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Objective: To investigate whether an earlier time to achieving and maintaining systolic blood pressure (SBP) at 120 to 140 mm Hg is associated with favorable outcomes in a cohort of patients with acute intracerebral hemorrhage., Methods: We pooled individual patient data from randomized controlled trials registered in the Blood Pressure in Acute Stroke Collaboration. Time was defined as time form symptom onset plus the time (hour) to first achieve and subsequently maintain SBP at 120 to 140 mm Hg over 24 hours. The primary outcome was functional status measured by the modified Rankin Scale at 90 to 180 days. A generalized linear mixed models was used, with adjustment for covariables and trial as a random effect., Results: A total of 5761 patients (mean age, 64.0 [SD, 13.0], 2120 [36.8%] females) were included in analyses. Earlier SBP control was associated with better functional outcomes (modified Rankin Scale score, 3-6; odds ratio, 0.98 [95% CI, 0.97-0.99]) and a significant lower risk of hematoma expansion (0.98, 0.96-1.00). This association was stronger in patients with bigger baseline hematoma volume (>10 mL) compared with those with baseline hematoma volume ≤10 mL (0.006 for interaction). Earlier SBP control was not associated with cardiac or renal adverse events., Conclusions: Our study confirms a clear time relation between early versus later SBP control (120-140 mm Hg) and outcomes in the one-third of patients with intracerebral hemorrhage who attained sustained SBP levels within this range. These data provide further support for the value of early recognition, rapid transport, and prompt initiation of treatment of patients with intracerebral hemorrhage., Competing Interests: Disclosures Dr Sandset reports consulting fees from Bayer, Boston Scientific Corporation, Bristol Myers Squibb, Daiichi Sankyo Company, Portola Pharmaceuticals, LLC. Dr Qureshi reports grant support/consultation by AstraZeneca and Chiesi USA. Dr Saver has received, for service on clinical trial steering committees and DSMBs advising on rigorous study design and conduct, contracted payments from Abbott, Aeromics, Biogen, Boehringer Ingelheim, BrainQ, BrainsGate, Johnson & Johnson, Medtronic, MindRhythm, MIVI Neuroscience, Neuronics Medical, and Roche. The other authors report no conflicts.

Background: In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 μg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion., Methods: Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration., Results: Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2-2.6). Median time from baseline CT to study drug was 62.5 (55-80) minutes, and from study drug to early post-dose CT was 19 (14.5-30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8-8.3) in the placebo arm ( P =0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm ( P =0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71-1.43]; P =0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994-1.003]; P =0.50; Table 3)., Conclusions: In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01359202.

Background: Definitive diagnosis of acute ischemic stroke is challenging, particularly in telestroke settings. Although the prognostic utility of CT perfusion (CTP) has been questioned, its diagnostic value remains under-appreciated, especially in cases without an easily visible intracranial occlusion. We assessed the diagnostic accuracy of routine CTP in the acute telestroke setting., Methods: Acute and follow-up data collected prospectively from consecutive suspected patients with stroke assessed by a state-wide telestroke service between March 2020 and August 2021 at 12 sites in Australia were analyzed. All patients in the final analysis had been assessed with multimodal CT, including CTP, which was post-processed with automated volumetric software. Diagnostic sensitivity and specificity were calculated for multimodal CT and each individual component (noncontrast CT [NCCT], CT angiogram [CTA], and CTP). Final diagnosis determined by consensus review of follow-up imaging and clinical data was used as the reference standard., Results: During the study period, complete multimodal CT examination was obtained in 831 patients, 457 of whom were diagnosed with stroke. Diagnostic sensitivity for ischemic stroke increased by 19.5 percentage points when CTP was included with NCCT and CTA compared with NCCT and CTA alone (73.1% positive with NCCT+CTA+CTP [95% CI, 68.8-77.1] versus 53.6% positive with NCCT+CTA alone [95% CI, 48.9-58.3], P <0.001). No difference was observed between specificities of NCCT+CTA and NCCT+CTA+CTP (98.7% [95% CI, 98.5-100] versus 98.7% [95% CI, 96.9-99.6], P =0.13). Multimodal CT, including CTP, demonstrated the highest negative predictive value (75.0% [95% CI, 72.1-77.7]). Patients with stroke not evident on CTP had small volume infarcts on follow-up (1.2 mL, interquartile range 0.5-2.7mL)., Conclusions: Acquisition of CTP as part of a telestroke imaging protocol permits definitive diagnosis of cerebral ischemia in 1 in 5 patients with normal NCCT and CTA.

