Neuropathology

Gross image showing changes of a stroke. (WC/Marvin 101)

This article is an introduction to neuropathology. There are separate articles for brain tumours, the pituitary gland, the spine, the eye, muscle pathologies, neurohistology and neuroanatomy.

Neuropathology is the bane of many anatomical pathologists in teaching hospitals... 'cause they have to fill in for the neuropathologist when he or she is on vacation.

Neuroanatomy

Main article: Neuroanatomy

This is a large topic. It covered in a separate article, that also covers grossing.

Neuroradiology

Key factors to consider in evaluation:

• 1) location
• 2) number of lesions - single vs. multiple
• 3) cystic vs. solid lesion
• 4) enhancement

Lesion location

In neuroradiology and neuropathology, real estate is crucial. Lesion location can often narrow your differential.

Cortical lesions (gray matter):

• oligodendroglioma
• DNET
• ganglioglioma
• pleomorphic xanthoastrocytoma
• extraventricular ependymoma

Cortical-subcortical junction:

• metastases
• abscesses (hematogenous spread)

Subcortical lesions (white matter):

• glioblastoma
• diffuse gliomas
• demyelinating plaques

Deep gray matter lesions (e.g. basal ganglia);

• gliomas
• hypertensive hemorrhage

Cerebellar lesions:

• medulloblastoma
• pilocytic astrocytoma
• AT/RT

Intraventricular lesions:

• ependymoma
• subependymoma
• pilocytic astrocytoma
• central neurocytoma
• rosette forming glioneuronal tumour of the fourth ventricle

Suprasellar (above the pituitary):

• craniopharyngioma
• germinoma
• pilomyxoid astrocytoma

Number of lesions

If single lesion = think primary, neoplastic If multiple lesions = think metastatic, neoplastic or infectious NB: glioblastoma can be multifocal (and the foci can be quite far apart)

Cystic vs. solid lesions

Some tumours are classically cystic with a small solid component (so-called cyst with a mural nodule) -- e.g. pilocytic astrocytoma, ganglioglioma, hemangioblastoma

Enhancing vs. non-enhancing:

• In adults, enhancing generally = high grade.
• In pediatrics, it often depends on the pattern.

Two main patterns to be mindful of -- ring enhancing lesions, and cystic lesions with a mural nodule.

Ring enhancing lesions

In HIV/AIDS patients... mass on CT if infection:

• Toxoplasmosis - most common.

Ring enhancing lesion (DDx) - mnemonic MAGICAL DR:

• Metstasis.
• Abscess.
• Glioblastoma.
• Infarct.
• Contusion.
• AIDS-related.
• Lymphoma + HIV assoc. disease (toxoplasma).
• Demyelination (e.g. multiple sclerosis).
• Resolving hematoma.

Cyst with enhancing mural nodule

• hemangioblastoma (#1 in adults)
• pilocytic astrocytoma (#1 in peds)
• pleomorphic xanthoastrocytoma
• ganglioglioma

Grossing

This is covered in the neuroanatomy article.

Gross pathology

The gross usually useless for arriving at a definitive diagnosis.

Exceptions:

• Sausage shape lesion of filum terminale = myxopapillary ependymoma.
• Soft & tan colour = pituitary adenoma.

Normal histology

Main article: Neurohistology

This is a big topic. It is covered in a separate article called neurohistology.

Histopathology

Neuronal changes

Anoxic neurons

• AKA red neurons.

Features:

• Intensely red cytoplasm.
• Pyknosis = nuclear shrinkage + darker staining.

Images

• 

  Anoxic neurons (WC)

• 

  Neurons in an acute stroke. (WC)

www:

• Anoxic neurons (neuropathologyweb.org).
• Anoxic neurons (ouhsc.edu).

Central chromatolysis

Features:

• Central clearing.
  • Nucleus and Nissl substance are pushed to cell periphery.

DDx:

• Axonal injury (traumatic).
• Vitamin deficiency (pellagra).

Images

• 

  Central chromatolysis - intermed. mag. (WC)

• 

  Central chromatolysis - NF stain - very high mag. (WC)

Axonal swellings

H&E:

• Eosinophilic (light pink) - ground glass-like appearance.
• Shape:
  • Round if sectioned perpendicular to axis of axon.
    • Bound by cell membrane.
    • Large ~ typically 2-4x RBC diameter.
  • Sausage-shaped if cut in along axis.

Images:

• Axonal swelling (frontalcortex.com).
• Axonal swelling (neuropathologyweb.org).

IHC

• APP.

