Pathophysiology and pathology of
cerebral ischemia
Pathophysiology
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Except for the lack of an external elastica lamina in the intracranial arteries, the
morphological structure of the cerebral vessels is similar to those in other
vascular beds.
The arterial wall consists of three layers: the outer layer, or adventitia; the middle
layer, or media; and the inner layer, or intima.
The intima is a smooth monolayer of endothelial cells providing a non-thrombotic
surface for blood flow. One of the major functions of the endothelium is active
inhibition of coagulation and thrombosis.
The brain microcirculation comprises the smallest components of the vascular
system, including arterioles, capillaries, and venules.
The arterioles are composed primarily of smooth muscle cells around the
endothelial-lined lumen and are the major sites of blood flow resistance.
The capillary wall consists of a thin monolayer of endothelial cells. Nutrients and
metabolites diffuse across the capillary bed.
The venules are composed of endothelium and a fragile smooth muscle wall and
function as collecting tubules.
The cerebral microcirculation distributes blood to its target organ by regulating
blood flow and distributing oxygen and glucose to the brain, while removing byproducts of metabolism.
A cascade of complex biochemical events occurs seconds to minutes after
cerebral ischemia. Cerebral ischemia is caused by reduced oxygen delivery to the
microcirculation. Ischemia causes impairment of brain energy metabolism, loss of
aerobic glycolysis, intracellular accumulation of sodium and calcium ions, release
of excitotoxic neurotransmitters, lactate elevation with local acidosis, free radical
production, cell swelling, overactivation of lipases and proteases, and cell death.
Many neurons undergo apoptosis after brain ischemia. Ischemic brain injury is
exacerbated by leukocyte infiltration and development of brain edema. These
biochemical changes have been the targets for many strategies aimed at
neuroprotection.
Complete interruption of cerebral blood flow (CBF) causes suppression of the
electrical activity within 12–15 seconds, inhibition of synaptic excitability of
cortical neurons after 2–4 minutes, and inhibition of electrical excitability after 4–
6 minutes.
Normal CBF at rest in the normal adult brain is approximately 50–55 mL/100
g/min, and the cerebral metabolic rate of oxygen is 165 mmol/100 g/min.
There are ischemic thresholds in experimental focal brain ischemia. When blood
flow decreases to 18 mL/100 g/min, the brain reaches a threshold for electrical
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failure. Although these neurons are not functioning normally, they do have
recovery potential. The second level, known as the threshold of membrane
failure, occurs when blood flow decreases to 8 mL/100 g/min. Cell death rapidly
results.
These thresholds mark the upper and lower limits of the ischemic penumbra. The
ischemic penumbra, or area of “misery perfusion,” is the area of the ischemic
brain between these two flow thresholds in which there are some neurons that are
functionally silent but structurally intact and potentially salvageable.
Pathology
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The pathological characteristics of ischemic stroke depend on the stroke
mechanism, the size of the obstructed artery, and the collateral blood flow
availability.
There may be advanced changes of atherosclerosis visible within arteries. The
brain surface in the area of infarction appears pale.
With ischemia caused by hypotension or hemodynamic changes, the arterial
border (or watershed) zones are most vulnerable. It appears along the
boundaries between different vascular territories.
A wedge-shaped area of infarction in the center of an arterial territory may
result if there is occlusion of a main artery in the presence of collateral blood
flow. In the absence of collateral blood flow, the entire territory supplied by an
artery may be infarcted (territorial infarction).
With occlusion of a major artery such as the internal carotid, there may be a
multilobar infarction. There may be evidence of flattening of the gyri and
obliteration of the sulci caused by cerebral edema.
A lacunar infarction is a deep infarction within the territory of a single, small
penetrating artery. It appears with a size of 1.5 cm or less in subcortical areas or
in the brainstem and may be rarely visible in the macroscopic analysis of the cut
brain.
Small emboli to the brain tend to lodge at the junction between the cerebral
cortex and the white matter. Reperfusion of the infarct may occur, leading to
hemorrhagic transformation.
The microscopic changes after cerebral infarction depend on the age of the
infarction. They do not occur immediately and may be delayed up to 6 hours
after onset.
 There is neuronal swelling initially, which is followed by shrinkage,
hyperchromasia, and pyknosis.
 Chromatolysis appears, and the nuclei become eccentric. Swelling and
fragmentation of the astrocytes and endothelial swelling occur.
 Neutrophil infiltrates appear as early as 4 hours after the ischemia and become
abundant by 36 hours.
 Within 48 hours, the microglia proliferate and ingest myelin breakdown
products and form foamy macrophages.
 Later there is neovascularization. The necrotic elements are gradually
reabsorbed, and a cavity consisting of glial and fibrovascular elements forms.
 In a large infarction, there are three distinct zones: an inner area of
coagulative necrosis; a middle zone of vacuolated neuropil, leukocytic
infiltrates, swollen axons, and thickened capillaries; and an outer marginal
zone of hyperplastic astrocytes and variable changes in nuclear staining.