Last Minute Review
Pathology — Last Minute Review
Rapid Review
A last-minute review of high-yield neuropathology facts for the RITE and board exams. Tables, key associations, and must-know one-liners — designed for a quick pass the night before.
CNS Tumors
| Tumor | WHO Grade | Location | Histology / Marker | Key Fact |
|---|---|---|---|---|
| Glioblastoma (GBM) | 4 | Cerebral hemispheres (adults) | Pseudopalisading necrosis, microvascular proliferation; GFAP+; IDH-wildtype | Most common primary malignant brain tumor in adults; “butterfly” pattern crosses corpus callosum |
| Astrocytoma, IDH-mutant | 2–4 | Cerebral hemispheres (young adults) | IDH1 R132H mutation; p53 loss; ATRX loss | Better prognosis than IDH-wildtype; 2-HG oncometabolite produced |
| Oligodendroglioma | 2–3 | Frontal lobe (adults) | “Fried egg” cells, chicken-wire vasculature; 1p/19q codeletion + IDH-mutant | Calcifications on imaging; chemosensitive (PCV); seizures common |
| Ependymoma | 2–3 | 4th ventricle (children), spinal cord (adults) | Perivascular pseudorosettes, true rosettes; GFAP+ | Posterior fossa → fills 4th ventricle; ZFTA fusion in supratentorial |
| Medulloblastoma | 4 | Posterior fossa (cerebellum, children) | Homer Wright rosettes; synaptophysin+ | Most common malignant pediatric brain tumor; WNT subtype → best prognosis; SHH subtype → PTCH1 mutation (Gorlin) |
| Meningioma | 1–3 | Dura (convexity, parasagittal, sphenoid wing) | Psammoma bodies, whorls; EMA+; loss of NF2/merlin | Most common primary intracranial tumor overall; extra-axial, dural tail sign |
| Schwannoma | 1 | CN VIII (vestibular, CPA); spinal nerve roots | Verocay bodies, Antoni A (compact) & B (loose); S100+ | Bilateral vestibular schwannomas → NF2; benign, encapsulated |
| Craniopharyngioma (Adamantinomatous) | 1 | Suprasellar (children & adolescents) | Wet keratin, calcifications, cholesterol crystals; β-catenin mutation (CTNNB1) | Bimodal age (5–14, 50–74); “machinery oil” cyst fluid; hypothalamic/pituitary dysfunction |
| Craniopharyngioma (Papillary) | 1 | Suprasellar / 3rd ventricle (adults) | Well-differentiated squamous epithelium; BRAF V600E mutation | Adults only; no calcification; solid; responds to BRAF inhibitors |
| Pituitary Adenoma | 1 | Sella turcica | Monomorphic cells; specific hormone stains; no reticulin network | Most common sellar tumor; prolactinoma most common functional type; bitemporal hemianopia from optic chiasm compression |
| Hemangioblastoma | 1 | Posterior fossa (cerebellar), spinal cord | Stromal cells with lipid vacuoles, rich capillary network | Associated with VHL syndrome (chromosome 3p); may cause secondary polycythemia (EPO production) |
| PCNSL | High-grade | Periventricular white matter (deep structures) | Diffuse large B-cell lymphoma; CD20+; perivascular cuffing | Immunocompromised (HIV/EBV) or elderly immunocompetent; “ghost tumor” — shrinks with steroids; do NOT biopsy after steroids |
| DNET (Dysembryoplastic Neuroepithelial Tumor) | 1 | Temporal lobe cortex (children/young adults) | Specific glioneuronal element, floating neurons in mucin pools | Chronic epilepsy; cortical-based, bubbly/multicystic on MRI; excellent prognosis |
| Ganglioglioma | 1–3 | Temporal lobe (children/young adults) | Ganglion cells + glial cells; CD34+; BRAF V600E common | Most common tumor causing chronic epilepsy in children; cystic + mural nodule |
| Pilocytic Astrocytoma | 1 | Posterior fossa / cerebellum (children); optic pathway | Rosenthal fibers, eosinophilic granular bodies; BRAF-KIAA1549 fusion | Most common pediatric brain tumor; cystic + enhancing mural nodule; optic pathway glioma → NF1 |
| Choroid Plexus Papilloma | 1 | Lateral ventricle (children), 4th ventricle (adults) | Papillary fronds, single-layer cuboidal epithelium | Overproduction of CSF → hydrocephalus; transthyretin+ |
