Introduction to Neuropathology:

J.J. Mercado, MD
Department of Pathology
jmerc3@lsuhsc.edu
• Pathologists correlate topographical (gross) and
morphological (microscopic) features to reach a
diagnosis.
• Diagnoses are related to multiple reactions to injury
that affect different components of the nervous
system (cells, vessels, meninges, connective tissue)
and can be seen or confirmed microscopically.
 Brain reactions to injury
• Cellular reactions
– Neuronal • Tissue reactions
– Astrocytic – Cerebral atrophy
– Microglial cells – Cerebral edema
– Oligodendrocytes – Hydrocephalus
– Ependymal – Herniation
Basic cellular reactions to CNS injury
– Neurons
– Astrocytes
– Oligodendrocytes
– Microglia
– Ependymal cells
 Neurons

The gross and microscopic anatomy of the CNS

varies from region to region
– Can be anatomically divided into nuclear groups and systems
based on geographic location and synaptic connections
– Can be histologically divided into neuronal subtypes based on
morphology, location, connections, neurotransmitters,
metabolic requirements, electrical activity, etc.
Neurons
 Neurons
Cerebellar
granule neurons

Pigmented
neurons
Purkinje
neuron
 Neuronal reactions to injury
• Acute neuronal necrosis(Acute ischemic injury)  death
• Central chromatolysis
• Vacuolated neurons
• Binucleated neurons
• Abnormal neuronal storage
• Neurofibrillary tangles and granulovacuolar degeneration
• Intraneuronal inclusion bodies
• Axonal Alterations
 Neuronal Reactions to Injury
• Acute ischemic injury –
red neurons
– Appears 12 – 24 hours
after cell death
– Cells shrunken
– Nuclei pyknotic
– Cytoplasm hyper-
eosinophilic
– Nucleoli and Nissl
substance lost
Neuronal
FerruginationIntracytoplasmic Inclusions
 Central Chromatolysis
• It can be reversible if injury stops, or continue to cell
death if injury continues
• Occurs in lower motor neurons: Anterior horn, cranial
nerve nuclei
– Microscopic features:
• Swelling of neuron cell body
• Disappearance of Nissl bodies starting centrally and extending
outward (margination of Nissl)
• Displacement of nucleus to the periphery(margination of nucleus)
 Vacuolated Neurons and neuropil
• Creutzfeldt-Jakob disease
 Multinucleated neurons
• Dysplastic/malformation
• Tuberous sclerosis
• Ganglion cell tumors
 Neuronal Storage
• Examples:

GM2 gangliosidosis Neuronal ceroid lipofuscinosis

 Alzheimer neurofibrillary tangles and
granulovacuolar degeneration

• Neurofibrillary degenerationseen in aged individuals,

senile dementia of Alzheimer type, other disorders
– Neurofibrillary tangles (NFTs)-composed of microtubule
associated protein tau in highly phosphorylated form
phosphorylated tau protein.
– Types:
• band shaped- early in both large and small pyramidal neurons
• flame shaped- in large pyramidal neurons
• small-compact globose- in small cortical neurons
• large globose- in nucleus basalis of Meynert and brainstem
• Ghost- final stages
Different types of neurofibrillary tangles (Bodian silver impregnation combined with Luxol fast blue): band-shaped perikaryal NFT (A);
triangular flame-shaped perikaryal NFT (B, C); small, compact, globose perikaryal NFT (D); large globose NFT (E); “ghost NFT” (F).

Chapter: Basic Pathology of the Central Nervous System

Author(s): Pedro de Sá Cavalcante Ciarlini, Danielle Seilhean, Umberto De Girolami, and Françoise Gray
From: Escourolle and Poirier's Manual of Basic Neuropathology

Downloaded from Oxford Medicine Online. © Françoise Gray, Charles Duyckaerts, Umberto De Girolami 2019
• Granulovacuolar degeneration- autophagic
lysosomal structures in which cytoskeletal structures
are being degraded. Small clear vacuoles 4-5µm in
diameter. Composed of phosphorylated
neurofilament, tau and ubiquitin.
GVD
 Intraneuronal inclusion bodies
– Pick bodies
– Lewy bodies
– Hirano bodies
– Bunina bodies
– Skein like inclusions
– Marinesco bodies
– Lafora bodies
– Viral
 Pick bodies
• Cytoplasmic
• Round homogeneous
• Pyramidal and dentate neurons and hippocampus
• Argyrophilic, immunoreactivity to ubiquitin, tau and
tubulin
• Associated with Frontotemporal lobar dementias
Ex: Pick disease.
Pick bodies
 Lewy bodies
• Cytoplasmic –one or more can be present
• Morphology depend on location:
– brainstem: spherical with an eosinophilic core surrounded by a paler halo
– Sympathetic ganglia: oval or elongated
– Cortical: less circumscribed, homogeneous zone of eosinophilia without
halo
• Immunoreactive to ubiquitin, αß crystallin, and α-synuclein
(synucleinopathies)
• They define “Lewy body disorders” of which the most common is
Parkinson disease
Alpha-synuclein
 Hirano bodies
• Cytoplasmic
• Brightly eosinophilic, rod shaped or elliptical
• CA1 (Sommer sector) of hippocampus
• Immunoreactivity to actin
• Numerous in Alzheimer disease, pick disease, Guam
parkinsonism-dementia complex
 Bunina bodies
• Cytoplasmic
• Eosinophilic
• Motor neurons
• Immunoreactivity for Cystatin-C
• Seen on ALS
 Skein-like inclusions
• Cytoplasmic
• Linear thread like structures , single or in networks
• Anterior horn cells
• IHC: ubiquitin, TDP-43
• Seen on ALS,
 Marinesco
• Intranuclear
• Small eosinophilic
• Exclusive of neuromelanin containing brainstem
neurons.
• Ihc: ubiquitin
Marinesco Body
 Lafora bodies
• Intracytoplasmic round structures
• Similar to corpora amylacea in composition and
staining
• Disease: Myoclonic epilepsy found in CNS and
extraneural sites such as: muscle, liver, and sweat
glands
• Made of Polyglucosan
• PAS positive
Viral inclusions
 Neuronal Reactions to Injury

