Protease activated receptor-1 mediates cytotoxicity during ischemia using in vivo and in vitro models.

Protease activated receptors (PARs) populate neurons and astrocytes in the brain. The serine protease thrombin, which activates PAR-1 during the first hours after stroke, appears to be associated with the cytotoxicity. Thrombin antagonists and PAR-1 inhibitors have been correlated with reduced cell death and behavioral protection after stroke, but no data yet support a mechanistic link between PAR-1 action and benefit. We sought to establish the essential role of PAR-1 in mediating ischemic damage. Using a short hairpin mRNA packaged with green fluorescent protein in a lentivirus vector, we knocked downPAR-1 in the medial caudate nucleus prior to rat middle cerebral artery occlusion (MCAo) and in rat neurons prior to oxygen-glucose deprivation. We also compared aged PAR-1 knockout mice with aged PAR-3, PAR-4 mice and young wild-type mice in a standard MCAo model. Silencing PAR-1 significantly reduced neurological deficits, reduced endothelial barrier leakage, and decreased neuronal degeneration in vivo during MCAo. PAR-1 knock-down in the ischemic medial caudate allowed cells to survive the ischemic injury; infected cells were negative for terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling (TUNEL) and c-Fos injury markers. Primary cultured neurons infected with PAR-1 short hairpin ribonucleic acid (shRNA) showed increased neuroprotection during hypoxic/aglycemic conditions with or without added thrombin. The aged PAR-1 knockout mice showed decreased infarction and vascular disruption compared to aged controls or young wild types. We demonstrated an essential role for PAR-1 during ischemia. Silencing or removing PAR-1 significantly protected neurons and astrocytes. Further development of agents that act at PAR-1 or its downstream pathways could yield powerful stroke therapy.

Does the cognitive measure Cog-4 show improvement among patients treated with thrombolysis after acute stroke?

BACKGROUND: Although the established measure of disability post stroke, the modified Rankin Scale emphasizes motor function and may underestimate the importance of cognitive impairment in more disabled patients. A subset of four items from the National Institutes of Health Stroke Scale has been proposed to assess cognitive function after stroke (Cog-4), and to correlate with modified Rankin Scale. Items correspond to orientation, executive function, language, and inattention. We investigated responsiveness of Cog-4 to treatment with thrombolysis and whether it offers information that supplements modified Rankin Scale. METHODS: We included 6268 patients from the Virtual International Stroke Trials Archive: 2734 received intravenous thrombolysis and 3534 were treated conservatively. We compared day 90 outcomes between treated and untreated groups, by modified Rankin Scale (illustrative) and by Cog-4 (primary measure) adjusting for age, baseline National Institutes of Health stroke scale, hemispheric lateralisation as well as baseline Cog-4 and baseline National Institutes of Health Stroke Scale excluding baseline Cog-4 separately. Analysis of Cog-4 was repeated within strata of 90 day modified Rankin Scale. Statistical analyses included proportional odds logistic regression and Cochran-Mantel-Haenszel test. RESULTS: Modified Rankin Scale showed a difference between treatment groups of expected magnitude (odds ratio 1·56; 95% confidence interval 1·43-1·72; P < 0·001). After adjustment for imbalance in baseline prognostic factors, the distribution of Cog-4 scores at 90 days was better in thrombolysed patients compared with nonthrombolysed patients (odds ratio 1·31; 95% confidence interval 1·18-1·47; P = 0·006). However, Cog-4 analysis stratified by 90-day modified Rankin Scale was neutral between treatment groups (OR 1·01; 95% CI 0·90-1·14), and Cog-4 was not responsive to treatment group even within modified Rankin Scale categories 4 and 5 despite substantial cognitive deficits in these patients. CONCLUSION: Although Cog-4 may be responsive to treatment effects, it does not provide additional information beyond modified Rankin Scale assessment.

Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes.