| Pineoblastoma | 4 | Pineal region (children) | Small round blue cells; synaptophysin+ | Trilateral retinoblastoma = bilateral retinoblastoma + pineoblastoma (RB1 loss) |
| Pineocytoma | 1 | Pineal region (adults) | Pineocytomatous rosettes; well-differentiated | Benign; Parinaud syndrome (dorsal midbrain compression) |
| Chordoma | Locally aggressive | Clivus / sacrum (midline) | Physaliphorous cells (bubbly, vacuolated); brachyury+ | Arises from notochord remnants; locally destructive; high recurrence |
| Colloid Cyst | Benign | Anterior 3rd ventricle (foramen of Monro) | Simple cuboidal/columnar epithelium; mucin-filled | Positional headaches; acute obstructive hydrocephalus → sudden death risk |
| Brain Metastases | N/A | Gray-white junction (hematogenous) | Resembles primary tumor; cytokeratin/TTF-1/etc. | Most common brain tumors overall; lung > breast > melanoma > renal > colon; melanoma & renal → hemorrhagic mets |
💎 Board Pearl
- IDH-mutant = better prognosis in gliomas — always check IDH status first
- 1p/19q codeletion is diagnostic of oligodendroglioma (must have both codeletion + IDH mutation)
- WHO 2021 classification: molecular markers trump histology for diagnosis
- Butterfly GBM: tumor crossing the corpus callosum — classic imaging finding
- MGMT promoter methylation → better temozolomide response in GBM
Neurocutaneous Syndromes (Phakomatoses)
| Syndrome | Gene | Chromosome | Inheritance | Key Features | Associated Tumors |
|---|---|---|---|---|---|
| NF1 (von Recklinghausen) | NF1 (neurofibromin) | 17q11 | AD | ≥6 café-au-lait macules, axillary freckling, Lisch nodules, bony dysplasia | Neurofibromas (plexiform), optic pathway glioma, MPNST, pheochromocytoma |
| NF2 | NF2 (merlin/schwannomin) | 22q12 | AD | Bilateral vestibular schwannomas (hallmark), cataracts, hearing loss | Schwannomas, meningiomas, ependymomas |
| Tuberous Sclerosis (TSC) | TSC1 (hamartin) / TSC2 (tuberin) | 9q34 / 16p13 | AD | Cortical tubers, ash-leaf spots, shagreen patch, facial angiofibromas, seizures, intellectual disability | Subependymal giant cell astrocytoma (SEGA), cardiac rhabdomyoma, renal angiomyolipoma |
| VHL | VHL | 3p25 | AD | Hemangioblastomas (CNS/retina), renal cysts, pheochromocytoma, secondary polycythemia | Hemangioblastomas, clear cell renal cell carcinoma, pheochromocytoma |
| Sturge-Weber | GNAQ (somatic) | 9q21 | Sporadic (not inherited) | Port-wine stain (V1), leptomeningeal angiomatosis, tram-track calcifications, seizures, glaucoma | No associated tumors; vascular malformation |
| Ataxia-Telangiectasia | ATM | 11q22 | AR | Cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, radiosensitivity, ↑ AFP | ↑ risk lymphoma & leukemia; DNA repair defect |
| Cowden Syndrome | PTEN | 10q23 | AD | Mucocutaneous lesions, macrocephaly, Lhermitte-Duclos (dysplastic gangliocytoma of cerebellum) | Breast, thyroid, endometrial carcinomas |
| Gorlin Syndrome (Basal Cell Nevus) | PTCH1 | 9q22 | AD | Multiple basal cell carcinomas, jaw keratocysts, calcified falx cerebri, skeletal anomalies | Medulloblastoma (desmoplastic/SHH subtype), basal cell carcinomas |
💎 Board Pearl
- NF1 = chromosome 17 (“17 letters in von Recklinghausen”); NF2 = chromosome 22 (“NF2 → 22”)
- Sturge-Weber is the only phakomatosis that is NOT inherited — somatic GNAQ mutation
- TSC: mTOR pathway → treated with everolimus (mTOR inhibitor) for SEGA
- Ataxia-telangiectasia: ↑ AFP + ↓ IgA + radiosensitivity = classic triad
Metabolic & Storage Diseases
| Disease | Enzyme Deficiency | Substrate Accumulated | Inheritance | Key Features |
|---|---|---|---|---|
| Tay-Sachs | Hexosaminidase A | GM2 ganglioside | AR | Cherry-red spot, startle response, progressive neurodegeneration, death by age 3–5; Ashkenazi Jewish |
