Neuropathology

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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.

Contents

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 versus multiple.
  3. Cystic versus 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):

Cortical-subcortical junction:

Subcortical lesions (white matter):

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

Cerebellar lesions:

Intraventricular lesions:

Suprasellar (above the pituitary):

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:

Ring enhancing lesion (DDx) - mnemonic MAGICAL DR:[2]

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:[3]

Normal histology

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

www:

Central chromatolysis

Features:[6]

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

DDx:

Images

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:

IHC
  • APP.

Image:

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.[11]
  • Peripheral nucleus.

Alzheimer type II astrocyte:[12]

Creutzfeldt cell:[14]

  • Astrocyte that mimics a mitoses; has moderate (identifiable) cytoplasm.
  • Finding associated with demyelinating disease.
  • Image: Crutzfeldt cell (upmc.edu).[15]

Gemistocytic astrocytes:[16]

  • Distinct eosinophilic cytoplasm - with ground-glass appearance.

Tufted astrocytes:[17]

  • 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):[14]

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

Image:

Reactive change vs. malignancy

Reactive changes vs. malignancy (mnemonic MIMICS):[18]

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

Inflammatory

DDx:

Encephalitis

see also:

General

DDx:

  • Viral encephalitis (Neurotrophic viruses):[19]
    • Human Herpesviruses (HSV1, HSV2, VZV, CMV, EBV, Roseola)
      • HSV encephalitis has high mortality without acyclovir treatment.
    • Measles virus( worldwide more than 100.000 deaths anually).
    • Seasonal influenza A virus (highest patogenic potential: avian influenza H5N1).
    • Polio and Non-Polio Enterovirus (mostly children).
      • Although massive eradication: Polio still existent in Pakistan, Afghanistan, Nigeria.
    • Rabies virus
    • Tick-borne encephalitis virus (Europe, Siberia, Russian far-east).
    • West-Nile virus (US, Southern europe).
    • St. Louis encephalitis virus (US).
    • Japanese encephalitis virus (South, south-east asia, high disability rate).
    • La Crosse virus (esp. children, midwest & eastern US).
    • Borna disease virus (VSBV-1).
    • Equine encephalitis viruses (EEEV, VEEV, WEEV, CHIKV).
  • Paraneoplastic syndromes.
  • Autoimmune antibody-mediated limbic encephalitis (NMDAR).
  • Purulent bacterial encephalitis
  • Septic metastatic encephalitis
    • microabscesses, local astrogliosis, two or more granulocytic infiltrates without relation to vessel.[20]
  • Septic embolic encephalitis
    • Embolic endocarditis, Stroke-like lesions.[21]
  • Non-purulent bacterial encephalitis
Gross
  • Frontal and temporal lobe - most common for HSV encephalitis.[22]
Microscopic

Features:[23]

  • Perivascular inflammation.
  • Microglia.
  • +/-Neuronophagia.
    • Phagocytosis of neurons.[24]
  • +/-Viral cytopathic changes.
  • +/-Perineuronal inflammation.

Notes:

  • Hemorrhage[25] and necrosis - characteristic of HSV encephalitis.

Image:

IHC

IHC stains for:

Vasculitis

DDx Cerebral vasculitis / angiitis:

Architecture

Rosettes

  • Rosette = circular/flower-like arrangement of cells.[27]
  • Homer-Wright rosette = (circular) rosette with a small (~100 micrometers ???) meshwork of fibers (neuropil) at the centre.[27]
  • Pineocytomatous/neurocytic rosette = irregular rosette with a large meshwork of fibers (neuropil) at the centre.[27]
  • Radial (cartwheel) profiles = neoplastic cells anchoring to stromal vessels, shorter processes than in ependymal pseudorosettes

Other important histological features

  • 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.
  • Eosinophilic granular bodies = related to Rosenthal fibres; round cytoplasmic hyaline droplets in astrocytes.[30]
  • 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:

