Andrew Slivka

A new model of temporary focal neocortical ischemia in the rat.

We describe a new rat model of temporary focal ischemia that produces neocortical ischemia without the need for prolonged anesthesia. Methods Temporary focal cerebral ischemia was initiated during halothane anesthesia, maintained for varying periods without anesthesia, and reversed by clip removal requiring brief anesthesia. Tandem carotid and middle cerebral artery occlusion for 1−4 hours and permanent occlusion were used to determine the duration and extent of ischemia necessary to produce predictable volumes of neocortical infarction in Wistar and spontaneously hypertensive rats. Results In Wistar rats, occlusion of the right middle cerebral and both common carotid arteries resulted in cerebral blood flow reductions to approximately 8% of baseline. One hour of transient ischemia with 23 hours of reperfusion did not result in infarction. Three hours of ischemia followed by 21 hours of reperfusion resulted in infarction comparable to that caused by 24 hours of permanent ischemia. In spontaneously hypertensive rats, unilateral right middle cerebral and common carotid artery occlusion reduced cerebral blood flow to approximately 11% of baseline. Minimal damage was seen with 1 hour of reversible ischemia, but intervals of 2 and subsequently 3 hours followed by 22–21 hours of reperfusion produced progressively larger infarcts. Damage indistinguishable from that seen with 24 hours of permanent ischemia was seen with 3 or 4 hours of transient ischemia followed by 21 or 20 hours of reperfusion. Conclusions For unanesthetized normothermic rats, cerebral blood flow reductions to 10–20% of baseline resulted in maximal infarction once ischemic durations exceeded 2–3 hours. To be effective, experimental therapies aimed at lessening infarct size or restoring blood flow must be initiated within this critical time interval.

Neuroprotective Properties of the Natural Vitamin E α-Tocotrienol

Background and Purpose— The current work is based on our previous finding that in neuronal cells, nmol/L concentrations of &agr;-tocotrienol (TCT), but not &agr;-tocopherol (TCP), blocked glutamate-induced death by suppressing early activation of c-Src kinase and 12-lipoxygenase. Methods— The single neuron microinjection technique was used to compare the neuroprotective effects of TCT with that of the more widely known TCP. Stroke-dependent brain tissue damage was studied in 12-Lox-deficient mice and spontaneously hypertensive rats orally supplemented with TCT. Results— Subattomole quantity of TCT, but not TCP, protected neurons from glutamate challenge. Pharmacological as well as genetic approaches revealed that 12-Lox is rapidly tyrosine phosphorylated in the glutamate-challenged neuron and that this phosphorylation is catalyzed by c-Src. 12-Lox-deficient mice were more resistant to stroke-induced brain injury than their wild-type controls. Oral supplementation of TCT to spontaneously hypertensive rats led to increased TCT levels in the brain. TCT-supplemented rats showed more protection against stroke-induced injury compared with matched controls. Such protection was associated with lower c-Src activation and 12-Lox phosphorylation at the stroke site. Conclusion— The natural vitamin E, TCT, acts on key molecular checkpoints to protect against glutamate- and stroke-induced neurodegeneration.

Tirilazad reduces cortical infarction after transient but not permanent focal cerebral ischemia in rats.

