CEREBRAL ISCHEMIA - University of Toronto



CEREBRAL ISCHEMIA AND INFARCTION

Structural Changes Resulting from Hypoxic-Ischemic Insults

-even with global ischemia, even though the entire brain is inadequately perfused, there is suprising focality to the pathological alterations seen

-cell populations selectively vulnerable:

-large neurons Sommer's sector of hippocampus

-Purkinje cells cerebellum

-Neurons of layers 3 and 5 of the cerebral cortex

-basis of this selective vulnerability is not entirely clear but may be related to local energy metabolism requirements, hemodynamic factors, and excitatory reflecting local neurotransmitters

-when ischemia leads to brain energy failure, membranes depolarize permitting uncontrolled release of neurotransmitters glutamate and aspartate; these neurotransmitters bind ligand-gated cation channels on the post-synaptic cell, opening the floodgates for entry of calcium and sodium; the sodium depolarizes the cell membrane and the calcium may activate intracellular proteases and quench mitochondrial energy production

-neurons are more vulnerable than oligodendroglia and astrocytes; is the structural damage is limited to neurons referred to as selective neuronal necrosis

-neurons of the phylogenetically older portions of the nervous system are more resistant than the newer

-grey matter of the spinal cord and most of that in the adult brain stem may be undamaged in the presence of almost total destruction of the cerebral cortex

-in contrast, in children the brain stem is more vulnerable

Alterations in Neurons

1) dark cell change - artefactual ; need to distinguish from ischemic change

2) water change- cell is swollen and cytoplasm stains less intensely than normal ; a result of incompletely fixed tissue and need to distinguish from ischemic changes

Ischemic Cell Processes

The earliest stage of ischemic cell proces is microvacuolation. The stage of ischemic cell change with incrustations and finally homogenizing cell change and eventual disappearance of the neuron follow.

Associated Glial Reactions

-while the time course of neuronal alteraltions is rapid, the astocytic and microglial ractions take place after the neurons have been irreversibly damaged and may contiue for months

-these reactions are proportional to the severity of the neuronal destruction

-alterations in the oligodendrocytes within a region of hypoxic damage are slight and seldom more than acute swelling

-the microglial are transformed into rod cells which are characteristically oriented at right angles to the pial surface of the neocortex, radially within the hippocampus and cerebellum; after 2-3 days , fine lipid droplets may be seen in their cytoplasm, and a little later division by mitosis takes place and the daughter cells develop into typical macrophages which are probably involved in the removal of myelin debris

Associated Changes in the White Matter

-with increasing neuronal destruction, some pallor of myelin staining is seen in the adjacent white matter

-hypoxic alterations in white matter may be diffuse or focal

-when diffuse there is loss of myelin in each centrum semiovale, spreading from the periventricular region into the digitate white matter but usually sparing the subcortical U-fibres; after survival of a few days, the region of myelin destruction presents a spongy and often finely cystic texture

Selective Vulnerability

-In its classic form this is diffuse and is seen after an episode of cardiorespiratory arrest. It may also be applicable in instances of focal ischemia.

-damage is usually greatest in the parietal and occipital lobes and decreases towards the temproal and frontal poles

-damage is commonly greater in the depths and sides of sulci than over the crests of gyri

-among the cortical layers, the third is most vulnerable; 5 and 6 intermediate; 2 and 4 most resistant

-within the hippocampus, Sommer sector CAI are most vulnerable , while CA2 is resistant. The dentate gyrus is the very least vulnerable zone of the hippocampus

-in the striatum, the outer halves of the head and body of caudate, and outer half of the putamen are most frequently affected.

-hypoxic-ischemic damage in the thalamus is most common in the anterior nuclear complex

-in the adult brain stem, the reticular zones of the substantia nigra, the inferior colliculi and the inferior olives are relatively vulnerable

-in the cerebellum, the Purkinje cells and basket cells are most vulnerable

Watersheds

-When ischemic brain damage occurs along the arterial boundary zones, the critical factor is a reduction in the availability of tissue oxygen, usually because of a local reduction in CBF. The vulnerability of the arterial boundary zones is a consequence of the anastomosis of small vessels. Once the capacity for autoregualtion of blood flow is lost as a result of reduced perfusion pressure and hypoxemia, oxygen falls to a critical level in those parts of the arterial territories that are most remote from the parent stems.

