line: Supervised exercise programmes; pharmacological options: amantadine (100–200 mg daily) or modafinil.
• Neuropathic Pain & Dysaesthesias: Gabapentin, pregabalin, or duloxetine.
• Bladder Dysfunction: Pre-treatment post-void residual volume must be checked via bladder ultrasound:
  • Detrusor overactivity (frequency, urgency, nocturia with low residual $< 100\text{ mL}$): Treat with antimuscarinics (tolterodine, solifenacin) or beta-3 agonist (mirabegron).
  • Detrusor sphincter dyssynergia / incomplete emptying (residual $> 100\text{ mL}$): Anticholinergics are contraindicated (precipitate acute urinary retention); institute Clean Intermittent Self-Catheterisation (CISC).

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6. Central Demyelinating Mimics: Neuromyelitis Optica Spectrum Disorder (NMOSD)

• Pathogenesis: Autoimmune astrocytopathy mediated by pathogenic autoantibodies directed against Aquaporin-4 (AQP4-IgG), a water channel densely concentrated on astrocytic end-feet at the blood-brain barrier. Binding triggers classical complement cascade activation, astrocytic swelling and lysis, with secondary granulocytic infiltration and extensive bystander demyelination.
• Clinical Presentation:
  1. Severe Optic Neuritis: Frequently bilateral, sequential or simultaneous, with poor recovery and high risk of permanent visual deficit.
  2. Longitudinally Extensive Transverse Myelitis (LETM): Spinal cord MRI shows a contiguous, unbroken T2 hyperintense lesion extending over $\ge 3$ vertebral segments (in contrast to MS lesions which are typically short, spanning $< 2$ segments and located eccentrically in the cord).
  3. Area Postrema Syndrome: Infiltration of the medullary vomiting centre at the floor of the fourth ventricle, presenting with intractable nausea, vomiting, or hiccups lasting days to weeks without an identifiable gastrointestinal cause.
• Diagnostic Distinctions from Multiple Sclerosis:
  • Brain MRI: Frequently normal or demonstrates non-specific, non-periventricular white matter lesions.
  • CSF: Prominent pleocytosis often $> 50\text{ cells/}\mu\text{L}$ with significant neutrophilic and eosinophilic predominance; CSF oligoclonal bands are absent in ~70–80% of patients.
  • Serology: AQP4-IgG seropositivity in $> 75%$; a subset of AQP4-negative patients are seropositive for myelin oligodendrocyte glycoprotein (MOG-IgG, defining MOG-antibody-associated disease / MOGAD).
• Acute and Preventive Treatment:
  • Acute Attacks: High-dose IV methylprednisolone (1 g daily for 5 days) followed by prompt, early Plasma Exchange (PLEX) if clinical response is incomplete.
  • Long-term Immunosuppressive Maintenance: Monoclonal therapies including eculizumab (terminal complement C5 inhibitor), inebilizumab (anti-CD19 B-cell depleter), satralizumab (IL-6 receptor antagonist), or rituximab (anti-CD20).
  • CRITICAL CONTRAINDICATION: Conventional MS disease-modifying therapies—specifically Beta-Interferon, Fingolimod, Natalizumab, and Alemtuzumab—are strictly contraindicated in NMOSD as they exacerbate the underlying disease and can precipitate catastrophic, irreversible clinical relapses.