Background and Purpose We examined the cytoprotective effect of the lipid peroxidation inhibitor tirilazad mesylate (U74006F) in rodent models of neocortical infarction induced by transient and permanent focal cerebral ischemia. Methods Wistar rats (experiment 1) and spontaneously hypertensive rats (experiment 2) were subjected to 2 hours of transient middle cerebral artery occlusion followed by 22 hours of reperfusion and pretreated with 10 mg/kg i.p. tirilazad, vehicle, or saline. Repeat doses were given at 4 and 10 hours after reperfusion. Spontaneously hypertensive rats were also subjected to permanent middle cerebral artery occlusion and either pretreated with tirilazad, vehicle, or saline intraperitoneally (experiment 3)or treated with either tirilazad or vehicle intravenously after ischemia (experiment 4). Cortical infarct volumes were measured 24 hours after the onset of either transient or permanent ischemia, and changes in core regional cerebral blood flow were monitored with laser Doppler flowmetry. Results Tirilazad reduced infarct volume after transient ischemia by 40% in Wistar rats (p=0.08) (experiment 1) and 23% in spontaneously hypertensive rats (p<0.05) (experiment 2) but did not reduce infarction after permanent ischemia whether it was given intraperitoneally (experiment 3) or intravenously (experiment 4). Ischemic core blood flows were not affected during ischemia, nor were they affected during reperfusion after transient ischemia. Conclusions Tirilazad reduces cortical infarction in transient but not permanent ischemia, an effect not related to improvement in regional cerebral blood flow. Tirilazad might prove to be useful as an adjuvant therapy after successful thrombolysis in acute stroke patients.

Clinical and Angiographic Features of Thunderclap Headache

Thunderclap headache is an acute high intensity headache similar to that seen in the setting of ruptured saccular aneurysm. We report four patients without subarachnoid hemorrhage who presented with thunderclap headache. Three patients had transient neurologic signs or symptoms. Cerebral angiography revealed diffuse segmental intracerebral arterial vasoconstriction which was reversible in the one patient in whom angiography was repeated. The headaches resolved spontaneously in all cases and after 1 week did not recur. These cases highlight the specific clinical and angiographic features and the self‐limited course of patients with thunderclap headache and suggest that thunderclap headache may represent a unique headache category. On the basis of these cases and others reported in the literature, we propose diagnostic criteria for thunderclap headache.

Predictors of hemorrhage following intra-arterial thrombolysis for acute ischemic stroke: the role of pial collateral formation.

BACKGROUND AND PURPOSE: The extent of pial collateral formation during acute ischemic stroke has been shown to influence outcomes. This study examines whether angiographic assessment of pial collateral formation is predictive of hemorrhagic transformation following intra-arterial thrombolysis (IAT) for acute ischemic stroke. MATERIALS AND METHODS: Rates of any hemorrhage and significant hemorrhage (>25 mL) were reviewed in 104 consecutive patients who underwent IAT following acute ischemic stroke. The influence of the anatomic extent of pial collateral formation on the rates of hemorrhage and significant hemorrhage relative to known predictors for hemorrhagic transformation (presenting systolic blood pressure, blood glucose level, platelet level, and National Institutes of Health Stroke Scale [NIHSS] score, history of diabetes, time to treatment, age, sex, occlusion site, and extent of reperfusion) was analyzed by using logistic regression models. RESULTS: Rates of any hemorrhage and significant hemorrhage were 25.2% (26/104) and 9.7% (10/104), respectively. The rate of significant hemorrhage was 25.0% (8/32) in patients with poor pial collaterals and 2.78% (2/72) in those with good pial collaterals (P = .0004, Pearson correlation). The rate of any hemorrhage was also significantly higher in patients with poor pial collaterals (40.6% versus 18.1%; P = .0142, Pearson correlation). Logistic regression analyses revealed that pial collateral formation (odds ratio [OR] = 3.04), history of diabetes (OR = 4.83), platelets <200,000/μL (OR = 2.95), and time to treatment <3 hours (OR = 12.0) were statistically significant predictors of hemorrhage, whereas pial collateral formation (OR = 13.1) and platelets <200,000/μL (OR = 8.1) were statistically significant predictors of significant hemorrhage. CONCLUSIONS: Poor pial collateral formation is associated with higher incidence and larger size of hemorrhage following IAT.

