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Background: Whether endovascular therapy (EVT) added on best medical management (BMM), as compared to BMM alone, is beneficial in acute ischemic stroke with isolated posterior cerebral artery occlusion is unknown. Methods: We conducted a multicenter international observational study of consecutive stroke patients admitted within 6 hours from symptoms onset in 26 stroke centers with isolated occlusion of the first (P1) or second (P2) segment of the posterior cerebral artery and treated either with BMM+EVT or BMM alone. Propensity score with inverse probability of treatment weighting was used to account for baseline between-groups differences. The primary outcome was 3-month good functional outcome (modified Rankin Scale [mRS] score 0–2 or return to baseline modified Rankin Scale). Secondary outcomes were 3-month excellent recovery (modified Rankin Scale score 0–1), symptomatic intracranial hemorrhage, and early neurological deterioration. Results: Overall, 752 patients were included (167 and 585 patients in the BMM+EVT and BMM alone groups, respectively). Median age was 74 (interquartile range, 63–82) years, 329 (44%) patients were female, median National Institutes of Health Stroke Scale was 6 (interquartile range 4–10), and occlusion site was P1 in 188 (25%) and P2 in 564 (75%) patients. Baseline clinical and radiological data were similar between the 2 groups following propensity score weighting. EVT was associated with a trend towards lower odds of good functional outcome (odds ratio, 0.81 [95% CI, 0.66–1.01]; P =0.06) and was not associated with excellent functional outcome (odds ratio, 1.17 [95% CI, 0.95–1.43]; P =0.15). EVT was associated with a higher risk of symptomatic intracranial hemorrhage (odds ratio, 2.51 [95% CI, 1.35–4.67]; P =0.004) and early neurological deterioration (odds ratio, 2.51 [95% CI, 1.64–3.84]; P Conclusions: In this observational study of patients with proximal posterior cerebral artery occlusion, EVT was not associated with good or excellent functional outcome as compared to BMM alone. However, EVT was associated with higher rates of symptomatic intracranial hemorrhage and early neurological deterioration. EVT should not be routinely recommended in this population, but randomization into a clinical trial is highly warranted.

Background: Clinical trial enrollment and completion is challenging, with nearly half of all trials not being completed or not completed on time. In 2014, the National Institutes of Health StrokeNet in collaboration with stroke epidemiologists from GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study) began providing proposed clinical trials with formal trial feasibility assessments. Herein, we describe the process of prospective feasibility analyses using epidemiological data that can be used to improve enrollment and increase the likelihood a trial is completed. Methods: In 2014, DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trialists, National Institutes of Health StrokeNet, and stroke epidemiologists from GCNKSS collaborated to evaluate the initial inclusion/exclusion criteria for the DEFUSE 3 study. Trial criteria were discussed and an assessment was completed to evaluate the percent of the stroke population that might be eligible for the study. The DEFUSE 3 trial was stopped early with the publication of DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct), and the Wilcoxon rank-sum statistic was used to analyze whether the trial would have been stopped had the proposed changes not been made, following the DEFUSE 3 statistical analysis plan. Results: After initial epidemiological analysis, 2.4% of patients with acute stroke in the GCNKSS population would have been predicted to be eligible for the study. After discussion with primary investigators and modifying 4 key exclusion criteria (upper limit of age increased to 90 years, baseline modified Rankin Scale broadened to 0–2, time since last well expanded to 16 hours, and decreased lower limit of National Institutes of Health Stroke Scale score to Conclusions: Objectively assessing trial inclusion/exclusion criteria using a population-based resource in a collaborative and iterative process including epidemiologists can lead to improved recruitment and can increase the likelihood of successful trial completion.

Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship.In a pooled, patient-level analysis of EXTEND-IA trials and SELECT study, we employed a mediation analysis framework to quantify infarct growth and cerebral edema(midline shift) mediation effect on successful reperfusion(mTICI≥2b) association with functional outcome(mRS distribution). Further, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift.542/665(81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful vs unsuccessful reperfusion. Median(IQR) infarct growth was 12.3(1.8-48.4)ml and median(IQR) midline shift was 0(0,2.2)mm. Of 249(37%) demonstrating a midline shift of ≥1mm, median(IQR) shift was 2.75(1.89, 4.21)mm). Successful reperfusion was associated with reductions in both predefined mediators; infarct growth (β, -1.19; 95%CI, -1.51to-0.88;p0.001) and midline shift (aOR:0.36,95%CI:0.23-0.57,p0.001). Successful reperfusion association with improved functional outcome (acOR:2.68; 95%CI:1.86-3.88,p0.001), became insignificant (acOR:1.39, 95%CI:0.95-2.04,p=0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect. Analysis considering alternative hypothesis demonstrated consistent results.In this mediation analysis from a pooled, patient-level cohort, a significant proportion(~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect and identify novel therapeutic targets to further enhance reperfusion benefits. This article is protected by copyright. All rights reserved.

OBJECTIVE Acute ischemic stroke patients with large-vessel occlusion and good collateral blood flow have significantly better outcomes than patients with poor collateral circulation. The purpose of this study was to evaluate the cost-effectiveness of endovascular thrombectomy (EVT) based on collateral status and, in particular, to analyze its effectiveness in ischemic stroke patients with poor collaterals. METHODS A decision analysis study was performed with Markov modeling to estimate the lifetime quality-adjusted life-years (QALYs) and associated costs of EVT based on collateral status. The study was performed over a lifetime horizon with a societal perspective in the US setting. Base-case analysis was done for good, intermediate, and poor collateral status. One-way, two-way, and probabilistic sensitivity analyses were performed. RESULTS EVT resulted in greater effectiveness of treatment compared to no EVT/medical therapy (2.56 QALYs in patients with good collaterals, 1.88 QALYs in those with intermediate collaterals, and 1.79 QALYs in patients with poor collaterals), which was equivalent to 1050, 771, and 734 days, respectively, in a health state characterized by a modified Rankin Scale (mRS) score of 0–2. EVT also resulted in lower costs in patients with good and intermediate collaterals. For patients with poor collateral status, the EVT strategy had higher effectiveness and higher costs, with an incremental cost-effectiveness ratio (ICER) of $44,326/QALY. EVT was more cost-effective as long as it had better outcomes in absolute numbers in at least 4%–8% more patients than medical management. CONCLUSIONS EVT treatment in the early time window for good outcome after ischemic stroke is cost-effective irrespective of the quality of collateral circulation, and patients should not be excluded from thrombectomy solely on the basis of collateral status. Despite relatively lower benefits of EVT in patients with poor collaterals, even smaller differences in better outcomes have significant long-term financial implications that make EVT cost-effective.

Background: Intravenous tPA (tissue-type plasminogen activator) is often administered before endovascular thrombectomy (EVT). Recent studies have questioned whether tPA is necessary given the high rates of arterial recanalization achieved by EVT, but whether tPA impacts venous outflow (VO) is unknown. We investigated whether tPA improves VO profiles on baseline computed tomography (CT) angiography (CTA) images before EVT. Methods: Retrospective multicenter cohort study of patients with acute ischemic stroke due to large vessel occlusion undergoing EVT triage. Included patients underwent CT, CTA, and CT perfusion before EVT. VO profiles were determined by opacification of the vein of Labbé, sphenoparietal sinus, and superficial middle cerebral vein on CTA as 0, not visible; 1, moderate opacification; and 2, full. Pial arterial collaterals were graded on CTA, and tissue-level collaterals were assessed on CT perfusion using the hypoperfusion intensity ratio. Clinical and demographic data were determined from the electronic medical record. Using multivariable regression analysis, we determined the correlation between tPA administration and favorable VO profiles. Results: Seven hundred seventeen patients met inclusion criteria. Three hundred sixty-five patients received tPA (tPA+), while 352 patients were not treated with tPA (tPA−). Fewer tPA+ patients had atrial fibrillation (n=128 [35%] versus n=156 [44%]; P =0.012) and anticoagulants/antiplatelet treatment before acute ischemic stroke due to large vessel occlusion onset (n=130 [36%] versus n=178 [52%]; P P P Conclusions: In patients with acute ischemic stroke due to large vessel occlusion undergoing thrombectomy triage, tPA administration was strongly associated with the presence of favorable VO profiles.