Image:

• Axonal swelling - APP (sagepub.com).

Glial changes

Astrocyte changes

Reactive astrocytes:

• Approximately equally-spaced; distance between neighbouring astrocytes is ~2x (or more) the cell size.
• Well-defined cell border.
• Eosinophilic cytoplasm with many branching processes.
  • Classically described as "funnel-shaped" in benign astrocytes.
• Peripheral nucleus.

• 

  Reactive astrocytes - high mag. (WC)

Alzheimer type II astrocyte:

• Large cleared nucleus - key feature.
• Indistinct cytoplasm.
• Found in the context of hepatic encephalopathy in basal ganglia and lower layers of cortex.
• Images:
  • Alzheimer type II astrocytes (neuroquiz.com).
  • Alzheimer type II astrocytes (neuropathologyweb.org) .

• 

  Alzheimer type II astrocytes. (WC)

Creutzfeldt cell:

• Astrocyte that mimics a mitoses; has moderate (identifiable) cytoplasm.
• Finding associated with demyelinating disease.
• Image: Crutzfeldt cell (upmc.edu).

Gemistocytic astrocytes:

• Distinct eosinophilic cytoplasm - with ground-glass appearance.

Tufted astrocytes:

• Cellular processes loaded with tau protein (as may be seen with tau IHC or Gallyas silver stain); Parisian-star-like appearance with special stain.
• +/-Multinucleated.
• A classic feature of progressive supranuclear palsy.

Other glial

Bergmann gliosis (in the cerebellum):

• Thin layer of cells (2-3 cells) with open nuclei that are larger than granular cell layer nuclei; seen with Purkinje cell loss.

• 

  Bergmann gliosis - intermed. mag. (WC)

• 

  Bergmann gliosis - high mag. (WC)

• 

  Bergmann gliosis due to compression by metastasis - intermed mag. (WC)

Image:

• Bergmann gliosis (sagepub.com).

Reactive change vs. malignancy

Reactive changes vs. malignancy (mnemonic MIMICS):

• MIcrovesicular pattern.
• Mitoses.
• Irregular spacing.
• Calcifications.
• Satellitosis, perineuronal.
  • Large "crowds" of glial cells associated with nuclei.

Inflammatory

DDx:

• Autoimmune - Multiple sclerosis.
• Neoplastic - CNS lymphoma.
• Infectious - HSV.

Encephalitis

General

DDx:

• Viral encephalitis.
• Paraneoplastic syndromes.

Gross

• Frontal and temporal lobe - most common for HSV encephalitis.

Microscopic

Features:

• Perivascular inflammation.
• Microglia.
• +/-Neuronophagia.
  • Phagocytosis of neurons.
• +/-Viral cytopathic changes.
• +/-Perineuronal inflammation.

Notes:

• Hemorrhage and necrosis - characteristic of HSV encephalitis.

Image:

• HSV encephalitis (neuropathology-web.org).

IHC

IHC stains for:

• Viral etiologies, e.g. HSV, CMV.
• Parasites, e.g. toxoplasma.
• Fungi, e.g. PASD.

Architecture

Rosettes

• Rosette = circular/flower-like arrangement of cells.

• Perivascular pseudorosette = circular/flower-like arrangement of cells with blood vessel at the centre.
  • Ependymoma.
  • Medulloblastoma, PNET.
  • Central neurocytoma.
  • Glioblastomas.

• Homer-Wright rosette = (circular) rosette with a small (~100 micrometers ???) meshwork of fibers (neuropil) at the centre.
  • Medulloblastoma.
    • Image: Medulloblastoma (ouhsc.edu).
  • PNET (can be thought of as a supratentorial medulloblastoma) .

• Flexner-Wintersteiner rosette = rosette with empty centre (donut hole).
  • Retinoblastomas.
  • Pineoblastomas.
  • Medulloepitheliomas.

• True ependymal rosette = surrounds a space.
  • Ependymoma.

• Pineocytomatous/neurocytic rosette = irregular rosette with a large meshwork of fibers (neuropil) at the centre.
  • Similar to Homer-Wright rosette.
  • Pineocytoma.
  • Neurocytoma.

Other

• Rosenthal fibres = worm-like or corkscrew-like (brightly) eosinophilic bodies; 10-40 micrometers.
  • Key feature: variable thickness; helps separate from RBCs.
  • Well-seen on trichrome stains.