BACKGROUND: Hematoma expansion (HE) is a surrogate marker in intracerebral hemorrhage (ICH) trials. However, the amount of HE necessary to produce poor outcomes in an individual is unclear; there is no agreement on a clinically meaningful definition of HE. We compared commonly used definitions of HE in their ability to predict poor outcome as defined by various cutpoints on the modified Rankin Scale (mRS). METHODS: In this cohort study, we analyzed 531 patients with ICH from the Virtual International Stroke Trials Archive. Primary outcome was mRS at 90 days, dichotomized into 0-3 vs 4-6. Secondary outcomes included other mRS cutpoints and mRS "shift analysis." Sensitivity, specificity, and predictive values for commonly used HE definitions were calculated. RESULTS: Between 13% and 32% of patients met the commonly used HE definitions. All definitions independently predicted poor outcome; positive predictive values increased with higher growth cutoffs but at the expense of lower sensitivities. All HE definitions showed higher specificity than sensitivity. Absolute growth cutoffs were more predictive than relative cutoffs when mRS 5-6 or 6 was defined as "poor outcome." CONCLUSION: HE robustly predicts poor outcome regardless of the growth definition or the outcome definition. The highest positive predictive values are obtained when using an absolute growth definition to predict more severe outcomes. Given that only a minority of patients may have clinically relevant HE, hemostatic ICH trials may need to enroll a large number of patients, or select for a population that is more likely to have HE.

Anti-adrenergic medications and edema development after intracerebral hemorrhage.

BACKGROUND: Use of antihypertensive medications is common after intracerebral hemorrhage (ICH). Medications that block adrenergic activation (e.g., beta-blockers and the alpha(2)-agonist, clonidine) may reduce the inflammatory response and therefore have secondary benefit after ICH. METHODS: The patients with acute ICH enrolled in the placebo arm of the CHANT trial were included. Univariate and multivariate analyses were undertaken for factors associated with blood pressure medication use, edema at 72 h, and clinical outcome at 90 days. RESULTS: Of the 303 patients, 87.8% received some antihypertensive treatment during the first 72 h of hospitalization. Edema volume on neuroimaging at 72 h was independently associated with clinical outcome. Use of anti-adrenergic medications was associated with less edema after controlling for hemorrhage volume and blood pressure. CONCLUSIONS: Antihypertensive medications that antagonize the sympathetic nervous system may reduce perihematomal edema after ICH.

Production and validation of Putonghua- and Cantonese-Chinese language National Institutes of Health Stroke Scale training and certification videos.

BACKGROUND AND PURPOSES: The National Institutes of Health Stroke Scale (NIHSS) is an integral part of acute stroke assessment. We report our experience with new Putonghua- and Cantonese-Chinese language NIHSS (PC-NIHSS and CC-NIHSS) training and certification videos. METHODS: A professional video production company was hired to create the training and certification videos for both PC-NIHSS and CC-NIHSS. Two training and certification workshops were held in Chengdu and Beijing, and two workshops in Hong Kong. The instruction, training and group A certification videos were presented to workshop attendees. Unweighted kappa statistics were used to measure the agreement among raters, and the inter-rater agreements for PC-NIHSS and CC-NIHSS videos were compared with those of original English language NIHSS (E-NIHSS) videos. RESULTS: The pass rates using PC-NIHSS and CC-NIHSS videos were 79% and 82%, respectively. All possible responses on individual scale items were included. Facial palsy and limb ataxia (13%) showed poor agreement, nine (60%) to 10 (67%) items showed moderate agreement (0.4

The modified National Institutes of Health Stroke Scale: its time has come.

The National Institutes of Health Stroke Scale (NIHSS) is a well known, reliable and valid stroke deficit scale. The NIHSS is simple, quick, and has shown significant reliability in diverse groups, settings, and languages. The NIHSS also contains items with poor reliability and redundancy. Recent investigations (include assessing a new training DVD, analyzing webbased or videotape certifications, and testing foreign language versions) have further detailed reliability issues. Items recurrently shown to have poor reliability include Level of Consciousness, Facial Palsy, Limb Ataxia, and Dysarthria. The modified NIHSS (mNIHSS) minimizes redundancy and eliminates poorly reliable items. The mNIHSS shows greater reliability in multiple settings and cohorts, including scores abstracted from records, when used via telemedicine, and when used in clinical trials. In a validation of the mNIHSS against the NIHSS, the number of elements with excellent agreement increased from 54% to 71%, while poor agreement decreased from 12% to 5%. Overall, 45% of NIHSS items had less than excellent reliability vs. only 29% for the mNIHSS. The mNIHSS is not the ideal stroke scale, but it is a significant improvement over the NIHSS. The mNIHSS has shown reliability at bedside, with record abstraction, with telemedicine, and in clinical trials. Since the mNIHSS is more reliable, it may allow for improved practitioner communication, improved medical care, and refinement of trial enrollments. The mNIHSS should now serve as the primary stroke clinical deficit scale for clinical and research aims. When it comes to the mNIHSS, its time has come!

