Demyelinating Diseases
Pathology · CNS · lean revision notes
Demyelinating Diseases
Demyelinating diseases are disorders in which there is preferential destruction of myelin with relative preservation of axons (at least early on). They form a favourite NEET PG cluster because each entity carries a signature antibody, a signature CSF finding, and a signature lesion location — and the examiner loves to swap them.
High-yield: The unifying theme is "myelin lost, axon spared." Where the axon is also lost early (e.g. severe MS, axonal GBS variants), prognosis worsens. Always separate CNS myelin (oligodendrocyte) from PNS myelin (Schwann cell) — one oligodendrocyte myelinates many internodes, one Schwann cell myelinates a single internode.
Classification
Demyelinating disorders are broadly split by site and mechanism.
| Category | Examples | Myelin-forming cell affected |
|---|---|---|
| Primary CNS demyelination (acquired) | Multiple sclerosis (MS), Neuromyelitis optica spectrum disorder (NMOSD), ADEM | Oligodendrocyte |
| Osmotic/metabolic CNS demyelination | Central pontine myelinolysis (CPM), Marchiafava–Bignami | Oligodendrocyte |
| Viral/immunosuppression-related | Progressive multifocal leukoencephalopathy (PML – JC virus) | Oligodendrocyte |
| Inherited dysmyelination (leukodystrophies) | Metachromatic leukodystrophy, Krabbe, adrenoleukodystrophy | Oligodendrocyte/Schwann |
| Primary PNS demyelination | Guillain–Barré syndrome (GBS/AIDP), CIDP, Charcot–Marie–Tooth (CMT) | Schwann cell |
High-yield: Acquired primary demyelination = destruction of normal myelin. Leukodystrophies = abnormal myelin synthesis or metabolism (dysmyelination). PML is demyelination caused by JC virus infection of oligodendrocytes in immunosuppressed (HIV, natalizumab).
Multiple Sclerosis (MS)
The prototype CNS demyelinating disease — an autoimmune, T-cell mediated attack producing lesions disseminated in space and time.
Epidemiology & etiology
- Onset typically 20–40 years, female:male ≈ 2–3:1.
- Prevalence increases with latitude (rare near equator); reduced sunlight/vitamin D deficiency and EBV infection are strong environmental associations.
- HLA association: HLA-DR2 (DRB1*15:01).
Pathophysiology
- Activated CD4+ Th1/Th17 cells cross the blood–brain barrier, recognise myelin antigens (MBP, PLP, MOG), and recruit macrophages.
- Macrophages strip myelin; oligodendrocytes are destroyed → conduction block.
- Remyelination occurs but is incomplete → shadow plaques (pale myelin staining at plaque edges).
Gross & microscopic pathology
- Plaques are the hallmark — well-demarcated, firm, glassy grey lesions.
- Classic locations: periventricular white matter, optic nerves/chiasm, corpus callosum, brainstem, cerebellum, spinal cord.
- Dawson fingers = periventricular plaques oriented perpendicular to the ventricles, following the deep medullary veins (radiologic and pathologic sign).
- Active plaque: perivascular lymphocytes, lipid-laden macrophages (myelin debris, Luxol fast blue +), preserved axons. Inactive plaque: gliosis, few oligodendrocytes, axonal loss.
High-yield: MS = demyelination with relative axonal sparing + periventricular plaques (Dawson fingers) + CSF oligoclonal IgG bands. These three are the most repeated NEET PG facts on this topic.
Clinical features
Symptoms scattered in space and time:
- Optic neuritis — painful monocular visual loss (often first attack); relative afferent pupillary defect (Marcus Gunn pupil).
- Internuclear ophthalmoplegia (INO) from medial longitudinal fasciculus lesion — highly suggestive of MS in a young adult, especially if bilateral.
- Uhthoff phenomenon — worsening with heat/fever.
- Lhermitte sign — electric-shock sensation down the spine on neck flexion (posterior column).
- Charcot neurologic triad: Scanning speech, Intention tremor, Nystagmus (SIN).
- Spasticity, bladder dysfunction, fatigue, sensory symptoms.
Clinical course patterns
| Pattern | Description |
|---|---|
| Relapsing–remitting (RRMS) | Most common (~85%); discrete attacks with recovery |
| Secondary progressive | RRMS that later steadily progresses |
| Primary progressive (PPMS) | Steady decline from onset; older, more spinal cord involvement |
| Clinically isolated syndrome | First single attack; may convert to MS |
Diagnosis
Approach: Clinical attacks → MRI → CSF → exclude mimics.
- MRI (investigation of choice) — T2/FLAIR hyperintense ovoid periventricular lesions; Dawson fingers; open-ring (incomplete ring) enhancement of active plaques on gadolinium. Old + new lesions = dissemination in time.
- CSF: oligoclonal bands (IgG) present in CSF but not serum (>2 bands), raised IgG index. Cells normal or mild lymphocytosis (<50).
- Visual evoked potentials — delayed latency (subclinical optic nerve demyelination).
- McDonald criteria — formalise dissemination in space and time (MRI can substitute for clinical relapses).
