Demyelinating Disorders
Medicine · Neurology · lean revision notes
Demyelinating Disorders
Demyelinating disorders are conditions in which the myelin sheath of central (CNS) or peripheral (PNS) nerves is destroyed while the axon is relatively spared, slowing or blocking saltatory conduction. For NEET PG the two superstar topics are multiple sclerosis (MS) — the prototype CNS demyelinating disease — and Guillain–Barré syndrome (GBS) — the prototype acquired PNS demyelinating disease. This note builds both side by side, then sweeps the high-yield differentials (NMOSD, ADEM, CIDP, central pontine myelinolysis).
Classification
Demyelination is broadly split by site (central vs peripheral) and by mechanism (primary inflammatory/autoimmune vs secondary toxic-metabolic).
| Category | CNS examples | PNS examples |
|---|---|---|
| Primary autoimmune/inflammatory | Multiple sclerosis, NMOSD, MOGAD, ADEM | GBS (AIDP), CIDP |
| Infection-related | Progressive multifocal leukoencephalopathy (JC virus), SSPE | Diphtheritic neuropathy |
| Toxic/metabolic | Central pontine myelinolysis, Marchiafava–Bignami, B12 deficiency (SACD) | — |
| Hereditary (dysmyelinating) | Leukodystrophies (metachromatic, Krabbe, adrenoleukodystrophy) | Charcot–Marie–Tooth type 1 |
High-yield: "Demyelinating" = myelin destroyed but axon initially preserved. "Dysmyelinating" (leukodystrophies) = abnormal myelin is formed in the first place. This wording distinction is examinable.
Multiple Sclerosis (MS)
Epidemiology & aetiopathogenesis
MS is a chronic immune-mediated disease causing multifocal CNS demyelination disseminated in space and time. Classic patient: a woman aged 20–40 living far from the equator (latitude gradient). Risk factors converge on a T-cell–mediated attack on oligodendrocyte myelin:
- Genetic: strongest association is HLA-DR2 (HLA-DRB1*15:01).
- Environmental: low vitamin D / low sunlight, smoking, obesity in adolescence, and Epstein–Barr virus infection (now considered a near-necessary trigger).
- Molecular mimicry by autoreactive CD4⁺ Th1/Th17 cells crossing the blood–brain barrier → plaque formation in periventricular white matter, optic nerves, brainstem, cerebellum and spinal cord.
Plaques evolve from acute (perivascular inflammation, oedema) to chronic (gliotic, hypocellular scars — hence sclerosis). Grey-matter and axonal loss drive the later progressive, irreversible disability.
Clinical course patterns
| Pattern | Description | Frequency |
|---|---|---|
| Relapsing–remitting (RRMS) | Discrete attacks with full/partial recovery; stable between | ~85% at onset (commonest) |
| Secondary progressive (SPMS) | Begins as RRMS, later steady decline | Many RRMS evolve here |
| Primary progressive (PPMS) | Steady decline from onset, no relapses; older men, spinal cord | ~10–15% |
| Progressive–relapsing | Progressive from onset with superimposed relapses | Rare |
Clinical features
A typical relapse develops over hours to days, plateaus, and resolves over weeks.
- Optic neuritis — the commonest presenting feature. Painful monocular vision loss (pain on eye movement), a relative afferent pupillary defect (Marcus Gunn pupil), central scotoma, red-colour desaturation. Fundus often normal acutely ("the patient sees nothing and the doctor sees nothing").
- Internuclear ophthalmoplegia (INO) — lesion of the medial longitudinal fasciculus; failure of ipsilateral eye adduction + nystagmus of the abducting eye. Bilateral INO in a young woman is MS until proven otherwise.
- Sensory: paraesthesiae, the Lhermitte sign (electric-shock sensation down the spine/limbs on neck flexion).
- Motor/cerebellar: spastic paraparesis, the Charcot neurologic triad = nystagmus + intention tremor + scanning (staccato) speech.
- Uhthoff phenomenon: transient worsening of symptoms with a rise in body temperature (hot bath, exercise, fever).
- Autonomic: neurogenic bladder, constipation, sexual dysfunction; fatigue is very common.
