Neuropathology Fundamentals
Neuropathology Fundamentals
What Do You Need to Know?
- Cell reactions to injury — red neurons (acute ischemia), chromatolysis (axonal injury), Wallerian degeneration (anterograde), gliosis (astrocytic scar)
- Neuropathology stains — H&E, Nissl, Luxol fast blue (myelin), Congo red (amyloid → apple-green birefringence), silver stains (tangles/plaques), GFAP (astrocytes)
- Immunohistochemical markers — synaptophysin/NeuN (neurons), CD68 (microglia), S-100 (Schwann cells), EMA (meningiomas), Ki-67 (proliferation), IDH1 R132H, ATRX, 1p/19q
- Protein aggregates — tau (AD, PSP, CBD, Pick), alpha-synuclein (PD, DLB, MSA), amyloid-beta (AD, CAA), TDP-43 (ALS, FTD), prion protein (CJD)
- Hallmark pathology findings — Lewy bodies (PD), Pick bodies (FTD), Negri bodies (rabies), Cowdry type A (HSV), Rosenthal fibers (Alexander disease), Verocay bodies (schwannoma)
- Muscle & nerve pathology buzzwords — ragged red fibers (mitochondrial), rimmed vacuoles (IBM), perifascicular atrophy (dermatomyositis), onion bulbs (CMT/CIDP)
- Selective vulnerability — hippocampal CA1, Purkinje cells, watershed zones, cortical laminar necrosis (layers 3, 5, 6)
- Patterns of CNS injury — global vs focal ischemia, hemorrhagic transformation, transtentorial herniation (PCA compression, Duret hemorrhages)
Cell Reactions to Injury
Neuronal Injury Responses
- Red neurons (eosinophilic neuronal necrosis): hallmark of acute ischemic injury (12–24 hours); shrunken cell body, pyknotic nucleus, bright eosinophilic cytoplasm on H&E
- Chromatolysis: cell body response to axonal injury; cell swelling, eccentric nucleus displaced to periphery, dissolution of Nissl substance (rough ER); represents metabolic shift toward repair proteins
- Apoptosis: programmed cell death; cell shrinkage, nuclear condensation, no inflammation; mediated by caspases; occurs in development and neurodegenerative disease
- Necrosis: cell swelling, membrane rupture, inflammatory infiltrate; occurs in ischemia, trauma, infection
- Ferrugination (mineralization): calcium and iron deposition in dead neurons; seen as basophilic encrustation on old infarcts
Board Pearl
Red neurons = acute ischemia (12–24 hours). Chromatolysis = axonal injury response (swollen cell body, peripheral nucleus, Nissl dissolution). These are the two most-tested neuronal injury patterns. Red neurons indicate irreversible injury; chromatolysis is potentially reversible if the axon regenerates.