Influence of maturity on brain damage

-Periventricular leucomalacia is the common hypoxic lesion in the preterm brain. It is widely accepted as being due to failure of perfusion along the boundary zones between the centripetal and centrifugal arteries within the brain.

-After birth asphyxia, the brain damage seen is variable and includes damage to the cerebral cortex, white matter, basal ganglia, cerebellum and brain stem.

Excitotoxicity

-injury done by neurotransmitters normally present , but in pathological conditions is abnormally released

-this mechanism may play a role in neurodegenerative disorders and epilepsy as well as stroke

i)Inappropriate activation of the NMDA receptor

ii) membrane depolarization

iii) influx of calcium

iv) activation of hydrolytic enzymes and quenching of mitochondria

CEREBRAL INFARCTION

A cerebral infarct is defined as a volume of tissue within which all cell bodies (neuronal and glial), blood vessels, and nerve fibers have undergone necrosis as a result of a reduction in blood supply. The principal causes of infarction are arterial occlusion by thrombus formation or embolis, spasm iin assocation with subarachnoid hemorrhage, and a failure of cerebral perfusion.

Gross

-in the fresh specimen, large recent infarcts are swollen (more in the white than in the grey); sometimes hyperemic, and soft

-in fixed state, the hyperemia is less marked, but there is a more marked distinction between the infarct and normal tissue

-may be hemorrhagic; associated with embolic stroke: 50-70% of embolic strokes, compared with 2-20% of non-embolic strokes

-the risk of hemorrhagic conversion is higher for large infarcts

-within a few weeks the swelling within and around an infarct decreases and the infarcted grey matter becomes soft and granular; white matter also shrinks and becomes rubbery

-over weeks to months the infarct matures into a cystic space sometimes accompanied with ventricular enlargement

Micro

-within grey matter the outlines of dead neurons are recognizable, their cytoplasm intensely eosinophilic , red neurons, and usually containing numerous vacuoles

-the nucleus stains poorly

-this picture, which is seen within the first 4-6 hours, is followed by decreasing staining of the nucleus and cytoplasm until a ghost cell is all that remains

-EM shows early necrosis and swelling of endothelial cells;

-within the white matter, myelin pallor and swelling of axons and myelin sheaths develop between 16 and 24 hours

-infiltration with polys at 24 hours after an infarct; blood vessels are prominent; tissue is soft and edematous

-macrophages appear after 4-5 days; in an infarct the microglia are destroyed and the two sources of lipid-containing macrophages are monocyutes and the adventitial fibroblasts in the walls of the remaining blood vessels; the infarct is frankly mushy

-during the second week, proliferating astrocytes join the macrophages, and over the following weeks to months form a dense fibrillary glial meshwork around the dead tissue; the infarct evolves into a cystic glial lined cavity at points traversed by delicate glial sheets and small vessels and invested with residual lipid and hemosiderin laden macrophages

Summary of Gross features of cerebral infarcts

-depths of sulci > crests

-not grossly evident for first 6-12 hours

-within 48-72 hours, gross necrosis evident

-days 3-5, cerebral edema maximal

-liquefaction of necrotic tissue for days to weeks

Summary of time sequence of neuronal ischemic death

-microvacuolation (min to hours) appears then regresses

-red neurons 6-24 hours; classically said to be the first sign of irreversible damage

-incrustation phase - small dense fragments of neuronal cytoplasm flake from dendrites ; 24-72 h

-homogenizing cell change- complete loss of cytoplasmic detail; nucleus disintegrates 24h- days

Summary of glial, microglial, and vascular reaction to ischemic injury

-if the astrocytes survive, they react by swelling (12-36 h) and multiplying (gliosis 48h - months)

-macrophages appear within 48 h and exhibit neuronophagy (consumption of necrotic neurons)

-polys invade within hours peaking at 48-72 hours, being replaced by macrophages which peak at about 14 days but persist for months to years

-small blood vessels are prominent by 48 hours

-blood brain barrier is not intact; both vasogenic and cytotoxic edema develop

-the end result of phagocytic activity is the creation of cysts

-the walls of some cysts are orange-brown in colour because of blood pigments

-the outer wall of the cysts may consist of pia and the heavily gliosed first layer of the cortex, but sometimes the latter is lacking

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