| Sandhoff | Hexosaminidase A & B | GM2 ganglioside + globoside | AR | Like Tay-Sachs + visceral involvement (hepatosplenomegaly) |
| Niemann-Pick A | Sphingomyelinase (acid) | Sphingomyelin | AR | Cherry-red spot, hepatosplenomegaly, “foam cells,” fatal by age 3 |
| Niemann-Pick C | NPC1/NPC2 (cholesterol transport) | Cholesterol / sphingolipids | AR | Vertical supranuclear gaze palsy, ataxia, dystonia, dementia; juvenile/adult onset possible |
| Gaucher (Type 1) | β-Glucocerebrosidase | Glucocerebroside | AR | “Crinkled paper” macrophages, hepatosplenomegaly, bone crises; no CNS involvement in type 1; most common lysosomal storage disease |
| Gaucher (Types 2 & 3) | β-Glucocerebrosidase | Glucocerebroside | AR | Type 2: acute neuropathic, fatal in infancy; Type 3: chronic neuropathic, seizures, eye movement abnormalities |
| Fabry | α-Galactosidase A | Globotriaosylceramide (Gb3) | X-linked recessive | Painful acroparesthesias, angiokeratomas, corneal verticillata, renal failure, stroke (young male); only X-linked lipidosis |
| Krabbe | Galactocerebrosidase | Galactocerebroside / psychosine | AR | Globoid cells (multinucleated macrophages), peripheral neuropathy, severe demyelination, irritability, death by age 2 |
| Metachromatic Leukodystrophy (MLD) | Arylsulfatase A | Sulfatide | AR | Metachromatic granules (brown with cresyl violet), diffuse demyelination, peripheral neuropathy, gait disturbance |
| Hurler (MPS I) | α-L-Iduronidase | Heparan & dermatan sulfate | AR | Coarse facies, corneal clouding, hepatosplenomegaly, dysostosis multiplex, intellectual disability; most severe MPS |
| Hunter (MPS II) | Iduronate-2-sulfatase | Heparan & dermatan sulfate | X-linked recessive | Like Hurler but NO corneal clouding; only X-linked MPS |
| Pompe (GSD II) | Acid maltase (α-glucosidase) | Glycogen | AR | Cardiomegaly (infantile), proximal myopathy, respiratory failure; ERT available (alglucosidase alfa) |
| GM1 Gangliosidosis | β-Galactosidase | GM1 ganglioside | AR | Cherry-red spot, hepatosplenomegaly, coarse facies, skeletal changes; resembles Hurler + Tay-Sachs combined |
| Neuronal Ceroid Lipofuscinosis (NCL/Batten) | Various (CLN1–CLN14) | Lipofuscin (autofluorescent) | AR | Seizures, vision loss, progressive dementia; “curvilinear bodies” or “fingerprint profiles” on EM |
💎 Board Pearl
- Cherry-red spot: Tay-Sachs, Niemann-Pick A, Sandhoff, GM1 gangliosidosis — ganglion cells full of lipid except at fovea
- Fabry & Hunter = X-linked (“Fabulous Hunters are X-linked”)
- Gaucher is the most common lysosomal storage disease; GBA mutations → ↑ risk of Parkinson disease
- Pompe = only glycogen storage disease that is also a lysosomal storage disease
Leukodystrophies
| Disease | Gene / Enzyme | Inheritance | MRI Pattern | Key Feature |
|---|---|---|---|---|
| Metachromatic Leukodystrophy (MLD) | Arylsulfatase A (ARSA gene) | AR | Confluent periventricular white matter → frontal predominant; spares subcortical U-fibers early | Metachromatic granules on nerve biopsy; peripheral neuropathy + central demyelination |
| Krabbe (Globoid Cell) | Galactocerebrosidase (GALC gene) | AR | Periventricular + cerebellar white matter; thalamic hyperdensity on CT | Globoid cells; extreme irritability in infancy; CSF protein elevated; psychosine toxicity |
| X-linked Adrenoleukodystrophy (X-ALD) | ABCD1 (peroxisomal VLCFA transport) | X-linked recessive | Posterior periventricular → splenium first; enhancing leading edge of demyelination | ↑ VLCFA; boys: cerebral form; adults: adrenomyeloneuropathy (spastic paraparesis); adrenal insufficiency |
| Canavan Disease | Aspartoacylase (ASPA gene) | AR | Diffuse white matter + subcortical U-fibers involved; macrocephaly | ↑ NAA on MRS and urine; Ashkenazi Jewish; spongiform degeneration; macrocephaly |
