Temporary Occlusion of the Middle Cerebral Artery in the Monkey: Clinical and Pathological Observations
TL;DR: The results suggest that reestablishment of flow by surgical means within a few hours after MCA occlusion in selected patients might result in significant restoration of neurological function.
Abstract: The right middle cerebral artery (MCA) was exposed in monkeys via a retro-orbital microsurgical approach. In 43 animals a temporary occlusive clip was placed on the MCA origin for one to 24 hours. In 20 animals, the origin of the MCA was permanently occluded. Clinical evaluation of the monkeys one to three days postoperatively showed that one to two-hour clipping caused no or mild neurological deficits, four-hour clipping caused mild to moderate deficits, six to eight-hour clipping caused moderate to severe deficits, and 24-hour clipping produced severe deficits or death, a result equivalent to that produced by permanent occlusion. Gross and microscopical evaluation of the brains showed that one to two-hour clipping usually caused no or mild damage, four-hour clipping caused mild to moderate damage (often with capsular sparing), and six to eight-hour clipping and 24-hour clipping produced severe extensive infarction not different from that caused by permanent occlusion. Six to eight-hour clipping and 24-h...
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TL;DR: Some cases of acute hemiplegia, with blood flow in the paralysis range, might be improved by surgical revascularization, and studies of local CBF might help identify suitable cases for emergency revascularized.
Abstract: An awake-primate model has been developed which permits reversible middle cerebral artery (MCA) occlusion during physiological monitoring. This method eliminates the ischemia-modifying effects of anesthesia, and permits correlation of neurological function with cerebral blood flow (CBF) and neuropathology. The model was used to assess the brain's tolerance to focal cerebral ischemia. The MCA was occluded for 15 or 30 minutes, 2 to 3 hours, or permanently. Serial monitoring evaluated neurological function, local CBF (hydrogen clearance), and other physiological parameters (blood pressure, blood gases, and intracranial pressure). After 2 weeks, neuropathological evaluation identified infarcts and their relation to blood flow recording sites. Middle cerebral artery occlusion usually caused substantial decreases in local CBF. Variable reduction in flow correlated directly with the variable severity of deficit. Release of occlusion at up to 3 hours led to clinical improvement. Pathological examination showed microscopic foci of infarction after 15 to 30 minutes of ischemia, moderate to large infarcts after 2 to 3 hours of ischemia, and in most cases large infarcts after permanent MCA occlusion. Local CBF appeared to define thresholds for paralysis and infarction. When local flow dropped below about 23 cc/100 gm/min, reversible paralysis occurred. When local flow fell below 10 to 12 cc/100 gm/min for 2 to 3 hours or below 17 to 18 cc/100 gm/min during permanent occlusion, irreversible local damage was observed. These studies imply that some cases of acute hemiplegia, with blood flow in the paralysis range, might be improved by surgical revascularization. Studies of local CBF might help identify suitable cases for emergency revascularization.
1,139 citations
TL;DR: Differences in the pump/leak relationship for calcium explain why calcium and glutamate antagonists may lack effect on the cardiac arrest type of ischemia, while decreasing infarct size in focal ischemIA.
Abstract: ✓ The mechanisms that give rise to ischemic brain damage have not been definitively determined, but considerable evidence exists that three major factors are involved: increases in the intercellular cytosolic calcium concentration (Ca++i), acidosis, and production of free radicals. A nonphysiological rise in Ca++i due to a disturbed pump/leak relationship for calcium is believed to cause cell damage by overactivation of lipases and proteases and possibly also of endonucleases, and by alterations of protein phosphorylation, which secondarily affects protein synthesis and genome expression. The severity of this disturbance depends on the density of ischemia. In complete or near-complete ischemia of the cardiac arrest type, pump activity has ceased and the calcium leak is enhanced by the massive release of excitatory amino acids. As a result, multiple calcium channels are opened. This is probably the scenario in the focus of an ischemic lesion due to middle cerebral artery occlusion. Such ischemic tissues ca...
1,136 citations
TL;DR: An association exists between body temperature and initial stroke severity, infarct size, mortality, and outcome in acute human stroke and only intervention trials of hypothermic treatment can prove whether this relation is causal.
854 citations
TL;DR: The pathophysiology of lesions caused by focal cerebral ischemia, a complex interplay between loss of cellular calcium homeostasis and acidosis, plays an important role in the pathogenesis of ischemic cell damage.
