Blood pressure, nimodipine, and outcome of ischemic stroke

OBJECTIVES: The reduction of blood pressure (BP) caused by nimodipine has been proposed as an explanation for the poor results in ischemic stroke trials. We evaluated further the relationships between BP, nimodipine, and outcome of ischemic stroke, and also searched for other possible explaining mechanisms. PATIENTS AND METHODS: All 350 participants of an earlier placebo controlled trial on oral nimodipine were included in this study. Among other variables, the admission BP, and the change of BP during the first day were noted. The 3 week and 3 month functional outcome was assessed with a modified Rankin grading. RESULTS: The severity of stroke was the utmost important predictor of outcome. Visible cerebral infarction on computed tomography (CT) was associated with severe stroke and an early commencement (within 24 h of stroke onset) of nimodipine treatment. In the nimodipine arm, high initial systolic and diastolic BP measured < or =24 h of stroke onset were independent predictors of good functional outcome (Rankin grades 1 and 2), whereas BP change was not. The survivors in the nimodipine arm with mild to moderately severe stroke had higher initial BP than the deceased ones, in severe strokes the situation was the opposite. CONCLUSIONS: Stroke severity, visible cerebral infarcts on CT, and early commencement of nimodipine treatment were associated. Overall, high initial systolic and diastolic BP predicted a good functional outcome in patients on nimodipine. In severe strokes, the combination of nimodipine and high initial BP was associated with increased risk of death.     

Extracorporeal rheopheresis in the treatment of acute ischemic stroke: A randomized pilot study

BACKGROUND AND PURPOSE: Extracorporeal rheopheresis is a safe method to optimize hemorheology. Our aim was to determine whether treatment with extracorporeal rheopheresis in patients with acute ischemic hemispheric stroke improves cerebral perfusion as assessed with serial 99mTc-ethyl-cysteinate-dimer single-photon emission CT (99mTc-ECD SPECT). We also investigated how clinical outcome is associated with treatment and imaging results. METHODS: Thirty-three patients (mean age, 64+/-10 years) with acute ischemic hemispheric stroke were included in a prospective, randomized, parallel group pilot study. First treatment with or without extracorporeal rheopheresis took place within 12 hours after the onset of symptoms and was repeated 3 times at intervals of 24 hours. Hemorheological parameters were measured before and after each session. Each patient underwent 99mTc-ECD SPECT immediately before treatment, 6 to 8 hours after treatment, and after 5 days. A semiquantitative SPECT graded scale was used to measure depth and extent of activity deficits and thus to quantify the perfusion deficit. RESULTS: Seventeen patients were actively treated with extracorporeal rheopheresis, and 16 patients did not receive extracorporeal rheopheresis. After 3 months, no differences were found in the functional or neurological outcome. Despite a rapid, sustained decrease of plasma viscosity and erythrocyte aggregation in the rheopheresis group, there was no significant difference in the SPECT graded scale after therapy between the 2 groups. Patients with early reperfusion (decrease in the SPECT graded scale >25% 6 to 8 hours after therapy compared with the baseline examination) experienced a better functional outcome (Modified Rankin Scale) after 3 months compared with patients without reperfusion (P=0.04). CONCLUSIONS: Since quantitative flow mapping and clinical follow-up did not reveal any differences between patients who were treated with extracorporeal rheopheresis and controls, it appears very unlikely that extracorporeal rheopheresis enhances reperfusion after acute cerebral ischemia.     

Serial study of apparent diffusion coefficient and anisotropy in patients with acute stroke.

BACKGROUND AND PURPOSE: We sought to characterize the evolution of apparent diffusion coefficient (ADC) and apparent diffusion anisotropy (ADA) in acute stroke and to evaluate their roles in predicting stroke evolution and outcome. METHODS: We studied 26 stroke patients acutely (<24 hours), subacutely (3 to 5 days), and at outcome (3 months). Ratios of the ADC and ADA within a region of infarction and the normal contralateral region were evaluated and compared with the Canadian Neurological Scale, Barthel Index, and Rankin Scale. RESULTS: Heterogeneity in ADC and ADA evolution was observed not only between patients but also within individual lesions. Three patterns of ADA evolution were observed: (1) elevated ADA acutely and subacutely; (2) elevated ADA acutely and reduced ADA subacutely; and (3) reduced ADA acutely and subacutely. At outcome, reduced ADA with elevated ADC was observed generally. We identified 3 phases of diffusion abnormalities: (1) reduced ADC and elevated ADA; (2) reduced ADC and reduced ADA; and (3) elevated ADC and reduced ADA. The ADA ratios within 12 hours correlated with the acute Canadian Neurological Scale (r=0.46, P=0.06), subacute Canadian Neurological Scale (r=0.55, P=0.02), outcome Barthel Index (r=0.62, P=0.01), and Rankin Scale (r=-0.77, P<0.0005) scores. CONCLUSIONS: Combined ADC and ADA provide differential patterns of stroke evolution. Early ADA changes reflect cellular alterations in acute ischemia and may provide a potential marker to predict stroke outcome.     