| Alexander Disease | GFAP (gain-of-function) | AD (de novo) | Frontal predominant; periventricular rim; basal ganglia/thalamic involvement | Rosenthal fibers (GFAP aggregates); macrocephaly; seizures; frontal → posterior progression |
| Pelizaeus-Merzbacher Disease (PMD) | PLP1 (proteolipid protein 1) | X-linked recessive | Diffuse T2 hyperintensity of white matter (“tigroid” pattern); lack of myelination | Nystagmus from birth; connatal form severe; hypomyelinating leukodystrophy |
| Vanishing White Matter Disease | eIF2B subunits (EIF2B1–5) | AR | Diffuse white matter → cystic rarefaction (CSF signal replacement) | Episodic deterioration with febrile illness or minor head trauma; ovarian failure in females (ovarioleukodystrophy) |
💎 Board Pearl
- MRI pattern helps differentiate: frontal-predominant (Alexander, MLD late) vs. posterior-predominant (X-ALD) vs. diffuse + U-fibers (Canavan)
- Canavan vs. Alexander: both have macrocephaly, but Canavan = ↑ NAA, Alexander = Rosenthal fibers
- ↑ NAA on MRS = Canavan disease (nearly pathognomonic)
- X-ALD: Lorenzo’s oil does NOT reverse existing CNS damage — HSCT is the only effective treatment for cerebral form
Mitochondrial Disorders
| Syndrome | Mutation | Inheritance | Key Features |
|---|---|---|---|
| MELAS | m.3243A>G (MT-TL1, tRNA-Leu) | Maternal (mtDNA) | Stroke-like episodes (not vascular territory), seizures, lactic acidosis, short stature, ↑ lactate; ragged red fibers |
| MERRF | m.8344A>G (MT-TK, tRNA-Lys) | Maternal (mtDNA) | Myoclonus epilepsy, ataxia, ragged red fibers, lipomas; “myoclonus epilepsy with ragged red fibers” |
| LHON | m.11778G>A (most common), m.3460, m.14484 | Maternal (mtDNA) | Bilateral painless subacute vision loss (young males), centrocecal scotoma, pseudoedema of disc; no ragged red fibers |
| Kearns-Sayre | Large-scale mtDNA deletion (>1 kb) | Sporadic (de novo deletion) | Onset <20 years, progressive external ophthalmoplegia (PEO), pigmentary retinopathy, cardiac conduction block, ↑ CSF protein |
| NARP | m.8993T>G or T>C (MT-ATP6) | Maternal (mtDNA) | Neuropathy, ataxia, retinitis pigmentosa; at high heteroplasmy (>90%) → Leigh syndrome |
| Leigh Syndrome | Various (nuclear & mtDNA) | Variable (AR, X-linked, maternal) | Bilateral symmetric basal ganglia/brainstem lesions; lactic acidosis; developmental regression; most common mitochondrial disease in children |
| CPEO | mtDNA deletions or point mutations (various) | Sporadic or maternal or AD/AR (nuclear genes: POLG, TWNK) | Progressive ptosis + ophthalmoplegia; ragged red fibers on biopsy; may overlap with Kearns-Sayre |
💎 Board Pearl
- MELAS strokes do NOT respect vascular territories — key differentiator from embolic stroke
- Ragged red fibers (Gomori trichrome) = accumulation of abnormal mitochondria; present in MELAS, MERRF, KSS, CPEO but NOT LHON
- Lactic acidosis is universal in mitochondrial disorders — check serum & CSF lactate
- Kearns-Sayre triad: PEO + retinopathy + cardiac block (onset <20 years)
- Leigh syndrome MRI: bilateral symmetric T2 hyperintensity in basal ganglia and/or brainstem
Embryology & Developmental Malformations
| Timing | Process | Malformation | Key Feature |
|---|---|---|---|
| Weeks 3–4 | Primary neurulation (neural tube closure) | Anencephaly (rostral closure failure) | Absent brain/calvarium above orbits; ↑ AFP; incompatible with life |
| Weeks 3–4 | Primary neurulation | Myelomeningocele (caudal closure failure) | Spina bifida aperta; ↑ AFP; associated with Chiari II; folate prevents |
| Weeks 3–4 | Primary neurulation | Encephalocele | Brain tissue herniates through skull defect; occipital most common (Western); frontal (Southeast Asian) |
| Week 5+ | Secondary neurulation | Spinal dysraphism (occult) | Tethered cord, lipomyelomeningocele, dermal sinus; skin markers (dimple, tuft, hemangioma) |
