How long does it take before ischemic injury happens in neural tissue?
>4 min (roughly)
What are some acute processes behind neuronal injury?
What are some chronic processes behind neuronal injury?
Often associated with accumulation of abnormal protein aggregates
- ie Parkinson's, dementia
What is seen, histologically, in acute neuronal injury?
shrinkage of the cell body,
pyknosis of the nucleus,
disappearance of the nucleolus, and
loss of Nissl substance,
with intense eosinophilia of the cytoplasm (red/pink color)
spectrum of changes that accompany acute CNS hypoxia/ischemia/hypoglycemia or other acute insults and reflect the earliest morphologic markers of neuronal cell death
How long after acute injury do red neurons appear? What are the implications of this?
“Red neurons” are evident by about 12 to 24 hours after an irreversible hypoxic/ischemic insult.
If someone immediately dies d/t massive ischemia of the brain, the brain might look normal grossly/histologically
What is another name for chronic neuronal injury?
Subacute and chronic neuronal injury
- neuronal death occurring as a result of a progressive disease of some duration
What is the histological appearance of degeneration?
The characteristic histologic feature is cell loss, often selectively involving functionally related groups of neurons, and reactive gliosis.
At an early stage, the cell loss is difficult to detect; the associated reactive glial changes are often the best indicator of neuronal injury.
What is axonal reaction? Where is it easiest to observe?
change observed in the cell body during regeneration of the axon
- best seen in anterior horn cells of the spinal cord when motor axons are cut or seriously damaged
What is seen histologically with axonal reaction?
increased protein synthesis associated with axonal sprouting
This is reflected in enlargement and rounding up of the cell body, peripheral displacement of the nucleus,
enlargement of the nucleolus,
and dispersion of Nissl substance from the center to the periphery of the cell (central chromatolysis)
What pathological processes are associated with neuronal inclusions?
Inborn errors of metabolism
Infections - esp viral
Degenerative CNS disorders
What neuronal inclusions are present d/t aging?
intracytoplasmic accumulations of complex lipids (lipofuscin), proteins, or carbohydrates
What neuronal inclusions are present d/t inborn errors of metabolism?
Abnormal cytoplasmic deposition of complex lipids and other substances also occurs in genetically determined disorders of metabolism in which substrates or intermediates accumulate
- Tay Sachs, something something Ashkenazi Jew
What neuronal inclusions are present d/t infection?
rabies - Negri bodies
HSV - Cowdry bodies
CMV - nucleus and cytoplasmic inclusions
What neuronal inclusions are present d/t degenerative CNS disorders?
neurofibrillary tangles of Alzheimer disease and Lewy bodies of Parkinson disease;
others cause abnormal vacuolization of the perikaryon and neuronal cell processes in the neuropil (Creutzfeldt-Jakob disease).
What is the most important histopath indicator of CNS injury?
characterized by hypertrophy & hyperplasia of astrocytes
Describe the histo appearance of an astrocyte.
The astrocyte derives its name from its star-shaped appearance.
These cells have multipolar, branching cytoplasmic processes that emanate from the cell body and contain glial fibrillary acidic protein (GFAP), a cell type-specific intermediate filament
What is the function of astrocytes in the brain?
metabolic buffers and detoxifiers within the brain
Maintenance of BBB
- through the foot processes, which surround capillaries or extend to the subpial and subependymal zones, they contribute to barrier functions controlling the flow of macromolecules between the blood, the cerebrospinal fluid (CSF), and the brain
What is the appearance of astrocytes during gliosis?
- get big nuclei, get pink, get grabby with cell processes
In gliosis, the nuclei of astrocytes,
(which are typically round to oval (10 µm wide) with evenly dispersed, pale chromatin,)
enlarge, become vesicular, and develop prominent nucleoli.
The previously scant cytoplasm expands to a bright pink, somewhat irregular swath around an eccentric nucleus, from which emerge numerous stout, ramifying processes; these cells are called gemistocytic astrocytes
What are Rosenthal fibers? Where are they found?
Found in areas of long-standing gliosis, or in pilocytic astrocytoma tumors
Thick, eosinophilic, elongated, irregular stuctures in astrocytic processes made of 2 heat shock proteins and a ubiquitin
(almost like a neurologist's mushroom stamp)
What is Alexander disease?
leukodystrophy, mutation in gene encoding GFAP
- has abundant Rosenthal fibers in periventricular, perivascular, and subpial locations
What is corpora amilacea?
PAS+, basophilic inclusions located in astrocytic end processes
- will be in subpial and perivascular zones
- increase in numbers with advancing age, thought to represent degenerative change in astrocyte
What are lafora bodies?
Cytoplasmic inclusion in neurons present in myoclonic epilepsy
What are microglia?
Microglia are mesoderm-derived phagocytic cells that serve as the resident macrophages of the CNS.
- share many surface markers with peripheral monocytes/macrophages (e.g., CR3 and CD68).
How do microglia respond to injury?
(2) developing elongated nuclei (rod cells) , as in neurosyphilis;
(3) forming aggregates around small foci of tissue necrosis (microglial nodules); or
(4) congregating around cell bodies of dying neurons (neuronophagia).
In addition to resident microglia, blood-derived macrophages may also be present in inflammatory foci
Describe the structure and function of oligodendrocytes.
Oligodendrocytes are cells that wrap their cytoplasmic processes around axons and form myelin.
Each oligodendrocyte myelinates numerous internodes on multiple axons, in contrast to the myelinating Schwann cell in peripheral nerve, which has a one-to-one correspondence between cells and internodes.
What diseases are associated with oligodendrocyte pathology?
