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Ischemic Stroke: Ischemic strokes (thromboembolic strokes) are the most common type of stroke. They are caused by an area of focal ischemia due to occlusion of a cerebral vessel by thrombus or embolism. The severity of the decrease in blood flow is dependent on the size of the involved vessel and the availability of collaterals. There is a dense ischemic core surrounded by a marginally perfused ischemic penumbra. The ischemia leads to intracellular acidosis and cytotoxic edema due to intracellular accumulation of sodium, chloride, and water. Eventually microvascular damage leads to breakdown of the blood-brain barrier and results in vasogenic edema. In experimental models it has been shown that after occlusion of a vessel this ischemic zone can be salvaged with reperfusion. The timing of reperfusion is critical; its success is limited to only a few hours. Later reperfusion can actually be harmful and cause additional edema formation. Controversies: Thrombolytic Therapy For Ischemic Stroke: Early studies utilizing thrombolytic therapy reported poor outcomes. However, these studies were undertaken prior to the availability and use of head CTs. The success of thrombolytic therapy in the treatment of acute myocardial infarction spurred new interest in its use for brain infarcts. Unfortunately there are a number of characteristics that are unique to stroke that make thrombolytic use more complex than its use for myocardial infarctions. Thrombolytic therapy can be given as a selective intra-arterial injection or as a systemic intravenous infusion. Intra-arterial thrombolytic therapy offers the advantage of direct treatment and so has less systemic complications but local complications persist. Numerous small open studies have been published but because of the small number of patients and unblinded study design, the results are inconclusive. There appears to be some benefit to intra-arterial infusions, but it is generally not used for several reasons: the risk of hemorrhagic transformation of the stroke persists; the therapy is technically difficult and requires a skilled invasive neuroradiologist; and it is not readily available at all centers at all times. Intravenous thrombolytic therapy has the advantage of ease of administration with no requirement of skilled interventional personnel. This therapy still requires a CT scan to be obtained promptly and correctly interpreted prior to initiation of treatment. Several multi-center randomized, double-blind trials of intravenous thrombolytic therapy have recently been completed. The European Cooperative Acute Stroke Study evaluated the efficacy of tissue plasminogen activator (TPA) versus placebo in patients with ischemic stroke up to six hours from onset. The study demonstrated some improvement in functional and neurologic measures in the TPA group but these did not outweigh the higher mortality at 30 and 90 days in the TPA treatment group. There was, however, a statistically significant number of protocol violations in those patients randomized to the TPA group, including misreadings of the initial CT scan, which may have accounted for the increased proportion of bleeding and death in the TPA treatment group. The Multicenter Acute Stroke Trial-Italy Group evaluated the efficacy of streptokinase with aspirin, streptokinase alone, aspirin alone versus placebo and enrolled patients up to six hours from onset of an ischemic stroke. The streptokinase group had a higher ten day case fatality rate. Aspirin and streptokinase seemed to reduce six month fatality and disability but the improvement was not statistically significant. The Multicenter Acute Stroke Trial-Europe Study Group evaluated streptokinase in the treatment of middle cerebral artery infarcts within six hours. This trial was halted because of the high frequency of hemorrhagic transformation and increased mortality in the treatment group. At six months streptokinase survivors did have greater functional improvement. It is unclear if the treatment truly improved function or if those more severely afflicted died early due to complications. The patients in this study had overall poor prognosis and high mortality as evidenced by the placebo group. It has been postulated that hemorrhagic transformations induced by thrombolytic therapy may occur more frequently in "severe" strokes. Patients with milder strokes may have a different response. The Australian Streptokinase Trial also enrolled patients up to six hours and measured an increase in mortality in the streptokinase treated group. The National Institute of Neurologic Disorders and Stroke TPA Stroke Study Group utilized TPA and enrolled patients within three hours of ischemic stroke onset. The TPA treated patients were 30% more likely to have minimal or no disability at three months by each of the four outcome measures utilized. TPA resulted in a more favorable outcome regardless of the subtype of stroke (small vessel thrombus, large vessel thrombus, or cardioembolic). There was no significant difference in mortality between the TPA and placebo groups. This study demonstrated a clear benefit for TPA treatment within three hours of ischemic stroke onset and has since been valided by prospective phase 4 trials. Of note, studies such as one from Cleveland have also demonstrated that good outcomes from thrombolytic use are dependent of careful adherence to protocols which ensure appropriate patient evaluations and pharmacologic interventions. Anticoagulation for Ischemic Stroke: The first studies of heparin use in ischemic stroke were conducted prior to the advent of CT scans. These very early studies suggested some benefit of heparin and led to its increased use. More recent studies have failed to substantiate the benefit of heparin in acute ischemic stroke. A randomized trial in 1986 failed to demonstrate any benefit but patients were enrolled up to 48 hours following symptom onset. A 1988 trial of heparin failed to prevent stroke progression in progressing ischemic infarction. In cardioembolic stroke, anticoagulation is thought to prevent recurrences and this has been substantiated by several studies. What remains controversial in embolic stroke is the timing of anticoagulation. Patients with embolic stroke are at risk for hemorrhagic transformation and therefore anticoagulation could cause deterioration. There has been a trend to delay heparin therapy in embolic strokes that have severe symptoms and large infarcts on CT because these factors are considered to increase the risk of hemorrhagic transformation. Low-molecular-weight heparin is thought to be at least as effective and easier to regulate than standard unfractionated heparin with decreased bleeding complications. It offers ease of administration with once or twice daily subcutaneous injection; increased reliability of anticoagulant effect with predictable bioavailability; fixed dosing based upon body weight; and a decreased incidence of thrombocytopenia. It may be that stroke patients who do not require a continuous intravenous infusion receive earlier mobilization and physical therapy; possibly resulting in a decreased length of hospital stay. A recent study of the low-moleculer-weight heparin nadroparin calcium enrolled patients within forty-eight hours of ischemic stroke and demonstrated improved outcome at six months with no significant increase in the rate of hemorrhagic transformation. Antiplatelet Agents for Ischemic Stroke: It was anticipated that antiplatelet agents would be of benefit in acute stroke in the same way that aspirin was shown to be of significant benefit in acute myocardial infarction. Antiplatelet agents have been proven beneficial in the prevention of stroke following transient ischemic attack and in the prevention of recurrent stroke. However, antiplatelet agents have not yet been shown to be efficacious in the acute treatment of stroke. Surgical Intervention for Ischemic Stroke: Immediate surgical intervention has also been considered for acute stroke. Emergency middle cerebral embolectomy may be of benefit in selected patients. Carotid endarterectomy has proven efficacy in the prevention of stroke in symptomatic patients with high grade carotid stenosis. Whether emergency carotid endarterectomy will be of value in the treatment of stroke remains unknown. |
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