| Weeks 5–6 | Prosencephalic development (cleavage) | Holoprosencephaly | Failed forebrain cleavage; alobar (most severe) → semilobar → lobar; SHH, ZIC2, SIX3 genes; trisomy 13 |
| Weeks 5–6 | Prosencephalic development | Septo-optic dysplasia | Absent septum pellucidum, optic nerve hypoplasia, hypothalamic-pituitary dysfunction; HESX1 gene |
| Weeks 8–16 | Neuronal migration | Lissencephaly (type 1 / classical) | Smooth brain (“agyria”); LIS1/PAFAH1B1 (Miller-Dieker, chr 17) or DCX (X-linked, males) |
| Weeks 8–16 | Neuronal migration | Lissencephaly (type 2 / cobblestone) | Overmigration through breached pial surface; Walker-Warburg, muscle-eye-brain disease; associated with congenital muscular dystrophies |
| Weeks 8–16 | Neuronal migration | Periventricular nodular heterotopia | Subependymal gray matter nodules that failed to migrate; FLNA gene (X-linked dominant, lethal in males); seizures |
| Weeks 8–16 | Neuronal migration | Subcortical band heterotopia (“double cortex”) | DCX gene (X-linked, females); band of gray matter between cortex and ventricle |
| Late fetal | Cortical organization | Polymicrogyria (PMG) | Excessive small, fused gyri; perisylvian most common; acquired (CMV infection) or genetic |
| Weeks 5–6 | Rhombencephalon development | Dandy-Walker Malformation | Hypoplastic/absent cerebellar vermis, cystic dilation of 4th ventricle, enlarged posterior fossa |
| N/A | Hindbrain/foramen magnum | Chiari I | Cerebellar tonsillar herniation ≥5 mm below foramen magnum; syringomyelia; headache with Valsalva |
| N/A | Hindbrain/neural tube | Chiari II | Cerebellar tonsillar + vermian herniation; ALWAYS with myelomeningocele; beaked tectum, small posterior fossa |
| Weeks 8–17 | Commissural development | Agenesis of Corpus Callosum | Colpocephaly (dilated occipital horns), parallel lateral ventricles, “racing car sign” on axial MRI; may be isolated or syndromic |
💎 Board Pearl
- Chiari II is ALWAYS associated with myelomeningocele — Chiari I is NOT
- Lissencephaly: LIS1 = posterior predominant, DCX = anterior predominant
- Folate supplementation prevents neural tube defects — start before conception
- Holoprosencephaly + midline facial defects + trisomy 13 = classic association
- Periventricular heterotopia (FLNA) → seizures in young females with normal intelligence
Neurogenetics
| Disease | Gene | Inheritance | Repeat / Mutation | Key Feature |
|---|---|---|---|---|
| Huntington Disease | HTT (huntingtin) | AD | CAG repeat ≥36 (chr 4p); anticipation (paternal) | Chorea, psychiatric symptoms, dementia; caudate atrophy; onset ~40s; juvenile form: rigidity + seizures (Westphal variant) |
| Friedreich Ataxia | FXN (frataxin) | AR | GAA repeat expansion (intron 1); loss of frataxin | Progressive ataxia, cardiomyopathy, diabetes, pes cavus, scoliosis; dorsal columns + spinocerebellar tracts + peripheral nerves; most common hereditary ataxia |
| SCA1 | ATXN1 | AD | CAG repeat | Cerebellar ataxia + pyramidal signs; brainstem/cerebellar atrophy |
| SCA2 | ATXN2 | AD | CAG repeat | Slow saccades (hallmark) + ataxia + neuropathy |
| SCA3 (Machado-Joseph) | ATXN3 | AD | CAG repeat | Most common SCA worldwide; bulging eyes, ataxia, dystonia, spasticity |
| SCA6 | CACNA1A | AD | CAG repeat (small expansion) | Pure cerebellar ataxia; allelic with episodic ataxia type 2 and familial hemiplegic migraine |
| SCA7 | ATXN7 | AD | CAG repeat | Ataxia + retinal degeneration (macular dystrophy) — only SCA with vision loss |
| Fragile X Syndrome | FMR1 | X-linked dominant | CGG repeat ≥200 (full mutation); premutation 55–200 | Most common inherited cause of intellectual disability; macroorchidism, long face, large ears; premutation carriers → FXTAS (tremor/ataxia in elderly males) |