Effect of intravenous nimodipine on blood pressure and outcome after acute stroke

BACKGROUND AND PURPOSE: The Intravenous Nimodipine West European Stroke Trial (INWEST) found a correlation between nimodipine-induced reduction in blood pressure (BP) and an unfavorable outcome in acute stroke. We sought to confirm this correlation with and without adjustment for prognostic variables and to investigate outcome in subgroups with increasing levels of BP reduction. METHODS: Patients with a clinical diagnosis of ischemic stroke (within 24 hours) were consecutively allocated to receive placebo (n=100), 1 mg/h (low-dose) nimodipine (n=101), or 2 mg/h (high-dose) nimodipine (n=94). The correlation between average BP change during the first 2 days and the outcome at day 21 was analyzed. RESULTS: Two hundred sixty-five patients were included in this analysis (n=92, 93, and 80 for placebo, low dose, and high dose, respectively). Nimodipine treatment resulted in a statistically significant reduction in systolic BP (SBP) and diastolic BP (DBP) from baseline compared with placebo during the first few days. In multivariate analysis, a significant correlation between DBP reduction and worsening of the neurological score was found for the high-dose group (beta=0.49, P=0. 048). Patients with a DBP reduction of > or =20% in the high-dose group had a significantly increased adjusted OR for the compound outcome variable death or dependency (Barthel Index <60) (n/N=25/26, OR 10. 16, 95% CI 1.02 to 101.74) and death alone (n/N=9/26, OR 4.336, 95% CI 1.131 16.619) compared with all placebo patients (n/N=62/92 and 14/92, respectively). There was no correlation between SBP change and outcome. CONCLUSIONS: DBP, but not SBP, reduction was associated with neurological worsening after the intravenous administration of high-dose nimodipine after acute stroke. For low-dose nimodipine, the results were not conclusive. These results do not confirm or exclude a neuroprotective property of nimodipine.     

Safety and efficacy of intravenous tissue plasminogen activator and heparin in acute middle cerebral artery stroke.

BACKGROUND AND PURPOSE: There is little reported of the safety and efficacy of high-dose intravenous recombinant tissue plasminogen activator (alteplase) in combination with heparin anticoagulation in patients presenting with acute ischemic stroke. METHODS: Thirty-two patients with severe hemispheric stroke syndrome caused by angiographically proven middle cerebral artery and/or intracranial internal carotid artery occlusion were treated with 100 mg alteplase by intravenous infusion over 90 minutes within a mean +/- SD of 226 +/- 68 minutes after symptom onset. Recanalization was assessed by digital subtraction angiography in all patients immediately after treatment and by transcranial Doppler monitoring (n = 30) and/or a third angiogram (n = 5) 12-24 hours later. RESULTS: Complete or partial reperfusion was observed in 11 patients (34%) 90 minutes after the initiation of alteplase infusion and in 17 patients (53%) within 12-24 hours. Hemorrhagic infarction without clinical deterioration was detected by follow-up computed tomography in nine patients (28%). Fatal parenchymal hemorrhage occurred in three patients (9%) with huge middle cerebral artery infarcts. Serious hemorrhage from the puncture site occurred in two patients (6%). Good clinical outcome correlated with reperfusion (p less than 0.05) and the presence of grade 2 collateral blood flow (p less than 0.01). CONCLUSIONS: When 100 mg of recombinant tissue plasminogen activator was given within the first 6 hours of acute stroke together with heparin the incidence of deleterious hemorrhage was less than 10%. Reperfusion and effective collateral blood flow seem to be two important factors associated with a small infarct volume and good clinical outcome.     

