STEPTRACKERNERVOUS SYSTEM | PATHOLOGY + IMMUNOLOGY + PHARMACOLOGY | HIGH-YIELD REVIEW

Demyelinating Disorders

Myelin attacked by the immune system, a virus, a sodium shift or an inherited enzyme defect.

FOCUS ON
Multiple sclerosis: young women, relapsing-remitting deficits separated in time and space — optic neuritis, INO, sensory loss, weakness, bladder; periventricular plaques; CSF oligoclonal bands; steroids for attacks, disease-modifying drugs to prevent. NMO: anti-aquaporin-4. PML: JC virus in the immunosuppressed. Leukodystrophies: arylsulfatase A, galactocerebrosidase, VLCFA.
DISORDER
MECHANISM
FEATURES
CLUE · TREATMENT
Multiple sclerosis — who
Autoreactive CD4 T cells (Th1/Th17) + B cells against CNS myelin; HLA-DR2 (DRB1*15:01)
Women 20–40; higher latitudes, low vitamin D, prior EBV, smoking
Relapsing-remitting most common
MS — features
Plaques disseminated in time and space
Optic neuritis (painful monocular loss, RAPD), INO, Lhermitte sign, sensory loss, weakness, spastic bladder; cerebellar (scanning speech, intention tremor, nystagmus)
Uhthoff: worse with heat
MS — diagnosis & pathology
Demyelination with relative axonal preservation; lymphocytes, macrophages, gliosis
MRI: periventricular ("Dawson fingers"), juxtacortical, infratentorial, cord lesions · CSF: oligoclonal IgG bands, ↑ IgG index
MRI is the key test
MS — treatment
Stop relapses and slow progression
Acute: IV steroids (± plasmapheresis) · disease-modifying: interferon-β, glatiramer, natalizumab, ocrelizumab, fingolimod, dimethyl fumarate · symptoms: baclofen, oxybutynin
Natalizumab → PML risk
Neuromyelitis optica
IgG against aquaporin-4 on astrocytes (complement-mediated)
Severe bilateral optic neuritis + longitudinally extensive transverse myelitis (≥ 3 segments); area postrema → hiccups, vomiting
Some MS drugs worsen it · rituximab, eculizumab
Acute disseminated encephalomyelitis
Post-infectious or post-vaccination immune attack; perivenular demyelination
Child, days–weeks after a viral illness: encephalopathy + multifocal deficits; usually monophasic
Steroids
Progressive multifocal leukoencephalopathy
JC virus reactivation infects oligodendrocytes in immunosuppression (AIDS, natalizumab, rituximab)
Rapidly progressive multifocal deficits; nonenhancing asymmetric white-matter lesions; enlarged oligodendrocyte nuclei with inclusions, bizarre astrocytes
Often fatal · restore immunity
Osmotic demyelination syndrome
Too-rapid correction of chronic hyponatremia → oligodendrocyte injury (central pons)
Dysarthria, dysphagia, quadriparesis, locked-in state
Water balance: 15.02
Metachromatic leukodystrophy
Arylsulfatase A deficiency (AR) → sulfatide accumulates
Central and peripheral demyelination: ataxia, neuropathy, regression, dementia
Metachromatic granules
Krabbe disease
Galactocerebrosidase deficiency (AR) → galactocerebroside, psychosine
Infant: irritability, spasticity, peripheral neuropathy, optic atrophy; globoid cells
Multinucleated macrophages
Adrenoleukodystrophy
X-linked ABCD1 → very-long-chain fatty acids accumulate
Boys: behavioral decline, vision loss, spasticity + adrenal insufficiency
↑ VLCFA · Lorenzo's oil (historic)

Mechanism — multiple sclerosis

Genes + environmentHLA-DR2, EBV, ↓ vitamin D
→
Autoreactive T cells cross BBBα4 integrin
→
Macrophages + B cellsOligoclonal IgG
→
Demyelinated plaqueSlowed/blocked conduction
→
Axon lossProgressive disability

Heat further slows conduction in demyelinated axons — symptoms flare in a hot shower (Uhthoff phenomenon).

MS disease-modifying drugs

DRUG
MECHANISM
WATCH FOR
Interferon-β
Immunomodulator
Flu-like symptoms, depression
Glatiramer
Myelin basic protein decoy
Injection reactions
Natalizumab
Anti-α4 integrin (blocks entry)
PML (JC virus)
Ocrelizumab
Anti-CD20 (B cells)
Infections
Fingolimod
S1P modulator (traps lymphocytes in nodes)
Bradycardia
Dimethyl fumarate
Nrf2 pathway
Flushing, lymphopenia

How it's tested

COMMON CONFUSIONOligoclonal bands support MS but also appear in other inflammatory CNS diseases. MS needs lesions separated in time and space.
THE TRAPA patient with MS on natalizumab who develops new progressive deficits without a typical relapse pattern may have PML, not an MS flare.
YOUR APPROACHAge + time course (monophasic, relapsing, rapidly progressive) + immune status → MRI pattern → CSF or antibody (oligoclonal, AQP4, JC) → enzyme test in children.

If you see… think…

Young woman, painful vision loss, months later numb leg → multiple sclerosis
Electric shock down the spine on neck flexion → Lhermitte sign (MS)
Symptoms worse in a hot bath → Uhthoff phenomenon
Bilateral INO in a 28-year-old → MS (MLF plaques)
CSF oligoclonal bands, periventricular plaques → MS
Bilateral optic neuritis + long cord lesion, anti-AQP4 ⁺ → neuromyelitis optica
Child with encephalopathy and multifocal lesions after measles → ADEM
AIDS patient with progressive deficits, nonenhancing white-matter lesions → PML (JC virus)
Toddler with neuropathy and regression, ↓ arylsulfatase A → metachromatic leukodystrophy
Infant with globoid cells and spasticity → Krabbe disease