Inclusion bodies

  • Negri bodies.
    • Cytoplasmic inclusions; classically in Purkinje cells of the cerebellum, pyramidal cells of Ammon's horn.
    • Rabies.
  • Owl eye inclusions.
    • Basiopilic neuronal inclusions in enlarged cells, typically seen in CMV encephalitis
  • Lewy bodies.
    • Eosinophilic cytoplasmic inclusion - composed mostly of alpha-synuclein.[32]

Table of inclusions

Feature Appearance Associated disease Comment Image
Grumose 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
Lewy Koerperchen.JPG
, [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
Rabies encephalitis Negri bodies PHIL 3377 lores.jpg
Hirano body concentric calcification/rod-shaped bright eosinophilic; overlap edge of neuron Alzheimer disease, Pick disease[33] actin crystals, may look like capillaries; location: CA1 of hippocampus [2][34]
Neurofibrillary tangles flame-shaped cytoplasmic thingy
~30 micrometers
aging, Alzheimer's disease seen with silver stain Schematic[34], [3][35]
Granulovacuolar degeneration cytoplasmic vacuoles 4-5 micrometers ageing, Alzheimer's disease,
Pick's disease
main found in Ammon horn[33] [4][35]
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

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.
  • MAP2C. [36]
  • Ki-67 (MIB-1).

Useful additional markers:

  • IDH1(R132H) in Astrocytic/Oligodendroglial tumors. [37]
  • ATRX in mixed gliomas. [38]
  • EMA in Ependymal tumors. [39]
  • OLIG-2 usually -ve in Ependymomas. [40][41]

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.[42]

Others

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

Brain tumours

Tumours are a big part of neuropathology. The most common brain tumour (in adults) is a metastasis. The most common primary tumours originating in the brain (in adults) are gliomas. More than 50% of these are classified as glioblastoma which has a horrible prognosis.

Non-tumour

Vascular disorders

Cerebral hemorrhage

See: Intracranial hematoma for intracranial bleeds

Includes discussion of:

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).[43]
  • Often fatal.[44]

Gross

  • Extravasated blood in midbrain and pons - usu. ventral (anterior) and paramedian (adjacent to the midline).[43]

Image:

Microscopic

Features:

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

Cerebral amyloid angiopathy

General

  • Abbreviated CAA.
  • Disease of the old.
  • Strong association with lobar haemorrhage (bleeds of the cerebellar cortex and cerebral cortex).[46]

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.[47]

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.[48]

Images

Stains

IHC

  • Abeta-amyloid (AKA beta-amyloid).

Vascular malformations

Types:[49]

Also see: Sturge-Weber syndrome.

Atherosclerosis

  • Intracranial atherosclerosis most common at circle of Willis.
  • Macroscopic yellow discoloration.
  • Luminal stenosis and eccentric intimal thickening.

Other large arterial diseases

Microangiopathy

  • Defined as Small vessel disease (<300µm in transverse section).
  • Includes atherosclerosis and cerebral amyloid angiopathy.

Other causes:

Hypoxic-ischemic encephalopathy

  • Abbreviated HIE.
    • Hypoxia: reduction in oxygen supply or utilization.
    • Ischemia: reduction in blood supply.

Cerebrovascular accident

  • Abbreviated CVA.
  • AKA stroke.
  • Stroke includes:
    • Infarction (ischemia in defined vascular distribution persisting for at least 24hrs).
    • Intracrebral hemorrhage (focal blood accumulation in the brain parenchyma).
    • Subarachnoid hemorrhage (SAH).
    • Cerebral venous thrombosis (CVT).