The Clomethiazole Acute Stroke Study in hemorrhagic stroke (Class-H): Final results

Background and Purpose: Clomethiazole (CMZ) is a neuroprotectant that may improve outcome in patients with acute major strokes. In a previous study that included 94 hemorrhagic stroke patients (CLASS), a mortality reduction and functional outcome favorable to CMZ was seen. We sought to establish the safety of CMZ in acute hemorrhagic stroke patients and to determine whether a trial of medical therapy for cerebral hemorrhage was feasible. Methods: The safety of CMZ (n = 96) versus a placebo (n = 102) in hemorrhagic stroke patients was evaluated in a randomized, double-blind trial. Treatment began after a computed tomography (CT) scan confirmed the presence of hemorrhage and within 12 hours from symptom onset. Patients received 68 mg/kg of CMZ intravenously over 24 hours. Safety was assessed by collecting serious adverse events (SAE), including deaths up to 90 days after treatment. Functional and neurologic outcome were also monitored. Results: Hemorrhage volumes were found to be similar between groups (26 ± 56 mL CMZ v 26 ± 35 mL placebo). Sedation was reported as an adverse event during therapy in 55% of the CMZ patients versus 13% of the placebo patients. The number of SAE reports was 53 in the CMZ group and 46 in the placebo group. Differences on functional outcome measures were minor. Death within 90 days occurred in 19 CMZ patients versus 11 placebo patients (Odds Ratio [OR] 2.04; 95% confidence interval [CI] 0.92, 4.55; P = .08). After adjusting for baseline covariate imbalances, the mortality difference was less apparent (OR 1.82; 95% CI 0.69, 4.81; P = .23). Conclusions: The feasibility of performing neuroprotectant trials for acute cerebral hemorrhage patients has been established, but requires careful balancing of important predictive indicators, including baseline severity, hematoma location, presence of intraventricular blood, and possibly, coumadin use. The clinical experience to date has identified no specific major safety concerns with the use of CMZ in acute hemorrhagic stroke patients. Additional clinical trials will be required to confirm safety and establish the efficacy of CMZ in acute hemorrhagic stroke patients.     

Effects of blood pressure lowering in the acute phase of total anterior circulation infarcts and other stroke subtypes

BACKGROUND: Lowering of blood pressure (BP) in the acute phase of stroke is reported both to worsen and to improve the outcome. To investigate whether heterogeneity exists between stroke subtypes in the response to BP lowering, we analysed data from the Intravenous Nimodipine West European Stroke Trial (INWEST). METHODS: INWEST enrolled acute ischaemic stroke patients within 24 h (n = 295) to the following groups: placebo (n = 100), 1 mg/h nimodipine (n = 101) or 2 mg/h nimodipine (n = 94). Patients were retrospectively classified as total anterior circulation infarct (TACI) (i.e. hemiparesis + hemianopia + dysphasia) and non-TACI (exclusion of any one of these). Main outcome measures were neurological (Orgogozo) and functional (Barthel) scores at day 21. RESULTS: 106 patients were labelled as TACI and 62 as non-TACI. No significant difference in BP was observed between the TACI and non-TACI subtypes at baseline, nor did the subtypes differ in BP course within the treatment groups. A higher proportion of non-TACI patients received postrandomisation antihypertensive agents in addition to the study drug compared with TACI patients (55% non-TACI vs. 26% TACI, p < 0.005). For TACI patients, there was no outcome difference between the placebo- and nimodipine-treated groups. For non-TACI patients, placebo had a significantly better neurological (p = 0.004) and functional (p = 0.04) outcome than the high-dose nimodipine group. In multivariate analysis for TACI patients, BP reduction and nimodipine treatment had no relation with outcome. Baseline stroke severity (p < 0.005) was the only significant predictor of the outcome at day 21. For non-TACI patients, diastolic BP (DBP) reduction (p = 0.03) and nimodipine treatment (p = 0.001) were related to neurological deterioration and nimodipine treatment (p = 0.01) to functional deterioration. Systolic BP reduction was associated with neurological (p < 0.005) and functional improvement (p = 0.01). Baseline stroke severity (p < 0.005) was related to both neurological and functional outcome. CONCLUSION: BP lowering and nimodipine treatment had no significant effect on outcome for TACI patients. For non-TACI patients, DBP lowering worsened the neurological outcome and high-dose nimodipine worsened both the neurological and functional outcome.     