High-yield: Oligoclonal bands in CSF (not in matched serum) indicate intrathecal IgG synthesis — classic for MS but not specific. Two or more bands absent from serum = positive.
Management
- Acute relapse: high-dose IV methylprednisolone; plasma exchange if steroid-refractory.
- Disease-modifying therapy (DMT): interferon-β, glatiramer acetate, dimethyl fumarate, fingolimod, natalizumab (anti-α4-integrin — risk of PML), ocrelizumab (anti-CD20; only DMT approved for PPMS).
- Symptomatic: baclofen (spasticity), gabapentin/pregabalin, amantadine (fatigue).
High-yield: Natalizumab → reactivation of JC virus → PML. Check anti-JCV antibody before/during therapy. This natalizumab–PML link is heavily tested.
Neuromyelitis Optica Spectrum Disorder (NMOSD / Devic disease)
An antibody-mediated astrocytopathy that mimics MS but is a distinct disease.
- Anti-aquaporin-4 (AQP4-IgG) antibodies — target the water channel on astrocyte foot processes → astrocyte destruction → secondary demyelination.
- A subset are AQP4-negative but anti-MOG positive (MOGAD).
- Classic dyad: severe optic neuritis (often bilateral) + longitudinally extensive transverse myelitis.
NMOSD vs MS
| Feature | Multiple sclerosis | NMOSD (Devic) |
|---|---|---|
| Target antigen | Myelin (oligodendrocyte) | Aquaporin-4 (astrocyte) |
| Antibody | None specific | AQP4-IgG |
| Optic neuritis | Usually unilateral | Often bilateral, severe |
| Spinal cord lesion | Short segment (<2 segments) | Longitudinally extensive (≥3 vertebral segments) |
| Brain MRI | Periventricular, Dawson fingers | Often normal early / area postrema lesions |
| CSF oligoclonal bands | Present (~85–95%) | Usually absent; neutrophilic pleocytosis |
| First-line acute Rx | IV steroids | IV steroids + plasma exchange |
| Maintenance | Interferons/DMTs | Rituximab, eculizumab; interferons can WORSEN NMOSD |
High-yield: AQP4-IgG = NMOSD. Spinal lesion ≥3 contiguous vertebral segments = "longitudinally extensive transverse myelitis" — points to NMOSD, not MS. MS-typical drugs (interferon-β) worsen NMOSD.
Central Pontine Myelinolysis (CPM / Osmotic Demyelination Syndrome)
Non-inflammatory demyelination of the central pons (and extrapontine sites) from rapid correction of hyponatraemia.
Pathophysiology
- In chronic hyponatraemia, brain cells extrude osmolytes to adapt.
- Too-rapid sodium correction → osmotic shift → water leaves cells → oligodendrocyte injury and demyelination in the pons.
- Risk groups: chronic alcoholics, malnutrition, liver transplant, severe burns, hypokalaemia.
Clinical features
- A characteristic biphasic course: hyponatraemic encephalopathy improves with correction, then 2–6 days later new signs appear.
- Spastic quadriparesis, pseudobulbar palsy, dysarthria, dysphagia, and the dreaded "locked-in" syndrome (preserved consciousness/vertical eye movement, total motor paralysis).
Diagnosis & prevention
- MRI: central pontine T2 hyperintensity sparing the periphery — classic "trident" / bat-wing sign on axial images. May lag clinically by days.
- Prevention is key: correct sodium no faster than 8–10 mmol/L in 24 hours (some say ≤8 in high-risk). Treat the underlying cause; replace potassium.
High-yield: "From low to high, the pons will die; from high to low, the brain will blow." Rapid correction of hyponatraemia → CPM. Rapid correction of hypernatraemia → cerebral oedema. Max safe Na⁺ rise ≈ 8 mmol/L/24 h.
Guillain–Barré Syndrome (GBS)
The prototype acquired PNS demyelinating disease — acute inflammatory demyelinating polyradiculoneuropathy (AIDP).
Etiology & pathophysiology
- Post-infectious, molecular mimicry: antibodies against pathogen antigens cross-react with peripheral nerve gangliosides.
- Classic triggers: Campylobacter jejuni (most common; axonal variants, anti-GM1), CMV, EBV, Mycoplasma, Zika; post-vaccination (rare).
- Macrophage-mediated stripping of myelin from peripheral nerves and roots → conduction block.
Clinical features
- Ascending, symmetric, flaccid paralysis (legs → arms).
- Areflexia / hyporeflexia — a key sign.
- Relative sensory sparing (sensory symptoms mild; weakness dominates).
- Autonomic dysfunction — arrhythmias, BP swings (a cause of death).
- Respiratory failure — monitor FVC / single-breath count; intubate before crisis.
- Miller Fisher variant: ophthalmoplegia + ataxia + areflexia, anti-GQ1b antibody.
GBS variants
| Variant | Feature | Antibody |
|---|---|---|
| AIDP | Classic demyelinating | — |
| AMAN | Acute motor axonal | anti-GM1, anti-GD1a |
| AMSAN | Motor + sensory axonal | anti-GM1 |
| Miller Fisher | Ophthalmoplegia, ataxia, areflexia | anti-GQ1b |
Diagnosis
Approach: Clinical ascending weakness + areflexia → LP → nerve conduction studies.