Pathological Evolution of Infarction
| Time After Ischemia | Pathological Findings | Key Cell Types |
|---|---|---|
| 0–12 hours | No visible changes on H&E (too early) | — |
| 12–24 hours | Red neurons (eosinophilic necrosis); early neutrophil infiltration | Neutrophils (PMNs) |
| 1–3 days | Tissue edema; neutrophilic infiltration peaks; coagulation necrosis | Neutrophils |
| 3–7 days | Macrophage invasion begins; liquefactive necrosis starts; gitter cells appear | Macrophages / gitter cells |
| 1–4 weeks | Reactive gliosis at periphery; macrophages clear necrotic debris; neovascularization | Macrophages, reactive astrocytes |
| Months–years | Cystic cavity lined by glial scar (GFAP+ astrocytes); hemosiderin-laden macrophages | Astrocytes |
Wallerian vs Retrograde Degeneration
| Feature | Wallerian (Anterograde) | Retrograde |
|---|---|---|
| Definition | Degeneration distal to injury site | Degeneration proximal to injury site (toward soma) |
| Mechanism | Axon and myelin fragment distally; macrophages clear debris | Cell body undergoes chromatolysis; may progress to death |
| Timeline | 3–5 days: Schwann cell proliferation; 7–10 days: complete | Hours to days post-injury |
| NCS/EMG | Reduced/absent distal CMAP/SNAP by 7–10 days; fibrillations at 2–5 weeks | Loss of proximal function |
| PNS recovery | Schwann cells form bands of Büngner → axon regrows at ~1 mm/day | Depends on severity of cell body injury |
Glial Responses to Injury
- Reactive gliosis (astrocytic response): GFAP+ astrocytes hypertrophy and proliferate → form a glial scar; barrier to axonal regeneration in the CNS
- Alzheimer type II astrocytes: swollen, pale nuclei; seen in hepatic encephalopathy (ammonia → glutamine synthetase → osmotic swelling)
- Rosenthal fibers: eosinophilic, corkscrew-shaped inclusions in astrocytes; seen in Alexander disease and pilocytic astrocytoma
- Corpora amylacea: round, basophilic polyglucosan bodies in astrocytic processes; increase with normal aging — not pathological
Microglial Responses
- Rod cells: elongated, activated microglia aligned along damaged neurons; seen in viral encephalitis, neurosyphilis
- Gitter cells (foamy macrophages): lipid-laden macrophages that phagocytose myelin and necrotic debris; seen in infarcts, demyelination
- Microglial nodules: clusters of activated microglia; hallmark of viral encephalitis, especially HIV
- Neuronophagia: microglia surrounding and engulfing a dying neuron; classic finding in viral encephalitis (especially poliovirus)
Demyelination vs Dysmyelination
- Demyelination: destruction of previously normal myelin (acquired) — MS, GBS, CIDP, ADEM, PML
- Dysmyelination: defective myelin formation from the start (hereditary) — leukodystrophies (MLD, Krabbe, ALD, Pelizaeus-Merzbacher, Alexander, Canavan)
- Key MRI distinction: demyelination = focal, asymmetric lesions; dysmyelination = diffuse, symmetric white matter changes
Board Pearl
Gitter cells (foamy macrophages) in an infarct = subacute stage (days to weeks). Neuronophagia (microglia engulfing neurons) is the hallmark of viral encephalitis. Alzheimer type II astrocytes = hepatic encephalopathy. Rod cells = viral encephalitis or neurosyphilis.
Neuropathology Staining Techniques
Histochemical Stains
| Stain | Target | Key Features / Use |
|---|---|---|
| H&E | General tissue morphology | Standard stain; nuclei = blue (hematoxylin), cytoplasm = pink (eosin); red neurons are bright eosinophilic |
| Nissl (cresyl violet) | Rough ER in neuronal cell bodies | Identifies neurons; lost in chromatolysis; absent from axon hillock and axon |
| Luxol fast blue (LFB) | Myelin phospholipids | Myelin stains blue; pale areas = demyelination or dysmyelination |
| Silver stains (Bielschowsky, Bodian) | Axons, neurofibrillary tangles, neuritic plaques | Essential for Alzheimer pathology; tangles and plaques stain dark (argyrophilic) |
| Congo red | Amyloid | Apple-green birefringence under polarized light; diagnostic for amyloid (A-beta, AL, AA, transthyretin) |