High-yield: Optic neuritis + INO + Lhermitte + Uhthoff are the four classic MS "named" clinical clues. Marcus Gunn pupil = afferent defect of optic neuritis.
Mnemonic — MS deficits "VITAMIN-ish": Visual (optic neuritis), INO, Tremor (cerebellar), Ataxia/Autonomic, Motor (spastic), Incontinence, Numbness (Lhermitte).
Diagnosis — the McDonald criteria
Diagnosis requires demonstrating lesions disseminated in space (DIS) and disseminated in time (DIT), while reasonably excluding alternatives. The current (2017 revision) McDonald criteria allow earlier diagnosis using MRI and CSF.
- DIS = ≥1 T2 lesion in ≥2 of 4 typical CNS sites: periventricular, cortical/juxtacortical, infratentorial, spinal cord.
- DIT = simultaneous presence of gadolinium-enhancing (active) + non-enhancing (old) lesions on a single scan, OR a new T2/enhancing lesion on follow-up MRI.
- Key 2017 update: presence of CSF-specific oligoclonal bands can substitute for demonstrating DIT in a patient with a typical clinical attack and DIS.
A first clinical episode suggestive of MS but not yet meeting full criteria is a clinically isolated syndrome (CIS).
Investigation of choice
- MRI brain and spine with gadolinium = investigation of choice. Look for:
- Dawson's fingers — ovoid periventricular plaques oriented perpendicular to the ventricles/callosocallosal axis (along deep medullary veins).
- Periventricular, juxtacortical, infratentorial and cord lesions; open-ring (incomplete-ring) enhancement of active plaques.
- CSF: oligoclonal bands (OCBs) present in CSF but not in serum (intrathecal IgG synthesis) — found in ~85–95%; raised IgG index. Cell count is normal or mild lymphocytosis (<50).
- Visual evoked potentials (VEP): delayed latency with preserved amplitude — evidence of past (clinically silent) optic nerve demyelination, useful for DIS.
High-yield: Dawson's fingers (MRI) and CSF oligoclonal bands are the two most-tested investigative buzzwords for MS. OCBs reflect intrathecal antibody synthesis, so they must be absent in matched serum to count.
Management
Approach: Treat the acute relapse → start a disease-modifying therapy (DMT) → manage symptoms.
- Acute relapse → IV methylprednisolone (high dose, e.g. 1 g/day for 3–5 days). Steroids speed recovery but do not change long-term disability. Plasma exchange for steroid-refractory severe relapses.
- Disease-modifying therapy (RRMS):
- First-line/platform: interferon-β, glatiramer acetate, teriflunomide, dimethyl fumarate.
- Higher-efficacy: monoclonal antibodies — natalizumab (anti-α4-integrin; risk of PML with JC-virus positivity), ocrelizumab/rituximab (anti-CD20; ocrelizumab is the only drug approved for PPMS), alemtuzumab; and fingolimod (S1P-receptor modulator, first oral DMT — watch first-dose bradycardia).
- Symptomatic: baclofen/tizanidine for spasticity, gabapentin/pregabalin or carbamazepine for neuropathic pain/Lhermitte, oxybutynin for bladder, amantadine/modafinil for fatigue, dalfampridine (4-aminopyridine, a K⁺-channel blocker) to improve walking.
High-yield: Natalizumab → progressive multifocal leukoencephalopathy (PML) in JC-virus-seropositive patients. Check JC-virus serology before/during use. Ocrelizumab is the landmark approval for primary progressive MS.
Complications & prognosis
Progressive disability (measured by the EDSS — Expanded Disability Status Scale), neurogenic bladder with recurrent UTIs, mobility loss, depression, cognitive decline. Better prognosis: female, young onset, optic neuritis/sensory presentation, RRMS, complete recovery from first attack. Worse: male, older onset, motor/cerebellar/brainstem onset, high early lesion load, PPMS.
