Histopathology of Brain Tissue Response to Stroke and Injury

Key Points

The four kinds of ischemia are transient focal, permanent focal, transient global, and permanent global.
Small vessel disease of arterioles can involve either blockage or breakage, and in hypertension, both can occur simultaneously.
Large vessel carotid artery pathology is comprised of endothelial ulceration, intramural hemorrhage into carotid plaque, and intraluminal thrombosis with detachment and embolization.
Infarction is a well-demarcated tissue lesion and a pH thresholded pan-necrosis, whereas selective neuronal loss is a lesser tissue lesion that clinically manifests most commonly with memory loss due to bilateral hippocampal neuronal loss after global ischemia.
Important diseases of the arteriole distinct from hypertension are amyloid angiopathy and CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy).
Animal models that replicate several key aspects of stroke pathology (including cellular responses in the penumbra of focal cerebral ischemia and selective hippocampal injury in global cerebral ischemia) may offer utility as experimental platforms to pursue mechanism and targets for therapy.

This chapter illustrates the pathology causing stroke due to large and small vessel disease, as well as heart disease. The pathologic reactions of the brain itself to the ischemic processes are also illustrated and discussed. The repertoire of brain tissue response to ischemia is remarkably limited to two tissue entities: selective neuronal death and infarction. Low blood flow may cause the neurons to selectively die (selective neuronal necrosis), sparing glia and neuropil. The second possibility is that the entire tissue undergoes necrosis (pan-necrosis), termed infarction in the setting of ischemia. All tissue responses to ischemia in the brain and spinal cord are variants of either selective neuronal loss or infarction.

When ischemia affects the entire brain, a much shorter duration of ischemia produces necrosis than in focal ischemia. Cardiac arrest can be tolerated for only a matter of minutes, whereas focal ischemia can be tolerated for much longer durations. This simple fact suggests that transsynaptic effects must operate and that they are detrimental in cerebral ischemia. We begin by considering the landscape of possible permutations of the general classes of ischemia.

Four Broad Categories of Cerebral Ischemia

Lack of blood flow can affect the entire brain (global ischemia) or just a portion of it (focal ischemia). Ischemia can also be permanent, or transient if reperfusion occurs. This gives rise to a natural permutation of four general types of cerebral ischemia ( Table 4.1 ).

TABLE 4.1

The Four Broad Types of Ischemia.

	Focal	Global
Transient	Embolus with reperfusion	Cardiac arrest with reperfusion
Permanent	End-vessel occlusion	Brain death

In addition to the basic type of ischemia, outcome is determined by basic physiologic parameters such as the degree of reduction in blood flow, the brain temperature, and the glucose levels. If blood flow to the entire brain is interrupted, reperfusion is accompanied by damage in remarkably restricted areas. This is termed selective vulnerability, and the principle of selective vulnerability obtains in most neurologic disease, not only stroke and cardiac arrest.

When ischemia is focal, the size and location of the vessel, together with the nature of the occlusion (or leak, in a hemorrhage), determine the outcome of the stroke. The disease is already focal by virtue of a locally occluded vessel, substituting for the principle of selective vulnerability in global ischemia to determine the final neurologic deficit of the patient.

Stroke is aptly named in English, being the most rapidly changing deficit of all neurologic conditions. There are exactly two potential underlying pathologic causes of a stroke: infarct or hemorrhage. This is because only two things can go wrong with a blood vessel: it can block or break.

The fact that vessels can only be blocked or broken in giving rise to brain tissue pathology has widespread implications for vessels of all sizes. The major named arteries of the brain can occlude, giving rise to large infarcts, or they can rupture, giving rise to fatal hemorrhages. At the level of the arteriole as well as the artery, the principle of blockage versus breakage applies. Lacunes are due to occlusions of arterioles, whereas microhemorrhages are due to leaking arterioles.

Some diseases affect brain arterioles in a manner that can produce both hemorrhage and occlusion. The classic example is hypertension, which can break and block arterioles, often simultaneously. In the retina, this blocked-or-broken principle applies as well, where cotton wool spots represent infarcts of the nerve fiber layer, whereas ophthalmoscopically visible hemorrhages represent leakage of retinal arterioles.

The sudden nature of occlusion or leakage of vessels is the feature that originally gave rise to the term stroke, engendering a rapidly changing clinical deficit that evolves over seconds, to minutes, to hours. There is nothing like it in neurology, with respect to speed of onset.

A slower clinical evolution is unusual and is seen mainly in the entity termed hemodynamic stroke, where progression can occur over hours to days. Hemodynamic stroke results from a cardiac cause that lowers the blood pressure to such an extent that critically low cerebral blood flow levels occur in either an artery that is only partially occluded, or in the watershed zone between two or three major cerebral arteries, leading to infarction. Hemodynamic stroke thus has its origin in the heart, not in a blood vessel of the brain, and comprises the major exception to the above principles of a “blocked or broken” vessel as a cause of the pathology of stroke.

Large Vessel Strokes

Most large vessel strokes of an ischemic nature arise from causes outside the brain (the carotid arteries or the heart), the most common being atherosclerosis ( Chapter 1 ). Atherosclerosis causes stroke in two major ways, the first being coronary atherosclerosis with consequent heart disease and the second being atherosclerosis of the carotid artery bifurcation. Both the heart ( Fig. 4.1 ) and the carotid ( Fig. 4.2 ) causes of stroke lead to brain infarcts by releasing emboli to the brain. The consequences of cardiac arrest or carotid thrombosis are quite different from the usual stroke. If the heart itself stops, the brain response is that of cardiac arrest encephalopathy, which can take several forms (neocortical, hippocampal, basal ganglia, or cerebellar impairment in various combinations). If the carotid artery occludes, this usually results in malignant ischemic hemispheric edema and death. We will first cover the common cardiac and carotid causes of stroke, following the flow of blood and the route emboli actually travel to cause stroke. The brain histopathologic response to these events will follow, in the context of stroke and the related conditions of global ischemia and edema.