Patients who have had a transient ischaemic attack or minor stroke have an increased risk of cardiovascular events for the following 5 years. We aimed to assess 5-year functional outcomes in patients with transient ischaemic attack or minor ischaemic stroke and to determine the factors associated with long-term disability.We analysed data from patients in TIAregistry.org, an international, prospective, observational registry of patients with transient ischaemic attack or minor ischaemic stroke from 61 specialised centres in 21 countries. Patients aged 18 years or older who had a transient ischaemic attack or minor stroke within the previous 7 days between May 30, 2009, and Dec 30, 2011, with a baseline modified Rankin scale (mRS) score of 0-1, and who had been followed up for 5 years, were eligible for inclusion in this study. We evaluated whether existing comorbidities and stroke recurrence, categorised as disabling (mRS score of1, including death) or non-disabling (mRS score of 0-1), at 5 years after baseline, were associated with poor functional outcome (defined as an mRS score of1). We used multivariable generalised equation models for factors associated with poor functional outcome at 5 years and multivariable cause-specific Cox hazard regression models in case of stroke recurrence.Between May 30, 2009, and Dec 30, 2011, 3847 eligible patients were included in the study, 3105 (80·7%) of whom had an mRS evaluation at 5 years of follow-up. Median follow-up duration was 5·00 years (IQR 4·78-5·00). 710 (22·9%) of 3105 patients had an mRS score greater than 1 at 5 years. Factors associated with poor functional outcome at 5 years were older age (per 10-year increase, odds ratio [OR] 2·18, 95% CI 1·93-2·46; p0·0001), diabetes of any type (1·45, 1·18-1·78; p=0·0001), history of stroke or transient ischaemic attack before the qualifying event (1·74, 1·37-2·22; p0·0001), hypertension (1·38, 1·00-1·92; p=0·050), atrial fibrillation or flutter (1·52, 1·04-1·94; p=0·030), congestive heart failure (1·73, 1·22-2·46; p=0·0024), valvular disease (2·47, 1·70-3·58; p0·0001), stroke as qualifying event (1·31, 1·09-1·57; p=0·0037), history of peripheral artery disease (1·98, 1·28-3·07; p=0·0023), history of coronary artery disease (1·32, 1·00-1·74; p=0·049), intracranial haemorrhage during follow up (4·94, 1·91-12·78; p=0·0013), and living alone (1·32, 1·10-1·59; p=0·0031). Regular physical activity before the index event was associated with reduced risk of poor functional outcome (OR 0·52, 95% CI 0·42-0·66; p0·0001). 345 recurrent strokes had occurred at 5 years of follow-up, 141 (40·9%) of which were disabling or fatal. Stroke recurrence increased the risk of having a disability at 5 years (OR 3·52, 95% CI 2·37-5·22; p0·0001). Recurrent disabling or fatal strokes were independently associated with older age (per 10-year increase, hazard ratio [HR] 1·61, 95% CI 1·35-1·92; p0·0001), diabetes of any type (2·23, 1·56-3·17; p0·0001), National Institutes of Health Stroke Scale score of greater than 5 at discharge (5·11, 2·15-12·13; p=0·0013), history of coronary artery disease (1·76, 1·17-2·65; p=0·0063), history of stroke or transient ischaemic attack before the qualifying event (1·54, 1·03-2·29; p=0·035), congestive heart failure (1·86, 1·01-3·47; p=0·044), stroke as qualifying event (1·73, 1·22-2·45; p=0·0024), mRS score of greater than 1 at discharge (2·48, 1·27-4·87; p=0·0083), and intracranial haemorrhage during follow-up (17·15, 9·95-27·43; p0·0001). Regular physical activity before the index event was associated with reduced risk of recurrent disabling stroke at 5 years (HR 0·56, 95% CI 0·31-0·99; p=0·046), and 5-year disability without recurrent stroke (0·61, 0·47-0·79; p=0·0001).We found a substantial burden of disability (mRS score of1) at 5 years after transient ischaemic attack or minor ischemic stroke, and most predictors of this disability were modifiable risk factors. Patients who did regular physical exercise before the index event had a significantly reduced risk of disability at 5 years compared with patients who did no exercise.AstraZeneca, Sanofi, Bristol Myers Squibb, SOS Attaque Cérébrale Association.