Abstract: This article examines the pathophysiology of lesions caused by focal cerebral ischemia. Ischemia due to middle cerebral artery occlusion encompasses a densely ischemic focus and a less densely ischemic penumbral zone. Cells in the focus are usually doomed unless reperfusion is quickly instituted. In contrast, although the penumbra contains cells "at risk," these may remain viable for at least 4 to 8 hours. Cells in the penumbra may be salvaged by reperfusion or by drugs that prevent an extension of the infarction into the penumbral zone. Factors responsible for such an extension probably include acidosis, edema, K+/Ca++ transients, and inhibition of protein synthesis. Central to any discussion of the pathophysiology of ischemic lesions is energy depletion. This is because failure to maintain cellular adenosine triphosphate (ATP) levels leads to degradation of macromolecules of key importance to membrane and cytoskeletal integrity, to loss of ion homeostasis, involving cellular accumulation of Ca++, Na+, and Cl-, with osmotically obligated water, and to production of metabolic acids with a resulting decrease in intra- and extracellular pH. In all probability, loss of cellular calcium homeostasis plays an important role in the pathogenesis of ischemic cell damage. The resulting rise in the free cytosolic intracellular calcium concentration (Ca++) depends on both the loss of calcium pump function (due to ATP depletion), and the rise in membrane permeability to calcium. In ischemia, calcium influx occurs via multiple pathways. Some of the most important routes depend on activation of receptors by glutamate and associated excitatory amino acids released from depolarized presynaptic endings. However, ischemia also interfers with the intracellular sequestration and binding of calcium, thereby contributing to the rise in intracellular Ca++. A second key event in the ischemic tissue is activation of anaerobic glucolysis. The main reason for this activation is inhibition of mitochondrial metabolism by lack of oxygen; however, other factors probably contribute. For example, there is a complex interplay between loss of cellular calcium homeostasis and acidosis. On the one hand, a rise in intracellular Ca++ is apt to cause mitochondrial accumulation of calcium. This must interfere with ATP production and enhance anaerobic glucolysis. On the other hand, acidosis must interfere with calcium binding, thereby contributing to the rise in intracellular Ca++.
790 citations
TL;DR: It is emphasized that gross brain damage, involving edema formation and infarction, is enhanced by tissue acidosis, and that neuronal damage appears related to a disturbed Ca2+ homeostasis, and to Ca2-triggered events such as lipolysis and proteolysis.
Abstract: Recent developments in the field of cerebral circulation and metabolism are reviewed, with emphasis on circulatory and metabolic events that have a bearing on brain damage incurred in ischemia. The first part of the treatise reviews aspects of cerebral metabolism that provide a link to the coupling of metabolism and blood flow, notably those that lead to a perturbation of cellular energy state, ionic homeostasis, and phospholipid metabolism. In the second part, attention is focused on the derangement of energy metabolism and its effects on ion fluxes, acid-base homeostasis, and lipid metabolism. It is emphasized that gross brain damage, involving edema formation and infarction, is enhanced by tissue acidosis, and that neuronal damage, often showing a pronounced selectivity in localization, appears related to a disturbed Ca2+ homeostasis, and to Ca2+-triggered events such as lipolysis and proteolysis.
547 citations
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TL;DR: The category of patients for whom revascularization seems most helpful is represented by those individuals whose totally or partially occlusive lesions produce transient ischemic attacks or chronic lowgrade insufficiency in the apparent absence of cerebral infarction.
Abstract: I N THE evaluation of the results of vascular reconstructive operations for cerebral vascular insufficiency it becomes necessary to divide the clinical syndromes of cerebral insufficiency into two broad categories. The category of patients for whom revascularization seems most helpful is represented by those individuals whose totally or partially occlusive lesions produce transient ischemic attacks or chronic lowgrade insufficiency in the apparent absence of cerebral infarction. In this category, when occlusive lesions are present in operable extracranial arteries, improvement in cerebral function following successful operations ordinarily is subject to clear evaluation on the basis of definable changes in neurologic symptoms or findings. An early unfavorable neurologic result may be considered to be caused largely by an error in performance of operation. The other category is represented by those patients whose occlusive lesions have caused frank cerebral infarction resulting in a fixed or progressive neurologic deficit. The numerous variations in the natural history of recovery of cerebral function in this group make it difficult to define the extent of improvement that properly may be credited to a successful arterial operation, particularly when operation is performed a few hours or days after the onset of a stroke. When improvement follows operation upon a patient with a recent acute stroke it may be difficult to determine whether this result represents a natural phase of recovery or whether it has occurred because of increased arterial flow to partially ischemic brain tissue at the periphery of the infarcted zone. Conversely,
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TL;DR: A group of apoplectics with a single pathogenesis, i.l.e., with acute occlusion of the middle cerebral artery, has been studied with the aim of collecting information on the regional cerebral blood flow (rCBF) and its regulation in a well-defined type of Apoplexy.
Abstract: THE XENON 133 INJECTION METHOD allows simultaneous measurement of the blood flow in many areas of the brain.l.2 It has been used for determination of the regional cerebral blood flow in several small series of patients with cerebrovascular diseases of various types.3-7a The regional flow responses of the braip to changes of arterial blood pressure and arterial pC0, have also been studied, and focal loss of autoregulation and of pC0,-induced vasodilatation in cases of cerebral apoplexy have been reported.\"6y7a In the present study, a group of apoplectics with a single pathogenesis, i.e., with acute occlusion of the middle cerebral artery, has been studied with the aim of collecting information on the regional cerebral blood flow (rCBF) and its regulation in a well-defined type of apoplexy. The results obtained in apoplexy without occlusion of a major cerebral artery and in transient ischemic attacks will be reported in subsequent paper^.^.^
192 citations