• 

  Rosenthal fibres. (WP)

• 

  Rosenthal fibres - smear (WC/AFIP)

• Eosinophilic granular bodies = related to Rosenthal fibres; round cytoplasmic hyaline droplets in astrocytes.
  • Image: [Image:Pilocytic_Micro.jpg EGBs (WC/AFIP)].
• Pseudopalisading - picket fence-like alignment of cells; long axis of cells perpendicular to interface with other structures/cells.
  • Pseudopalisading of tumour cells (around necrotic regions) is seen in glioblastoma.

Note:

• Good set of articles: Neuropathology for radiologists (ncbi.nlm.nih.gov).

Inclusion bodies

• Negri bodies.
  • Cytoplasmic inclusions; classically in Purkinje cells of the cerebellum, pyramidal cells of Ammon's horn.
  • Rabies.

• 

  Negri bodies. (WC/CDC)

• Lewy bodies.
  • Eosinophilic cytoplasmic inclusion - composed mostly of alpha-synuclein.

• 

  Lewy body. (WC)

Table of inclusions

Feature	Appearance	Associated disease	Comment	Image
Grumous bodies AKA granular bodies	granular and eosinophilic ~50 micrometers	neurodegenerative disease, neuroaxonal dystrophies, aging	?Comment	?Image
Cowdry type 1 AKA Cowdry type A	eosinophilic & round + halo	herpes simplex virus	can be confused with Lewy body, Marinesco body	?Image
Lewy body	round cytoplasmic eosinophilic body +/- pale halo	Parkinson disease, dementia with Lewy bodies	morphology dependent on location in brain; +ve for alpha-synuclein, alpha-B crystallin, ubiquitin	, [1]
Lafora body	round	myoclonic epilepsy	look like corpora amylacea; location: dentate nucleus, liver, skeletal muscle, sweat glands	?Image
Lipofuscin	yellow & granular	aging	olive, dendate	?Image
Negri body	small eosinophic bodies	rabies	found in hippocampal neurons and Purkinje cells
Hirano body	concentric calcification/rod-shaped bright eosinophilic; overlap edge of neuron	Alzheimer disease, Pick disease	actin crystals, may look like capillaries; location: CA1 of hippocampus	[2]
Neurofibrillary tangles	flame-shaped cytoplasmic thingy ~30 micrometers	aging, Alzheimer's disease	seen with silver stain	Schematic, [3]
Granulovacuolar degeneration	cytoplasmic vacuoles 4-5 micrometers	ageing, Alzheimer's disease, Pick's disease	main found in Ammon horn	[4]
Pick bodies	round, homogenous, intracytoplasmic, ~10 micrometers	Pick's disease	pyramidal neurons, dentate granule cells (hippocampus); +ve for tau, tubulin, ubiquitin	[5]
Bunina body	size of Nissl granules, eosinophilic	amyotrophic lateral sclerosis (ALS)	EM: membrane-bound bodies; ubiquitin +ve	[6]

Image collection: Inclusion bodies (photobucket.com).

Immunohistochemistry

Main article: Immunohistochemistry

General

• S-100.
  • Sensitive... but non-specific, e.g. also stains melanoma.

Glial

• GFAP (glial fibrillary acidic protein) - should stain perikaryon.

Glial tumours

Standard work-up:

• GFAP.
• p53.
• Ki-67.

Neuronal

• Synaptophysin.
• Chromogranin.

Carcinoma vs. glial tumours

• AE1/AE3 often +ve in glial tumours (e.g. astrocytomas, oligodendrogliomas); CAM5.2 is usu. -ve in glial tumours.

Others

• APP (amyloid precursor protein) - detects axonal swellings.
• NF (neurofilament) - detects axonal swellings.

Brain tumours

Main article: Neuropathology tumours

Tumours are a big part of neuropathology. The most common brain tumour is a metastasis. The most common primary tumour (in adults) is glioblastoma which has a horrible prognosis.

Non-tumour

Cerebral hemorrhage

See: Intracranial hematoma for intracranial bleeds

Includes discussion of:

• Epidural hematoma.
• Subdural hematoma.
• Subarachnoid hematoma.
• Intracerebral hematomas.

Duret hematoma

• AKA Duret hemorrhage.

General

• Bleed in the upper brainstem (midbrain and pons).
  • Thought to be due to transtentorial herniation secondary to supratentorial mass effect (e.g. supratentorial tumour, intracranial hemorrhage).
• Often fatal.

Gross

• Extravasated blood in midbrain and pons - usu. ventral (anterior) and paramedian (adjacent to the midline).

Image:

• Duret hemorrhage (med.utah.edu).

Microscopic

Features:

• RBC extravasation.
• +/-Hemosiderin-laden macrophages.
• +/-Ischemic neurons.