To investigate whether unfavorable cerebral venous outflow (VO) predicts reperfusion hemorrhage after endovascular treatment (EVT), we conducted a retrospective multicenter cohort study of patients with acute ischemic stroke and large vessel occlusion (AIS-LVO). 629 AIS-LVO patients met inclusion criteria. VO profiles were assessed on admission CT angiography using the Cortical Vein Opacification Score (COVES). Unfavorable VO was defined as COVES ≤ 2. Reperfusion hemorrhages on follow-up imaging were subdivided into no hemorrhage (noRH), hemorrhagic infarction (HI) and parenchymal hematoma (PH). Patients with PH and HI less frequently achieved good clinical outcomes defined as 90-day modified Rankin Scale scores of ≤ 2 (PH: 13.6% vs. HI: 24.6% vs. noRH: 44.1%; p

Background: Extended thromboprophylaxis has not been widely implemented in acutely ill medical patients because of bleeding concerns. The MAGELLAN (Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Medically Ill Patients Comparing Rivaroxaban With Enoxaparin) and MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) trials evaluated whether rivaroxaban compared with enoxaparin or placebo could prevent venous thromboembolism without increased bleeding. We hypothesized that patients with major bleeding but not those with nonmajor clinically relevant bleeding would be at an increased risk of all-cause mortality (ACM). Methods: We evaluated all bleeding events in patients taking at least 1 dose of study drug and their association with ACM in 4 mutually exclusive groups: (1) no bleeding, or first event was (2) nonmajor clinically relevant bleeding, (3) major bleeding, or (4) trivial bleeding. Using a Cox proportional hazards model adjusted for differences in baseline characteristics associated with ACM, we assessed the risk of ACM after such events. Results: Compared with patients with no bleeding, the risk of ACM for patients with nonmajor clinically relevant bleeding was not increased in MARINER (hazard ratio, 0.43; P =0.235) but was increased in MAGELLAN (hazard ratio, 1.74; P =0.021). Major bleeding was associated with a higher incidence of ACM in both studies, whereas trivial bleeding was not associated with ACM in either study. Conclusions: Patients with major bleeding had an increased risk of ACM, whereas nonmajor clinically relevant bleeding was not consistently associated with an increased risk of death. These results inform the risk-benefit calculus of extended thromboprophylaxis in medically ill patients. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: MAGELLAN, NCT00571649. URL: https://www.clinicaltrials.gov ; Unique identifier: MARINER, NCT02111564.

BackgroundIn contrast to conventional CT perfusion (CTP) imaging, flat panel detector CT perfusion (FD-CTP) imaging can be acquired directly in the angiosuite.ObjectiveTo evaluate time-resolved whole brain FD-CTP imaging and assess clinically important qualitative and quantitative perfusion parameters in correlation with previously acquired conventional CTP using the new RAPID for ANGIO software.MethodsWe included patients with internal carotid artery occlusions and M1 or M2 occlusions from six centers. All patients underwent mechanical thrombectomy (MT) with preinterventional conventional CTP and FD-CTP imaging. Quantitative performance was determined by comparing volumes of infarct core, penumbral tissue, and mismatch. Eligibility for MT according to the perfusion imaging criteria of DEFUSE 3 was determined for each case from both conventional CTP and FD-CTP imaging.ResultsA total of 20 patients were included in the final analysis. Conventional relative cerebral blood flow (rCBF) 2=0.84). Comparisons of conventional CTP Tmax >6 s versus FD-CTP Tmax >6 s and CTP mismatch versus FD-CTP mismatch showed more variability (R2=0.57, and R2=0.33, respectively). Based on FD-CTP, 16/20 (80%) patients met the inclusion criteria for MT according to the DEFUSE 3 perfusion criteria, in contrast to 18/20 (90%) patients based on conventional CTP. The vessel occlusion could be correctly extrapolated from the hypoperfusion in 18/20 cases (90%).ConclusionsIn our multicenter study, time-resolved whole brain FD-CTP was technically feasible, and qualitative and quantitative perfusion results correlated with those obtained with conventional CTP.