| Myotonic Dystrophy Type 1 (DM1) | DMPK | AD | CTG repeat (3’ UTR); anticipation (maternal for congenital) | Distal weakness, myotonia, cataracts, cardiac conduction, frontal balding, insulin resistance; most common adult muscular dystrophy |
| Myotonic Dystrophy Type 2 (DM2) | CNBP (ZNF9) | AD | CCTG repeat (intron 1) | Proximal weakness (“PROMM”); less severe than DM1; no congenital form; myotonia less prominent |
| Duchenne Muscular Dystrophy (DMD) | DMD (dystrophin) | X-linked recessive | Frameshift/nonsense → absent dystrophin | Onset <5 yrs; pseudohypertrophy of calves, Gowers sign; CK >10,000; loss of ambulation by ~12 yrs; cardiomyopathy |
| Becker Muscular Dystrophy (BMD) | DMD (dystrophin) | X-linked recessive | In-frame deletion → reduced/truncated dystrophin | Milder than DMD; ambulation preserved into teens/adulthood; cardiomyopathy may predominate |
| Spinal Muscular Atrophy (SMA) | SMN1 (survival motor neuron) | AR | Homozygous deletion of SMN1 (5q13); SMN2 copy number modifies severity | LMN disease; Type 1 (Werdnig-Hoffmann) — floppy infant, never sits; Type 2 — sits, never walks; Type 3 (Kugelberg-Welander) — walks |
| CMT1A | PMP22 | AD | PMP22 duplication (17p12) | Demyelinating; slow NCVs (<38 m/s); pes cavus, distal atrophy, onion bulbs on biopsy; most common CMT |
| CMT1B | MPZ (P0) | AD | Point mutations | Demyelinating; similar to CMT1A but earlier onset and more severe |
| CMT2A | MFN2 (mitofusin 2) | AD | Point mutations | Axonal; normal NCVs; reduced CMAP amplitudes; most common axonal CMT |
| HNPP | PMP22 | AD | PMP22 deletion (opposite of CMT1A) | Episodic, painless, pressure-sensitive palsies; tomaculae (“sausage-shaped” myelin thickenings) on biopsy |
| Wilson Disease | ATP7B | AR | Various point mutations (chr 13) | Copper accumulation → Kayser-Fleischer rings, dystonia, parkinsonism, psychiatric, liver disease; ↓ ceruloplasmin, ↑ 24h urine copper |
| Familial ALS (SOD1) | SOD1 | AD | Point mutations (most common: A4V — aggressive) | ~2% of all ALS; posterior column involvement may occur (unlike sporadic); copper-zinc superoxide dismutase |
| Familial ALS (C9orf72) | C9orf72 | AD | GGGGCC hexanucleotide repeat expansion | Most common genetic cause of ALS and FTD; ALS-FTD spectrum; RNA foci + dipeptide repeat proteins |
💎 Board Pearl
- Trinucleotide repeat + anticipation = Huntington (CAG), DM1 (CTG), Fragile X (CGG), Friedreich (GAA), SCAs (CAG)
- CMT1A = PMP22 duplication; HNPP = PMP22 deletion — mirror disorders of the same gene
- DM1 vs DM2: DM1 = distal, DM2 = proximal; DM1 has congenital form, DM2 does not
- C9orf72 = most common genetic cause of BOTH familial ALS and familial FTD
- SMA: SMN2 copy number determines severity — nusinersen, onasemnogene, risdiplam all target SMN2
Neuropathology Buzzwords
| Finding | Diagnosis |
|---|---|
| Rosenthal fibers | Pilocytic astrocytoma; Alexander disease |
| Eosinophilic granular bodies (EGBs) | Pilocytic astrocytoma; ganglioglioma; pleomorphic xanthoastrocytoma |
| “Fried egg” cells | Oligodendroglioma (artifact of formalin fixation) |
| Chicken-wire capillary pattern | Oligodendroglioma |
| Pseudopalisading necrosis | Glioblastoma (GBM) |
| Psammoma bodies | Meningioma; papillary thyroid carcinoma; serous ovarian carcinoma |
| Whorls | Meningioma |
| Homer Wright rosettes | Medulloblastoma; neuroblastoma; pineoblastoma |
| Perivascular pseudorosettes | Ependymoma |
| True ependymal rosettes | Ependymoma (rare but specific) |
| Verocay bodies | Schwannoma |
| Antoni A (compact, palisading) & Antoni B (loose, myxoid) | Schwannoma |
| Physaliphorous cells (bubbly vacuolated cytoplasm) | Chordoma |
| Cherry-red spot (macula) | Tay-Sachs, Niemann-Pick A, Sandhoff, GM1 gangliosidosis; also central retinal artery occlusion |
| Crinkled/wrinkled paper macrophages | Gaucher disease |
| Foam cells | Niemann-Pick disease |
