Neurohistology & Glial Cells
Neurohistology & Glial Cells
What Do You Need to Know?
- Neuron structure — Nissl substance (rough ER) absent from axon hillock and axon; axon hillock = AP initiation site
- Neuron classification — unipolar, bipolar, pseudounipolar (DRG), multipolar (most CNS neurons)
- Axonal transport — anterograde (kinesin) vs retrograde (dynein); rabies, herpes, and tetanus toxin travel retrograde
- Glial cells — astrocytes (BBB, GFAP+), oligodendrocytes (CNS myelin, 1:50), Schwann cells (PNS myelin, 1:1), microglia (mesoderm-derived), ependymal cells (line ventricles)
- Myelin composition — 70% lipid / 30% protein; CNS proteins (MBP, PLP, MOG, MAG) vs PNS proteins (P0, PMP22, MBP)
- Demyelination vs dysmyelination — acquired (MS, GBS) vs hereditary leukodystrophies (MLD, Krabbe, ALD, PMD)
- Degeneration & regeneration — Wallerian degeneration, chromatolysis, PNS regenerates (1 mm/day), CNS does not (Nogo, MAG)
- Staining methods & tumors — Nissl, Luxol fast blue, GFAP, silver stains; tumors arise from specific glial cell types
🚩 Don’t Miss — Test-Day Priorities
- Axon hillock: AP initiation site — highest density of voltage-gated Na⁺ channels, lowest threshold; Nissl substance (rER) is ABSENT here and throughout the axon
- Kinesin = anterograde, Dynein = retrograde: rabies, HSV, poliovirus, and tetanus toxin exploit retrograde (dynein) transport to reach CNS/soma
- Astrocyte foot processes + AQP4: support and induce the BBB — the primary paracellular barrier is the cerebral endothelial tight junctions (with basement membrane and pericytes); astrocytic AQP4 is important for water handling and is the antibody target in NMOSD; GFAP is the astrocyte marker
- Oligodendrocyte vs Schwann ratio: one oligo myelinates many CNS internodes (1:up to 50); one Schwann cell myelinates ONE PNS internode (1:1)
- Microglia origin = mesoderm (yolk sac): the ONLY non-neuroectodermal glia; CNS resident macrophages — activated in HIV (microglial nodules + multinucleated giant cells), neurodegeneration; markers IBA1, CD68
- Rosenthal fibers: Alexander disease (GFAP mutation, frontal leukodystrophy, macrocephaly), pilocytic astrocytoma, chronic gliosis
- Chromatolysis: central Nissl loss + eccentric nucleus + swollen soma after AXONAL injury — signals attempted regeneration
- Wallerian degeneration: axon + myelin breakdown DISTAL to transection; PNS Schwann cells form BAND OF BÜNGNER to guide regen at ~1 mm/day; CNS does NOT regenerate (Nogo, MAG inhibition)
- Red (eosinophilic) neurons: earliest histologic marker of ischemic/hypoxic injury — shrunken pyknotic neurons within hours
- NfL (neurofilament light chain): serum/CSF biomarker of axonal damage — elevated in MS, ALS, AD, TBI
🔍 Buzzwords & Pathognomonic FindingsCell type / marker · Architecture / transport · Disease / inclusion
Cell type / marker
- GFAP⁺ → astrocyte (fibrous = white matter, protoplasmic = gray matter)
- MBP, PLP, MOG, MAG, OLIG2 → oligodendrocyte / CNS myelin (MOG = antibody in MOGAD)
- IBA1, CD68, CR3 → microglia (mesodermal / yolk sac origin)
- S100⁺, GAP43 (regen), P0, PMP22 → Schwann cell / PNS myelin
- Synaptophysin, chromogranin, NeuN, NSE, NCAM/CD56 → neuronal markers
- AQP4 antibody → NMOSD (targets astrocyte foot processes)
Architecture / transport
- Kinesin → anterograde axonal transport (soma → terminal; vesicles, mitochondria)
- Dynein → retrograde axonal transport (terminal → soma; NGF, viruses, toxins)
- Schmidt-Lanterman incisures → cytoplasmic clefts in PNS (Schwann) myelin
- Nodes of Ranvier → Nav clusters; paranodal Caspr/contactin/NF155, juxtaparanodal Kv1.1/1.2