| Thioflavin S / Thioflavin T | Amyloid (fluorescence) | Yellow-green fluorescence; more sensitive than Congo red; highlights plaques and vascular amyloid |
| PAS (Periodic acid-Schiff) | Glycogen, fungi, basement membranes | Highlights glycogen storage (Lafora bodies, polyglucosan bodies); PAS+ fungi |
| GMS (Grocott methenamine silver) | Fungi | Fungal cell walls stain black; Aspergillus, Cryptococcus, Mucor |
| Ziehl-Neelsen | Acid-fast organisms | Mycobacterium tuberculosis; acid-fast bacilli appear red |
| Modified trichrome (Gomori) | Mitochondrial abnormalities in muscle | Ragged red fibers = subsarcolemmal mitochondrial accumulation; mitochondrial myopathies |
Immunohistochemical Markers
| Marker | Target Cell / Structure | Clinical Application |
|---|---|---|
| GFAP | Astrocytes (intermediate filament) | Astrocytoma, GBM, reactive gliosis; Alexander disease (GFAP mutation) |
| Synaptophysin | Presynaptic vesicles (neurons) | Neuronal/neuroendocrine tumors; medulloblastoma, ganglioglioma |
| NeuN | Neuronal nuclei | Identifies mature neurons; absent in Purkinje cells and some neuroendocrine tumors |
| CD68 | Microglia / macrophages | Microglial activation, infarction, demyelination |
| S-100 | Schwann cells, astrocytes, melanocytes | Schwannoma (strongly +); also melanoma |
| EMA | Epithelial membrane antigen | Meningioma, ependymoma (perivascular dot-like pattern) |
| Ki-67 / MIB-1 | Proliferating cells (all phases except G0) | Proliferation index; high Ki-67 = aggressive tumor (GBM typically >10%) |
| Olig2 | Oligodendrocyte lineage | Oligodendroglioma, diffuse gliomas |
| Desmin | Muscle (intermediate filament) | Rhabdomyosarcoma; myogenic differentiation |
Molecular / Genetic Markers in Neuro-Oncology
| Marker | What It Detects | Significance |
|---|---|---|
| IDH1 R132H | Isocitrate dehydrogenase mutation | Defines diffuse gliomas (astrocytoma, oligodendroglioma); IDH-mutant = better prognosis vs IDH-wildtype (GBM) |
| ATRX | Chromatin remodeling protein | Loss of ATRX = astrocytoma (IDH-mutant); retained in oligodendroglioma |
| p53 | Tumor suppressor | Mutant p53 overexpression in astrocytoma (IDH-mutant); TP53 mutation common in GBM |
| 1p/19q codeletion | Chromosomal arms 1p and 19q | Defines oligodendroglioma (IDH-mutant + 1p/19q codeleted); better prognosis, chemo-responsive |
| MGMT methylation | O-6-methylguanine-DNA methyltransferase promoter | Methylated = silenced DNA repair → better response to temozolomide in GBM |
| INI1 / SMARCB1 | SWI/SNF chromatin remodeling | Loss of INI1 = atypical teratoid/rhabdoid tumor (AT/RT); pediatric posterior fossa |
| BRAF V600E | BRAF kinase mutation | Pleomorphic xanthoastrocytoma, ganglioglioma; some pilocytic astrocytomas have BRAF fusion |
| H3K27M | Histone H3 mutation | Diffuse midline glioma (thalamus, brainstem, spinal cord); poor prognosis; WHO grade 4 |
WHO 2021 Glioma Classification Algorithm
- Step 1: Is IDH mutated?
- If IDH-mutant + 1p/19q codeleted → Oligodendroglioma (grade 2 or 3)
- If IDH-mutant + ATRX loss + no 1p/19q codeletion → Astrocytoma (grade 2, 3, or 4)
- If IDH-wildtype + any of: TERT promoter mutation, EGFR amplification, +7/−10 → Glioblastoma (grade 4)
- Molecular markers now override histology in classification — an IDH-mutant tumor is never classified as glioblastoma
Board Pearl
Congo red with apple-green birefringence under polarized light = amyloid (the most-tested staining fact). For WHO 2021 glioma classification: IDH-mutant + 1p/19q codeletion = oligodendroglioma; IDH-mutant + ATRX loss = astrocytoma; IDH-wildtype + TERT/EGFR/+7/−10 = glioblastoma. MGMT methylation predicts temozolomide response.
Clinical Pearl
When interpreting brain biopsy: GFAP+ confirms glial lineage, but does not distinguish reactive gliosis from low-grade glioma. Ki-67 proliferation index helps — reactive gliosis is typically <1%, while gliomas show higher indices. Always correlate with IDH1, ATRX, and 1p/19q for definitive classification.