• Axons
– Axonal swellings (spheroids) – dilation and organelle
accumulation due to disruptions in anterograde and
retrograde transport in response to adjacent injury
– Wallerian degeneration – degeneration distal to the
site of a transection
– Regeneration – axonal sprouts attempt to reform the
axon in the original Schwann tube
 Astrocytic Reactions to Injury

• Gliosis (astrogliosis) – reactive hypertrophy and

hyperplasia
– A reactive process to injury
– Increase in number, nuclear enlargement, coarse
chromatin, prominent nucleoli, expanded eosinophilic
cytoplasm and arborization
– When reactive astrocytes accumulate glycogen
gemistocytes
 Gliosis
GFAP
 Astrocytic Reactions to Injury

• Alzheimer type 2 astrocytosis – reactive

hypertrophy of gray matter astrocytes without
expanded cytoplasm
– Enlarged nuclei (2-3x), irregular nuclear borders,
marginalized chromatin, small nucleoli, and
intranuclear glycogen granules
– Associated with alcoholism, liver failure, uremia,
Wilson disease
Alzheimer Type 2 Astrocytes
 Astrocytic Reactions to Injury

• Piloid gliosis– reactive hypertrophy of spindled

(hair-like) astrocytes
– Form Rosenthal fibers – sausage shaped, brightly
eosinophilic cytoplasmic inclusions composed of GFAP
and crystalline proteins
– A non-specific reaction to chronic injury and
associated with some tumors.
Piloid Gliosis
 Ependymal Reactions to Injury

• Injury to ependymal cells stimulates the nodular

proliferation of subependymal astrocytes –
ependymal granulations
Ependymal Granulation
 Microglial Reactions to Injury

• Microglial activation – reactive hypertrophy and

hyperplasia of resident macrophages (CNS
dendritic cells) – rod cells
• A non-specific reaction to injury
 Microglial Reactions to Injury

• Microglial nodules – aggregates of activated

microglial cells, reactive astrocytes, and
lymphocytes
– A non-specific reaction, but often seen with viral
encephalidites
– Neuronophagia – a microglial nodule surrounding a
degenerating neuron
 Microglial Reactions
Activation

Nodule Neuronophagia
 Tissue reactions to injury

• Atrophy
• Cerebral edema
• Herniation
• Hydrocephalus
 Atrophy
Normal
 Cerebral Edema
• Excess fluid accumulation within the brain parenchyma ICP
– Vasogenic edema – increased fluid in the intercellular space driven by disruption
of the blood brain barrier and increased vascular permeability
– Can be focal or global
– Cytotoxic edema – increased intracellular water driven by cell membrane injury
• Both processes often occur in tandem
• Morphology – gyri widened and flattened, sulci narrowed, ventricles
compressed, gray-white junction blurred
Global Cerebral Edema
Global Cerebral Edema
 Hydrocephalus
• Increased volume of cerebrospinal fluid in the ventricles
• Increased production
– Choroid plexus papillomas – rare
• Decreased resorption
– Arachnoid granulation fibrosis in response to
meningitis or subarachnoid hemorrhage
• Impaired flow due to focal obstruction
– Intra-axial or extra-axial mass lesions
– Focal edema
 Hydrocephalus
• Communicating
• Non-communicating
• Hydrocephalus Ex-vacuo
Hydrocephalus
 Hydrocephalus Ex Vacuo
• Compensatory enlargement of the ventricles due to atrophy
 Herniation
• Displacement of brain tissue from one compartment
to another
• Compartments are separated by rigid structures:
Falx cerebri
Cerebellar tentorium
Foramen magnum
Most common types of herniation
 Herniation
• Increased intracranial pressure will result in a herniation
syndrome
– Focal – a space occupying mass, such as hemorrhages, tumors, or
abscesses
– Global – cerebral edema or hydrocephalus
 Types of Herniation
• Subfalcine – cingulate gyrus
– Compression of the anterior cerebral artery with infarction
 Types of Herniation

• Transtentorial – unilateral uncus or medial temporal lobe

(uncal notch)
– Ipsilateral third cranial nerve compression  fixed dilated pupil.
Contralateral hemiparesis
– Compression of the contralateral cerebral peduncle against the
cerebellar tentorium (Kernohan notch)  hemiparesis ipsilateral to
the mass, a false localizing sign
 Types of Herniation
• Transtentorial (cont)
– Ipsilateral or contralateral posterior cerebral artery
compression  hemorrhagic infarction in the medial
occipital-temporal lobes (primary visual cortex)
– Midbrain compression with cerebral aqueduct
occlusion  decerebration and obstructive
hydrocephalus
– Midline (Duret) hemorrhages in the midbrain, pons,
and thalamus
Transtentorial Herniation
Midline Pontine Hemorrhages (Duret)
 Types of Herniation
• Tonsillar – displacement of the cerebellar tonsils
through the foramen magnum
– Compression of the medulla and pons leads to ischemia
of respiratory and autonomic activating centers resulting
in death