Expanding the window for thrombolytic therapy in acute stroke. The potential role of acute MRI for patient selection.

BACKGROUND: Effective therapy was not available for treatment of acute stroke until 1995, when tissue plasminogen activator (tPA) was shown to improve neurological and functional outcome in stroke patients who were treated within 3 hours of symptom onset. SUMMARY OF REVIEW: Currently, many patients do not qualify for tPA therapy because they present for evaluation beyond 3 hours after stroke onset. Attempts to expand the treatment window to 6 hours, using CT to select patients, have failed. Use of early MR imaging may provide significant advantages over CT for identification of patients who are likely to benefit from thrombolytic therapy because (1) the early perfusion-weighted imaging (PWI) lesion estimates the region of acute dysfunctional brain tissue, whereas the acute diffusion-weighted imaging (DWI) lesion appears to correspond to the core of the early infarction; (2) the mismatch between the acute PWI lesion and the smaller DWI lesion represents potentially salvageable brain tissue (an estimate of the ischemic penumbra); and (3) in patients with a PWI/DWI mismatch, early reperfusion is often associated with substantial clinical improvement and reversal or reduction of DWI lesion growth. CONCLUSIONS: Clinical trials that use new MRI techniques to screen patients may be able to identify a subset of acute stroke patients who are ideal candidates for thrombolytic therapy even beyond 3 hours after stroke onset.     

Flunarizine in stroke treatment (FIST): a double-blind, placebo-controlled trial in Scandinavia and the Netherlands

Introduction - An international, multicenter trial was conducted in 331 patients to determine the effect of a large dose of flunarizine (a calcium entry blocker) in the treatment of acute ischemic stroke in the territory of the Middle cerebral artery. Methods - The administration of the trial medication should start within 24 h after the initial symptoms of stroke. According to a random schedule, the patients were assigned to a 4-weeks double-blind treatment with either flunarizine ( n = 166) or placebo ( n = 165): one week intravenous administration (50 mg daily), followed by 3 weeks oral treatment (week 2, 21 mg daily; week 3–4, 7 mg daily). All patients had to be investigated by computerized tomography (CT) within 7 days after stroke onset; 36 patients were secundarily excluded because the CT showed another pathology. During the treatment period, other "stroke therapies" were not allowed. Patients were followed up for 24 weeks. Results - After the 24 weeks trial period, the percentage of patients who were dead or pendent (modified Rankin score 3–5) was similar in both treatment groups (flunarizine 67%, placebo 65%). During the trial, the scores for handicap severity (modified Rankin scale), neurological status (Orgogozo) and activities of daily living (modified Barthel index) strongly improved in both treatment groups, but no differences were found between the treatment groups. In this trial, the administration of trial treatment started relatively late after stroke onset (flunarizine group: mean time interval 13.5 h; placebo 12.3 h). A subgroup of patients received trial medication within 6 h after stroke onset (flunarizine n = 31; placebo n = 29). Also in this subgroup, no differences were found between the flunarizine and placebo group. Conclusion - Flunarizine did not improve neurologic and functional outcome in patients with acute ischemic stroke.     

The Clomethiazole Acute Stroke Study in tissue-type plasminogen activator-treated stroke (CLASS-T): final results

OBJECTIVE: To assess the safety of tissue-type plasminogen activator (t-PA) plus clomethiazole in patients with acute ischemic stroke and determine the feasibility of combination stroke therapy. BACKGROUND: Clomethiazole is a neuroprotectant that appeared to improve outcome in patients with clinical deficits of a major stroke (total anterior circulation syndrome [TACS]) in a previous study, the Clomethiazole Acute Stroke Study (CLASS). Combining a neuroprotectant such as clomethiazole with thrombolysis may augment the beneficial effects of the two agents. CLASS-t-PA (CLASS-T) was a pilot study to explore the safety of the combination and the feasibility of performing combination treatment in the setting of acute ischemic stroke. METHODS: In a randomized, double-blind design (stratified for age, severity at admission, and time since onset of stroke), all patients received 0.9 mg/kg t-PA beginning within 3 hours of stroke onset and then either 68 mg/kg clomethiazole (n = 97) IV over 24 hours or placebo (n = 93) beginning within 12 hours of stroke onset. Patients were followed for 90 days. The main measures of safety were mortality and serious adverse events, and the main measure of functional outcome was the Barthel Index. RESULTS: The number of serious adverse event reports was 47 in the clomethiazole group and 48 in the placebo group. Death during the 90 days after treatment occurred in 15 clomethiazole and nine placebo patients (p = 0.26). Sedation was reported as an adverse event during therapy in 42% of clomethiazole patients vs 13% of placebo patients. The proportion of patients with TACS was 53% in the clomethiazole group and 41% in the placebo group. In the TACS subgroup, 52.9% of the clomethiazole patients scored a Barthel Index greater than 60 vs 44.7% of placebo patients (odds ratio 1.39; 95% CI 0.60 to 3.23). CONCLUSION: In this pilot study, there were no safety concerns related to the combination of t-PA and clomethiazole. The combination paradigm proved feasible, although many patients received clomethiazole several hours after thrombolysis; future studies must require prompt administration of the neuroprotectant either before or during administration of the thrombolytic. Patients with major strokes (TACS) may have the potential to benefit from the combination of t-PA and clomethiazole.     