Background and Purpose- Patients with transient ischemic attack (TIA) and minor ischemic stroke are at risk for early recurrent cerebral ischemia. Anticoagulants are associated with reduced recurrence but also increased hemorrhagic transformation (HT). The safety of the novel oral anticoagulant dabigatran in acute stroke has not been evaluated. Methods- DATAS II (Dabigatran Treatment of Acute Stroke II) was a phase II prospective, randomized open label, blinded end point trial. Patients with noncardioembolic stroke/transient ischemic attack (National Institutes of Health Stroke Scale score, ≤9; infarct volume, ≤25 mL) were randomized to dabigatran or aspirin. Magnetic resonance imaging was performed before randomization and repeated at day 30. Imaging end points were ascertained centrally by readers blinded to treatment. The primary end point was symptomatic HT within 37 days of randomization. Results- A total of 305 patients, mean age 66.59±13.21 years, were randomized to dabigatran or aspirin a mean of 42.00±17.31 hours after symptom onset. The qualifying event was a transient ischemic attack in 21%, and ischemic stroke in 79% of patients. Median National Institutes of Health Stroke Scale (interquartile range) was 1 (0-2), and mean infarct volume 3.2±6.5 mL. No symptomatic HT occurred. Asymptomatic petechial HT developed in 11/142 (7.8%) of dabigatran-assigned patients and 5/142 (3.5%) of aspirin-assigned patients (relative risk, 2.301 [95% CI, 0.778-6.802]). Baseline infarct volume predicted incident HT (odds ratio, 1.07 [95% CI, 1.03-1.12]; P =0.0026). Incident covert infarcts on day 30 imaging occurred in 9/142 (6.3%) of dabigatran-assigned and 14/142 (9.8%) of aspirin-assigned patients (relative risk, 0.62 [95% CI, 0.26, 1.48]). Conclusions- Dabigatran was associated with a risk of HT similar to aspirin in acute minor noncardioembolic ischemic stroke/transient ischemic attack. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02295826.

Background and Purpose- Endovascular therapy has been shown to be highly efficacious based on 90-day modified Rankin Scale score. We examined actual daily healthcare utilization from stroke onset to 1 year afterward from the ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Time) and registry data. Methods- We examined patients from Alberta, Canada, that was enrolled into the ESCAPE trial and the Quality Improvement and Clinical Research registry in the 2016/2017 fiscal year. Through data linkages to several administrative data sets, the daily location of each patient was assessed in various healthcare settings. Results- A total of 286 patients were analyzed, 52 patients were in the treatment arm, and 47 patients were in the control arm of the ESCAPE trial while 187 patients received endovascular therapy as usual care (2016/2017 fiscal year). The odds of a patient being out of a healthcare setting over 1 year was significantly higher when they received endovascular therapy: 3.46 (1.68-7.30) in ESCAPE trial patients and 2.00 (1.08-3.75) in the Quality Improvement And Clinical Research patients. Conclusions- Endovascular therapy significantly reduces healthcare utilization up to 1 year after a stroke.

Objective: We assessed patient clinical outcomes based on occlusion location, focusing on distal occlusions to understand if occlusion location was an independent predictor of outcome, and tested the relationship between occlusion location and baseline ischemic core, a known predictor of modified Rankin Scale (mRS) score at 90 days., Methods: We analyzed a prospectively collected cohort of thrombolysis-eligible ischemic stroke patients from the International Stroke Perfusion Imaging Registry who underwent multimodal CT pretreatment. For the primary analysis, logistic regression was used to predict the effect of occlusion location and ischemic core on the likelihood of excellent (mRS 0-1) and favorable (mRS 0-2) 90-day outcomes., Results: This study included 945 patients. The rates of excellent and favorable outcome in patients with distal occlusion (M2, M3 segment of middle cerebral artery, anterior cerebral artery, and posterior cerebral artery) were higher than M1 occlusions (mRS 0%-1%, 55% vs 37%; mRS 0%-2%, 73% vs 50%, p < 0.001). Vessel occlusion location was not a strong predictor of outcomes compared to baseline ischemic core (area under the curve, mRS 0-1, 0.64 vs 0.83; mRS 0-2, 0.70 vs 0.86, p < 0.001). There was no interaction between occlusion location and ischemic core (interaction coefficient 1.00, p = 0.798)., Conclusions: Ischemic stroke patients with a distal occlusion have higher rate of excellent and favorable outcome than patients with an M1 occlusion. The baseline ischemic core was shown to be a more powerful predictor of functional outcome than the occlusion location, but the relationship between ischemic core and outcome does not different by occlusion locations., (© 2019 American Academy of Neurology.)