| Globoid cells (multinucleated macrophages) | Krabbe disease |
| Metachromatic granules (brown with cresyl violet) | Metachromatic leukodystrophy |
| Negri bodies (intracytoplasmic eosinophilic inclusions) | Rabies |
| Cowdry type A inclusions (intranuclear eosinophilic with halo) | HSV encephalitis; VZV; CMV |
| Cowdry type B inclusions (ground-glass intranuclear) | Poliomyelitis; other enteroviruses |
| Owl-eye inclusions | CMV (cytomegalovirus) |
| Lewy bodies (intracytoplasmic, eosinophilic, halo) | Parkinson disease; Lewy body dementia |
| Neurofibrillary tangles (hyperphosphorylated tau) | Alzheimer disease; CTE; PSP; other tauopathies |
| Amyloid plaques (Aβ42) | Alzheimer disease |
| Pick bodies (round, intracytoplasmic tau inclusions) | Pick disease (bvFTD variant) |
| Hirano bodies (rod-shaped, eosinophilic, actin-rich) | Alzheimer disease (hippocampus); also normal aging |
| Granulovacuolar degeneration | Alzheimer disease (hippocampal neurons) |
| Bunina bodies (small eosinophilic, intracytoplasmic) | ALS (motor neurons) |
| TDP-43 inclusions (ubiquitinated, cytoplasmic) | ALS; frontotemporal dementia (FTD-TDP) |
| Ragged red fibers (Gomori trichrome) | Mitochondrial myopathies (MELAS, MERRF, KSS) |
| Onion bulbs (Schwann cell concentric layers) | Chronic demyelinating neuropathy (CMT1A, CIDP) |
| Tomaculae (“sausage-shaped” myelin swellings) | HNPP (hereditary neuropathy with pressure palsies) |
| Zebra bodies (lamellar inclusions on EM) | Fabry disease; other storage diseases |
| Curvilinear profiles / fingerprint bodies (EM) | Neuronal ceroid lipofuscinosis (NCL/Batten) |
Clinical Pearl
If a board question describes a histological finding, match it to the diagnosis using this table. These associations are tested repeatedly. “Pseudopalisading necrosis” = GBM and “fried egg cells” = oligodendroglioma are the two most commonly tested neuropathology buzzwords.
Neurotoxicology & Nutritional Deficiencies
| Toxin / Deficiency | Key Neurological Finding |
|---|---|
| Lead (Pb) | Children: encephalopathy, cognitive decline, ↓ IQ, lead lines on gingiva, basophilic stippling; Adults: peripheral neuropathy (wrist/foot drop), abdominal colic; ↑ free erythrocyte protoporphyrin |
| Mercury (organic/methyl) | Visual field constriction, ataxia, paresthesias, cognitive decline; Minamata disease; prenatal → cerebral palsy |
| Arsenic | Painful sensorimotor axonal neuropathy, Mees lines (white transverse nail lines), GI symptoms, “rice water” diarrhea, skin changes |
| Manganese | Parkinsonism (“manganism”) — gait abnormality, dystonia, psychiatric; globus pallidus T1 hyperintensity on MRI; does NOT respond to levodopa |
| Carbon monoxide (CO) | Acute: headache, confusion, cherry-red skin; Delayed: parkinsonism, cognitive decline; globus pallidus necrosis; white matter demyelination |
| Thallium | Painful sensory neuropathy, alopecia, Mees lines; rat poison |
| Organophosphates | Cholinergic crisis (SLUDGE: salivation, lacrimation, urination, defecation, GI distress, emesis); intermediate syndrome (proximal weakness days later); delayed polyneuropathy |
| Methanol | Visual loss (retinal toxicity → optic nerve), metabolic acidosis with ↑ osmolar gap; putaminal necrosis |
| Vitamin B1 (thiamine) deficiency | Wernicke encephalopathy: confusion, ophthalmoplegia, ataxia (classic triad); mammillary body/periaqueductal hemorrhage; Korsakoff: anterograde amnesia, confabulation |
| Vitamin B6 (pyridoxine) deficiency | Peripheral neuropathy, seizures (neonates); isoniazid-induced; EXCESS B6 also causes sensory neuropathy |
| Vitamin B12 (cobalamin) deficiency | Subacute combined degeneration (dorsal columns + lateral corticospinal tracts), megaloblastic anemia, cognitive decline; ↑ methylmalonic acid, ↑ homocysteine |