Placebo-controlled trial of nimodipine in the treatment of acute ischemic cerebral infarction

Nimodipine is a 1,4-dihydropyridine derivative that shows a preferential cerebrovascular activity in experimental animals. Clinical data suggest that nimodipine has a beneficial effect on the neurologic outcome of patients suffering an acute ischemic stroke. Our double-blind placebo-controlled multicenter trial was designed to assess the effects of oral nimodipine on the mortality rate and neurologic outcome of patients with an acute ischemic stroke. One hundred sixty-four patients were randomly allocated to receive either nimodipine tablets (30 mg q.i.d.) or identical placebo tablets for 28 days. Treatment was always started less than or equal to 48 hours after the acute event. The Mathew Scale, slightly modified by Gelmers et al, was used for neurologic assessment. Mortality rate and neurologic outcome after 28 days were used as evaluation criteria. We considered 123 patients to be valid for the analysis of efficacy. Mortality rates did not differ significantly between groups. Neurologic outcome after 28 days of therapy did not differ between groups. However, when only those patients most likely to benefit from any intervention (Mathew Scale sum score of less than or equal to 65 at baseline) were analyzed separately in post hoc-defined subgroups, the nimodipine-treated subgroups showed a significantly better neurologic outcome. This result suggests that some patients with acute ischemic stroke will benefit from treatment with nimodipine tablets.     

The Use of PWI and DWI Measures in the Design of "Proof-of-Concept" Stroke Trials

BACKGROUND AND PURPOSE: The authors used serial magnetic resonance perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) to determine whether major reperfusion and the attenuation of infarct expansion are associated with improved stroke outcome. METHODS: Forty-nine patients were studied with serial magnetic resonance imaging within 6 hours of stroke onset and again at 4 days (subacute studies) and 3 months (outcome studies). Two imaging parameters were examined: infarct expansion between acute and outcome studies and major reperfusion between acute and subacute studies. RESULTS: Patients with major reperfusion (45% of those with acute PWI lesions) were more likely to have little or no disability at outcome (National Institutes of Health Stroke Scale [NIHSS] score < or = 4, P = .0176; Barthel Index [BI] score > or = 90, P = .0547) after adjustment for baseline differences. In contrast, patients with infarct expansion (48%) were more likely to be dead or dependent at outcome (BI < 90, P = .0414; NIHSS score P = .082; modified Rankin Scale score > 2, P < .0001). These measures were used to generate sample size calculations based on hypothetical treatment effects. Therapies postulated to double the proportion of patients with major reperfusion from one third to two thirds would require 41 patients in each group (treated and untreated) to be sufficiently powered to show a difference. Interventions postulated to halve the number of patients with infarct expansion from 50% to 25% would require 66 patients in each group to show a difference. CONCLUSIONS: Infarct expansion and major reperfusion are associated with clinically meaningful changes in stroke outcome. These measures could be used as surrogate markers of outcome in late phase II proof-of-concept stroke studies designed to provide efficacy signals before embarking on large phase III studies with definitive clinical endpoints.     