- Remak bundles → unmyelinated C fibers ensheathed by ONE Schwann cell
- Band of Büngner → Schwann cell columns guiding PNS axonal regeneration
- Subventricular zone (SVZ) + subgranular zone (SGZ) → adult neurogenesis niches (SVZ → olfactory bulb; SGZ → dentate gyrus)
- Virchow-Robin (perivascular) spaces → astrocytic foot processes surrounding penetrating vessels
Disease / inclusion
- Rosenthal fibers → Alexander disease (GFAP mutation), pilocytic astrocytoma, chronic gliosis
- Gemistocytes → reactive astrocytosis / gliosis (plump eosinophilic astrocytes)
- Microglial nodules + multinucleated giant cells → HIV encephalitis
- Chromatolysis (central Nissl loss + eccentric nucleus) → axonal injury response in soma
- Red (eosinophilic) neurons → acute hypoxic-ischemic injury
- Band of Büngner → PNS Wallerian regeneration scaffold
- Schwannoma / bilateral vestibular schwannomas → NF2; neurofibroma / plexiform neurofibroma → NF1
- Negri bodies → rabies (cytoplasmic, hippocampus/Purkinje — retrograde transport entry)
Neuron Structure
Cell Body & Processes
- Nissl substance: rough ER + free polyribosomes; basophilic on staining; present in cell body and dendrites
- Nissl is absent from: axon hillock and axon → no local protein synthesis in the axon
- Axon hillock: lowest threshold for AP generation (highest density of voltage-gated Na⁺ channels)
- Dendrites: receive synaptic input; dendritic spines = sites of excitatory synapses
- Axon: single process; conducts AP away from soma; contains neurofilaments and microtubules for transport
Neuron Classification by Morphology
| Type | Processes | Location / Example |
|---|---|---|
| Unipolar | Single process | Rare in humans; invertebrate nervous systems |
| Bipolar | One axon + one dendrite | Retina, vestibular ganglion, olfactory epithelium |
| Pseudounipolar | Single process that bifurcates | Dorsal root ganglia (DRG), cranial nerve sensory ganglia |
| Multipolar | One axon + multiple dendrites | Most CNS neurons (motor neurons, pyramidal cells, Purkinje cells) |
Board Pearl
Nissl substance = rough ER; it is absent from the axon hillock and axon. Chromatolysis (dissolution of Nissl substance) occurs in the cell body after axonal injury. Pseudounipolar neurons in the DRG are often called "unipolar" on exams — they have a single process that splits into two branches.
Axonal Transport
Anterograde vs Retrograde Transport
| Feature | Anterograde | Retrograde |
|---|---|---|
| Direction | Soma → axon terminal | Axon terminal → soma |
| Motor protein | Kinesin (+ end of microtubules) | Dynein (− end of microtubules) |
| Fast rate | 200–400 mm/day | ~100–200 mm/day (approximately half the rate of fast anterograde) |
| Fast cargo | Vesicles, mitochondria, ion channels | Endosomes, lysosomes, signaling molecules |
| Slow rate | 1–5 mm/day | N/A |
| Slow cargo | Cytoskeletal proteins (neurofilaments, tubulin) | N/A |
| Clinical relevance | Colchicine and vinca alkaloids disrupt microtubule-based transport in BOTH directions (anterograde kinesin + retrograde dynein both require intact microtubules) | NGF, BDNF; exploited by rabies, herpes, poliovirus, tetanus toxin |
Board Pearl
Retrograde axonal transport pathogens: rabies (canonical), HSV (retrograde to ganglion for latency, anterograde for reactivation), tetanus toxin. Poliovirus reaches CNS primarily hematogenously; retrograde axonal transport contributory. Tetanus toxin travels retrograde to inhibitory interneurons, cleaves synaptobrevin → blocks GABA/glycine release → spastic paralysis.