Background and Purpose: In alteplase-treated patients with acute ischemic stroke, we investigated the relationship between penumbral reperfusion at 24 hours and clinical outcomes, with and without adjustment for baseline ischemic core volume., Methods: Data were collected from consecutive acute ischemic stroke patients with baseline and follow-up perfusion imaging presenting to hospital within 4.5 hours of symptom onset at 7 hospitals. Logistic regression models were used for predicting the effect of the reperfused penumbral volume on the dichotomized modified Rankin Scale (mRS) at 90 days and improvement of National Institutes of Health Stroke Scale at 24 hours, both adjusted for baseline ischemic core volume., Results: This study included 1507 patients. Reperfused penumbral volume had moderate ability to predict 90-day mRS 0 to 1 (area under the curve, 0.77; R 2 , 0.28; P <0.0001). However, after adjusting for baseline ischemic core volume, the reperfused penumbral volume was a strong predictor of good functional outcome (area under the curve, 0.946; R 2 , 0.55; P <0.0001). For every 1% increase in penumbral reperfusion, the odds of achieving mRS 0 to 1 at day 90 increased by 7.4%. Improvement in acute 24-hour National Institutes of Health Stroke Scale was also significantly related to the degree of reperfused penumbra ( R 2 , 0.31; P<0.0001). This association was again stronger after adjustment for baseline ischemic core volume ( R 2 , 0.41; P <0.0001). For each 1% of penumbra that was reperfused, the 24-hour National Institutes of Health Stroke Scale decreased by 0.069 compared with baseline., Conclusions: In patients treated with alteplase, the extent of the penumbra that is reperfused is a powerful predictor of early and late clinical outcomes, particularly when baseline ischemic core is taken into account., (© 2017 American Heart Association, Inc.)

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.)

Objective: The aim of the present systematic review and meta-analysis was to evaluate the safety and efficacy of intensive blood pressure (BP) reduction in patients with acute-onset intracerebral hemorrhage (ICH) using data from randomized controlled trials., Methods: We conducted a systematic review and meta-analysis according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines of all available randomized controlled trials that randomized patients with acute ICH to either intensive or guideline BP-reduction protocols., Results: We identified 4 eligible studies, including a total of 3,315 patients (mean age 63.4 ± 1.4 years, 64% men). Death rates were similar between patients randomized to intensive BP-lowering treatment and those receiving guideline BP-lowering treatment (odds ratio = 1.01, 95% confidence interval: 0.83-1.23; p = 0.914). Intensive BP-lowering treatment tended to be associated with lower 3-month death or dependency (modified Rankin Scale grades 3-6) compared with guideline treatment (odds ratio = 0.87, 95% confidence interval: 0.76-1.01; p = 0.062). No evidence of heterogeneity between estimates (I(2) = 0%; p = 0.723), or publication bias in the funnel plots (p = 0.993, Egger statistical test), was detected. Intensive BP reduction was also associated with a greater attenuation of absolute hematoma growth at 24 hours (standardized mean difference ± SE: -0.110 ± 0.053; p = 0.038)., Conclusions: Our findings indicate that intensive BP management in patients with acute ICH is safe. Fewer intensively treated patients had unfavorable 3-month functional outcome although this finding did not reach significance. Moreover, intensive BP reduction appears to be associated with a greater attenuation of absolute hematoma growth at 24 hours., (© 2014 American Academy of Neurology.)

