Demyelinating Neuropathology
What You'll Learn
- The pathology of multiple sclerosis — active vs chronic plaques — and its fulminant variants
- Antibody-mediated demyelination (NMOSD, MOGAD) and how it differs from MS on tissue
- PML and other secondary / metabolic demyelination (osmotic demyelination, B12, Marchiafava-Bignami)
- The classic inherited leukodystrophies and their diagnostic buzzwords
The neuropathology view. Clinical diagnosis and treatment of MS/NMOSD live in the Demyelinating / Neuroimmunology notes.
- True demyelination = myelin loss with relative axonal sparing + lipid-laden macrophages. Luxol fast blue (LFB) pallor alone is only myelin loss — look for preserved axons (neurofilament/Bielschowsky) and Gitter cells.
- Active MS plaque: sheets of myelin-laden macrophages (LFB-positive debris) throughout; chronic plaque: sharply demarcated, hypocellular, gliotic, macrophages only at the rim.
- NMOSD is vasculocentric and destructive — AQP4 loss, complement/immunoglobulin deposition, granulocytes, necrosis — unlike the macrophage-driven, axon-sparing MS plaque.
- PML: enlarged oligodendrocytes with ground-glass intranuclear inclusions + bizarre reactive astrocytes; SV40 immunostain is polyoma-family — confirm JC virus by PCR/ISH.
- Osmotic demyelination (central pontine ± extrapontine) follows rapid correction of chronic hyponatremia; symmetric, sharply defined, neuron- and axon-sparing.
Multiple Sclerosis
Immune-mediated demyelinating plaques disseminated in space and time, favoring periventricular white matter, corpus callosum, optic nerves, brainstem, cerebellar peduncles and spinal cord. Gross: grey, translucent, well-demarcated plaques; “Dawson's fingers” along deep medullary veins.
Plaque stages (know the contrast)
| Plaque | Histology | Stains |
|---|
| Active | Hypercellular; sheets of foamy macrophages full of myelin debris; perivascular lymphocytes; relative axonal sparing | LFB+ debris in macrophages; CD68+; axons preserved (neurofilament) |
| Chronic active (smoldering) | Gliotic center, rim of iron-laden macrophages/microglia at the expanding edge | Rim macrophages CD68+; iron stain rim+ |
| Chronic inactive | Sharply demarcated, hypocellular, dense astrogliosis, oligodendrocyte and axon loss | LFB pale (myelin lost); GFAP+ gliosis |
| Shadow plaque | Partial remyelination — thin myelin, blurred border | LFB pale-but-present |
Fulminant & Monophasic Variants
| Variant | Pathology | Buzzword |
|---|
| Marburg | Massive, destructive demyelination with axonal loss & edema | Fulminant, often fatal |
| Baló concentric sclerosis | Alternating rings of preserved and lost myelin | “Onion-bulb / tree-ring” on MRI |
| Tumefactive demyelination | Large solitary lesion mimicking tumor; macrophages, Creutzfeldt-Peters cells (reactive astrocytes with fragmented nuclei), open ring enhancement | Don't call it glioma — look for the macrophage sheet |
| ADEM | Perivenular (“sleeves of Virchow-Robin”) demyelination & inflammation; monophasic, post-infectious/vaccinal | Perivenular vs confluent (MS) |
Antibody-Mediated (NMOSD & MOGAD)
| NMOSD (AQP4) | MOGAD (MOG) |
|---|
| Target | Astrocyte aquaporin-4 (foot processes) | Oligodendrocyte/myelin MOG |
| Pathology | Vasculocentric loss of AQP4 & GFAP; complement (C9neo) + Ig deposition; eosinophils/neutrophils; necrosis, cavitation | Perivenous confluent demyelination, relative AQP4/astrocyte preservation; less necrosis |
| Sites | Optic nerve, longitudinally extensive cord, area postrema | ADEM-like brain, optic nerve (anterior), conus |
PML & Viral Demyelination
Progressive multifocal leukoencephalopathy (JC virus): multifocal asymmetric white-matter demyelination in the immunosuppressed. Triad: enlarged oligodendrocytes with ground-glass amphophilic intranuclear inclusions, bizarre “monstrous” reactive astrocytes, and lipid-laden macrophages. IHC: SV40 (polyoma) positive — confirm JC specifically by PCR / in-situ hybridization. SubacuteSSPE and HIV encephalitis are separate viral processes.
Metabolic & Toxic Demyelination
| Entity | Pathology | Trigger / clue |
|---|
| Osmotic demyelination (CPM ± extrapontine) | Symmetric, sharply marginated central pontine demyelination sparing neurons & axons | Rapid correction of chronic hyponatremia; alcoholism, malnutrition |
| Subacute combined degeneration | Vacuolar demyelination of dorsal & lateral columns, spongy change | Vitamin B12 deficiency; also nitrous oxide |
| Marchiafava-Bignami | Demyelination/necrosis of the corpus callosum (central layers) | Chronic alcoholism |
| Toxic/hypoxic leukoencephalopathy | Diffuse white-matter injury ± necrosis | Chemo (methotrexate), radiation, CO, heroin (“chasing the dragon”) |
Inherited Leukodystrophies
| Leukodystrophy | Defect | Pathology buzzword |
|---|
| Metachromatic (MLD) | Arylsulfatase A; sulfatide accumulation | Metachromatic brown granules with toluidine blue; nerve involvement |
| Krabbe | Galactocerebrosidase | Globoid (multinucleated) macrophages around vessels |
| X-linked adrenoleukodystrophy | Peroxisomal VLCFA (ABCD1) | Parieto-occipital demyelination + adrenal insufficiency; perivascular inflammation |
| Alexander | GFAP mutation (astrocyte) | Rosenthal fibers (subpial/perivascular); frontal, megalencephaly |
| Pelizaeus-Merzbacher | PLP1 | “Tigroid” perivascular myelin islands |
| Canavan | Aspartoacylase (NAA) | Spongy vacuolar myelin; megalencephaly |
| Finding | Association |
|---|
| Macrophages stuffed with LFB+ myelin | Active MS plaque |
| Sharp, gliotic, hypocellular plaque | Chronic inactive MS |
| Perivenular “sleeves” of demyelination | ADEM |
| Vasculocentric AQP4/GFAP loss + necrosis | NMOSD |
| Ground-glass oligodendrocyte nuclei + bizarre astrocytes | PML (JC) |
| Symmetric central pontine demyelination, neurons spared | Osmotic demyelination |
| Globoid cells | Krabbe |
| Rosenthal fibers (diffuse) | Alexander disease |
References
- Love S, et al. Greenfield's Neuropathology. 9th ed. 2015.
- Lucchinetti C, et al. Heterogeneity of MS lesions. Ann Neurol. 2000.
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