Alcohol & CNS

Clinical

• Wernicke's encephalopathy
  • Mnemonic WACO:
    • Wernicke's.
    • Ataxia.
    • Confusion, confabulation -- Korsakoff.
    • Ocular Sx (CN IV palsy).
  • Cause: thiamine deficiency.

Pathology

Features:

• Morel's laminar sclerosis = spongy degeneration and gliosis of the cerebral cortex usu. prominent in the third layer of the cortex (outer pyramidal layer) and especially in the lateral-frontal cortex.
• Central pontine myelinolysis (CPM).
  • Just what it sound like - myelin loss in the central pons.
  • Classically associated with rapid correction of hyponatremia.
• Mammillary body shrinkage.
• Anterior cerebellar vermis atrophy; weak finding - as also age-related.
  • Vermis atrophy is also seen in schizophrenia.

Marchiafava-Bignami Disease

• Rare.
• Demyelination of the corpus callosum.

Wernicke's encephalopathy

General:

• Due to thiamine deficiency.
  • Malnourishment often accompanies alcoholism.

Features:

• Neurons of mammillary bodies preserved - key.
• Loss of myelin.
• Hemorrhage.
• Edema.
• Reactive blood vessels.

Note:

• The thalamus and inferior olives show neuronal loss.

Common non-specific findings

• Intracranial haemorrhage - due to trauma.

Meningitis

General

• Definition: inflammation of the meninges (pia mater, arachnoid membranes, dura mater).

Classic clinical presentation:

• Neck stiffness.
• Fever.
• +/-Headache.
• +/-Decreased level of consciousness.

CSF findings:

Type	Glucose	Protein	Cells
Bacterial, acute	low	high	neutrophils
Viral	normal	slight elevation	lymphocytes

Etiology

• Infectious.
  • Bacterial.
  • Viral.
  • Parasitic
• Autoimmune.
• Toxic.
• Aseptic - see Mollaret's meningitis.

Bacterial meningitis - most probably cause by age:

Age	Organism
Neonate	Escherichia coli, Group B Streptococcus
Infants, children	Streptococcus pneumoniae
Adolescents, young adults	Neisseria meningitidis
Elderly	Streptococcus pneumoniae, Listeria monocytogenes

Gross

Features:

• +/-Clouded appearance of the meninges.
• +/-Pus.
• +/-Petechiae.
• +/-Cerebral edema.

Image

• 

  Meningitis. (WC)

Microscopic

Features:

• Inflammation of the meninges:
  • +/-Neutrophils.
  • +/-Lymphocytes.
  • +/-Plasma cells.
• +/-Microorganisms (infectious meningitis):
  • Bacteria.
  • Fungi, e.g. aspergillosis (may be intravascular).

Main DDx:

• Lymphoma.

Image

• 

  Bacterial meningitis. (WC)

Cerebral abscess

General

• May mimic malignancy clinically.

Microscopic

Features:

• Sheets of neutrophils surrounded by fibrosing brain.
  • Fibrosing brain: pale (lighter pink than normal brain tissue), dense.

Images:

• Cerebral abscess - very low mag. (kmu.edu.tw).
• Cerebral abscess - low mag. (kmu.edu.tw).

Neurodegenerative diseases

Main article: Neurodegenerative diseases

This is a hueueuge topic. It is covered in its own article and includes a general discussion of dementia.

Epilepsy

Main article: Epilepsy

Cerebrovascular accident

• Abbreviated CVA.
• AKA stroke.

Main article: Cerebrovascular accident

Hypoxic-ischemic encephalopathy

• Abbreviated HIE.

Main article: Hypoxic-ischemic encephalopathy

Multiple sclerosis

• Abbreviated MS.

Main article: Multiple sclerosis

Cerebral amyloid angiopathy

General

• Abbreviated CAA.
• Disease of the old.
• Strong association with lobar haemorrhage (bleeds of the cerebellar cortex and cerebral cortex).

Etiology:

• Amyloid deposition in the basal lamina of smooth muscle (in the cerebellar cortex and cerebral cortex).

Gross

• Bleeds typically superficial (cortex and subcortical white matter) and in the frontal lobe or parietal lobe.

Microscopic

Features:

• Amorphous, acellular eosinophilic material within walls of small arteries.
  • This is a high power diagnosis with congo red staining.

Notes:

• Amyloidosis is seen in all individuals with Alzheimer's disease; the amount of amyloid is what differs -- in CAA it is lots and lots.
• The white matter is typically spared by CAA.