Glial Cell Types
Master Comparison Table
| Glial Cell | Location | Origin | Marker | Key Functions | Pathology |
|---|---|---|---|---|---|
| Astrocytes | CNS | Neuroectoderm | GFAP (lead marker); AQP4 (NMOSD target); EAAT1 (GLAST) & EAAT2 (GLT-1) glutamate transporters; Kir4.1 (K⁺ buffering); S-100 (broader — also Schwann, melanocytes) | BBB (foot processes), glutamate uptake (EAAT2), K⁺ buffering, glycogen storage, scar formation | Reactive gliosis; astrocytoma / GBM |
| Oligodendrocytes | CNS | Neuroectoderm | Olig2 (lineage marker); MBP/PLP/MOG/MAG are myelin products (not cell-body IHC markers) | CNS myelination; 1 cell : up to 50 axon segments | MS; oligodendroglioma |
| Schwann cells | PNS | Neural crest | S-100, P0, PMP22 | Myelinating Schwann cell = 1 internode of 1 axon (1:1). Nonmyelinating Schwann cells (Remak cells) ensheath multiple unmyelinated axons in Remak bundles. Bands of Büngner. | GBS, CIDP, CMT; schwannoma |
| Microglia | CNS | Mesoderm — yolk-sac primitive macrophages (Ginhoux 2010); bone-marrow-derived monocytes can infiltrate CNS in pathology but are NOT the source of resident microglia | CD68, Iba1 | Resident macrophages; immune surveillance, phagocytosis | Activated in neurodegeneration |
| Ependymal cells | CNS (ventricles) | Neuroectoderm | S-100 | Line ventricles; ciliated (CSF flow). Choroid plexus epithelium (specialized modified ependyma) produces CSF; general ventricular ependymal cells do NOT produce CSF. | Ependymoma (4th ventricle in children) |
Astrocytes — Key Details
- Protoplasmic: gray matter; Fibrous: white matter
- BBB: foot processes wrap capillary endothelial cells; induce tight junctions
- Glutamate recycling: uptake via EAAT2 → glutamine synthetase → glutamine shuttled back to neurons
- K⁺ spatial buffering: redistribute excess extracellular K⁺ to prevent hyperexcitability
- Reactive gliosis: hypertrophy after CNS injury → glial scar (GFAP+); inhibits axonal regeneration
Microglia — Key Details
- Only glial cell NOT from neuroectoderm — yolk-sac primitive macrophage origin (mesoderm)
- Resting: ramified; Activated: amoeboid, phagocytic; release TNF-α, IL-1, IL-6
- Rod cells: elongated microglia — classic for neurosyphilis (also seen in subacute encephalitis)
- Gitter cells: lipid-laden foamy macrophages of chronic ischemia / infarct cavity
- HIV encephalitis: microglia = primary CNS reservoir for HIV; microglial nodules on pathology
Board Pearl
Microglia are the only glial cells derived from mesoderm (not neuroectoderm). All other glia (astrocytes, oligodendrocytes, ependymal cells) derive from neuroectoderm. Schwann cells derive from neural crest. Microglia are the primary CNS reservoir for HIV.
Clinical Pearl
Astrocyte dysfunction in hepatic encephalopathy: ammonia is converted to glutamine by glutamine synthetase in astrocytes → osmotic swelling → Alzheimer type II astrocytes (large, pale nuclei) on histology.
Osmotic demyelination syndrome (ODS / central pontine myelinolysis): rapid correction of chronic hyponatremia → astrocyte death precedes oligodendrocyte death (astrocytes are osmotically more vulnerable). The pattern reinforces that astrocyte–oligodendrocyte coupling underlies myelin integrity — primary astrocyte injury triggers secondary demyelination. Same principle applies to Alexander disease.
VEGF and BBB permeability: astrocyte-derived VEGF destabilizes the BBB in tumors, inflammation, and ischemia → vasogenic edema. Anti-VEGF therapy (bevacizumab) reduces edema in glioblastoma and radiation necrosis.
Myelination
Myelin Composition & Structure
- Composition: ~70% lipid, ~30% protein (highest lipid-to-protein ratio of any biological membrane)
- Lipids: cholesterol, galactocerebroside, sulfatides, phospholipids, plasmalogen
- Nodes of Ranvier: gaps between myelin sheaths; high density of Nav1.6 channels → saltatory conduction
- Juxtaparanodal K⁺ channels (Kv1.1/1.2): normally covered; exposed in demyelination → K⁺ leak → conduction failure. The paranode contains Caspr/contactin septate-like junctions (no K channels).