Injury or apoptosis of oligodendroglial cells is a feature of acquired demyelinating disorders and leukodystrophies.
Oligodendroglial nuclei may harbor viral inclusions in progressive multifocal leukoencephalopathy.
Glial cytoplasmic inclusions, primarily composed of α-synuclein, are found in oligodendrocytes in multiple system atrophy (MSA).
What is the response of ependymal cells to injury?
Ependymal cells - ciliated columnar epithelial cells lining the ventricles
In a nutshell, ependymal cells don't respond, astrocytes do:
inflammation or marked dilation of the ventricular system, disruption of the ependymal lining is paired with proliferation of subependymal astrocytes to produce small irregularities on the ventricular surfaces (ependymal granulations). Certain infectious agents, particularly CMV, may produce extensive ependymal injury, with viral inclusions in ependymal cells. However, neither oligodendrocytes nor ependymal cells mediate significant responses to most forms of injury in the CNS.
What is cerebral edema? What are the 3 pathways to it?
Cerebral edema (more precisely, brain parenchymal edema) is the result of increased fluid leakage from blood vessels or injury to various cells of the CNS
How does vasogenic edema happen? Does it result in general or localized edema?
increase in extracellular fluid caused by blood-brain barrier disruption and increased vascular permeability
- allows fluid shift from the intravascular compartment to the intercellular spaces of the brain
- no lymphatics = no resorption of excess extracellular fluid.
Vasogenic edema may be either localized (e.g., adjacent to inflammation or neoplasms) or generalized, as can follow ischemic injury.
How does cytotoxic edema happen?
increase in intracellular fluid secondary to neuronal, glial, or endothelial cell membrane injury
When might you encounter cytotoxic edema?
someone with a generalized hypoxic/ischemic insult
or with a metabolic derangement that prevents maintenance of the normal membrane ionic gradient
What is interstitial edema?
occurs especially around the lateral ventricles
when an increase in intravascular pressure causes an abnormal flow of fluid from the intraventricular CSF across the ependymal lining to the periventricular white matter
What is hydrocephalus? What causes it?
Hydrocephalus is the accumulation of excessive CSF within the ventricular system
Most cases of hydrocephalus are a consequence of impaired flow and resorption of CSF;
overproduction is a rare cause that can accompany tumors of the choroid plexus
What happens with increased volume of CSF? (All ages, in the cerebrum and outside)
hydrocephalus develops in infancy before closure of the cranial sutures, there is enlargement of the head, manifested by an increase in head circumference
Hydrocephalus developing after this period, in contrast, is associated with expansion of the ventricles and increased intracranial pressure, without a change in head circumference
What is the difference between communicating and non-communicating hydrocephalus?
ventricular system in communication with the subarachnoid space, enlargement of the entire ventricular system.
The term hydrocephalus ex vacuo refers to a compensatory increase in ventricular volume secondary to a loss of brain parenchyma.
ventricular system is obstructed and does not communicate with the subarachnoid space
may occur because of a mass in the third ventricle
After sutures have fused, hydrocephalus can cause increased intracranial pressure. Why is this bad? What happens during the bad process?
Increased intracranial pressure can lead to herniation
Herniation is the displacement of brain tissue past rigid dural folds (the falx and tentorium) or through openings in the skull because of increased intracranial pressure.
What principle is generally associated with herniation? Is it local or diffuse? Can it self-perpetuate?
Herniation is mostly associated with mass effect, either diffuse (generalized brain edema) or focal (tumors, abscesses, or hemorrhages). Elevated intracranial pressure may also reduce perfusion of the brain, further exacerbating cerebral edema.
Name the 3 types of herniation?
What structures (vascular and cerebral) are affected in subfalcine herniation? What is it due to?
herniation occurs when unilateral or asymmetric expansion of a cerebral hemisphere displaces the cingulate gyrus under the falx.
This may lead to compression of the anterior cerebral artery and its branches.
What structures (vascular and cerebral) are affected in transtentorial herniation? What is it due to?
occurs when the medial aspect of the temporal lobe is compressed against the free margin of the tentorium
Why is transtentorial herniation associated with ocular symptoms?
With increasing displacement of the temporal lobe, the third cranial nerve is compromised, resulting in pupillary dilation and impairment of ocular movements on the side of the lesion.
The posterior cerebral artery may also be compressed, resulting in ischemic injury to the territory supplied by that vessel, including the primary visual cortex.
Why is transtentorial herniation associated with hemiparesis?
When the extent of herniation is large enough the contralateral cerebral peduncle may be compressed, resulting in hemiparesis ipsilateral to the side of the herniation; the compression in the peduncle in this setting is known as the Kernohan notch
What are Duret hemorrhages?
Progression of transtentorial herniation is often accompanied by secondary hemorrhagic lesions in the midbrain and pons, termed Duret hemorrhages
linear or flame-shaped lesions usually in the midline and paramedian regions and are believed to be due to distortion or tearing of penetrating veins and arteries supplying the upper brainstem
To sum, what are the structures impacted by transtentorial herniation, and what are the associated SSXs?
CN III compromised --> pupil dilation, ipsilateral loss of ocular movements
PCA compromised --> ischemic injury to primary visual cortex
(blindness, pupil dilation ipsi on lesion side)
Contralateral cerebral peduncle compromised --> Kernohan notch, hemiparesis ipsi to herniation
Duret hemorrhage --> midbrain/pons hemorrhage
What/where is tonsillar herniation? Why should you care?
Tonsillar herniation refers to displacement of the cerebellar tonsils through the foramen magnum
life-threatening because it causes brainstem compression and compromises vital respiratory and cardiac centers in the medulla