Imaging of the brain in acute ischaemic stroke: comparison of computed tomography and magnetic resonance diffusion-weighted imaging

BACKGROUND AND OBJECTIVES: Controversy exists about the optimal imaging technique in acute stroke. It was hypothesised that CT is comparable with DWI, when both are read systematically using quantitative scoring. METHODS: Ischaemic stroke patients who had CT within six hours and DWI within seven hours of onset were included. Five readers used a quantitative scoring system (ASPECTS) to read the baseline (b) and follow up CT and DWI. Use of MRI in acute stroke was also assessed in patients treated with tissue plasminogen activator (tPA) by prospectively recording reasons for exclusion. Patients were followed clinically at three months. RESULTS: bDWI and bCT were available for 100 consecutive patients (admission median NIHSS = 9). The mean bDWI and bCT ASPECTS were positively related (p<0.001). The level of interrater agreement ranged from good to excellent across all modalities and time periods. Bland-Altman plots showed more variability between bCT and bDWI than at 24 hours. The difference between bCT and bDWI was < or =2 ASPECTS points. Of bCT scans with ASPECTS 8-10, 81% had DWI ASPECTS 8-10. Patients with bCT ASPECTS of 8-10 were 1.9 times more likely to have a favourable outcome at 90 days than those with a score of 0-7 (95% CI 1.1 to 3.1, p = 0.002). The relative likelihood of favourable outcome with a bDWI ASPECTS 8-10 was 1.4 (95% CI 1.0 to 1.9, p = 0.10). Of patients receiving tPA 45% had contraindications to urgent MRI. CONCLUSION: The differences between CT and DWI in visualising early infarction are small when using ASPECTS. CT is faster and more accessible than MRI, and therefore is the better neuroimaging modality for the treatment of acute stroke.     

Remacemide hydrochloride: a double-blind, placebo-controlled, safety and tolerability study in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Remacemide hydrochloride and its principal active desglycinyl metabolite are low-affinity noncompetitive N-methyl-D-aspartate (NMDA)-receptor channel blockers. Remacemide hydrochloride has demonstrated neuroprotection in animal models of hypoxia and ischemic stroke. This study assessed the safety, tolerability, and pharmacokinetics of ascending doses of remacemide hydrochloride in patients with recent onset (within 12 hours) ischemic stroke. METHODS: This was a placebo-controlled, dose escalating, parallel group study. Groups of 8 patients (6 active, 2 placebo) were planned to receive twice-daily treatment, with l00 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg remacemide hydrochloride given as 2 intravenous infusions followed by 6 days' oral treatment. Patients who were unable to swallow discontinued study medication but continued to be monitored for safety; these patients were replaced. A CT or MRI scan was performed within 48 hours of admission to establish the cause of focal neurological deficit. Patients with ischemic stroke continued in the study. Patients with other causes of focal neurological deficit were withdrawn and replaced. Because the frequency of dysphagia after stroke in the first dose group (100 mg BID) was higher than had been anticipated, the protocol was amended so that subsequent dose groups received 6 intravenous infusions (2 doses per day for 3 days). Neurological and functional outcome data were collected, but the study was not powered to demonstrate drug efficacy. Patient safety was assessed by clinical observation, laboratory tests, and ECGs, while tolerability was assessed by recording adverse events. Blood sampling was included to determine plasma concentrations of remacemide and the desglycinyl metabolite at fixed points during the dosing period. RESULTS: The most common adverse events considered by the investigator to be possibly treatment related were related to the central nervous system (CNS), and these events appeared to increase with dose. Four patients were withdrawn from the study because of CNS-related events: 1 in the placebo group, 1 in the 500 mg BID group, and 2 in the 600 mg BID group. Infusion site reactions and gastrointestinal upset were also reported and considered to be treatment related. One patient in the placebo group and 4 patients in the 600 mg BID dose group experienced vomiting, whereas this event was not reported by patients in the other dose groups. CONCLUSIONS: On the evidence of this study, the maximum well-tolerated dose for remacemide hydrochloride in acute stroke is 400 mg BID. Doses of 200 mg BID or higher attained the putative neuroprotective plasma concentrations of remacemide predicted from animal models (250 to 600 ng/mL). The expected gradual accumulation of active metabolite might suggest that optimal neuroprotective concentrations are unlikely to be achieved within the early hours of treatment at this dose. However, plasma concentrations do not directly reflect brain concentrations, because studies in rats show that remacemide and the desglycinyl metabolite rapidly reach comparable brain concentrations within 1 hour, despite a lower plasma concentration of the metabolite.     