CNS vs PNS Myelin Proteins
| Protein | Location | Function | Clinical Significance |
|---|---|---|---|
| MBP | CNS + PNS | Compacts cytoplasmic faces | Target in EAE (animal model of MS) |
| PLP | CNS only | Most abundant CNS myelin protein | PLP1 mutation → Pelizaeus-Merzbacher disease |
| MOG | CNS only (outermost) | Structural integrity | MOG antibodies → MOGAD (optic neuritis, ADEM) |
| MAG | CNS + PNS | Axon-glia interaction; inhibits CNS regeneration | Anti-MAG neuropathy (IgM); widened myelin lamellae |
| P0 | PNS only | Most abundant PNS myelin protein | P0 mutation → CMT1B |
| PMP22 | PNS only | Myelin compaction | Duplication → CMT1A; Deletion → HNPP |
Myelination Timeline
- Begins: 2nd trimester (PNS before CNS)
- Progression: caudal → rostral, posterior → anterior; brainstem myelinated at birth, cortex incomplete
- Continues: into mid-20s (prefrontal cortex last)
- MRI: T1 brightens and T2 darkens as myelination progresses in infancy
Board Pearl
PMP22 duplication = CMT1A (most common CMT); PMP22 deletion = HNPP. PLP1 mutation = Pelizaeus-Merzbacher (X-linked). P0 = most abundant PNS myelin protein; PLP = most abundant CNS myelin protein. MOG antibodies cause MOGAD, distinct from MS and AQP4+ NMOSD.
Demyelination vs Dysmyelination
Key Distinction
- Demyelination: destruction of previously normal myelin (acquired, immune-mediated or toxic)
- Dysmyelination: defective myelin formation from the start (hereditary enzyme or structural protein deficiency)
Comparison Table
| Feature | Demyelination (Acquired) | Dysmyelination (Hereditary) |
|---|---|---|
| Mechanism | Immune attack on normal myelin | Inherited defect in myelin synthesis |
| Onset | Usually adult (MS) or acute (GBS, ADEM) | Usually childhood |
| Course | Relapsing-remitting or monophasic | Progressive, often fatal |
| CNS examples | MS, NMOSD, MOGAD, ADEM, PML | Leukodystrophies (MLD, Krabbe, ALD, PMD) |
| PNS examples | GBS, CIDP | CMT1A, CMT1B, HNPP |
| MRI | Focal, asymmetric lesions | Diffuse, symmetric white matter changes |
Leukodystrophies — High-Yield Table
| Disease | Enzyme / Defect | Substrate | Inheritance | Key Features |
|---|---|---|---|---|
| Metachromatic (MLD) | Arylsulfatase A | Sulfatides | AR | Metachromatic granules; tigroid radial demyelination on MRI; dementia, spasticity, peripheral neuropathy |
| Krabbe | Galactocerebrosidase | Psychosine (toxic) | AR | Globoid cells; irritability, spasticity, optic atrophy; rapid course |
| ALD | ABCD1 transporter | VLCFA | X-linked | Posterior → frontal WM; adrenal insufficiency; adult = AMN |
| Pelizaeus-Merzbacher | PLP1 mutation | Abnormal PLP | X-linked recessive | Diffuse hypomyelination, nystagmus from birth, X-linked recessive (PLP1); spasticity, ataxia |
| Alexander — primary astrocytopathy | GFAP mutation (GOF) | Rosenthal fibers | AD (de novo) | Classic astrocytopathy: primary astrocyte dysfunction (GFAP aggregates) drives secondary oligodendrocyte injury and demyelination. Megalencephaly, frontal predominance, seizures. Rosenthal fibers also seen in pilocytic astrocytoma + chronic reactive gliosis (around craniopharyngioma, syrinx, old lesions) — NOT specific to Alexander disease. |
| Canavan | Aspartoacylase | NAA | AR | Megalencephaly, spongiform WM; elevated urine NAA; Ashkenazi |
Hereditary Demyelinating Neuropathies
- CMT1A: PMP22 duplication; NCV uniformly slow (<38 m/s); onion bulbs on biopsy
- CMT1B: P0 (MPZ) mutation; demyelinating
- HNPP: PMP22 deletion; recurrent compressive neuropathies; tomaculae on biopsy
Clinical Pearl
Leukodystrophies show diffuse, symmetric white matter changes on MRI — unlike MS (asymmetric, periventricular). ALD starts parieto-occipital and progresses anteriorly with a leading edge of enhancement. Alexander disease is the exception — frontal predominance.