| Vitamin E (α-tocopherol) deficiency | Spinocerebellar syndrome resembling Friedreich ataxia; ataxia, proprioceptive loss, areflexia; fat malabsorption, abetalipoproteinemia |
| Copper deficiency | Myelopathy mimicking B12 deficiency (subacute combined degeneration); anemia, neutropenia; zinc excess or gastric surgery causes copper depletion |
| Wernicke Encephalopathy | Thiamine deficiency; give thiamine BEFORE glucose; mammillary bodies, medial thalami, periaqueductal gray, tectal plate |
| Marchiafava-Bignami Disease | Corpus callosum demyelination/necrosis; associated with chronic alcoholism and nutritional deficiency; acute: coma/seizures; chronic: dementia, gait abnormalities |
💎 Board Pearl
- Always give thiamine BEFORE glucose in suspected Wernicke — glucose without thiamine worsens the condition
- B12 deficiency vs. copper deficiency: clinically identical myelopathy — check copper if B12 is normal
- Manganese: T1 hyperintensity in globus pallidus (not T2) — unique MRI finding
- Lead in children = encephalopathy; lead in adults = neuropathy
- Vitamin E deficiency mimics Friedreich ataxia — treatable cause, always check levels
Classic Board Traps
Board Traps — Do Not Get Fooled
- Meningioma vs. metastasis: Both are extra-axial and enhance, but meningioma has dural tail, broad dural base, and calcifications; metastasis has no dural tail and is often multiple
- Oligodendroglioma vs. astrocytoma: Both are infiltrative gliomas, but oligodendroglioma requires 1p/19q codeletion + IDH mutation — histology alone is insufficient under WHO 2021
- Pilocytic astrocytoma vs. GBM: Both can enhance, but pilocytic is grade 1 (cystic + mural nodule, children, posterior fossa) while GBM is grade 4 (ring-enhancing, necrosis, adults, hemispheric)
- PCNSL vs. GBM: Both are deep hemispheric lesions, but PCNSL → homogeneous enhancement, periventricular, responds to steroids (“ghost tumor”); GBM → ring enhancement with necrosis
- NF1 vs. NF2: NF1 = neurofibromas + optic glioma + café-au-lait spots (chromosome 17); NF2 = schwannomas + meningiomas (chromosome 22). Do NOT confuse the tumor types
- Tay-Sachs vs. Niemann-Pick A: Both have cherry-red spot, but only Niemann-Pick has hepatosplenomegaly (Tay-Sachs = NO visceral involvement)
- Canavan vs. Alexander: Both cause macrocephaly in infants with leukodystrophy, but Canavan = ↑ NAA (MRS) and Alexander = Rosenthal fibers + frontal predominance on MRI
- X-ALD MRI pattern: Posterior white matter → anterior (parieto-occipital); Alexander is the opposite (frontal → posterior)
- MELAS strokes: Do NOT follow vascular territories — if a young patient has “stroke” that crosses vascular boundaries + lactic acidosis, think MELAS, not embolic stroke
- Friedreich ataxia: AR, NOT AD — do not confuse with the SCAs which are AD; also Friedreich = GAA repeat (not CAG)
- CMT1A vs. HNPP: Both involve PMP22 on chromosome 17, but CMT1A = duplication (too much PMP22) and HNPP = deletion (too little PMP22)
- DM1 vs. DM2: DM1 = distal weakness + congenital form possible; DM2 = proximal weakness + NO congenital form
- Copper deficiency vs. B12 deficiency: Identical myelopathy (subacute combined degeneration) — if B12 is normal, check copper before diagnosing idiopathic myelopathy
- Manganese parkinsonism: T1 hyperintensity (not T2) in globus pallidus; does NOT respond to levodopa — distinguishes from idiopathic Parkinson disease
- Chiari I vs. Chiari II: Chiari I = tonsillar herniation only, NO myelomeningocele; Chiari II = ALWAYS with myelomeningocele + more extensive herniation
- Lissencephaly genetics: LIS1 (17p) = posterior-predominant smooth brain; DCX (Xq) = anterior-predominant (males) or subcortical band heterotopia (females)
- Kearns-Sayre vs. CPEO: Both have PEO, but Kearns-Sayre adds pigmentary retinopathy + cardiac conduction block + onset before age 20