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: Transient or minor ischemic stroke is associated with an early risk of deterioration. Baseline perfusion-diffusion mismatch may predict clinical deterioration and infarct growth in this population., Methods: High-risk transient ischemic attack and minor stroke (National Institutes of Health Stroke Scale ≤3) subjects were prospectively enrolled and imaged with MRI within 24 hours of symptom onset as part of sequential derivation and validation cohorts. Baseline diffusion-weighted imaging, perfusion-weighted imaging (Tmax≥4 s), mismatch (Tmax≥4 s-diffusion-weighted imaging), and follow-up fluid-attenuated inversion recovery infarct volumes were measured. Primary outcome was infarct growth on fluid-attenuated inversion recovery, and secondary outcome was symptom progression., Results: One hundred thirty-seven and 281 subjects were included in the derivation and validation cohorts, respectively. Infarct growth occurred in 18.5% of the derivation and 5.5% of the validation cohorts. Symptom progression occurred in 9.5% of the derivation and 4.5% of the validation cohorts. In the derivation cohort, subjects with baseline mismatch were significantly more likely to show infarct growth on fluid-attenuated inversion recovery (relative risk [RR], 13.5; 95% confidence interval [CI], 4.2-38.9) and symptom progression (RR, 7.0; 95% CI, 2.0-7.3). A baseline mismatch volume of 10 mL in the derivation cohort was the optimal threshold to predict infarct growth (area under the curve, 0.89; 95% CI, 0.80-0.98). This threshold was highly predictive of infarct growth in the validation cohort (P=0.001). Baseline mismatch was associated with clinical deterioration in the derivation (area under the curve, 0.81; 95% CI, 0.67-0.96) and validation cohorts (area under the curve, 0.66; 95% CI, 0.46-0.85)., Conclusions: Among subjects with high-risk transient ischemic attack and minor stroke, diffusion-weighted imaging-perfusion-weighted imaging mismatch predicts infarct growth and clinical deterioration. These findings suggest that reperfusion strategies would be beneficial in this population.

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: Anticoagulant-associated intracranial hemorrhage (aaICH) presents with larger hematoma volumes, higher risk of hematoma expansion, and worse outcome than spontaneous intracranial hemorrhage. Prothrombin complex concentrates (PCCs) are indicated for urgent reversal of anticoagulation after aaICH. Given the lack of randomized controlled trial evidence of efficacy, and the potential for thrombotic complications, we aimed to determine outcomes in patients with aaICH treated with PCC., Methods: We conducted a prospective multicenter registry of patients treated with PCC for aaICH in Canada. Patients were identified by local blood banks after the release of PCC. A chart review abstracted clinical, imaging, and laboratory data, including thrombotic events after therapy. Hematoma volumes were measured on brain CT scans and primary outcomes were modified Rankin Scale at discharge and in-hospital mortality., Results: Between 2008 and 2010, 141 patients received PCC for aaICH (71 intraparenchymal hemorrhages). The median age was 78 years (interquartile range, 14), 59.6% were male, and median Glasgow Coma Scale was 14. Median international normalized ratio was 2.6 (interquartile range, 2.0) and median parenchymal hematoma volume was 15.8 mL (interquartile range, 31.8). Median post-PCC therapy international normalized ratio was 1.4: 79.5% of patients had international normalized ratio correction (<1.5) within 1 hour of PCC therapy. Patients with intraparenchymal hemorrhage had an in-hospital mortality rate of 42.3% with median modified Rankin Scale of 5. Significant hematoma expansion occurred in 45.5%. There were 3 confirmed thrombotic complications within 7 days of PCC therapy., Conclusions: PCC therapy rapidly corrected international normalized ratio in the majority of patients, yet mortality and morbidity rates remained high. Rapid international normalized ratio correction alone may not be sufficient to alter prognosis after aaICH.

Background and Purpose: The mismatch lesion volumes defined by perfusion-weighted imaging exceeding diffusion-weighted imaging have been used as a marker of ischemic penumbral tissue. Defining the perfusion lesion by thresholding has shown promise as a practical tool; several positron emission tomography studies have indicated a more probabilistic relationship between perfusion and infarction. Here, we used a randomized controlled trial dataset of tissue-type plasminogen activator 3 to 6 hours after stroke to: (1) quantify the relationship between severity of hypoperfusion (measured by Tmax) and risk of infarction; (2) exploit this relationship to present a novel definition of mismatch based on infarct probabilities rather than dichotomies; and (3) examine the treatment response in the subgroup of patients with mismatch by the new definition., Methods: Patients from the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) were included. Baseline perfusion-weighted imaging and 90-day T2-weighted imaging were coregistered. Perfusion-weighted imaging lesion volumes were divided into 10 Tmax delay strata, and infarct risk was defined as the fraction of the tissue at a given Tmax strata that progressed to infarction by day 90., Results: Sixty-two patients were studied. Infarct risk was an increasing function of Tmax for all subgroups, including the whole cohort. The probabilistic approach outperformed all Tmax thresholds, with exception of the Tmax ≥ 10 threshold, for which it was only favored by a trend., Conclusions: Infarct risk and treatment effect increased with severity of perfusion abnormalities. This suggests that a severity-weighted mismatch definition may define penumbral tissue more accurately.