Neurodegenerative Protein Aggregates
Major Pathological Proteins
| Protein | Inclusion Type | Associated Diseases | Key Features |
|---|---|---|---|
| Tau | Neurofibrillary tangles, Pick bodies, tufted astrocytes, astrocytic plaques | AD, PSP, CBD, Pick disease, CTE | Hyperphosphorylated tau; 3R vs 4R isoforms; tauopathy classification |
| Alpha-synuclein | Lewy bodies, Lewy neurites, glial cytoplasmic inclusions (GCIs) | PD, DLB, MSA | Lewy bodies = round, eosinophilic with pale halo; GCIs in oligodendrocytes (MSA) |
| Amyloid-beta (Aβ) | Senile (neuritic) plaques, diffuse plaques, vascular deposits | AD, CAA | Derived from APP cleavage (beta + gamma secretase); Congo red+, Thioflavin S+ |
| TDP-43 | Cytoplasmic inclusions (with nuclear clearing) | ALS, FTD (most forms), LATE | Normally nuclear RNA-binding protein; mislocalized to cytoplasm; ubiquitinated |
| FUS | Basophilic inclusions | ALS (rare), FTD | RNA-binding protein; resembles TDP-43 proteinopathy; younger ALS patients |
| Prion protein (PrPSc) | Spongiform change, synaptic/perivacuolar deposits | CJD, GSS, FFI, kuru | Misfolded PrPC → PrPSc; resistant to protease digestion; no nucleic acid |
| Polyglutamine (polyQ) | Intranuclear inclusions | Huntington disease, SCAs (1, 2, 3, 6, 7), DRPLA, SBMA | CAG trinucleotide repeat expansion; anticipation (earlier onset in successive generations) |
| Ubiquitin | Tags many aggregates | Nonspecific; found in most neurodegenerative inclusions | Marks misfolded proteins for proteasomal degradation; present in Lewy bodies, tangles, TDP-43 inclusions |
Tau Isoform Classification
- 3R tau: Pick disease (Pick bodies)
- 4R tau: PSP (tufted astrocytes, globose tangles), CBD (astrocytic plaques, ballooned neurons)
- 3R + 4R tau: Alzheimer disease (neurofibrillary tangles), CTE
Braak Staging (Alzheimer Disease — NFT Progression)
| Braak Stage | NFT Location | Clinical Correlation |
|---|---|---|
| I–II (Transentorhinal) | Entorhinal cortex, transentorhinal region | Preclinical; no symptoms |
| III–IV (Limbic) | Hippocampus, amygdala, limbic structures | Mild cognitive impairment (MCI) |
| V–VI (Neocortical) | Widespread neocortical involvement | Clinical dementia |
Synucleinopathy Comparison
| Disease | Inclusion Type | Inclusion Location | Key Differentiator |
|---|---|---|---|
| Parkinson disease | Lewy bodies, Lewy neurites | Substantia nigra, brainstem → cortex | Predominantly brainstem; motor predominant |
| DLB | Cortical Lewy bodies | Cortex (especially limbic, temporal, frontal) | Cortical predominance; dementia, hallucinations, fluctuations |
| MSA | Glial cytoplasmic inclusions (GCIs) | Oligodendrocytes (striatonigral, olivopontocerebellar) | Oligodendroglial (not neuronal); cerebellar ataxia or parkinsonism |
Board Pearl
TDP-43 is the most common pathological protein in ALS and sporadic FTD. It is normally a nuclear protein that mislocalizes to the cytoplasm. Alpha-synuclein forms Lewy bodies in PD/DLB but glial cytoplasmic inclusions (GCIs) in oligodendrocytes in MSA — this distinction is frequently tested. Prion diseases are unique: no immune response, no nucleic acid, protease-resistant.
