of ischemic strokes [56]. SUMMARY Under normal conditions, the rate of cerebral blood flow is primarily determined by the amount of resistance within cerebral blood vessels. Dilation of vessels leads to an increased volume of blood in the brain and increased cerebral blood flow, whereas constriction of vessels has the opposite effect. Cerebral blood flow is also determined by variation in the cerebral perfusion pressure. (See 'Cerebral autoregulation' above.) The brain is exquisitely sensitive to even short durations of ischemia. Multiple mechanisms are involved in tissue damage that results from brain ischemia. (See 'Consequences of reduction in blood flow during stroke' above.) Brain ischemia initiates a cascade of events that eventually lead to cell death, including depletion of adenosine triphosphate (ATP); changes in ionic concentrations of sodium, potassium, and calcium; increased lactate; acidosis; accumulation of oxygen free radicals; intracellular accumulation of water; and activation of proteolytic processes. (See 'Mechanisms of ischemic cell injury and death' above.). https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 12/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate Cell death following cerebral ischemia or stroke can occur by either necrosis or by apoptosis. Low levels of ATP within the core infarct are insufficient to support apoptosis, and cell death occurs by necrosis. In the ischemic penumbra, ATP levels are sufficiently high that cell death by apoptosis can occur. 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Topic 14085 Version 27.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 16/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate GRAPHICS TOAST classification of subtypes of acute ischemic stroke Large-artery atherosclerosis Cardioembolism Small-vessel occlusion Stroke of other determined etiology Stroke of undetermined etiology Two or more causes identified Negative evaluation Incomplete evaluation Graphic 62571 Version 1.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 17/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate The progression of a dissection, thrombus development, and total vessel occlusion Courtesy of Dr. Mounzer Kassab. Graphic 57866 Version 2.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 18/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate Normal cerebral autoregulation and its disturbance during acute ischemic stroke Courtesy of Dr. Mounzer Kassab. Graphic 66923 Version 1.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 19/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate Effects of decreased cerebral blood flow on vital brain functions Courtesy of Dr. Mounzer Kassab. Graphic 77705 Version 2.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 20/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate Contributor Disclosures Arshad Majid, MB, ChB, FRCP No relevant financial relationship(s) with ineligible companies to disclose. Mounzer Kassab, MD Speaker's Bureau: UCB Pharma [Anticonvulsant]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 21/21