Neil J. Spratt

A Randomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke

BACKGROUND Intravenous alteplase is the only approved treatment for acute ischemic stroke. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, is an alternative thrombolytic agent. METHODS In this phase 2B trial, we randomly assigned 75 patients to receive alteplase (0.9 mg per kilogram of body weight) or tenecteplase (0.1 mg per kilogram or 0.25 mg per kilogram) less than 6 hours after the onset of ischemic stroke. To favor the selection of patients most likely to benefit from thrombolytic therapy, the eligibility criteria were a perfusion lesion at least 20% greater than the infarct core on computed tomographic (CT) perfusion imaging at baseline and an associated vessel occlusion on CT angiography. The coprimary end points were the proportion of the perfusion lesion that was reperfused at 24 hours on perfusion-weighted magnetic resonance imaging and the extent of clinical improvement at 24 hours as assessed on the National Institutes of Health Stroke Scale (NIHSS, a 42-point scale on which higher scores indicate more severe neurologic deficits). RESULTS The three treatment groups each comprised 25 patients. The mean (±SD) NIHSS score at baseline for all patients was 14.4±2.6, and the time to treatment was 2.9±0.8 hours. Together, the two tenecteplase groups had greater reperfusion (P=0.004) and clinical improvement (P<0.001) at 24 hours than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events. The higher dose of tenecteplase (0.25 mg per kilogram) was superior to the lower dose and to alteplase for all efficacy outcomes, including absence of serious disability at 90 days (in 72% of patients, vs. 40% with alteplase; P=0.02). CONCLUSIONS Tenecteplase was associated with significantly better reperfusion and clinical outcomes than alteplase in patients with stroke who were selected on the basis of CT perfusion imaging. (Funded by the Australian National Health and Medical Research Council; Australia New Zealand Clinical Trials Registry number, ACTRN12608000466347.).

Perfusion CT in acute stroke: a comprehensive analysis of infarct and penumbra.

PURPOSE To perform a large-scale systematic comparison of the accuracy of all commonly used perfusion computed tomography (CT) data postprocessing methods in the definition of infarct core and penumbra in acute stroke. MATERIALS AND METHODS The collection of data for this study was approved by the institutional ethics committee, and all patients gave informed consent. Three hundred fourteen patients with hemispheric ischemia underwent perfusion CT within 6 hours of stroke symptom onset and magnetic resonance (MR) imaging at 24 hours. CT perfusion maps were generated by using six different postprocessing methods. Pixel-based analysis was used to calculate sensitivity and specificity of different perfusion CT thresholds for the penumbra and infarct core with each postprocessing method, and receiver operator characteristic (ROC) curves were plotted. Area under the ROC curve (AUC) analysis was used to define the optimum threshold. RESULTS Delay-corrected singular value deconvolution (SVD) with a delay time of more than 2 seconds most accurately defined the penumbra (AUC = 0.86, P = .046, mean volume difference between acute perfusion CT and 24-hour diffusion-weighted MR imaging = 1.7 mL). A double core threshold with a delay time of more than 2 seconds and cerebral blood flow less than 40% provided the most accurate definition of the infarct core (AUC = 0.86, P = .038). The other SVD measures (block circulant, nondelay corrected) were more accurate than non-SVD methods. CONCLUSION This study has shown that there is marked variability in penumbra and infarct prediction among various deconvolution techniques and highlights the need for standardization of perfusion CT in stroke. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120971/-/DC1.

Defining the Extent of Irreversible Brain Ischemia Using Perfusion Computed Tomography

Background: Perfusion computed tomography (PCT) shows promise in acute stroke assessment. However, the accuracy of CT perfusion thresholds in defining the acute infarct core remains uncertain. Method: Concurrent PCT and MRI-DWI performed 3–6 h after symptoms onset were assessed in 57 ischemic stroke patients. PCT was compared to DWI images to define the infarct core using a pixel-based receiver operating characteristic curve analysis to calculate the area under the curve (AUC) for thresholds from PCT maps that were coregistered with the DWI slice location. Results: A relative cerebral blood flow (CBF) of 45% of the contralateral hemisphere was found to be the most accurate threshold for describing the infarct core (AUC 0.788), and it was also by far the most frequent threshold with the highest AUC across patients. Conclusion: CBF thresholds on PCT define the acute infarct core more accurately than do other PCT thresholds, including a cerebral blood volume of 2 ml/100 g.

Seasonal variation in stroke in the Hunter Region, Australia: a 5-year hospital-based study, 1995-2000

Background and Purpose— Seasonal variation in stroke has long been recognized. To date, there are minimal published data on seasonal variations in rates of stroke and subsequent case fatality in the Southern Hemisphere. The aim of this study was to examine stroke seasonality through the use of data from a hospital-based stroke register in the Hunter Region of New South Wales, Australia. Methods— From July 1, 1995, to June 30, 2000, 3803 stroke events were registered in residents of the Hunter Region, New South Wales, Australia. We analyzed the trend of seasonal and monthly stroke attack rates and case-fatality rates using Poisson regressions with age and sex as covariates. Results— Stroke attack rates were highest in the winter and lowest in the summer. From February (summer) to July (winter), there was a significant trend in increasing stroke attack rates (rate ratio, 1.07; 95% confidence interval, 1.05 to 1.10;P <0.001). This increase was seen mainly in those ≥65 years of age. Case-fatality rates showed similar trends with a 1- to 2-month lag compared with attack rates. Conclusions— There is an increase in stroke attack rates and case-fatality rate from summer to winter in the Hunter Region, Australia. These trends are similar to those found in the Northern Hemisphere.

Acute ischemic stroke Imaging-guided tenecteplase treatment in an extended time window

Background: Tenecteplase is a modified tissue plasminogen activator with a longer half-life and higher fibrin specificity than alteplase. Methods: We conducted a prospective, nonrandomized, pilot study of 0.1 mg/kg IV tenecteplase given 3 to 6 hours after ischemic stroke onset. For a control group, we used patients contemporaneously treated with sub–3-hour 0.9 mg/kg IV alteplase following standard selection criteria. All patients underwent pretreatment and 24-hour perfusion/angiographic imaging with CT or MRI. Eligibility criteria for tenecteplase (but not alteplase) treatment included a perfusion lesion at least 20% greater than the infarct core, with an associated vessel occlusion. Primary outcomes, assessed blind to treatment group, were reperfusion (reduction in baseline–24-hour mean transit time lesion) and major vessel recanalization. Results: Fifteen patients received tenecteplase, and 35 patients received alteplase. The tenecteplase group had greater reperfusion (mean 74% vs 44% in the alteplase group, p = 0.01) and major vessel recanalization (10/15 tenecteplase vs 7/29 alteplase, p = 0.01). Despite later time to treatment, more tenecteplase patients (10/15 vs 7/35 alteplase, p = 0.001) had major neurologic improvement at 24 hours (NIH Stroke Scale reduction ≥8). Four of the alteplase patients and none of the tenecteplase patients had parenchymal hematoma at 24 hours. Conclusions: Tenecteplase 0.1 mg/kg, using advanced imaging guidance in an extended time window, may have significant biologic efficacy in acute ischemic stroke. The imaging selection differences between the tenecteplase and alteplase groups prevent a conclusive efficacy comparison. Nonetheless, these results lend support for randomized trials comparing tenecteplase with alteplase, preferably incorporating penumbral/angiographic imaging selection. CBV = cerebral blood volume; CTA = CT angiography; CTP = perfusion CT; DWI = diffusion-weighted echo-planar spin-echo sequence; ICH = intracranial hemorrhage; MNI = major neurologic improvement; MR = magnetic resonance; mRS = modified Rankin Scale; MTT = mean transit time; NCCT = noncontrast CT; NIHSS = NIH Stroke Scale; PH = parenchymal hematoma; TIMI = Thrombolysis in Myocardial Infarction.

Assessment of leptomeningeal collaterals using dynamic CT angiography in patients with acute ischemic stroke

Whole-brain dynamic time-resolved computed tomography angiography (CTA) is a technique developed on the new 320-detector row CT scanner capable of generating time-resolved cerebral angiograms from skull base to vertex. Unlike a conventional cerebral angiogram, this technique visualizes pial arterial filling in all vascular territories, thereby providing additional hemodynamic information. Ours was a retrospective study of consecutive patients with ischemic stroke and M1 middle cerebral artery +/– intracranial internal carotid artery occlusions presenting to our center from June 2010 and undergoing dynamic time-resolved CTA and perfusion CT within 6 hours of symptom onset. Leptomeningeal collateral status was assessed by determining relative prominence of pial arteries in the ischemic region, rate and extent of retrograde flow, and various topographical patterns of pial arterial filling. Twenty-five patients were included in the study. We demonstrate the existence of the following novel properties of leptomeningeal collaterals in humans: (a) posterior (posterior cerebral artery (PCA)–MCA) dominant collateralization, (b) intra-territorial ‘within MCA region’ leptomeningeal collaterals, and (c) significant variability in size, extent, and retrograde filling time in pial arteries. We also describe a simple and reliable collateral grading template that, for the first time on dynamic CTA, incorporates back-filling time as well as size and extent of collateral filling.

Modification of the method of thread manufacture improves stroke induction rate and reduces mortality after thread-occlusion of the middle cerebral artery in young or aged rats.

Improving models of human stroke by the use of aged animals has been advocated; however the commonly used rat middle cerebral artery thread-occlusion model has produced suboptimal stroke induction and excess mortality in aged rats. We report the development of a modified method for silicone-coating the tip of occluding threads which produces a malleable silicone-coated tip which is firmly bonded and of highly consistent diameter, and overcomes problems of thread insertion through the narrowed carotid canal found in aged animals. Comparison of stroke outcomes and mortality were made between these threads and heat-treated poly-L-lysine coated threads. The rate of successful stroke induction in aged rats was significantly improved (from 14% to 86%). Similarly, mortality fell from 21-31% to 3-7% or less in both young and old rats with or without diabetes and hypertension. An occluding thread tip diameter of 0.35-0.38 mm was optimal for induction of mid-sized strokes in both young and old rats. This method of thread manufacture overcomes problems of inconsistency of diameter and bonding of the silicone-coated tip, and these threads produce significant improvements in stroke induction by MCA occlusion, particularly in aged animals and those with co-morbidities.

An Enriched Environment Improves Sensorimotor Function Post-Ischemic Stroke

Objective. An enriched environment (EE) refers to conditions that facilitate or enhance sensory, cognitive, motor, and social stimulation relative to standard (laboratory) conditions. Despite numerous published studies investigating this concept in animal stroke models, there is still debate around its efficacy. The authors performed a systematic review and meta-analysis to determine the efficacy of an EE on neurobehavioral scores, learning, infarct size, and mortality in animal models of ischemic stroke. Methods. Systematic review of controlled studies of the use of an EE in experimental stroke was conducted. Data extracted were analyzed using weighted mean difference meta-analysis. For pooled tests of neurobehavioral scores, a random effects standardized method was used. Results. Animals recovering in an EE poststroke had mean neurobehavioral scores 0.9 standard deviations (95% confidence interval [CI] = 0.5-1.3; P < .001) above the mean scores of animals recovering in standard conditions and showed a trend toward improvement in learning (25.1% improvement; 95% CI = 3.7-46.6; P = .02). There was no significant increase in death. Animals exposed to an EE had 8.0% larger infarcts than control animals (95% CI = 1.8-14.1; P = .015). Conclusions. The results indicate significant improvements in sensorimotor function with EE poststroke but suggest a small increase in infarct volume. Clarification of the underlying mechanisms requires further study but should not overshadow the observed functional improvements and their application to clinical trials during stroke rehabilitation.

An enriched environment increases activity in stroke patients undergoing rehabilitation in a mixed rehabilitation unit: a pilot non-randomized controlled trial

Abstract Purpose: An enriched environment (EE) facilitates physical, cognitive and social activity in animal models of stroke. The aim of this pilot study was to determine whether enriching the environment of a mixed rehabilitation unit increased stroke patient activity. Methods: A non- randomized controlled trial was conducted. Direct observation was used to determine the difference in change in physical, cognitive, social or any activity over 2 weeks in patients exposed to an enriched versus non-enriched environment. Results: Stroke patients in the EE (n = 15) were 1.2 (95% CI 1.0–1.4) times more likely to be engaged in any activity compared with those in a non-enriched environment (n = 14). They were 1.7 (95% CI 1.1–2.5) times more likely to be engaged in cognitive activities, 1.2 (95% CI 1.0–1.5) times more likely to be engaged in social activities, 0.7 (95% CI 0.6–0.9) times as likely to be inactive and alone and 0.5 (95% CI 0.4–0.7) times as likely to be asleep than patients without enrichment. Conclusions: This preliminary trial suggests that the comprehensive model of enrichment developed for use in a rehabilitation unit was effective in increasing activity in stroke patients and reducing time spent inactive and alone. Implications for Rehabilitation Stroke patients within a mixed rehabilitation unit who are exposed to an enriched environment (EE) are more likely to be engaged in activity than those not exposed to the enriched environment. Patients in enriched conditions are less likely to be “inactive and alone” or asleep during waking hours. These results suggest a comprehensive model of enrichment is effective in increasing activity levels.

Perfusion computed tomography to assist decision making for stroke thrombolysis

The use of perfusion imaging to guide selection of ischaemic stroke patients for thrombolytic therapy remains controversial. Using two large independent cohorts, Bivard et al. demonstrate that perfusion imaging is able to identify patients who will benefit from treatment and that these patients are not readily identifiable using clinical assessments.