Fig. 4.1, Heart causes of stroke include both myocardial and valvular disease. (A) Mural clots (white) adhere, and then detach, to ischemic myocardium due to the altered kinetic properties of ischemic heart muscle. (B) Nonbacterial thrombotic endocarditis is seen (red) on the aortic valve of a cancer patient. The detached clots embolize to brain in both cases.

Fig. 4.2, Carotid artery causes of stroke. Hemorrhage into atherosclerotic plaque regularly occurs as the plaque enlarges, as seen in an autopsy specimen, where internal carotid artery mural hemorrhage has occurred into a plaque (A) located just above the bifurcation. Section B through an endarterectomy reveals the degree of luminal compression, the lumen (Lum) here equal in size to the intramural hematoma (Hem) . An endarterectomy specimen opened and pinned to a cork (C) reveals an ulcer (white arrow) in the right carotid of a 79-year-old man with a right hemisphere infarct. Gross appearance (D) reveals smooth covering of the atheroma on the left, but an ulcer interrupting the normal white appearance of the endothelial and subendothelial connective tissue on the upper aspect of the lumen on the right. A major portion of the atheroma is blood, revealed by a Masson trichrome stain (E) that shows the hemorrhage as violet, admixed with collagen seen as blue. A ball-like thrombus (arrow) seen angiographically (F) prior to endarterectomy is revealed to be an adherent “red clot” macroscopically (G) and microscopically (H) after endarterectomy.

Heart Disease and Cerebral Emboli

In ischemic heart disease, poorly contracting or akinetic myocardial segments accumulate mural clot that can dislodge emboli to the brain, from the left ventricle (see Fig. 4.1A ). Heart disease need not be ischemic to give rise to embolic brain infarcts: the many forms of valvular disease can also do this, including, for example, rheumatic endocarditis, nonbacterial thrombotic endocarditis, and bacterial endocarditis (see Fig. 4.1B ).

Carotid Artery Atherosclerosis

Atherosclerosis is a generalized disease of large and medium-sized arteries that begins in the descending abdominal aorta. Over time, atherosclerosis tends to involve the thoracic aorta and iliac arteries, often affecting the renal arteries. Despite the ascending aorta and aortic arch having greater flow than the distal aorta, they show less atherosclerosis than the descending aorta. Less frequently a source than the carotid artery, the aortic arch and the great vessels that branch from the aortic arch ( Chapter 33 ) can also emboli to the brain.

The atherosclerotic carotid plaque consists of an accumulation of lipid, cholesterol, smooth muscle, fibroblasts, capillaries, and hemorrhage. The intramural expansion gives rise to a space-occupying effect of these atheromatous tissue components, and their slow accumulation can lead to occlusion of the carotid artery. However, with a smooth overlying endothelium, such slow occlusion is not the usual mechanism of stroke, because collateral circulation can develop when occlusion occurs slowly due to the mass of atheroma building up over years to decades.

The mechanism of stroke in carotid atherosclerosis is not slow, steady occlusion; this allows time for growth of collateral vessels to circumvent the blockage. Instead, carotid atherosclerosis commonly results in a sudden event that breaches the endothelial integrity. The endothelial rent exposes subendothelial connective tissue to blood, causing platelet aggregation and accounting for emboli sent to the brain from a locus of atherosclerosis in the neck.

Two major mechanisms seem to play a role in generating this sudden endothelial breach. One is hemorrhage into the atherosclerotic plaque (see Fig. 4.2A and B). The second is ulceration of the plaque (see Fig. 4.2C and D). Hemorrhage into the wall occurs too rapidly for endothelial cell cytoplasm to maintain complete integrity of the endothelial lining, resulting in a rent. An ulcer, by definition, involves a more permanent denudation of endothelium. Thus both of these complications of carotid atherosclerosis breach the integrity of the endothelium, expose subendothelial connective tissue, activate clotting systems, and release thromboemboli. Endothelial breach explains the therapeutic benefit of aspirin, ^, which inhibits platelet aggregation and emboli formed as a result of such carotid disease. Such mural mechanisms are important because, when carotid stenosis is less than 70%, hemodynamic factors poorly account for stroke.

Hemorrhage into the plaque (see Fig. 4.2B, D, and E ) has become increasingly recognized in the pathogenesis of carotid artery–induced stroke. The suddenness of the hemorrhage means the overlying endothelial cells are torn apart. Any rent in the intercellular junctions of endothelial cells will expose subendothelial collagen, leading to clot formation. The blood clotting system, especially Hageman factor (XII, initiating the intrinsic coagulation pathway), is very sensitive to collagen connective tissue components located beneath the endothelium. This may lead to clot formation seen in endarterectomy specimens (see Fig. 4.2F–H ) where the clot has not yet detached and embolized to the brain. Intraluminal clot can, if it can persist without detachment and embolization, show a pavement-like growth of endothelium (see Fig. 4.2I ) over it. Such endothelial overgrowth reduces the chances further, of subsequent detachment, and may eventuate in the clot scarring and becoming incorporated into the carotid artery wall as a healed mural nodule.

Other than blood clot, the pathology of embolic infarction may reveal embolism of atheromatous material itself (see Fig. 4.2J ), with fragments of atheroma including cholesterol clefts and giant cells seen lodged in brain vessels (see Fig. 4.2K ). Some clots contain calcium (see Fig. 4.2L ). When the emboli consist of simple clot, there is recanalization leading to a new lumen within the old lumen giving a “lumen-within-a-lumen” appearance of telescoped vessels (see Fig. 4.2M ).

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