Alcohol & CNS

Clinical

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

Pathology

Features:[50]

  • Morel's laminar sclerosis = spongy degeneration and gliosis of the cerebral cortex[51] usu. prominent in the third layer of the cortex (outer pyramidal layer) and especially in the lateral-frontal cortex.[52]
  • Central pontine myelinolysis (CPM).[53]
    • Just what it sound like - myelin loss in the central pons.
    • Classically associated with rapid correction of hyponatremia.[54]
  • Mammillary body shrinkage.[55]
  • Anterior cerebellar vermis atrophy; weak finding - as also age-related.[56]
    • Vermis atrophy is also seen in schizophrenia.[57]

Marchiafava-Bignami Disease

  • Rare.
  • Demyelination of the corpus callosum.[52]

Wernicke's encephalopathy

General:

  • Due to thiamine deficiency.

Features:[58]

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

Note:

  • The thalamus and inferior olives show neuronal loss.[58]

Common non-specific findings

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 Cytopathology
Bacterial, acute low high neutrophils
Purulent CSF.jpg
Cytophathology
Viral normal slight elevation lymphocytes Cytophathology


Etiology

Bacterial meningitis - most probably cause by age:[59]

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

Microscopic

Features:

Main DDx:

Image

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:

Neurodegenerative diseases

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

Epilepsy

Focal cortical dysplasia (FCD)

  • Localized malformations of the cortex.
  • Frequently associated with epilepsy in children.
  • Includes cortical dyslamination, cytoarchitectural changes and white matter abnormalities.
  • Current consensus: ILAE classification scheme 2011 [61](based on previous classification by Palmini 2004):


  • Type I FCD (focal)
    • Ia: Abnormal radial cortical lamination.
    • Ib: Abnormal tangential cortical lamination.
    • Ic: Abnormal radial and tangential cortical lamination.


  • Type II FCD (focal)
    • IIa: Presence of dysmorphic neurons.
    • IIb: Presence of dysmorphic neurons and balloon cells.


  • Type III FCD (associated with other lesion)
    • IIIa: FCD associated with hippocampal sclerosis.
    • IIIb: FCD adjacent to a brain tumor.
    • IIIc: FCD adjacent to vascular malformation.
    • IIIc: FCD associated with previous injury (trauma, inflammation...).


Demyelination

Multiple sclerosis

  • Abbreviated MS.


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.[62]
  • Tacrolimus post-liver transplant.[63]
  • Associated with alcoholism and malnourishment.

Clinical:[64]

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

Microscopic: Features:[65]

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

Images:

Acute disseminated encephalomyelitis

  • Abbreviated ADEM.

Neuromyelitis optica

  • Abbreviated NMO.

General:

  • Rare autoimmune disease - once considered a variant of multiple sclerosis.
    • Autoantibodies directed at aquaporin-4.[66]

Diagnosis:

  • NMO-IgG.

Clinical - preferentially:

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

Microscopic:

  • Inflammation - lymphocytes, macrophages.
  • Reactive astrocytes.

Images:

IHC:

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

Progressive multifocal leukoencephalopathy

  • Abbreviated PML.


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.
  • Dermoid cyst.
    • Skin + adnexal structures.
    • ... think of ovarian dermoid.
  • Epidermoid cyst.
  • Choroid plexus cyst.
  • Neuroenteric cyst.
    • Foregut cyst with connection to dura.[67]
      • Gastrointestinal tract epithelium.
      • Usually seen with vertebral anomalies.
  • Epithelial cyst.
  • Others.

Colloid cyst

General

Classic presentation:[68]

Gross

  • Fluid filled cyst - classically in the third ventricle.

Images

www:

Microscopic

Features:[71]

  • Simple epithelium with ciliated cells and goblet cells.

Images

www:

Paediatric pathology

Kernicterus

General

  • Due to hyperbilirubinemia.[72]

Gross

  • Yellow staining:[73]
    • Basal ganglia.[74]
    • Hippocampus.[75]
    • Subthalamic nucleus.

Note:

  • May not be specific.[72]

Image:

Microscopic

Features - similar to HIE:[73]

  • +/-Red neurons.
  • +/-Gliosis.

Joubert syndrome

  • Malformation of the cerebellar vermis.[76]

Epidemiology

  • Autosomal recessive - mutation in a number of genes including NPHP1, AHI1, and CEP290.[76]

See also

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