Cervene (Nalmefene) in acute ischemic stroke : final results of a phase III efficacy study. The Cervene Stroke Study Investigators

BACKGROUND AND PURPOSE: The goals of the present study were to assess the efficacy and safety of nalmefene (Cervene) in patients with acute (< or =6 hours) ischemic stroke and to investigate the safety of combined recombinant tissue plasminogen activator and nalmefene in a separate subset of patients. Nalmefene, an opioid antagonist with relative kappa receptor selectivity, has shown neuroprotective effects in multiple experimental central nervous system injury and ischemic models. Results from an earlier phase II study in patients with acute ischemic stroke suggested that nalmefene was safe and tolerable and may be effective for patients <70 years old. METHODS: This investigation was a phase III, placebo-controlled, double-blind, randomized study of a 24-hour infusion of nalmefene. Patients with acute ischemic stroke who had an onset of symptoms within 6 hours and a baseline score of > or =4 on the NIH Stroke Scale were randomized to receive either 60 mg nalmefene administered as a 10-mg bolus over 15 minutes and then a 50-mg infusion over 23.75 hours or placebo. The primary efficacy outcome was the proportion of patients achieving a score of > or =60 on the Barthel Index and a rating of "moderate disability" or better on the Glasgow Outcome Scale at 12 weeks. Assessments were performed at baseline (predose), hours 12 and 24, days 2 and 7, and week 12. RESULTS: A total of 368 patients were randomized at 42 centers, including 32 patients treated with recombinant tissue plasminogen activator and study drug. Nalmefene was well tolerated. Overall, there was no significant difference in 3-month functional outcome for nalmefene treatment compared with placebo on any of the planned analyses. A prospective secondary analysis also failed to find a treatment effect in patients <70 years old. CONCLUSIONS: Although nalmefene appears to be safe and well tolerated, this study failed to find any treatment benefit in stroke patients treated within 6 hours.     

Prophylactic antipyretic treatment with acetaminophen in acute ischemic stroke: a pilot study.

Fever is associated with poor outcome in acute stroke. Forty-two consecutive, normothermic patients with acute ischemic stroke were, within 24 hours from symptom onset, randomized to either receive 4 g acetaminophen daily (n = 20) or matched placebo (n = 22). Fever of greater than 37.5 degrees C occurred in 36.4% of patients in the placebo group, compared with 5.0% in the acetaminophen group (Fisher's exact test, p = 0.014). Prophylactic antipyretic treatment with acetaminophen may be effective in the prevention of fever after acute ischemic stroke.     

Early [(11)C]Flumazenil/H(2)O positron emission tomography predicts irreversible ischemic cortical damage in stroke patients receiving acute thrombolytic therapy

BACKGROUND AND PURPOSE: Central benzodiazepine receptor ligands, such as [(11)C]flumazenil (FMZ), are markers of neuronal integrity and therefore might be useful in the differentiation of functionally and morphologically damaged tissue early in ischemic stroke. We sought to assess the value of a benzodiazepine receptor ligand for the early identification of irreversible ischemic damage to cortical areas that cannot benefit from reperfusion. METHODS: Eleven patients (7 male, 4 female, aged 52 to 75 years) with acute, hemispheric ischemic stroke were treated with alteplase (recombinant tissue plasminogen activator; 0.9 mg/kg according to National Institute of Neurological Disorders and Stroke protocol) within 3 hours of onset of symptoms. At the beginning of thrombolysis, cortical cerebral blood flow ([(15)O]H(2)O) and FMZ binding were assessed by positron emission tomography (PET). Those early PET findings were related to the change in neurological deficit (National Institutes of Health Stroke Scale) and to the extent of cortical damage on MRI or CT 3 weeks after the stroke. RESULTS: Hypoperfusion was observed in all cases, and in 8 patients the values were below critical thresholds estimated at 12 mL/100 g per minute, comprising 1 to 174 cm(3) of cortical tissue. Substantial reperfusion was seen in most of these regions 24 hours after thrombolysis. In 4 cases, distinct areas of decreased FMZ binding were detected. Those patients suffered permanent lesions in cortical areas corresponding to their FMZ defects (112 versus 146, 3 versus 3, 2 versus 1, and 128 versus 136 cm(3)). In the other patients no morphological defects were detected on MRI or CT, although blood flow was critically decreased in areas ranging in size up to 78 cm(3) before thrombolysis. CONCLUSIONS: These findings suggest that imaging of benzodiazepine receptors by FMZ PET distinguishes between irreversibly damaged and viable penumbra tissue early after acute stroke.     