Images

• 

  CAA - congo red - very high mag. (WC)

• 

  CAA - congo red - low mag. (WC)

• 

  CAA - beta-amyloid - high mag. (WC)

Stains

• Congo red.

IHC

• Abeta-amyloid (AKA beta-amyloid).

Central pontine myelinolysis

• Abbreviated CPM.
• AKA pontine myelinolysis.

General

• Classically in the pons, ergo "pontine" is in the name.
• Classically midline, ergo "central" is in the name.
  • May occur elsewhere -- known as extrapontine myelinolysis.

Etiology:

• Rapid correction of hyponatremia.
• Tacrolimus post-liver transplant.
• Associated with alcoholism and malnourishment.

Clinical:

• Decreased level of consciousness - most common.
• Quadriplegia.
• Poor prognosis.

Microscopic

Features:

• Myelin loss.
• No inflammation.
• Relative preservation of neurons.

Images:

• CPM (neuropathology-web.org).
• CPM (dartmouth.edu).

Vascular malformations

Main article: Vascular malformations

Types:

1. Arteriovenous malformation.
   • Most important clinically - highest risk of bleeding.
2. Varix.
   • One large (dilated) vein.
3. Venous angioma.
   • Many small veins.
4. Cavernous malformation.
   • Vessels are back-to-back (no intervening parenchyma).

Also see: Sturge-Weber syndrome.

Cysts

General

• All are "benign", but some may be fatal due to spatial constraints.

List of cysts

• Colloid cyst.
  • Columnar epithelium.
• Arachnoid cyst - considered precursor of meningioma.
  • Psammoma bodies.
  • Clumps of cells.
  • Whorled pattern.
• Dermoid cyst.
  • Skin + adnexal structures.
  • ... think of ovarian dermoid.
• Epidermoid cyst.
• Choroid plexus cyst.
• Neuroenteric cyst.
  • Foregut cyst with connection to dura.
    • Gastrointestinal tract epithelium.
    • Usually seen with vertebral anomalies.
• Epithelial cyst.
• Others.

Colloid cyst

General

Classic presentation:

• Headache - may be relieved by lying down.
• Can cause sudden natural death.

Gross

• Fluid filled cyst - classically in the third ventricle.

Images

• 

  Colloid cyst at autopsy. (Shaktawat et al.)

www:

• Colloid cyst of third ventricle (ajnr.org).

Microscopic

Features:

• Simple epithelium with ciliated cells and goblet cells.

Images

• 

  Colloid cyst. (WC)

www:

• Colloid cyst (ajnr.org).

Paediatric pathology

Kernicterus

General

• Due to hyperbilirubinemia.

Gross

• Yellow staining:
  • Basal ganglia.
  • Hippocampus.
  • Subthalamic nucleus.

Note:

• May not be specific.

Image:

• Kernicterus (flickr.com).

Microscopic

Features - similar to HIE:

• +/-Red neurons.
• +/-Gliosis.

Joubert syndrome

• Malformation of the cerebellar vermis.

Epidemiology

• Autosomal recessive - mutation in a number of genes including NPHP1, AHI1, and CEP290.

Weird stuff

Acute disseminated encephalomyelitis

• Abbreviated ADEM.

Main article: Acute disseminated encephalomyelitis

Neuromyelitis optica

• Abbreviated NMO.

General

• Rare autoimmune disease - once considered a variant of multiple sclerosis.
  • Autoantibodies directed at aquaporin-4.

Diagnosis:

• NMO-IgG.

Clinical - preferentially:

• Eye (optic neuritis).
• Spinal cord (myelitis).

Microscopic

Features:

• Inflammation - lymphocytes, macrophages.
• Reactive astrocytes.

Images:

• Neuromyelitis optica - several images (upmc.edu).

IHC

• Mixed lymphocyte population with CD3 > CD20.
• Aquaporin-4 loss.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

• Commonly abbreviated CADASIL.

Main article: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Progressive multifocal leukoencephalopathy

• Abbreviated PML.

Main article: Progressive multifocal leukoencephalopathy

See also

• Brain tumours.
• Pituitary gland.
• Histiocytoses.
• Intracranial hematomas.
• Spine.

External links

• Neuropathology (neuropathologyweb.org).
  • Quiz (neuropathologyweb.org).
• Neuropathology cases (lib.umn.edu).
• Neuropathology micrographs - identifying the site (stonybrookmedicalcenter.org).
• Neurocytopathology quiz (ouhsc.edu).
• WikiCNS (wiki.cns.org).