Cerebral Edema After Temporary and Permanent Middle Cerebral Artery Occlusion in the Rat

BACKGROUND AND PURPOSE The potential of thrombolytic agents to improve outcome after ischemic stroke could be negated if recanalization of an occluded artery exacerbates cerebral edema. We examined whether infarctions associated with reperfusion have more edema than those without reperfusion and whether the time course for the development of cerebral edema varied with and without reperfusion. METHODS Infarct volumes were measured 24 hours after permanent and 1, 2, and 3 hours of temporary right middle cerebral artery (MCA) occlusion in spontaneously hypertensive rats. Hemispheric volume, water, sodium, and potassium were measured 3, 6, 12, 24, 36, and 48 hours after permanent and 3 hours of temporary MCA occlusion and also determined 24 hours after permanent and 2 and 3 hours of temporary MCA occlusion. RESULTS Minimal tissue damage occurred after 1 hour of temporary ischemia. Infarct sizes were similar after permanent and 3 hours of temporary MCA occlusion and significantly greater than after 2 hours of temporary ischemia. Hemispheric volume, water, and sodium from the infarcted right hemisphere were significantly greater than those from the left hemisphere beginning 6 hours after MCA occlusion and continuing for 48 hours, with a peak at 24 hours. Right hemispheric water measured 24 hours after 2 hours of temporary ischemia was significantly less than after permanent or 3 hours of temporary ischemia. CONCLUSIONS This study demonstrates that cerebral edema after focal stroke is related to infarct size and is independent of reperfusion status. The results suggest that exacerbation of cerebral edema will not occur after thrombolytic treatment or spontaneous recanalization of occluded cerebral vessels.

Altered cerebral vasoregulation in hypertension and stroke

Background: Autoregulation of blood flow that maintains steady perfusion over the range of systemic blood pressure is compromised by stroke. Objectives: To determine whether cerebral vasoregulation is impaired in stroke during orthostatic stress. Methods: Subjects included 30 control subjects, 30 with hypertension, and 20 with minor stroke and were studied using transcranial Doppler. Bilateral blood flow velocities (BFVs) from middle cerebral arteries, heart rate, blood pressure (BP), and CO2 were obtained during hyperventilation and CO2 rebreathing during supine rest and tilt at 80°. Side-to-side BFV difference, vasomotor range (VMR), and cerebrovascular resistance (CVR) were calculated during normo-, hypo-, and hypercapnia. Results: Mean BFVs were similar between groups in supine position but differed during tilt. BFV diminished on the stroke side during tilt with hyperventilation and CO2 rebreathing (p < 0.0001). CVR increased (p < 0.0001) and VMR decreased (p < 0.01) on the stroke side. Vasoregulation was preserved on the normal side. BFV asymmetry differentiated patients with stroke from the other groups (p < 0.0001). BFV difference between the normal vs stroke side was the largest in stroke-normotensive (n = 7) compared with stroke-hypertensive (n = 13) patients and the two other groups (p < 0.0001). BFV asymmetry in stroke was associated with lower orthostatic BP (p < 0.0001). Conclusions: Cerebral vasoregulation is impaired with minor stroke, and cerebral blood flow depends on blood pressure. Decline of blood flow velocities during orthostatic stress may pose a risk of silent hypoperfusion.

Mitral Valve Strands in Patients With Focal Cerebral Ischemia

BACKGROUND AND PURPOSE Filamentous strands attached to the mitral valve are a recently described finding in occasional patients undergoing transesophageal echocardiography (TEE), but the frequency and clinical significance of these strands remain poorly defined. The purpose of the present study was to review the prevalence of mitral valve strands in patients undergoing TEE examination and to explore the relation of these strands to cardioembolic cerebral ischemia. METHODS All patients with native mitral valves referred for clinically indicated TEE over a 2-year period at our institution were evaluated for the presence of mitral valve strands (defined as highly mobile filamentous masses <1 mm thick attached to the atrial surface of mitral leaflets). RESULTS Of 968 study patients, mitral valve strands were identified in 22 individuals (2.3%). Mitral valve strands were significantly more common in patients referred for TEE as a result of a recent ischemic cerebrovascular event compared with patients referred for other study indications (6.3% versus 0.3%, respectively; P<.00001). Among patients < or = 50 years of age with likely cardioembolic stroke or transient ischemic attack, 16% were found to have mitral valve strands on TEE examination. In 9% of these young patients, no other TEE finding associated with cardioembolic risk was present. CONCLUSIONS Filamentous strands attached to the mitral valve appear to represent another risk factor for embolic cerebral ischemia, particularly in patients < or = 50 years of age.