Natural history of complications after intracerebral haemorrhage.

BACKGROUND AND PURPOSE: Numerous trials of haemostatic and neuroprotective agents for intracerebral haemorrhage (ICH) have failed. We characterized the risk of complications after ICH in a trial-eligible patient population, to inform safety in future trials. METHODS: We used the Virtual International Stroke Trials Archive database to identify placebo-treated patients with spontaneous ICH, who were not comatose at admission, where randomization took place within 4 h of symptom onset, and where serious complication and outcome data were available. We described the complications encountered and assessed whether the absence of common complications influenced attainment of good functional outcome (mRS < or =4) at 90 days using logistic regression. RESULTS: Of 201 patients examined, 70.2% experienced at least one serious complication. Neurological complications occurred in 21%, infections amongst 11%, and thromboembolic complications in 2%. Extension of the haemorrhage occurred most frequently: its absence was a significant predictor of good functional outcome (P < 0.0001, adjusted OR for good functional outcome = 21.9, 95% CI: [5.5, 88.3]). Neither infection, nor cardiac, nor thromboembolic complications influenced functional outcome at 90 days. CONCLUSIONS: Three month outcome in ICH patients depends on initial stroke severity and on enlargement of the haemorrhage. Our results should inform safety in future clinical trials of putative ICH therapies.

Prior antiplatelet use does not affect hemorrhage growth or outcome after ICH.

OBJECTIVE: To examine whether antiplatelet medication use at onset of intracerebral hemorrhage (ICH) is associated with hemorrhage growth and outcome after spontaneous ICH using a large, prospectively collected database from a recent clinical trial. METHODS: The Cerebral Hemorrhage and NXY-059 Treatment trial was a randomized, placebo-controlled trial of NXY-059 after spontaneous ICH. We analyzed patients in the placebo arm, and correlated antiplatelet medication use at the time of ICH with initial ICH volumes, ICH growth in the first 72 hours, and modified Rankin Score at 90 days. Patients on oral anticoagulation were excluded. RESULTS: There were 282 patients included in this analysis, including 70 (24.8%) who were taking antiplatelet medications at ICH onset. Use of antiplatelet medications at ICH onset had no association with the volume of ICH at presentation, growth of ICH at 72 hours, initial edema volume, or edema growth. In multivariable analysis, there was no association of use of antiplatelet medications with any hemorrhage expansion (relative risk [RR] 0.85 [upper limit of confidence interval (UCI) 1.03], p = 0.16), hemorrhage expansion greater than 33% (RR 0.77 [UCI 1.18], p = 0.32), or clinical outcome at 90 days (odds ratio 0.67, 95% confidence interval 0.39-1.14, p = 0.14). CONCLUSIONS: Use of antiplatelet medications at intracerebral hemorrhage (ICH) onset is not associated with increased hemorrhage volumes, hemorrhage expansion, or clinical outcome at 90 days. These findings suggest that attempts to reverse antiplatelet medications after ICH may not be warranted.

Real-time cerebral angiography: sensitivity of a new contrast-specific ultrasound technique.

BACKGROUND AND PURPOSE: To test a new contrast-specific sonography imaging method that offers visualization of the intracranial vasculature in a manner similar to that seen on angiography. MATERIALS AND METHODS: Thirty patients (35 sonography studies total) were included in the study after they provided written informed consent. The patients were scanned through the temporal bone window from both sides after intravenous injection of an ultrasound contrast agent (UCA; perflexane lipid microspheres [Imagent]). The goal was to visualize the intracranial arteries, including the middle (M1-M3), anterior (A1 and A2), and posterior (P1-P3) cerebral arteries, using an axial scanning plane. The studies were performed using a contrast-specific imaging mode, based on a phase inversion technique (transcranial ultrasound angiography [tUSA]). For sensitivity, the results were compared with x-ray angiography as the "gold standard." For interobserver reliability, 24 of 35 sonography studies were evaluated by 2 physicians with little training in transcranial sonography and by a seasoned sonographer. RESULTS: The sensitivity of tUSA ranged between 0.778 (95% confidence interval [CI] of 0.577-0.914) and 0.963 (95% CI of 0.810-0.999). The sensitivities were similar among physicians with little training in transcranial sonography and the seasoned sonographer, indicating high inter-rater reliability. Overall, tUSA provided high anatomic resolution and vascular delineation even of small vessels in the millimeter range. At peak intensity, no UCA-related artifacts were observed. CONCLUSION: tUSA provides images of the intracranial arteries similar to those obtained at angiography with high anatomic resolution, reasonable sensitivity, and interobserver reliability.