Hallmark Pathology Findings & Associated Diseases
CNS Inclusions & Findings
| Pathological Finding | Associated Disease(s) | Key Details |
|---|---|---|
| Neurofibrillary tangles | Alzheimer disease | Hyperphosphorylated tau; flame-shaped in cortical neurons; correlate with disease severity (Braak staging) |
| Senile (neuritic) plaques | Alzheimer disease | Extracellular Aβ core + dystrophic neurites + activated microglia; silver stain+, Congo red+ |
| Hirano bodies | Alzheimer disease | Eosinophilic, rod-shaped actin inclusions in hippocampal CA1 neurons |
| Granulovacuolar degeneration | Alzheimer disease | Intracytoplasmic vacuoles with dense granules; hippocampal pyramidal neurons |
| Lewy bodies | Parkinson disease, DLB | Round, eosinophilic, intracytoplasmic with pale halo; alpha-synuclein+; substantia nigra (PD), cortical (DLB) |
| Pick bodies | Pick disease (FTD) | Round, tau+ (3R), silver stain+; frontotemporal neurons; “knife-edge” frontal/temporal atrophy |
| Glial cytoplasmic inclusions (GCIs) | Multiple system atrophy (MSA) | Alpha-synuclein+ inclusions in oligodendrocytes; “Papp-Lantos bodies” |
| Bunina bodies | ALS | Small, eosinophilic, cystatin C+ inclusions in motor neurons; pathognomonic for ALS |
| Spongiform change | Prion diseases (CJD, GSS, FFI) | Vacuolation of gray matter neuropil; no inflammation; PrP immunostaining confirms |
| Negri bodies | Rabies | Eosinophilic, intracytoplasmic inclusions in Purkinje cells and hippocampal pyramidal neurons |
| Cowdry type A inclusions | HSV encephalitis, CMV, VZV | Large, eosinophilic intranuclear inclusions with peripheral clearing (“halo”); Cowdry A = herpesviruses |
| Cowdry type B inclusions | Poliomyelitis | Small, multiple intranuclear inclusions without halo |
| Owl-eye inclusions | CMV | Large intranuclear + smaller intracytoplasmic inclusions; infected cells are enlarged |
| Rosenthal fibers | Alexander disease, pilocytic astrocytoma | Eosinophilic, corkscrew-shaped; GFAP+ astrocytic inclusions; contain alpha-B-crystallin and HSP27 |
| Lafora bodies | Lafora body disease (PME) | PAS+ polyglucosan inclusions in neurons, myocardium, liver, skin; EPM2A or NHLRC1 mutations |
| Marinesco bodies | Normal aging | Eosinophilic intranuclear inclusions in substantia nigra and locus coeruleus; NOT pathological |
| Corpora amylacea | Normal aging | Round, basophilic polyglucosan bodies in subpial/periventricular astrocytes; PAS+; increase with age |
Tumor-Related Pathology Findings
| Pathological Finding | Associated Tumor | Key Details |
|---|---|---|
| Psammoma bodies | Meningioma | Laminated calcified concretions; also seen in papillary thyroid carcinoma, serous ovarian tumors |
| Verocay bodies | Schwannoma | Palisading nuclei in Antoni A areas; S-100+; bilateral CN VIII = NF2 |
| Homer Wright rosettes | Medulloblastoma, neuroblastoma | Tumor cells surround a central neuropil core (no lumen); synaptophysin+ |