- CSF: albuminocytologic dissociation — raised protein with normal cell count (appears after ~1 week). Cells usually <10/µL.
- Nerve conduction studies (NCS): demyelinating pattern — prolonged distal latency, conduction block, prolonged/absent F-waves (early sign of proximal/root demyelination).
High-yield: Albuminocytologic dissociation (high CSF protein, normal cells) = GBS. If CSF shows many cells, think HIV seroconversion, Lyme, or polio — not classic GBS.
Management
- IVIG or plasma exchange — equally effective; do NOT combine.
- Steroids are NOT effective in GBS (contrast with MS and CIDP).
- Supportive: airway/ventilation monitoring (serial FVC), cardiac monitoring for autonomic instability, DVT prophylaxis.
High-yield: In GBS, steroids do not work; use IVIG or plasmapheresis. In CIDP (the chronic counterpart, >8 weeks), steroids DO work.
Acute Disseminated Encephalomyelitis (ADEM)
- Monophasic, post-infectious/post-vaccination demyelination, usually in children.
- Pathology: perivenular ("sleeve") demyelination and inflammation — multifocal but of the same age (vs MS lesions of different ages).
- Encephalopathy (altered consciousness) is required for diagnosis — distinguishes from MS first attack.
- Treatment: IV steroids; usually good recovery.
Progressive Multifocal Leukoencephalopathy (PML)
- JC polyomavirus reactivation infecting oligodendrocytes in the immunosuppressed (AIDS with CD4 <200, natalizumab, rituximab).
- Multifocal asymmetric subcortical demyelination; no mass effect, no enhancement (non-inflammatory).
- Histology: enlarged oligodendrocytes with glassy intranuclear inclusions, bizarre astrocytes.
- Diagnosis: JC virus DNA PCR in CSF; MRI subcortical white-matter lesions.
Key differentials at a glance
| Disease | Site | Signature antibody | Signature CSF/test |
|---|---|---|---|
| MS | CNS, periventricular | none | Oligoclonal bands, ↑IgG index |
| NMOSD | Optic nerve + long cord | AQP4-IgG | Often no oligoclonal bands |
| MOGAD | Optic nerve/ADEM-like | MOG-IgG | — |
| GBS | PNS roots/nerves | anti-GM1/GQ1b | Albuminocytologic dissociation |
| CPM | Central pons | none | Hx of rapid Na⁺ correction |
| PML | Subcortical CNS | none | JC virus PCR |
| ADEM | CNS, perivenular | (sometimes MOG) | monophasic, encephalopathy |
Recently asked / exam angle
- MS plaque location (periventricular, Dawson fingers) and CSF oligoclonal bands — repeatedly asked one-liners.
- "Most appropriate investigation for MS" → MRI brain with gadolinium (open-ring enhancement is a clue).
- Aquaporin-4 antibody → NMOSD/Devic disease; "longitudinally extensive transverse myelitis ≥3 segments."
- "Rapid correction of hyponatraemia → central pontine myelinolysis"; identify the trident/bat-wing pontine lesion.
- GBS: albuminocytologic dissociation, ascending paralysis with areflexia, Campylobacter jejuni trigger, steroids ineffective / IVIG–plasma exchange are management staples.
- Miller Fisher → anti-GQ1b; AMAN → anti-GM1.
- Natalizumab/ rituximab → PML (JC virus) — immunosuppression-related demyelination.
- Image-based: open-ring enhancement (MS), trident sign (CPM), Dawson fingers (MS).
- Charcot triad (SIN — Scanning speech, Intention tremor, Nystagmus) and INO as MS clinical clues.
Rapid revision
- Demyelination = myelin lost, axon (relatively) spared; oligodendrocyte = CNS, Schwann cell = PNS.
- MS = T-cell autoimmune; HLA-DR2, EBV, low vitamin D; F > M, ages 20–40.
- Dawson fingers = periventricular plaques perpendicular to ventricles along medullary veins.
- MRI is the investigation of choice in MS; open-ring enhancement = active plaque.
- Oligoclonal IgG bands in CSF but not serum = intrathecal synthesis = MS.
- MS relapse → IV methylprednisolone; natalizumab → PML (JC virus).
- AQP4-IgG → NMOSD (Devic); astrocytopathy, bilateral optic neuritis + ≥3-segment cord lesion; interferons worsen it.
- CPM from rapid hyponatraemia correction; keep Na⁺ rise ≤8 mmol/L/24 h; "trident" pontine sign; locked-in syndrome.
- GBS = ascending flaccid paralysis + areflexia, post-Campylobacter; watch FVC for respiratory failure.
- GBS CSF = albuminocytologic dissociation; treat with IVIG or plasma exchange, NOT steroids.
- Miller Fisher → anti-GQ1b; AMAN → anti-GM1; CIDP is chronic GBS and responds to steroids.
- PML = JC virus in oligodendrocytes of the immunosuppressed; diagnose by CSF JC virus PCR, non-enhancing lesions.