Qureshi grading scheme for angiographic occlusions strongly correlates with the initial severity and in-hospital outcome of acute ischemic stroke.

Background. The thrombolysis in myocardial infarction (TIMI) grading scheme and other classification systems have limitations in evaluating patients with ischemic stroke because they do not account for occlusion location or collateral circulation. The Qureshi grading scheme has been recently proposed to evaluate the severity of arterial occlusion in acute ischemic stroke because of limitations in existing grading systems. Methods. The Qureshi grading scheme assigns a score from 0 to 5 on the basis of occlusion site and collateral supply. The authors determined the relationship between initial severity of stroke and outcome at discharge measured by the National Institutes of Health Stroke Scale (NIHSS) and the Qureshi grading scale assessed from initial angiography (by a neuroradiologist blinded to the clinical examination) in 57 patients who underwent intra arterial therapy for acute ischemic stroke within 6 hours of symptom onset. Results. A strong association was observed between the initial severity of neurological deficits and Qureshi scheme on angiography (F ratio = 2.6, P = .03). The initial NIHSS for grade 1 was 11 ± 4 and progressively increased to 23 ± 6 for grade 5. In the multivariate analysis, initial NIHSS was significantly associated with Qureshi scheme on angiography (R2 = 358, P = .03). The mean discharge NIHSS was 12 ± 10 (range, 0–40). There was also a direct relationship between the Qureshi scheme and discharge NIHSS (F ratio = 2.8, P = .02).Conclusion. The Qureshi grading scheme can be effectively used to determine the severity of ischemic stroke (brain at risk) from the initial angiography.

Intraarterial thrombolytic therapy within 3 hours of the onset of stroke.

OBJECTIVEThe National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue Plasminogen Activator Stroke Study Group showed that recombinant tissue plasminogen activator (rt-PA) administered intravenously within 3 hours of the onset of ischemic stroke can improve clinical outcome. Intraarterial (IA) thrombolysis has been shown to offer advantages over intravenous (IV) thrombolysis, but experience with this type of therapy within 3 hours of the onset of symptoms has not been reported previously. This study is the first retrospective analysis of a two-institution experience with IA thrombolysis within 3 hours of stroke onset. METHODSA total of 36 patients with angiographically demonstrated occlusions were treated with urokinase or rt-PA within 3 hours of stroke onset. Outcome measures included the percentage of patients with no or minimal neurological disability at 30 to 90 days as measured by the modified Rankin Scale, percentage recanalization, incidence of symptomatic intracranial hemorrhage, and mortality rate. The results were compared with those of the NINDS rt-PA study. RESULTSThe median admission National Institutes of Health Stroke Scale score was 14. Fifty percent of treated patients had a modified Rankin Scale score of 0 or 1 indicating no or little disability at 1 to 3 months compared with 39% of treated patients in the NINDS trial. Recanalization was 75%, symptomatic intracranial hemorrhage was 11% (versus 6.4% with IV rt-PA in the NINDS trial), and the mortality rate was 22% (versus 17% with IV rt-PA in the NINDS trial). CONCLUSIONThe results suggest that IA thrombolysis administered within 3 hours of stroke onset is a feasible and viable alternative to IV rt-PA on the basis of improved clinical outcomes, high recanalization percentage, and comparable mortality rate and despite increased symptomatic intracranial hemorrhage. Whether IA thrombolysis is superior to IV therapy awaits further study.