| Perivascular pseudorosettes | Ependymoma | Tumor cells radiating around blood vessels with anuclear perivascular zone; GFAP+, EMA+ |
| “Fried egg” cells | Oligodendroglioma | Artifact of formalin fixation; round nuclei with perinuclear clearing; chicken-wire capillaries |
| Pseudopalisading necrosis | Glioblastoma (GBM) | Tumor cells line up around necrotic areas; ring-enhancing on MRI; IDH-wildtype |
| Flexner-Wintersteiner rosettes | Retinoblastoma | Tumor cells surround a true central lumen; differentiated photoreceptor cells |
Muscle & Nerve Pathology Findings
| Pathological Finding | Associated Disease | Key Details |
|---|---|---|
| Ragged red fibers | Mitochondrial myopathies (MELAS, MERRF) | Subsarcolemmal mitochondrial accumulation on modified Gomori trichrome; SDH+ (“ragged blue”) |
| Nemaline rods | Nemaline myopathy | Rod-shaped inclusions (Z-disc origin) on Gomori trichrome; actin, nebulin, or tropomyosin mutations |
| Central cores | Central core disease | Central zone devoid of mitochondria and oxidative enzyme activity; RYR1 mutations; MH susceptibility |
| Ring fibers | Myotonic dystrophy | Peripheral myofibrils running circumferentially around the fiber; also see sarcoplasmic masses, increased internalized nuclei |
| Rimmed vacuoles | Inclusion body myositis (IBM) | Basophilic-rimmed vacuoles + eosinophilic cytoplasmic inclusions; TDP-43+, p62+; IBM is most common acquired myopathy >50 years |
| Perifascicular atrophy | Dermatomyositis | Atrophy of muscle fibers at fascicle periphery; complement C5b-9 (MAC) on perimysial capillaries; humorally-mediated |
| Target fibers | Denervation (any cause) | Three-zone pattern on NADH stain; central pale zone, dark intermediate, normal outer; indicates reinnervation attempt |
| Torpedo bodies | Cerebellar degeneration | Fusiform swelling of Purkinje cell axons in the granular layer; seen in SCA, alcohol, aging |
| Onion bulb formations | CMT, CIDP (chronic demyelination) | Concentric Schwann cell proliferation around thinly myelinated axons; repeated demyelination-remyelination cycles |
| Sural nerve amyloid deposits | Familial amyloid polyneuropathy (FAP) | Transthyretin (TTR) amyloid; Congo red+ birefringence on sural nerve biopsy; small fiber > large fiber |
Board Pearl
The “bodies” you must know for boards: Lewy bodies (PD/DLB), Pick bodies (Pick disease/FTD), Negri bodies (rabies), Cowdry type A (HSV/CMV), Bunina bodies (ALS), Lafora bodies (PME). For tumors: psammoma bodies (meningioma), Verocay bodies (schwannoma), Homer Wright rosettes (medulloblastoma). For muscle: ragged red fibers (mitochondrial), rimmed vacuoles (IBM), perifascicular atrophy (dermatomyositis).
Clinical Pearl
Perifascicular atrophy on muscle biopsy is highly specific for dermatomyositis and may be present even when skin findings are absent (amyopathic DM). In contrast, IBM shows rimmed vacuoles + endomysial inflammation + invasion of non-necrotic fibers — and critically, does not respond to immunosuppression, unlike other inflammatory myopathies.
