Ischemic Stroke Pathophysiology

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Although the human brain accounts for 2% of the total body weight, it utilizes 20% of the cardiac output to supply the required oxygen and glucose necessary for its incessant metabolic needs. Because the brain does not store or produce these substances, any interruption in their delivery results in some kind of dysfunction. Blood-flow alterations or limitations can, at times, be tolerated, because of compensatory mechanisms such as collateral circulation. Progressive ischemia can lead to brain infarction which, in turn, leads to local vasodilatation, edema, stasis of the blood column and segmentation of the red blood cells and, eventually, brain tissue necrosis. The local vasodilatation leads to an increase in cerebral blood volume and enhanced oxygen extraction from the capillaries.

Cellular edema occurs because of ischemic-induced changes in membrane permeability. This allows for a net ionic influx. There is an associated failure of the Na+/K+ pump, the release of excitatory neurotransmitters such as glutamate, and the opening of calcium channels. The opening of these calcium channels leads to further calcium influx, which results in cell injury, as a consequence of organelle dysfunction and disruption of neuronal metabolism. Calcium activates degradative enzymes, such as lipases, proteases and endonucleases. There is also an accumulation of free fatty acids from membrane phospholipid degradation, which are not oxidized by the cyclooxygenase or lipooxygenase pathways. As a result, prosta-glandins, leukotrienes and free radicals are formed, which, in turn, lead to altered membrane permeability, vasoconstriction and the destruction of cellular membranes.

CBF regulation is an important mechanism, which plays a role in protecting the brain from ischemia. Blood-flow thresholds have been correlated to the degree of neuronal dysfunction and ischemic damage. Resting CBF is usually 50-55 ml/100 g/minute, with flow through gray matter higher than through white matter. Blood flow to the brain is coupled to neuronal activity and metabolism. There is an increase in cerebral blood flow during direct electrical excitation, seizure activity and the performance of certain intellectual tasks. Cerebral autoregulation refers to the ability of the brain to maintain a constant CBF, despite changes in arterial perfusion pressure. During cerebral ischemia, auto-regulation is impaired [2]. At blood-flow levels of about 20 ml/100 g/minute, cortical electrical activity is not detectable. At levels of 10 ml/100 g/minute, there is an increase in extracellular potassium concentration - a finding consistent with membrane pump failure and cell death [3].

The ischemic penumbra is defined as that area of brain tissue surrounding the center of the infarct in which neuronal function is impaired but can be salvaged. Reduced perfusion or prolonged ischemia leads to incorporation of the penumbra region into the infarcted region, which, in turn, leads to more extensive tissue necrosis and death. Restoration of blood flow to this region allows for the delivery of vital substrates to the brain and eventual resolution of neuronal dysfunction. Most stroke therapy modalities now in use have as their goal the prompt restoration of blood flow to this region, so as to prevent the neurological dysfunction associated with massive tissue necrosis. Following infarction, the brain softens and liquifies and the necrotic tissue is removed by microglia. Astroglia from the surrounding brain tissue proliferate to occupy the remaining space.

The ischemic insult can be worsened by factors such as individual anatomical vascular variations and the presence and extent of collateral circulation. The vascular supply to the brain can vary from person to person, and arterial territories and their boundaries are even different within the same individual at different times. Changes in hemodynamic conditions can have an effect on these vascular territories and potentially worsen cerebral ischemia. Adequate supplementary blood flow through collateral vessels is also variable between individuals. In the presence of vessel occlusion or stenosis, pressure gradients help to supply, through anastomotic networks, blood to compromised territories.

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