Neuronal Degeneration & Regeneration
Wallerian Degeneration
- Definition: degeneration of axon and myelin distal to the site of injury
- 0–48 hours: distal axon and myelin begin to fragment
- 3–5 days: Schwann cells proliferate; macrophages infiltrate to clear debris
- 7–10 days: degeneration complete; NCS shows absent or reduced distal responses
- Schwann cells form bands of Büngner → guide regenerating axons
Chromatolysis
- Definition: cell body reaction to axonal injury (proximal response)
- Features: cell body swelling, nucleus displaced peripherally, Nissl substance dissolution
- Purpose: metabolic shift from neurotransmitter production to repair proteins
PNS vs CNS Regeneration
| Feature | PNS | CNS |
|---|---|---|
| Capacity | Good | Very poor |
| Rate | ~1 mm/day (~1 inch/month) | Minimal / absent |
| Support | Schwann cells → bands of Büngner + neurotrophic factors | Oligodendrocytes do not support regrowth |
| Inhibitors | Minimal | Nogo-A, MAG, OMgp, glial scar (CSPGs) |
| Guidance | Intact endoneurial tubes | No equivalent structure |
Board Pearl
CNS does not regenerate because of Nogo-A (oligodendrocytes), MAG, and astrocytic glial scar. PNS regenerates at ~1 mm/day via Schwann cell bands of Büngner. Chromatolysis = cell body swelling + peripheral nucleus + Nissl dissolution. Motor end plates degenerate by 12–18 months, setting a time limit for reinnervation.
Staining Methods
Neurohistological Stains
| Stain / Marker | Target | Clinical Use |
|---|---|---|
| Nissl (cresyl violet) | Rough ER in neuronal cell bodies | Neuron identification; lost in chromatolysis |
| Luxol fast blue (LFB) | Myelin phospholipids | Demyelination (pale areas = myelin loss) |
| Silver stains (Bielschowsky) | Axons, tangles, plaques | Alzheimer pathology |
| GFAP | Astrocytes | Astrocytoma, GBM, reactive gliosis |
| CD68 | Microglia / macrophages | Inflammation, infarction |
| S-100 | Schwann cells, astrocytes, melanocytes | Schwannoma (strongly positive) |
| Synaptophysin | Presynaptic vesicles | Neuronal / neuroendocrine tumors |
| NeuN | Neuronal nuclei | Mature neurons (absent in Purkinje cells) |
| Olig2 | Oligodendrocyte lineage | Oligodendroglioma, diffuse astrocytoma |
| EMA | Epithelial membrane antigen | Meningioma, ependymoma |
Clinical Pearl
On nerve biopsy: LFB stains myelin (pale = demyelination), toluidine blue semithin sections show onion bulbs (CMT1A), EM reveals widened myelin lamellae (anti-MAG neuropathy) or tomaculae (HNPP).
Tumors by Glial Cell of Origin
Cell of Origin → Tumor Type
| Cell of Origin | Tumor | Marker | High-Yield Features |
|---|---|---|---|
| Astrocyte | Astrocytoma / GBM | GFAP+ | GBM: pseudopalisading necrosis, ring enhancement; IDH-wildtype |
| Oligodendrocyte | Oligodendroglioma | Olig2+ | Fried egg cells, chicken-wire vessels; 1p/19q co-deletion; IDH-mutant |
| Ependymal cell | Ependymoma | EMA+, GFAP+ | Perivascular pseudorosettes; 4th ventricle (children), spinal cord (adults) |
| Schwann cell | Schwannoma | S-100+ | Antoni A/B pattern, Verocay bodies; CN VIII; bilateral = NF2 |
| Arachnoid cap cell | Meningioma | EMA+, vimentin+ | Psammoma bodies; dural-based, extra-axial; NF2-associated |
| B lymphocyte (not microglia) | Primary CNS lymphoma (DLBCL, ABC subtype) | CD20+, MYD88 L265P, CD79B mutations | Primary CNS lymphoma is a B-cell lymphoma (DLBCL, ABC subtype) — CD20+, MYD88 L265P, CD79B mutations; B cells use perivascular space (angiocentric/perivascular cuffing) but do NOT arise from microglia. HIV/immunosuppression; "ghost tumor" with steroids |
Board Pearl
Oligodendroglioma = 1p/19q co-deletion + IDH-mutant; fried egg cells. GBM = pseudopalisading necrosis, IDH-wildtype. Schwannoma = S-100+, bilateral CN VIII = NF2. Primary CNS lymphoma is a B-cell lymphoma (DLBCL, ABC subtype, CD20+, MYD88 L265P, CD79B) — the angiocentric/perivascular cuffing reflects B-cell trafficking through perivascular spaces, NOT a microglial cell of origin. Always think HIV/immunosuppression.