Patterns of CNS Injury
Selective Vulnerability
- Hippocampus (CA1 > CA3): most vulnerable to hypoxic-ischemic injury; “Sommer sector” (CA1) undergoes selective neuronal necrosis first
- Purkinje cells (cerebellum): highly susceptible to hypoxia, hyperthermia, and alcohol toxicity
- Watershed zones: border zones between vascular territories (ACA/MCA, MCA/PCA); vulnerable to global hypoperfusion
- Basal ganglia (globus pallidus): vulnerable to carbon monoxide poisoning, cyanide, hypoxia
- Deep cortical layers (3, 5, 6): most susceptible to ischemia → laminar necrosis
Global vs Focal Ischemia
| Feature | Global Ischemia | Focal Ischemia |
|---|---|---|
| Mechanism | Cardiac arrest, severe hypotension, asphyxiation | Arterial occlusion (thrombus, embolus) |
| Distribution | Bilateral, symmetric; selectively vulnerable regions | Unilateral, follows vascular territory |
| Pathology | Laminar necrosis, watershed infarcts, hippocampal CA1 loss, Purkinje cell death | Wedge-shaped infarct; cytotoxic → vasogenic edema; possible hemorrhagic transformation |
| Outcome | Persistent vegetative state, memory impairment, cortical blindness | Focal neurological deficit based on territory |
Laminar Necrosis
- Selective necrosis of cortical layers 3, 5, and 6 (large pyramidal neurons with high metabolic demand)
- Results from global hypoxic-ischemic injury
- On MRI: cortical ribbon of T1 hyperintensity (due to cortical calcification/gliosis) weeks after injury
- Layer 4 (granular layer) is relatively spared — contains smaller neurons with lower metabolic demand
Hemorrhagic vs Bland Infarction
| Feature | Bland (Anemic) Infarction | Hemorrhagic Infarction |
|---|---|---|
| Appearance | Pale, well-demarcated wedge | Petechial or confluent hemorrhage within infarcted tissue |
| Mechanism | Persistent arterial occlusion (thrombosis) | Reperfusion into damaged vasculature with leaky BBB |
| Common causes | Large-artery atherosclerosis, lacunar | Cardioembolic stroke, CVT, post-tPA/thrombectomy |
| Risk factors for conversion | — | Large infarct size, anticoagulation, hypertension, early reperfusion |
| CT appearance | Hypodense area | Hyperdensity (blood) within hypodense infarct |
Pathology of Venous Infarction
- Venous infarcts are hemorrhagic from the onset due to venous congestion and backpressure
- Often bilateral, parasagittal (superior sagittal sinus thrombosis) or temporal (transverse/sigmoid sinus)
- Do not conform to arterial vascular territories — key distinguishing feature on imaging
Transtentorial Herniation Pathology
- Uncal herniation: medial temporal lobe herniates through tentorial notch → compresses CN III (ipsilateral pupil dilation) → compresses cerebral peduncle (contralateral hemiparesis)
- Kernohan notch: contralateral cerebral peduncle compressed against opposite tentorial edge → ipsilateral hemiparesis (false localizing sign)
- PCA compression: occipital infarction from compression of PCA against tentorium
- Duret hemorrhages: secondary brainstem (pontine/midbrain) hemorrhages from stretching of perforating arteries; indicates irreversible brainstem damage
- Tonsillar herniation: cerebellar tonsils through foramen magnum → medullary compression → respiratory arrest
- Subfalcine herniation: cingulate gyrus under falx cerebri → ACA compression → contralateral leg weakness; can lead to secondary hydrocephalus
- Upward (transtentorial) herniation: posterior fossa mass pushes cerebellum upward through tentorial notch → aqueduct compression → acute hydrocephalus
Herniation Pathology Summary
| Herniation Type | Structure Displaced | Key Complication |
|---|---|---|
| Uncal (transtentorial) | Medial temporal lobe | CN III palsy → PCA infarct → Duret hemorrhages |
| Subfalcine | Cingulate gyrus | ACA compression; contralateral leg weakness |
| Tonsillar | Cerebellar tonsils | Medullary compression → cardiorespiratory arrest |
| Upward (ascending) | Superior cerebellum | Aqueduct compression → obstructive hydrocephalus |
Board Pearl
Selective vulnerability hierarchy: hippocampal CA1 (Sommer sector) > Purkinje cells > cortical layers 3, 5, 6 > watershed zones. Kernohan notch = false localizing sign (ipsilateral hemiparesis from contralateral peduncle compression). Duret hemorrhages in the brainstem = irreversible; indicate downward herniation has occurred.
Clinical Pearl
After cardiac arrest with return of circulation, the pattern of MRI injury reflects selective vulnerability: DWI restriction in hippocampi, cortex (especially parieto-occipital), basal ganglia, and cerebellum. If the patient survives, hippocampal damage manifests as anterograde amnesia, and cortical injury may produce cortical blindness, myoclonus (Lance-Adams syndrome), or persistent vegetative state.