The clinical significance of periodic lateralized epileptiform discharges in acute ischemic stroke

Objective: To evaluate the incidence and the clinical significance of periodic lateralized epileptiform discharges (PLEDs) in acute ischemic stroke. Methods: Fortyseven consecutive patients with acute ischemic stroke in the anterior circulation who had an electroencephalogram (EEG) within 24 hours of the onset of symptoms were included. A second EEG was performed at 36 ± 12 hours and a third one at 60 ± 12 hours. The functional outcome was assessed at day 90. Results: Overall, we found PLEDs in 13 (27.7%) patients. The first EEG demonstrated PLEDs in 9 patients. Only 1 patient had a seizure. PLEDs were associated with age, early ischemic changes on baseline computed tomography (CT) scan, high mortality, and poor functional outcome. PLEDs on the first EEG were associated with increased risk of early clinical deterioration. Conclusion: PLEDs are common in acute ischemic stroke. In this setting they are not associated with seizures. PLEDs may be a marker of severe brain injury.     

Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial

BACKGROUND: Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3-6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI). METHODS: We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3-6 h after onset of ischaemic stroke. PWI and DWI were done before and 3-5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537. FINDINGS: We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71.6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1.24 with alteplase and 1.78 with placebo (ratio 0.69, 95% CI 0.38-1.28; Student's t test p=0.239); the median relative infarct growth was 1.18 with alteplase and 1.79 with placebo (ratio 0.66, 0.36-0.92; Wilcoxon's test p=0.054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0.001), better neurological outcome (p<0.0001), and better functional outcome (p=0.010) than was no reperfusion. INTERPRETATION: Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted.     

The Prognostic Significance of Visible Infarction on Computed Tomography Following Lacunar Stroke: Results of a Long-Term Follow-Up Study

BACKGROUND AND PURPOSE: Substantial variability in functional outcome and relatively few factors predictive of death or degree of recovery have been observed in patients with lacunar stroke. Such indicators are of great use in the selection of optimal rehabilitation strategies after stroke. Although computed tomography (CT) of patients with a clinical diagnosis of lacunar stroke performed within the first 10 days shows evidence of cerebral infarction in 50% to 60%, the prognostic significance of a visible ischemic lesion on CT is unclear. METHODS: 633 patients who presented with symptoms consistent with lacunar stroke between June 1990 and February 1998 were studied. One hundred fourteen patients imaged with magnetic resonance, 41 patients with nonischemic diagnoses (hemorrhage or tumor), 57 patients imaged within 12 hours of ictus, and 17 patients with incomplete follow-up were excluded from the analysis. The remaining 404 patients were divided into 2 groups, depending on the appearance of the CT scan. Patients with a low-attenuation area on the CT scan consistent with an ischemic lesion in an appropriate region of the brain to explain the presenting symptoms were classified as "CT positive." Patients with either a normal CT scan of the brain or a scan that showed a lesion in an area inconsistent with the presenting symptoms were classified as "CT negative." A series of known or suspected prognostic factors were recorded for each patient: blood pressure, age, smoking, plasma glucose level, serum cholesterol level, and serum triglyceride level. Delay from stroke onset to scanning was also noted. The authors considered 3 outcome measures: survival time, outcome at 6 months after the stroke, and total length of hospital stay for the stroke admission. Six-month outcome was categorized as good (alive at home) or poor (alive in care or dead). RESULTS: There was no difference in survival between the 2 groups (P= .29, log-rank test). After adjusting for other significant prognostic factors (age; relative hazard per additional decade 1.67, P< .0001: plasma glucose level; relative hazard per additional mmol/l 1.08, P= .03) in a proportional hazards model, presence of visible infarction remained nonsignificant (relative hazard 0.84, P= .40). After adjustment for the other significant factor (age, P= .0001), there was no significant difference in 6-month outcome between CT positive and CT negative patients (P= .61). Median total length of hospital stay was not significantly different between the 2 groups (CT positive, 9 days; CT negative, 8 days; Mann-Whitney test, P= .29). CONCLUSION: The authors conclude that in their cohort of patients, having corrected for other prognostic variables, the presence of visible infarction on CT brain scan performed between 12 hours and 30 days of onset of lacunar symptoms is not predictive of duration of hospital stay or of longer term outcome.