Glymphatic System
- AQP4-mediated waste-clearance pathway along astrocytic endfeet
- CSF flow along perivascular (Virchow-Robin) spaces; exchange with interstitial fluid
- Sleep-enhanced (~60% increased flow) — major nocturnal clearance window
- Clears β-amyloid and tau; proposed role in Alzheimer disease, CTE, and other neurodegenerative disorders
Adult Neurogenesis
- SVZ (subventricular zone) → olfactory bulb via the rostral migratory stream (RMS)
- SGZ (subgranular zone of dentate gyrus) → hippocampal granule cells
- Doublecortin (DCX) marks immature migrating neurons
Synapse Types
| Type | Mechanism | Properties | Examples |
|---|---|---|---|
| Chemical | Vesicular neurotransmitter release across synaptic cleft | Unidirectional; synaptic delay (~0.5 ms); modulable; plasticity | Most CNS synapses |
| Electrical (gap junctions) | Connexin 36 in CNS; direct ionic coupling | Fast, bidirectional, no delay | Inferior olive, retina, brainstem reticular formation |
Astrocyte–Neuron Lactate Shuttle (ANLS)
- Astrocytes take up synaptic glutamate (EAAT1/EAAT2) → activates glycolysis
- Glycolysis → lactate exported to neurons via MCT1/MCT4
- Neurons import lactate via MCT2 → oxidative metabolism (TCA cycle)
- Couples synaptic activity to metabolic supply; substrate for fMRI BOLD signal
IHC / Molecular Glioma Markers
| Marker | Significance |
|---|---|
| IDH1 R132H | IDH-mutant gliomas (astrocytoma, oligodendroglioma) |
| ATRX loss | IDH-mutant astrocytoma (alternative lengthening of telomeres) |
| p53 | TP53 mutation (astrocytic lineage) |
| INI1 / SMARCB1 loss | Atypical teratoid/rhabdoid tumor (ATRT) |
| H3K27M | Diffuse midline glioma (pons, thalamus, spinal cord) |
Quick Reference
High-Yield Summary Table
| Topic | Key Fact | Board Buzzword |
|---|---|---|
| Nissl substance | Rough ER; absent from axon hillock and axon | Chromatolysis = Nissl dissolution |
| Neuron types | Pseudounipolar in DRG; multipolar = most CNS | Bipolar = retina, vestibular, olfactory |
| Axonal transport | Kinesin (anterograde) vs dynein (retrograde) | Rabies, herpes, tetanus = retrograde |
| Astrocytes | BBB, glutamate uptake, K⁺ buffering, scar | GFAP+; Alzheimer type II in hepatic encephalopathy |
| Oligodendrocytes | CNS myelin; 1 cell : up to 50 axons | Destroyed in MS |
| Schwann cells | PNS myelin; 1 cell : 1 internode | Bands of Büngner; S-100+ |
| Microglia | Mesoderm origin; CNS macrophage | CD68+; HIV reservoir |
| Myelin | 70% lipid / 30% protein | PLP = CNS; P0 = PNS most abundant |
| CMT1A | PMP22 duplication; demyelinating | Onion bulbs on biopsy |
| MLD | Arylsulfatase A; sulfatides | Metachromatic granules |
| Krabbe | Galactocerebrosidase | Globoid cells |
| ALD | ABCD1; VLCFA | X-linked; parieto-occipital → frontal |
| Wallerian degen. | Distal axon dies; NCS changes 7–10 days | Fibrillations at 2–5 weeks |
| CNS regen. failure | Nogo-A, MAG, glial scar | PNS = 1 mm/day |
| GBM | GFAP+; IDH-wildtype | Pseudopalisading necrosis |
| Oligodendroglioma | 1p/19q co-deletion + IDH-mutant | Fried egg cells, calcification |
Board Pearl
Do not confuse demyelination (acquired destruction of normal myelin) with dysmyelination (hereditary defect in myelin formation). Leukodystrophies show diffuse, symmetric white matter changes — unlike MS (focal, asymmetric, periventricular). Alexander disease (GFAP mutation, Rosenthal fibers) and Canavan disease (aspartoacylase, elevated NAA) both cause megalencephaly — distinguish by frontal MRI predominance (Alexander) vs spongiform degeneration with elevated urine NAA (Canavan).
References
- Kandel ER, Schwartz JH, Jessell TM, et al. Principles of Neural Science. 6th ed. McGraw-Hill; 2021.
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology. 12th ed. McGraw-Hill; 2023.
- Love S, Budka H, Ironside JW, Perry A. Greenfield’s Neuropathology. 9th ed. CRC Press; 2015.
- Waxman SG. Clinical Neuroanatomy. 29th ed. McGraw-Hill; 2020.
- van der Knaap MS, Bugiani M. Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol. 2017;134(3):351–382.
- Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231–1251.
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