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.

Background and Purpose: The Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) tests the hypothesis that perfusion-weighted imaging (PWI)-diffusion-weighted imaging (DWI) mismatch predicts the response to thrombolysis. There is no accepted standardized definition of PWI-DWI mismatch. We compared common mismatch definitions in the initial 40 EPITHET patients., Methods: Raw perfusion images were used to generate maps of time to peak (TTP), mean transit time (MTT), time to peak of the impulse response (Tmax) and first moment transit time (FMT). DWI, apparent diffusion coefficient (ADC), and PWI volumes were measured with planimetric and thresholding techniques. Correlations between mismatch volume (PWIvol-DWIvol) and DWI expansion (T2(Day 90-vol)-DWI(Acute-vol)) were also assessed., Results: Mean age was 68+/-11, time to MRI 4.5+/-0.7 hours, and median National Institutes of Health Stroke Scale (NIHSS) score 11 (range 4 to 23). Tmax and MTT hypoperfusion volumes were significantly lower than those calculated with TTP and FMT maps (P<0.001). Mismatch > or =20% was observed in 89% (Tmax) to 92% (TTP/FMT/MTT) of patients. Application of a +4s (relative to the contralateral hemisphere) PWI threshold reduced the frequency of positive mismatch volumes (TTP 73%/FMT 68%/Tmax 54%/MTT 43%). Mismatch was not significantly different when assessed with ADC maps. Mismatch volume, calculated with all parameters and thresholds, was not significantly correlated with DWI expansion. In contrast, reperfusion was correlated inversely with infarct growth (R=-0.51; P=0.009)., Conclusions: Deconvolution and application of PWI thresholds provide more conservative estimates of tissue at risk and decrease the frequency of mismatch accordingly. The precise definition may not be critical; however, because reperfusion alters tissue fate irrespective of mismatch.

Purpose of Review: Use of intravenous thrombolytic therapy in ischaemic stroke is restricted to a 3-h time window because of the proof of this time window in pivotal clinical trials. Thrombolysis is aimed at recanalization of occluded arteries and reperfusion of the ischaemic penumbra, a region of critically hypoperfused, functionally impaired, but potentially viable brain. There are a number of current prospective trials that are testing the hypothesis that the presence of the penumbra will predict thrombolytic responders beyond 3 h., Recent Findings: Using magnetic resonance imaging, a mismatch between a larger perfusion-weighted imaging lesion and smaller diffusion-weighted imaging lesion is considered to represent the ischaemic penumbra. Perfusion-weighted imaging provides semiquantitative cerebral blood flow imaging and diffusion-weighted imaging is an index of the largely irreversible ischaemic core. This definition has been modified with the recognition that the perfusion-weighted imaging lesion includes benign oligaemia and that a portion of the diffusion-weighted imaging core is potentially salvageable with rapid reperfusion. Most acute stroke patients have a magnetic resonance imaging-penumbral signature within 6 h of stroke onset. The penumbra is commonly, but not invariably, associated with proximal arterial occlusion and is time-dependent. Preliminary studies have shown benefit from thrombolytic therapy beyond the established 3-h window., Summary: Penumbral imaging using magnetic resonance imaging with perfusion over diffusion weighted imaging mismatch can provide a physiological 'tissue clock' in individual patients. Based on this hypothesis, a number of prospective trials are being performed. These include EPITHET, DEFUSE, DIAS, MR RESCUE and ROSIE.

Background and Purpose: The mechanisms of perihematomal injury in primary intracerebral hemorrhage (ICH) are incompletely understood. An MRI study was designed to elucidate the nature of edema and blood flow changes after ICH., Methods: Perihematomal blood flow and edema were studied prospectively with perfusion-weighted MRI (PWI) and diffusion-weighted MRI in 21 ICH patients. MRI and computed tomography (CT) images were coregistered to ensure perfusion and diffusion changes were outside of the hematoma. Edema volumes were measured on T2-weighted images. Apparent diffusion coefficient (ADC) values of the edematous regions were calculated., Results: Mean patient age was 64.2 years (45 to 89), and median National Institutes of Health stroke scale score was 12 (3 to 24). Median time to MRI was 21 hours (4.5 to 110). Average hematoma volume on CT was 26.1 (4 to 84) mL. PWI demonstrated perihematomal relative mean transit time (rMTT) was significantly correlated with hematoma volume (r=0.60; P=0.004) but not edema volume. Perihematomal oligemia (rMTT >2 s) was present in patients with hematoma volumes of >15 mL (average rMTT 4.6+/-2.0 s). Perihematomal edema was present in all patients. ADC values within this region (1178+/-213x10(-6) mm2/s) were increased 29% relative to contralateral homologous regions. Increases in perihematomal ADC predicted edema volume (r=0.54; P=0.012) and this was confirmed with multivariate analysis., Conclusions: Acute perihematomal oligemia occurs in acute ICH but is not associated with MRI markers of ischemia and is unrelated to edema formation. Increased rates of water diffusion in the perihematomal region independently predict edema volume, suggesting the latter is plasma derived.

Background and Purpose: Acute poststroke hyperglycemia has been associated with larger infarct volumes and a cortical location, regardless of diabetes status. Stress hyperglycemia has been attributed to activation of the hypothalamic-pituitary-adrenal axis but never a specific cortical location. We tested the hypothesis that damage to the insular cortex, a site with autonomic connectivity, results in hyperglycemia reflecting sympathoadrenal dysregulation., Methods: Diffusion-weighted MRI, glycosylated hemoglobin (HbA1c), and blood glucose measurements were obtained in 31 patients within 24 hours of ischemic stroke onset. Acute diffusion-weighted imaging (DWI) lesion volumes were measured, and involvement of the insular cortex was assessed on T2-weighted images., Results: Median admission glucose was significantly higher in patients with insular cortical ischemia (8.6 mmol/L; n=14) compared with those without (6.5 mmol/L; n=17; P=0.006). Multivariate linear regression demonstrated that insular cortical ischemia was a significant independent predictor of glucose level (P=0.001), as was pre-existing diabetes mellitus (P=0.008). After controlling for the effect of insular cortical ischemia, DWI lesion volume was not associated with higher glucose levels (P=0.849). There was no association between HbA1c and glucose level (P=0.737)., Conclusions: Despite the small sample size, insular cortical ischemia appeared to be associated with the production of poststroke hyperglycemia. This relationship is independent of pre-existing glycemic status and infarct volume. Neuroendocrine dysregulation after insular ischemia may be 1 aspect of a more generalized acute stress response. Future studies of poststroke hyperglycemia should account for the effect of insular cortical ischemia.

Background and Purpose: Increases in sympathetic activity and frequency of myocardial damage occur after middle cerebral artery occlusion (MCAO) in Wistar rats, while MCAO in the spontaneously hypertensive rat (SHR) decreases sympathoadrenal activity. Autonomic changes have been suggested to result from damage to the insular cortex (IC)., Methods: A lesion of the IC was made using the excitotoxin D,L-homocysteic acid (DLH; 1 mol/L), in urethane-anesthetized Wistar rats and SHRs. Mean arterial pressure (MAP), heart rate, renal sympathetic nerve discharge (SND), ECG, and plasma catecholamines were measured in 14 SHRs and 14 Wistar male rats after a 500-nL injection of DLH or phosphate-buffered saline (PBS) into the IC., Results: Histological examination showed that DLH resulted in neuronal damage throughout the IC. DLH injection initially elevated MAP (at approximately 10 minutes after injection) in Wistar rats but not in SHRs. At 4 hours after the DLH injection, there was a secondary, longer-term increase in MAP in the Wistar rats. MAP decreased in the SHRs after IC lesion such that at 6 hours, lesioned SHRs had a MAP that was significantly lower than that of sham-lesioned SHRs. SND initially increased (at 10 minutes) after DLH injection in Wistar rats. In the SHRs, SND decreased significantly from the initial values, by 3 hours after DLH injection. Plasma catecholamine levels were not significantly changed as a result of IC lesion in the Wistar rats or the SHRs. Heart rates increased in all animals, with no differences between groups. There were no changes in the ECG or in the frequency of cardiac myocytolysis in either strain (sham or lesioned animals)., Conclusions: IC lesion in the SHR and Wistar rat therefore appears to result in autonomic changes similar to that seen after MCAO. Unlike MCAO, however, the autonomic changes do not appear to be sufficient to produce myocardial damage.