The STRokE DOC trial technique: 'video clip, drip, and/or ship'.

RATIONALE: To describe the clinical trial methods of a site-independent telemedicine system used in stroke. AIMS: A lack of readily available stroke expertise may partly explain the low rate of rt-PA use in acute stroke. Although telemedicine systems can reliably augment expertise available to rural settings, and may increase rt-PA use, point-to-point systems do require fixed base stations. Site-independent systems may minimize delay. The STRokE DOC trial assesses whether site-independent telemedicine effectively and efficiently brings rt-PA to a remote population. DESIGN: STRokE DOC is a 5-year, 400-participant, noninvasive trial, comparing two consultative techniques at four remote sites. Participants are randomized to acute 'STRokE DOC telemedicine' or 'telephone' consultations. Treatment decision accuracy is adjudicated at two time points, using three levels of data availability and an independent auditor. STUDY OUTCOMES: The primary outcome measure is whether there was a 'correct decision to treat or not to treat using rt-PA' at each of three adjudication levels (primarily at Level #2). Secondary outcomes include the number of thrombolytic recommendations, intracerebral hemorrhage, and 90-day outcomes. Using the STRokE DOC system (or telephone evaluation), medical history, neurologic scales, CT interpretations, and recommendations have been completed on over 200 participants to date. Of the initial 11, nonrandomized, 'run-in' patients, six (65%) were evaluated wirelessly, and five (45%) were evaluated with a site-independent LAN or cable modem. Three (27%) received rt-PA. The adjudication methodology was able to show both agreements and disagreements in these 11 cases. It is feasible to perform site-independent stroke consultations, and adjudicate those cases, using the STRokE DOC system and trial design. Telemedicine efficacy remains to be proven.

Prospective reliability of the STRokE DOC wireless/site independent telemedicine system.

The authors evaluated a site-independent telemedicine system. Telemedicine may be limited by the need for fixed connectivity. Wireless and site-independent technologies eliminate this limitation. Twenty-five stroke patients underwent evaluations by remote and bedside examiners. Ten of 15 (67%) NIH Stroke Scale and 9 of 11 (82%) Modified NIH Stroke Scale items showed excellent interrater reliability. Spearman correlations were > or =0.93. This Internet system is reliable and valid. Further studies should assess its use in acute stroke.

Lack of hemispheric dominance for consciousness in acute ischaemic stroke.

BACKGROUND: Previous reports have suggested left hemispheric dominance for maintaining consciousness, although there is controversy over this claim. OBJECTIVE: To compare early impairment of level of consciousness between patients with right and left hemispheric stroke. METHODS: Data from 564 patients with ischaemic stroke enrolled in the placebo arm of a trial of a putative neuroprotectant were analysed. All patients had major hemispheric stroke with cortical dysfunction, visual field deficit, and limb weakness, with symptom onset within 12 hours of enrolment. Patients were prospectively evaluated on a predefined scale (1-6; 1 = fully awake, higher scores representing greater impairment) to measure level of consciousness at multiple time points over the initial 24 hours after presentation. The National Institutes of Health (NIH) stroke scale score at presentation and infarct volume at 30 days were determined. RESULTS: Some degree of impairment in level of consciousness was observed in 409 of the 564 patients (73%). Median maximum sedation score was 2 for both right and left hemispheric stroke (p = 0.91). Mean sedation score over 24 hours was 1.5 for both right and left stroke (p = 0.75). There was no difference between level of consciousness scores in right and left stroke at any individual time point during the 24 hour monitoring period. No association between side and impairment in level of consciousness was seen after adjustment for stroke severity and infarct volume. CONCLUSIONS: In contrast to previous reports, there was no evidence for hemispheric dominance for consciousness in the setting of a major hemispheric stroke.

Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial.

BACKGROUND: Hyperglycemia during acute ischemic stroke may augment brain injury, predispose to intracerebral hemorrhage (ICH), or both. METHOD: To analyze the relationship between admission glucose level and clinical outcomes from acute ischemic stroke, the authors performed multivariate regression analysis with the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator (rt-PA) Stroke Trial data. Neurologic improvement was defined as improvement on the NIH Stroke Scale by 4 or more points from baseline to 3 months, or a final score of zero. Favorable outcome was defined as both Glasgow Outcome score of 1 and Barthel Index 95 to 100 at 3 months. Symptomatic ICH was defined as CT-documented hemorrhage temporally related to clinical deterioration within 36 hours of treatment. Potential confounding factors were controlled, including acute treatment (rt-PA or placebo), age, baseline NIH Stroke Scale score, history of diabetes mellitus, stroke subtype, and admission blood pressure. RESULTS: There were 624 patients enrolled within 3 hours after stroke onset. As admission glucose increased, the odds for neurologic improvement decreased (odds ratio [OR] = 0.76 per 100 mg/dL increase in admission glucose, 95% CI 0.61 to 0.95, p = 0.01). The relation between admission glucose and favorable outcome depended on admission mean blood pressure (MBP): as admission MBP increased, the odds for favorable outcome related to increasing admission glucose levels progressively decreased (p = 0.02). As admission glucose increased, the odds for symptomatic ICH also increased (OR = 1.75 per 100 mg/dL increase in admission glucose, 95% CI 1.11 to 2.78, p = 0.02). Admission glucose level was not associated with altered effectiveness of rt-PA. CONCLUSIONS: In patients with acute ischemic stroke, higher admission glucose levels are associated with significantly lower odds for desirable clinical outcomes and significantly higher odds for symptomatic ICH, regardless of rt-PA treatment. Whether this represents a cause and effect relationship remains to be determined.

Clomethiazole Acute Stroke Study in ischemic stroke (CLASS-I): final results.

BACKGROUND AND PURPOSE: A previous trial (the Clomethiazole Acute Stroke Study) generated the hypothesis that clomethiazole is effective in patients with a major ischemic stroke (total anterior circulation syndrome), and this was tested in the present study. METHODS: A total of 1198 patients with major ischemic stroke and a combination of limb weakness, higher cortical dysfunction, and visual field deficits were randomly assigned to clomethiazole (68 mg/kg IV over 24 hours) or placebo. The study drug was initiated within 12 hours of symptom onset. Functional outcome and neurological recovery were assessed at days 7, 30, and 90, with the proportion of patients with a Barthel Index > or =60 at last follow-up as the primary outcome measure. RESULTS: The patients were randomly assigned equally, and the two treatment groups were well matched for baseline characteristics, including stroke severity (mean National Institutes of Health Stroke Scale score 16.9+/-5.2). Ninety-six percent were classified as total anterior circulation syndrome. The proportion of patients reaching a Barthel Index score of > or =60 was 42% in the clomethiazole-treated group and 46% in the placebo-treated group (odds ratio, 0.81; 95% CI, 0.62 to 1.05; P=0.11). There was no evidence of efficacy on any secondary outcome variables (modified Rankin Score, National Institutes of Health Stroke Scale, Scandinavian Stroke Scale, and 30-day CT infarct volumes) compared with placebo. Subgroup analysis showed a similar lack of treatment effect in patients treated early (<6 hours) and in those treated later (6 to 12 hours). Somnolence was an expected pharmacological effect of clomethiazole, and this occurred during treatment as an adverse event in half of the patients randomly assigned to study drug. CONCLUSIONS: The target population was selected, and sufficient drug was given to produce the expected pharmacological effect in the brain. Clomethiazole does not improve outcome in patients with major ischemic stroke.

Lack of clinical significance of early ischemic changes on computed tomography in acute stroke.