Guillain–Barré Syndrome (GBS)
Definition & pathophysiology
GBS is an acute, immune-mediated polyradiculoneuropathy — the commonest cause of acute flaccid paralysis worldwide since polio control. It typically follows an infection by 1–3 weeks, the classic antecedent being Campylobacter jejuni gastroenteritis (also CMV, EBV, Mycoplasma, Zika, and historically certain vaccines). Molecular mimicry between microbial lipo-oligosaccharide and nerve gangliosides triggers an autoimmune attack.
| Variant | Target/feature | Antibody |
|---|---|---|
| AIDP (acute inflammatory demyelinating polyradiculoneuropathy) | Commonest in West; demyelinating | — |
| AMAN (acute motor axonal neuropathy) | Axonal, pure motor; common in Asia, post-Campylobacter | anti-GM1 / GD1a |
| AMSAN | Axonal, motor + sensory; more severe | anti-GM1/GD1a |
| Miller–Fisher syndrome | Triad: ophthalmoplegia + ataxia + areflexia | anti-GQ1b (>90%) |
Clinical features
- Ascending, symmetric, flaccid weakness beginning in the legs and progressing upward (Landry's ascending paralysis).
- Areflexia / hyposeflexia — a hallmark.
- Relatively spared/minor sensory symptoms (paraesthesiae) despite often severe weakness; back/limb pain common.
- Cranial nerve involvement: bilateral facial palsy, bulbar weakness.
- Autonomic dysfunction: arrhythmias, labile BP, ileus — a leading cause of death.
- Respiratory failure from diaphragmatic/intercostal weakness — the most feared complication; ~25–30% need ventilation.
- Nadir is reached by ≤4 weeks (distinguishes from CIDP, which progresses >8 weeks).
High-yield: GBS classically presents as ascending symmetrical weakness with areflexia and minimal sensory loss after a diarrhoeal/respiratory illness. Campylobacter jejuni is the commonest trigger and is linked to the axonal (AMAN) variant.
Diagnosis & investigation
- CSF — albuminocytological dissociation: raised protein with normal/near-normal cell count (<10 cells/µL). This is the classic finding but may be normal in the first week (protein rises after ~1 week).
- Nerve conduction studies (NCS) = investigation of choice for subtyping: demyelinating pattern (prolonged distal latencies, conduction block, slowed velocities, prolonged/absent F-waves) in AIDP vs reduced CMAP amplitudes in axonal variants.
- Spirometry / serial vital capacity is the key bedside monitor — not the diagnostic test, but the one that decides ICU/ventilation.
- Antiganglioside antibodies (GM1, GQ1b) support specific variants.
High-yield: Albuminocytological dissociation (↑protein, normal cells) in CSF is the signature of GBS. A high cell count should make you reconsider (e.g. HIV, leptomeningeal/infective causes).
Management
Approach: Admit & monitor respiration/autonomics → immunotherapy → supportive care.
- Monitor: serial forced vital capacity (FVC); intubate if FVC falls (rule of thumb ~20/30/40: VC <20 mL/kg, etc.), bulbar failure, or autonomic instability. Cardiac monitoring for arrhythmias; DVT prophylaxis.
- Immunotherapy — IVIG or plasmapheresis (equally effective):
- IVIG 0.4 g/kg/day × 5 days — usually preferred (easier, fewer line/haemodynamic issues).
- Plasma exchange (plasmapheresis) — equally efficacious first-line.
- Do NOT combine the two (no added benefit). Steroids are NOT effective in GBS — a favourite exam trap (contrast with MS, where steroids treat relapses).
- Pain control, physiotherapy, nutrition, psychological support.
High-yield: IVIG and plasmapheresis are equivalent and first-line; corticosteroids are ineffective in GBS. Combining IVIG + plasma exchange gives no extra benefit. Most patients recover well, but ~3–7% die (autonomic/respiratory).