Quick Reference Summary Table
Neuropathology High-Yield Facts
| Topic | Key Fact | Board Buzzword |
|---|---|---|
| Red neurons | Acute ischemia (12–24 hrs); eosinophilic, shrunken | H&E: bright pink, pyknotic nucleus |
| Chromatolysis | Axonal injury response; swollen soma, eccentric nucleus | Nissl substance dissolution |
| Congo red | Amyloid stain | Apple-green birefringence (polarized light) |
| Luxol fast blue | Myelin stain | Pale areas = demyelination |
| Silver stains | Axons, tangles, plaques | Bielschowsky for Alzheimer pathology |
| Tau | AD, PSP, CBD, Pick, CTE | 3R = Pick; 4R = PSP/CBD; 3R+4R = AD |
| Alpha-synuclein | PD (Lewy bodies), MSA (GCIs) | Lewy body = pale halo; GCI = oligodendrocytes |
| TDP-43 | ALS, FTD | Nuclear → cytoplasmic mislocalization |
| Amyloid-beta | AD plaques, CAA | APP → beta + gamma secretase cleavage |
| Prion | CJD, GSS, FFI | Spongiform change; no immune response |
| Negri bodies | Rabies | Purkinje cells, hippocampus |
| Cowdry type A | HSV, CMV, VZV | Intranuclear + halo |
| Rosenthal fibers | Alexander disease, pilocytic astrocytoma | GFAP mutation (Alexander) |
| Lafora bodies | Lafora body disease (PME) | PAS+ polyglucosan; skin biopsy diagnostic |
| Ragged red fibers | Mitochondrial myopathy | Gomori trichrome; subsarcolemmal mitochondria |
| Rimmed vacuoles | IBM | Most common acquired myopathy >50 yrs |
| Perifascicular atrophy | Dermatomyositis | Complement on capillaries (humoral) |
| Onion bulbs | CMT, CIDP | Concentric Schwann cell layers |
| Selective vulnerability | CA1 > Purkinje > layers 3/5/6 > watershed | Global ischemia pattern |
| Duret hemorrhages | Transtentorial herniation | Brainstem (pontine); irreversible |
| Kernohan notch | Contralateral peduncle compression | False localizing sign (ipsilateral hemiparesis) |
| IDH1 R132H | Diffuse gliomas (astrocytoma, oligo) | IDH-mutant = better prognosis |
| 1p/19q codeletion | Oligodendroglioma | Chemo-responsive; better prognosis |
| MGMT methylation | GBM | Predicts temozolomide response |
| Braak staging | NFT spread: entorhinal → limbic → neocortex | Correlates with clinical severity |
| Verocay bodies | Schwannoma (Antoni A palisading) | S-100+; bilateral CN VIII = NF2 |
| Psammoma bodies | Meningioma | Laminated calcified concretions |
| Homer Wright rosettes | Medulloblastoma, neuroblastoma | Cells around neuropil core (no lumen) |
| Fried egg cells | Oligodendroglioma | 1p/19q codeletion + IDH-mutant |
| Pseudopalisading necrosis | GBM | IDH-wildtype; ring-enhancing on MRI |
| Owl-eye inclusions | CMV | Intranuclear + intracytoplasmic |
| Central cores | Central core disease | RYR1 mutation; MH susceptibility |
| Target fibers | Denervation | Three-zone pattern on NADH stain |
References
- Love S, Budka H, Ironside JW, Perry A. Greenfield’s Neuropathology. 9th ed. CRC Press; 2015.
- Prayson RA. Neuropathology. 2nd ed. Elsevier; 2012.
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- Ellison D, Love S, Chimelli L, et al. Neuropathology: A Reference Text of CNS Pathology. 3rd ed. Mosby; 2012.
- 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.
- Dickson DW, Weller RO. Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. 2nd ed. Wiley-Blackwell; 2011.
- Dubowitz V, Sewry CA, Oldfors A. Muscle Biopsy: A Practical Approach. 5th ed. Elsevier; 2020.
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology. 12th ed. McGraw-Hill; 2023.