Ischemic stroke

Pathogenesis and pathophysiology
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By Brian Silver MD

Pathogenesis. An ischemic stroke results when cerebral blood flow to an area of the brain is interrupted. Ischemia produces impaired energy metabolism and depolarization of cells that leads to an accumulation of calcium ions in the intracellular space, elevated lactate levels, acidosis, and production of free radicals. If the disruption is severe enough, cell death occurs. Activation of the N-methyl-D-aspartate receptor by an increase in glutamate leads to a cascade of chemical reactions that ultimately leads to cell death (“theory of excitotoxicity”). Modulators of this receptor include polyamines, glycine, magnesium, zinc, and phencyclidine. Magnesium delivered during ambulance transfer is under active investigation as a neuroprotective agent (Saver et al 2004). However, magnesium delivered in the first hour after stroke fails to improve outcome (Saver et al 2015b). Normal adult brain cerebral blood flow is 50 to 60 mL/100g/minute. When cerebral blood flow falls below 18 mL/100g/minute in baboons, sensory evoked potentials disappear (Symon 1980). In the same experiment, when cerebral blood flow fell below 12 mL/100g/minute, infarction occurred. Therefore, cerebral blood flow between 10 and 20 mL/100g/minute is considered consistent with ischemic penumbra. Cerebral blood flow below 10 mL/100g/minute is considered compatible with infarction. These delineations are not absolute because time is also a factor in the fate of tissue. Cerebral blood flows of 5 mL/100g/minute result in infarction within 30 minutes, whereas those between 5 and 15 mL/100g/minute result in infarction after 1 to 3 hours (Marcoux et al 1982).

Gross pathology. The pathological characteristics of ischemic stroke are dependent on the mechanism of the stroke, the size of the obstructed artery, and the availability of collateral blood flow. There may be advanced changes of atherosclerosis visible within arteries. The surface of the brain in the area of infarction appears pale. With ischemia due to hypotension or hemodynamic changes, the arterial border zones may be involved. 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. With occlusion of a major artery, such as the internal carotid artery, there may be a multilobar infarction with surrounding edema. There may be flattening of the gyri and obliteration of the sulci with cerebral edema. A lacunar infarction in subcortical regions or the brainstem may be barely visible, with a size of 1.5 cm or less. Emboli to the brain tend to lodge at the junction between the cerebral cortex and the white matter. There may be early reperfusion of the infarct when the clot lyses, leading to hemorrhagic transformation. Over time the necrotic tissue is absorbed (leaving a cystic cavity) and is surrounded by a glial scar.

The initiation, progression, and activation of atherosclerosis are predominantly inflammatory conditions produced by a “response to injury” mechanism after exposure to certain injurious vascular risk factors. Individual genetic profiles can affect pathophysiological mediators of plaque development, symptomatic manifestations, and recovery from strokes associated with cerebrovascular atherosclerosis. A number of stimuli can initiate endothelial injury, which, in turn, leads to a cascade of events that result in lipid deposition and inflammatory cell migration (de Boer et al 2000; Worrall and Degraba 2002). This inflammatory process includes the increased expression of adhesion molecules, cytokines, chemokines, metalloproteinases, and antigen-mediated activation of macrophages and T-lymphocytes. As the plaque matures, platelet aggregation and clot formation with or without plaque rupture may ensue. The clinical result is an atherothrombotic ischemic stroke.

Microscopic pathology. Microscopic changes after infarction depend on the age of the infarction and may be delayed up to 6 hours after infarction. Initially there is neuronal swelling, followed by shrinkage, hyperchromasia, and pyknosis. Chromatolysis appears and the nuclei become eccentric. There is swelling and fragmentation of the astrocytes and endothelial swelling. Neutrophils infiltrate as early as 4 hours after the ischemia and become abundant by 36 hours. Within 48 hours, the microglia proliferate and ingest the products of myelin breakdown and form macrophages. There is neovascularity with proliferation of capillaries and increased prominence of the existing capillaries. The elements in the area of necrosis are gradually reabsorbed and a cavity, consisting of glial and fibrovascular elements, forms. In a large infarction, there are 3 distinct zones: an inner area of coagulative necrosis; a central 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.

Genetics. As with most diseases, stroke is a result of the interaction between genetics and environmental exposure (Flossmann et al 2004). There are a number of genetic causes of stroke (Meschia et al 2005). These disorders often result in an early age of stroke onset (ie, younger than 40 years of age). Some inherited diseases predispose to accelerated atherosclerosis, such as the hereditary dyslipoproteinemias. A number of inherited diseases are associated with nonatherosclerotic vasculopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Joutel et al 1996), Ehlers-Danlos (type 4) syndrome, Marfan's syndrome, Rendu-Osler-Weber disease, and Sturge-Weber syndrome. Inherited cardiac disorders that predispose to stroke include familial atrial myxomas, hereditary cardiomyopathies, and hereditary cardiac conduction disorders. Inherited hematologic abnormalities that are associated with venous stroke include deficiencies of protein C, S, and antithrombin III. Other hematologic abnormalities including mutation of factor V Leiden, polymorphism of thermolabile methylenetetrahydrofolate reductase, and G20210A mutation of the prothrombin gene have been associated with venous and arterial stroke. Sickle cell disease is a well-known cause of stroke and frequently leads to strokes during childhood (Carson et al 1963). Finally, rare inherited metabolic disorders that can cause stroke include mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (Pavlakis et al 1984), Fabry disease (Mitsias and Levine 1996), and homocystinuria.

Other potential genetic factors, particularly for carotid atherosclerosis, include PDE4D (Gretarsdottir et al 2003), interleukin-1 receptor antagonist (IL-1ra) (Worrall et al 2003), toll-like receptor-4 (TL4) (Reismann et al 2004), 5-lipoxygenase (5-LO) (Dwyer et al 2004), interleukin-6 (IL-6) (Chapman et al 2003), hepatic lipases (Rundek et al 2002), cyclooxygenase 2 (COX-2) (Cipollone et al 2004), and matrix metalloproteinase polymorphisms (MMP) (Abilleira et al 2006). More recently, the potential importance of certain microRNAs (miRNAs) has been demonstrated in the walls of unstable plaques (Cipollone et al 2011).

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited