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Importance: Intravenous alteplase reduces disability after ischemic stroke in patients 4.5 to 9 hours after onset and with wake-up onset stroke selected using perfusion imaging mismatch. However, whether the benefit is consistent across the 4.5- to 6-hours, 6- to 9-hours, and wake-up stroke epochs is uncertain., Objective: To examine the association of reperfusion with reduced disability, including by onset-to-randomization time strata in the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) randomized clinical trials., Design, Setting, and Participants: Individual patient meta-analysis of randomized clinical trials performed from August 2001 to June 2018 with 3-month follow-up. Patients had acute ischemic stroke with 4.5-to 9-hours poststroke onset or with wake-up stroke were randomized to alteplase or placebo after perfusion mismatch imaging. Analysis began July 2019 and ended May 2020., Exposures: Reperfusion was defined as more than 90% reduction in time to maximum of more than 6 seconds' lesion volume at 24- to 72-hour follow-up., Main Outcomes and Measures: Ordinal logistic regression adjusted for baseline age and National Institutes of Health Stroke Scale score was used to analyze functional improvement in day 90 modified Rankin Scale score overall, including a reperfusion × time-to-randomization multiplicative interaction term, and in the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata. Symptomatic hemorrhage was defined as large parenchymal hematoma with a National Institutes of Health Stroke Scale score increase of 4 points or more., Results: Reperfusion was assessable in 270 of 295 patients (92%), 68 of 133 (51%) in the alteplase group, and 38 of 137 (28%) in the placebo reperfused group (P < .001). The median (interquartile range) age was 76 (66-81) years in the reperfusion group vs 74 (64.5-81.0) years in the group with no reperfusion. The median (interquartile range) baseline National Institutes of Health Stroke Scale score was 10 (7-15) in the reperfusion group vs 12 (8.0-17.5) in the no reperfusion group. Overall, reperfusion was associated with improved functional outcome (common odds ratio, 7.7; 95% CI, 4.6-12.8; P < .001). Reperfusion was associated with significantly improved functional outcome in each of the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata, with no evidence of association between time to randomization and beneficial effect of reperfusion (P = .63). Symptomatic hemorrhage, assessed in all 294 patients, occurred in 3 of 51 (5.9%) in the 4.5- to 6-hours group, 2 of 28 (7.1%) in the 6- to 9-hours group, and 4 of 73 (5.5%) in the wake-up stroke in patients treated with alteplase (Fisher P = .91)., Conclusions and Relevance: Strong benefits of reperfusion in all time strata without differential risk in symptomatic hemorrhage support the consistent treatment effect of alteplase in perfusion mismatch-selected patients throughout the 4.5- to 9-hours and wake-up stroke time window.

Background Subacute ischemic lesions in intracerebral hemorrhage ( ICH ) have been hypothesized to result from hypoperfusion. Although studies of cerebral blood flow ( CBF ) indicate modest hypoperfusion in ICH , these investigations have been limited to early time points. Arterial spin labeling ( ASL ), a magnetic resonance imaging technique, can be used to measure CBF without a contrast agent. We assessed CBF in patients with ICH using ASL and tested the hypothesis that CBF is related to systolic blood pressure ( SBP ). Methods and Results In this cross-sectional study, patients with ICH were assessed with ASL at 48 hours, 7 days, and/or 30 days after onset. Relative CBF ( rCBF ; ratio of ipsilateral/contralateral perfusion) was measured in the perihematomal regions, hemispheres, border zones, and the perilesional area in patients with diffusion-weighted imaging hyperintensities. Twenty-patients (65% men; mean± SD age, 68.5±12.7 years) underwent imaging with ASL at 48 hours (N=12), day 7 (N=6), and day 30 (N=11). Median (interquartile range) hematoma volume was 13.1 (6.3-19.3) mL. Mean± SD baseline SBP was 185.4±25.5 mm Hg. Mean perihematomal rCBF was 0.9±0.2 at 48 hours at all time points. Baseline SBP and other SBP measurements were not associated with a decrease in rCBF in any of the regions of interest ( P≥0.111). r CBF did not differ among time points in any of the regions of interest ( P≥0.097). Mean perilesional rCBF was 1.04±0.65 and was unrelated to baseline SBP ( P=0.105). Conclusions ASL can be used to measure rCBF in patients with acute and subacute ICH . Perihematomal CBF was not associated with SBP changes at any time point. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT00963976.

Background and Purpose: Although blood pressure reduction has been postulated to result in a fall in cerebral perfusion pressure in patients with intracerebral hemorrhage, the latter is rarely measured. We assessed regional cerebral perfusion pressure in patients with intracerebral hemorrhage by using CT perfusion source data., Materials and Methods: Patients with acute primary intracerebral hemorrhage were randomized to target systolic blood pressures of <150 mm Hg (n = 37) or <180 mm Hg (n = 36). Regional maps of cerebral blood flow, cerebral perfusion pressure, and cerebrovascular resistance were generated by using CT perfusion source data, obtained 2 hours after randomization., Results: Perihematoma cerebral blood flow (38.7 ± 11.9 mL/100 g/min) was reduced relative to contralateral regions (44.1 ± 11.1 mL/100 g/min, P = .001), but cerebral perfusion pressure was not (14.4 ± 4.6 minutes(-1) versus 14.3 ± 4.8 minutes(-1), P = .93). Perihematoma cerebrovascular resistance (0.34 ± 0.11 g/mL) was higher than that in the contralateral region (0.30 ± 0.10 g/mL, P < .001). Ipsilateral and contralateral cerebral perfusion pressure in the external (15.0 ± 4.6 versus 15.6 ± 5.3 minutes(-1), P = .15) and internal (15.0 ± 4.8 versus 15.0 ± 4.8 minutes(-1), P = .90) borderzone regions were all similar. Borderzone cerebral perfusion pressure was similar to mean global cerebral perfusion pressure (14.7 ± 4.7 minutes(-1), P ≥ .29). Perihematoma cerebral perfusion pressure did not differ between blood pressure treatment groups (13.9 ± 5.5 minutes(-1) versus 14.8 ± 3.4 minutes(-1), P = .38) or vary with mean arterial pressure (r = -0.08, [-0.10, 0.05])., Conclusions: Perihematoma cerebral perfusion pressure is maintained despite increased cerebrovascular resistance and reduced cerebral blood flow. Aggressive antihypertensive therapy does not affect perihematoma or borderzone cerebral perfusion pressure. Maintenance of cerebral perfusion pressure provides physiologic support for the safety of blood pressure reduction in intracerebral hemorrhage., (© 2016 by American Journal of Neuroradiology.)

Background and Purpose: There are limited data on the extent of blood-brain barrier (BBB) compromise in acute intracerebral hemorrhage patients. We tested the hypotheses that BBB compromise measured with permeability-surface area product (PS) is increased in the perihematoma region and predicts perihematoma edema growth in acute intracerebral hemorrhage patients., Methods: Patients were randomized within 24 hours of symptom onset to a systolic blood pressure (SBP) treatment of <150 (n=26) or <180 mm Hg (n=27). Permeability maps were generated using computed tomographic perfusion source data acquired 2 hours after randomization, and mean PS was measured in the hematoma, perihematoma, and hemispheric regions. Hematoma and edema volumes were measured on noncontrast computed tomographic scans obtained at baseline, 2 hours and 24 hours after randomization., Results: Patients were randomized at a median (interquartile range) time of 9.3 hours (14.1) from symptom onset. Treatment groups were balanced with respect to baseline SBP and hematoma volume. Perihematoma PS (5.1±2.4 mL/100 mL per minute) was higher than PS in contralateral regions (3.6±1.7 mL/100 mL per minute; P<0.001). Relative edema growth (0-24 hours) was not predicted by perihematoma PS (β=-0.192 [-0.06 to 0.01]) or SBP change (β=-0.092 [-0.002 to 0.001]). SBP was lower in the <150 target group (139.2±22.1 mm Hg) than in the <180 group (159.7±12.3 mm Hg; P<0.0001). Perihematoma PS was not different between groups (4.9±2.4 mL/100 mL per minute for the <150 group, 5.3±2.4 mL/100 mL per minute for the <180 group; P=0.51)., Conclusions: BBB permeability is focally increased in the hematoma and perihematoma regions of acute intracerebral hemorrhage patients. BBB compromise does not predict acute perihematoma edema volume or edema growth. SBP reduction does not affect BBB permeability., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00963976., (© 2015 American Heart Association, Inc.)

Background and Purpose: Multimodal imaging in acute ischemic stroke defines the extent of arterial collaterals, resultant penumbra, and associated infarct core, yet limitations abound. We identified superficial and deep venous drainage patterns that predict outcomes in patients with a proximal arterial occlusion of the anterior circulation., Methods: An observational study that used computed tomography (CT) angiography to detail venous drainage in a consecutive series of patients with a proximal anterior circulation arterial occlusion. The principal veins that drain the cortex (superficial middle cerebral, vein of Trolard, vein of Labbé, and basal vein of Rosenthal) and deep structures were scored with a categorical scale on the basis of degree of contrast enhancement. The Prognostic Evaluation based on Cortical vein score difference In Stroke score encompassing the interhemispheric difference of the composite scores of the veins draining the cortices (superficial middle cerebral+vein of Trolard+vein of Labbé+basal vein of Rosenthal) was analyzed with respect to 90-day modified Rankin Scale outcomes., Results: Thirty-nine patients were included in the study. A Prognostic Evaluation based on Cortical vein score difference In Stroke score of 4 to 8 accurately predicted poor outcomes (modified Rankin Scale, 3-6; odds ratio, 20.53; P<0.001). On stepwise logistic regression analyses adjusted for CT Alberta stroke program early CT score, CT angiography collateral grading and National Institutes of Health Stroke Scale score, a Prognostic Evaluation based on Cortical vein score difference In Stroke score of 4 to 8 (odds ratio, 23.598; P=0.009) and an elevated admission National Institutes of Health Stroke Scale (odds ratio, 1.423; P=0.023) were independent predictors of poor outcome., Conclusions: The Prognostic Evaluation based on Cortical vein score difference In Stroke score, a novel measure of venous enhancement on CT angiography, accurately predicts clinical outcomes. Venous features on computed tomography angiography provide additional characterization of collateral perfusion and prognostication in acute ischemic stroke.

Background and Purpose: Acute blood pressure (BP) reduction aimed at attenuation of intracerebral hemorrhage (ICH) expansion might also compromise cerebral blood flow (CBF). We tested the hypothesis that CBF in acute ICH patients is unaffected by BP reduction., Methods: Patients with spontaneous ICH <24 hours after onset and systolic BP > 150 mm Hg were randomly assigned to an intravenous antihypertensive treatment protocol targeting a systolic BP of <150 mm Hg (n=39) or <180 mm Hg (n=36). Patients underwent computed tomography perfusion imaging 2 hours postrandomization. The primary end point was perihematoma relative (relative CBF)., Results: Treatment groups were balanced with respect to baseline systolic BP: 182±20 mm Hg (<150 mm Hg target group) versus 184±25 mm Hg (<180 mm Hg target group; P=0.60), and for hematoma volume: 25.6±30.8 versus 26.9±25.2 mL (P=0.66). Mean systolic BP 2 hours after randomization was significantly lower in the <150 mm Hg target group (140±19 vs 162±12 mm Hg; P<0.001). Perihematoma CBF (38.7±11.9 mL/100 g per minute) was lower than in contralateral homologous regions (44.1±11.1 mL/100 g per minute; P<0.001) in all patients. The primary end point of perihematoma relative CBF in the <150 mm Hg target group (0.86±0.12) was not significantly lower than that in the <180 mm Hg group (0.89±0.09; P=0.19; absolute difference, 0.03; 95% confidence interval -0.018 to 0.078). There was no relationship between the magnitude of BP change and perihematoma relative CBF in the <150 mm Hg (R=0.00005; 95% confidence interval, -0.001 to 0.001) or <180 mm Hg target groups (R=0.000; 95% confidence interval, -0.001 to 0.001)., Conclusions: Rapid BP lowering after a moderate volume of ICH does not reduce perihematoma CBF. These physiological data indicate that acute BP reduction does not precipitate cerebral ischemia in ICH patients. Clinical Trial Registration Information- URL:http://clinicaltrials.gov. Unique Identifier: NCT00963976.

Background and Purpose: Collateral flow augmentation using partial aortic occlusion may improve cerebral perfusion in acute stroke. We assessed the safety and feasibility of partial aortic occlusion immediately after intravenous tissue plasminogen activator., Methods: We conducted an open-label pilot study of partial aortic occlusion after thrombolysis. The primary end point was all serious adverse events within 30 days of treatment., Results: None of the 22 patients enrolled developed symptomatic parenchymal hemorrhages. Asymptomatic hemorrhagic transformation occurred in 9 patients. Procedure-related adverse events were limited to groin complications (n=13). Seventy-seven percent of patients experienced neurological improvement (≥4-point improvement of the National Institutes of Health Stroke Scale score)., Conclusions: Partial aortic occlusion as an adjunct to thrombolysis in the treatment of acute stroke appears safe. Studies aimed at determining the efficacy of this therapeutic approach are warranted., Clinical Trial Registration Information: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01006993.

Purpose: To assess the relationship between sodium signal intensity changes and oligemia, measured with perfusion-weighted imaging (PWI), in ischemic stroke patients., Materials and Methods: Nine ischemic stroke patients (55 ± 13 years), four with follow-up scans, underwent sodium and proton imaging 4-32 hours after symptom onset. Relative sodium intensity was calculated as the ratio of signal intensities in core (identified as hypertintense lesions on diffusion-weighted imaging [DWI]) or putative penumbra (PWI-DWI mismatch) to contralateral homologous regions., Results: Sodium intensity increases in the core were not correlated with the severity of hypoperfusion, measured with either cerebral blood flow (rho = 0.157; P = 0.61) or cerebral blood volume (rho = -0.234; P = 0.44). In contrast, relative sodium intensity was not elevated (4-7 hours 0.96 ± 0.07; 17-32 hours 1.00 ± 0.07) in PWI-DWI mismatch regions., Conclusion: Sodium signal intensity cannot be predicted by the degree of hypoperfusion acutely. Sodium intensity also remains unchanged in PWI-DWI mismatch tissue, indicating preservation of ionic homeostasis. Sodium magnetic resonance imaging (MRI), in conjunction with PWI and DWI, may permit identification of patients with viable tissue, despite an unknown symptom onset time., (Copyright © 2010 Wiley-Liss, Inc.)

Background and Purpose: Currently, diffusion-weighted imaging (DWI) lesion volume is the most useful magnetic resonance imaging predictor of hemorrhagic transformation (HT). Preliminary studies have suggested that very low cerebral blood volume (VLCBV) predicts HT. We compared HT prediction by VLCBV and DWI using data from the EPITHET study., Methods: Normal-percentile CBV values were calculated from the nonstroke hemisphere. Whole-brain masks with CBV thresholds of the <0, 2.5, 5, and 10th percentiles were created. The volume of tissue with VLCBV was calculated within the acute DWI ischemic lesion. HT was graded as per ECASS criteria., Results: HT occurred in 44 of 91 patients. Parenchymal hematoma (PH) occurred in 13 (4 symptomatic) and asymptomatic hemorrhagic infarction (HI) in 31. The median volume of VLCBV was significantly higher in cases with PH. VLCBV predicted HT better than DWI lesion volume and thresholded apparent diffusion coefficient lesion volume in receiver operating characteristic analysis and logistic regression. A cutpoint at 2 mL VLCBV with the <2.5th percentile had 100% sensitivity for PH and, in patients treated with tissue plasminogen activator, defined a population with a 43% risk of PH (95% CI, 23% to 66%, likelihood ratio=16). VLCBV remained an independent predictor of PH in multivariate analysis with traditional clinical risk factors for HT., Conclusions: VLCBV predicted HT after thrombolysis better than did DWI or apparent diffusion coefficient volume in this large patient cohort. The advantage was greatest in patients with smaller DWI volumes. Prediction was better in patients who recanalized. If validated in an independent cohort, the addition of VLCBV to prethrombolysis decision making may reduce the incidence of HT.

Background: For MR perfusion-diffusion mismatch to be clinically useful as a means of selecting patients for thrombolysis, it needs to occur in real time at the MRI console. Visual mismatch assessment has been used clinically and in trials but has not been systematically validated. We compared the accuracy of visually rating console-generated images with offline volumetric measurements using data from the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET)., Methods: Perfusion time-to-peak (TTP) and diffusion-weighted images (DWI) (as generated by commercial MRI console software) and T(max) perfusion maps (which required offline calculation) were visually rated. Perfusion-diffusion mismatch, defined as a ratio of perfusion:diffusion lesion volume of >1.2, was independently scored by 1 expert and 2 inexperienced raters blinded to calculated volumes and clinical information. Visual mismatch was compared with region-of-interest-based volumetric calculation, which was used as the gold standard., Results: Volumetric calculation demonstrated perfusion-diffusion mismatch in 85/99 patients. Visual TTP-DWI mismatch was correctly classified by the experienced rater in 82% of the cases (sensitivity: 0.86; specificity: 0.54) compared to 73% for the inexperienced raters (sensitivity: 0.75; specificity: 0.57). The interrater reliability for TTP-DWI mismatch was moderate (kappa = 0.50). Visual T(max)-DWI mismatch performed better (agreement - 93 and 87%, sensitivity - 95 and 88%, specificity - 77 and 82% for the experienced and inexperienced raters, respectively)., Conclusions: The assessment of visual TTP-DWI mismatch at the MRI console is insufficiently reliable for use in clinical trials. Differences in perfusion analysis technique and visual inaccuracies combine to make visual TTP-DWI mismatch substantially different to volumetric T(max)-DWI mismatch. Automated software that applies perfusion thresholds may improve the reproducibility of real-time mismatch assessment., (Copyright 2010 S. Karger AG, Basel.)