CONTEXT: The prevalence and clinical significance of early ischemic changes (EICs) on baseline computed tomography (CT) scan of the head obtained within 3 hours of ischemic stroke are not established. OBJECTIVE: To determine the frequency and significance of EIC on baseline head CT scans in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA (recombinant tissue plasminogen activator) Stroke Trial. DESIGN AND SETTING: The original study, a randomized controlled trial, took place from January 1991 through October 1994 at 43 sites, during which CT images were obtained within 3 hours of symptom onset and prior to the initiation of rt-PA or placebo. For the current analysis, detailed reevaluation was undertaken after October 1994 of all baseline head CT scans with clinical data available pretreatment (blinded to treatment arm). PATIENTS: Of 624 patients enrolled in the trial, baseline CT scans were retrieved and reviewed for 616 (99%). MAIN OUTCOME MEASURES: Frequency of EICs on baseline CT scans; association of EIC with other baseline variables; effect of EICs on deterioration at 24 hours (>/=4 points increase from the baseline National Institutes of Health Stroke Scale [NIHSS] score); clinical outcome (measured by 4 clinical scales) at 3 months, CT lesion volume at 3 months, death at 90 days; and symptomatic intracranial hemorrhage (ICH) within 36 hours of treatment. RESULTS: The prevalence of EIC on baseline CT in the combined rt-PA and placebo groups was 31% (n = 194). The EIC was significantly associated with baseline NIHSS score (rho = 0.23; P<.001) and time from stroke onset to baseline CT scan (rho = 0.11; P =.007). After adjusting for baseline variables, there was no EIC x treatment interaction detected for any clinical outcome, including deterioration at 24 hours, 4 clinical scales, lesion volume, and death at 90 days (P>/=.25), implying that EIC is unlikely to affect response to rt-PA treatment. After adjusting for NIHSS score (an independent predictor of ICH), no EIC association with symptomatic ICH at 36 hours was detected in the group treated with rt-PA (P>/=.22). CONCLUSIONS: Our analysis suggests that EICs are prevalent within 3 hours of stroke onset and correlate with stroke severity. However, EICs are not independently associated with increased risk of adverse outcome after rt-PA treatment. Patients treated with rt-PA did better whether or not they had EICs, suggesting that EICs on CT scan are not critical to the decision to treat otherwise eligible patients with rt-PA within 3 hours of stroke onset.

Thrombolysis in patients with transient neurologic deficits.

What is the risk of thrombolysis in patients with acute stroke who might recover without treatment? In the National Institute of Neurological Disorders and Stroke rt-PA for Acute Stroke Trial, 2.6% of patients taking placebo showed spontaneous 24-hour recovery, compared to 11.5% of recombinant tissue-type plasminogen activator (rt-PA)-treated patients (p < 0.001). There were no symptomatic ICH in the patients taking placebo; one hypertensive, rt-PA-treated patient hemorrhaged. Assuming the National Institute of Neurological Disorders and Stroke protocol is followed rigorously, patients with acute stroke rarely recover spontaneously and the thrombolytic risk is low.

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.

Angiogenesis after stroke is correlated with increased numbers of macrophages: the clean-up hypothesis.

Brain cells manufacture and secrete angiogenic peptides after focal cerebral ischemia, but the purpose of this angiogenic response is unknown. Because the maximum possible regional cerebral blood flow is determined by the quantity of microvessels in each unit volume, it is possible that angiogenic peptides are secreted to generate new collateral channels; other possibilities include neuroprotection, recovery/regeneration, and removal of necrotic debris. If the brain attempts to create new collaterals, microvessel density should increase significantly after ischemia. Conversely, if angiogenic-signaling molecules serve some other purpose, microvessel densities may increase slightly or not at all. To clarify, the authors measured microvessel densities with quantitative morphometry. Left middle cerebral arteries of adult male Sprague-Dawley rats were occluded with intraluminal nylon suture for 4 hours followed by 7, 14, 19, or 30 days of reperfusion. Controls received no surgery or suture occlusion. Changes in microvessel density and macrophage numbers were measured by light microscopic morphometry using semiautomated stereologic methods. Microvessel density increased only in the ischemic margin adjacent to areas of pannecrosis and was always associated with increased numbers of macrophages. Ischemic brain areas without macrophages displayed no vascularity changes compared with normal animals. These data suggest that ischemia-induced microvessels are formed to facilitate macrophage infiltration and removal of necrotic brain.