Pathology of Demyelinating Diseases: MS, NMO, ADEM, CPM

--- IX: DEMYELINATING DISEASES Definition Acquired conditions with preferential myelin damage, relative axonal preservation . Deficits arise from impaired electrical impulse transmission. CNS has limited remyelination capacity; axonal damage accumulates over time. --- Multiple Sclerosis (MS) Most common demyelinating disorder — prevalence ~1/1000. Onset usually 20–40s; women 2× more affected. Pathogenesis Autoimmune — Th1/Th17 cells react against myelin antigens Th1 → IFN-γ → macrophage activation; Th17 → leukocyte recruitment → demyelination Infiltrate: CD4+ CD8+ T cells + macrophages Oligoclonal IgG bands in CSF → B-cell involvement Genetic : 15× risk if 1st-degree relative affected; 150× if monozygotic twin; strong HLA-DR association; IL-2R/IL-7R gene associations Environmental : Higher prevalence away from equator (low vitamin D); EBV implicated but unconfirmed Morphology Gross : Firm, gray-tan, glassy "plaques" — well-circumscribed, depressed lesions in white matter Location : Periventricular (most common), corpus callosum, optic nerves/chiasm, brainstem, cerebellum, spinal cord Active plaque : Foamy macrophages (myelin debris), perivascular lymphocytes, myelin absent, axons preserved Inactive plaque : No inflammation, gliosis prominent, oligodendrocytes ↓, axons greatly reduced Shadow plaques : Thinned myelin = partial remyelination by surviving oligodendrocytes Clinical Features Relapsing-remitting episodes (weeks–years), partial recovery, eventual progression Optic neuritis — unilateral visual loss; common 1st presentation Brainstem : Cranial nerve signs, ataxia, nystagmus, internuclear ophthalmoplegia (MLF interruption) Spinal cord : Motor/sensory deficits, spasticity, bladder dysfunction CSF: Mild ↑ protein, pleocytosis (1/3), ↑ IgG, oligoclonal bands MRI: Plaques may be clinically silent Rx : Immunosuppressive/immunomodulatory agents (disease modifying, not curative) --- Neuromyelitis Optica (NMO / Devic Disease) Bilateral optic neuritis + spinal cord demyelination (synchronous or near-synchronous) Distinct from MS — greater female skew, poorer recovery from first attack Pathognomonic : Anti-aquaporin-4 (AQP4) antibodies — AQP4 is the major astrocyte water channel Histology: Necrosis, neutrophils + eosinophils, vascular Ig/complement deposition Rx acute : Glucocorticoids or plasma exchange; long-term: B-cell depletion or anti-C5 complement inhibitors --- Acute Disseminated Encephalomyelitis (ADEM) Diffuse, monophasic demyelinating disease post-viral infection or vaccination (1–2 weeks later) All lesions same age (cf. MS — different ages) Symptoms: Headache, lethargy, coma (not focal like MS) Mortality ~20%; survivors usually recover fully Mechanism : Likely autoimmune reaction to myelin (analogous to experimental allergic encephalomyelitis) Acute Necrotizing Hemorrhagic Encephalomyelitis (Weston Hurst Disease) Hyperacute variant of ADEM — follows URTI More severe tissue damage; often fatal; significant deficits in survivors --- Central Pontine Myelinolysis (Osmotic Demyelination Syndrome) Acute myelin loss in base of pons (± extra-pontine), symmetric pattern Cause : Rapid correction of hyponatremia (2–6 days after correction) → rapid ↑ osmolality → oligodendrocyte injury Histology: No inflammation; neurons/axons preserved; all lesions same stage (synchronous onset) Spared : Periventricular and subpial regions; never below pontomedullary junction Clinical: Quadriplegia → "locked-in" syndrome (conscious but unresponsive) Key rule : Correct hyponatremia slowly to prevent this --- --- X: GENETIC / METABOLIC DISEASES Vitamin Deficiencies Thiamine (B1) Deficiency — Wernicke-Korsakoff Syndrome Feature Wernicke Encephalopathy Korsakoff Syndrome --- --- --- Nature Acute Chronic, largely irreversible Symptoms Psychosis + ophthalmoplegia Short-term memory loss + confabulation Response to thiamine Reversible Poor Cause : Chronic alcoholism (most common), gastric carcinoma, persistent vomiting, chronic gastritis Morphology : Hemorrhage + necrosis in mammillary bodies and walls of 3rd/4th ventricles → dilated capillaries → leakage → hemosiderin-laden macrophages → cystic space Dorsomedial thalamic nucleus lesions correlate best with memory disturbance Vitamin B12 Deficiency — Subacute Combined Degeneration of Spinal Cord Degeneration of ascending AND descending tracts (posterior columns + lateral corticospinal tracts) Mechanism : Defect in myelin formation (exact mechanism unknown) Progression : Bilateral numbness/tingling + ataxia (lower limbs) → spastic weakness → complete paraplegia (late) Mid-thoracic cord preferentially affected first Histology : Myelin layer swelling → vacuoles → axonal degeneration Rx : Prompt B12 replacement → improvement; if complete paraplegia → poor recovery --- Metabolic Disturbances Hypoglycemia Brain effects resemble hypoxia (same energy substrates) Vulnerable regions: Large cortical pyramidal neurons (layers III/V) → pseudolaminar cortical necrosis (deep layers); CA1 (Sommer sec