Key differentials
| Feature | Multiple sclerosis | NMOSD (Devic) | GBS | CIDP |
|---|---|---|---|---|
| Site | CNS | Optic nerve + cord (longitudinal) | PNS (acute) | PNS (chronic) |
| Time course | Relapsing/progressive | Relapsing, often severe | Nadir ≤4 wk | Progresses >8 wk |
| Hallmark antibody | none (OCB+) | anti-AQP4 (aquaporin-4) / anti-MOG | anti-GM1/GQ1b | — |
| Optic neuritis | Unilateral, mild | Bilateral, severe | — | — |
| Cord MRI | Short segment | Longitudinally extensive (≥3 segments) | — | — |
| Steroid response | Yes (relapse) | Yes; also rituximab/eculizumab | No | Yes (responsive) |
- NMOSD (neuromyelitis optica / Devic disease): anti-aquaporin-4 antibody, longitudinally extensive transverse myelitis + severe bilateral optic neuritis. Crucial: interferon-β and other MS DMTs can worsen NMOSD — so distinguishing it from MS changes treatment.
- ADEM (acute disseminated encephalomyelitis): monophasic, post-infectious/post-vaccinial demyelination in children, with encephalopathy (altered mentation) — distinguishes it from MS.
- CIDP: the "chronic GBS" — demyelinating polyneuropathy progressing over >8 weeks, responds to steroids (unlike GBS).
- Central pontine myelinolysis (osmotic demyelination): from overly rapid correction of hyponatraemia; flaccid → spastic quadriparesis, locked-in syndrome; correct Na⁺ ≤8–10 mmol/L per 24 h to prevent it.
High-yield: Three antibody one-liners — MS = oligoclonal bands, NMOSD = anti-AQP4, Miller–Fisher = anti-GQ1b, AMAN = anti-GM1.
Recently asked / exam angle
- MRI buzzwords: "ovoid periventricular lesions perpendicular to ventricles" → Dawson's fingers (MS); "longitudinally extensive cord lesion ≥3 vertebral segments + bilateral optic neuritis" → NMOSD.
- CSF distinction (very high yield): oligoclonal bands → MS; albuminocytological dissociation → GBS.
- Drug-toxicity link: natalizumab → PML (JC virus); clinical-vignette favourite.
- Treatment traps: steroids treat MS relapses but are useless in GBS; interferon-β can worsen NMOSD; ocrelizumab is the answer for PPMS.
- Clinical-sign questions: painful monocular vision loss with RAPD → optic neuritis; bilateral INO in a young woman → MS; electric shock on neck flexion → Lhermitte; symptoms worsening in a hot bath → Uhthoff.
- GBS subtype matching: Campylobacter + axonal + anti-GM1 → AMAN; ophthalmoplegia + ataxia + areflexia → Miller–Fisher (anti-GQ1b).
- First step in GBS: monitor vital capacity / respiratory function, not start steroids.
- Osmotic demyelination: "rapid correction of hyponatraemia → quadriparesis" → central pontine myelinolysis.
Rapid revision
- MS = CNS demyelination disseminated in space and time; young woman, high latitude, HLA-DR2, EBV-linked.
- Optic neuritis (painful monocular loss + Marcus Gunn pupil) is the commonest MS presentation; bilateral INO is highly suggestive.
- Lhermitte = shock on neck flexion; Uhthoff = worsening with heat; Charcot triad = nystagmus + intention tremor + scanning speech.
- MRI is the investigation of choice in MS — Dawson's fingers; CSF shows oligoclonal bands (absent in serum).
- McDonald criteria require DIS + DIT; 2017 update lets OCBs substitute for DIT.
- MS relapse → IV methylprednisolone; RRMS DMTs include interferon-β, glatiramer, natalizumab, ocrelizumab; ocrelizumab is the only PPMS drug.
- Natalizumab → PML in JC-virus-positive patients.
- GBS = acute ascending flaccid paralysis with areflexia, minimal sensory loss, after Campylobacter infection.
- GBS CSF = albuminocytological dissociation (↑protein, normal cells); NCS confirms/subtypes.
- GBS treatment = IVIG OR plasmapheresis (equal, never combined); steroids do NOT work. Monitor vital capacity; respiratory/autonomic failure kills.
- NMOSD = anti-AQP4, longitudinally extensive myelitis + bilateral optic neuritis; avoid interferon-β (worsens it).
- ADEM = monophasic, post-infectious, encephalopathy in children; central pontine myelinolysis = too-rapid hyponatraemia correction.