Background and Purpose: Computed tomography perfusion imaging allows estimation of tissue status in patients with acute ischemic stroke. We aimed to improve prediction of the final infarct and individual infarct growth rates using a deep learning approach. Methods: We trained a deep neural network to predict the final infarct volume in patients with acute stroke presenting with large vessel occlusions based on the native computed tomography perfusion images, time to reperfusion and reperfusion status in a derivation cohort (MR CLEAN trial [Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands]). The model was internally validated in a 5-fold cross-validation and externally in an independent dataset (CRISP study [CT Perfusion to Predict Response to Recanalization in Ischemic Stroke Project]). We calculated the mean absolute difference between the predictions of the deep learning model and the final infarct volume versus the mean absolute difference between computed tomography perfusion imaging processing by RAPID software (iSchemaView, Menlo Park, CA) and the final infarct volume. Next, we determined infarct growth rates for every patient. Results: We included 127 patients from the MR CLEAN (derivation) and 101 patients of the CRISP study (validation). The deep learning model improved final infarct volume prediction compared with the RAPID software in both the derivation, mean absolute difference 34.5 versus 52.4 mL, and validation cohort, 41.2 versus 52.4 mL ( P Conclusions: We validated a deep learning-based method which improved final infarct volume estimations compared with classic computed tomography perfusion imaging processing. In addition, the deep learning model predicted individual infarct growth rates which could enable the introduction of tissue clocks during the management of acute stroke.

Background: In patients with acute ischemic stroke due to large vessel occlusion (AIS–LVO), development of extensive early ischemic brain edema is associated with poor functional outcomes, despite timely treatment. Robust cortical venous outflow (VO) profiles correlate with favorable tissue perfusion. We hypothesized that favorable VO profiles (VO+) correlate with a reduced early edema progression rate (EPR) and good functional outcomes. Methods: Multicenter, retrospective analysis to investigate AIS–LVO patients treated by mechanical thrombectomy between May 2013 and December 2020. Baseline computed tomography angiography (CTA) was used to determine VO using the cortical vein opacification score (COVES); VO+ was defined as COVES ⩾ 3 and unfavorable as COVES ⩽ 2. EPR was determined as the ratio of net water uptake (NWU) on baseline non-contrast CT and time from symptom onset to admission imaging. Multivariable regression analysis was performed to assess primary (EPR) and secondary outcome (good functional outcomes defined as 0–2 points on the modified Rankin scale). Results: A total of 728 patients were included. Primary outcome analysis showed VO+ (β: –0.03, SE: 0.009, p = 0.002), lower presentation National Institutes of Health Stroke Scale (NIHSS; β: 0.002, SE: 0.001, p = 0.002), and decreased time from onset to admission imaging (β: –0.00002, SE: 0.00004, p Conclusions: Favorable VO profiles were associated with slower infarct edema progression and good long-term functional outcomes as well as better neurological status and ischemic brain alterations at admission.

Trials examining the benefit of thrombectomy in anterior circulation proximal large vessel occlusion stroke have enrolled patients considered to have salvageable brain tissue, who were randomly assigned beyond 6 h and (depending on study protocol) up to 24 h from time last seen well. We aimed to estimate the benefit of thrombectomy overall and in prespecified subgroups through individual patient data meta-analysis.We did a systematic review and individual patient data meta-analysis between Jan 1, 2010, and March 1, 2021, of randomised controlled trials of endovascular stroke therapy. In the Analysis Of Pooled Data From Randomized Studies Of Thrombectomy More Than 6 Hours After Last Known Well (AURORA) collaboration, the primary outcome was disability on the modified Rankin Scale (mRS) at 90 days, analysed by ordinal logistic regression. Key safety outcomes were symptomatic intracerebral haemorrhage and mortality within 90 days.Patient level data from 505 individuals (n=266 intervention, n=239 control; mean age 68·6 years [SD 13·7], 259 [51·3%] women) were included from six trials that met inclusion criteria of 17 screened published randomised trials. Primary outcome analysis showed a benefit of thrombectomy with an unadjusted common odds ratio (OR) of 2·42 (95% CI 1·76-3·33; p0·0001) and an adjusted common OR (for age, gender, baseline stroke severity, extent of infarction on baseline head CT, and time from onset to random assignment) of 2·54 (1·83-3·54; p0·0001). Thrombectomy was associated with higher rates of independence in activities of daily living (mRS 0-2) than best medical therapy alone (122 [45·9%] of 266 vs 46 [19·3%] of 238; p0·0001). No significant difference between intervention and control groups was found when analysing either 90-day mortality (44 [16·5%] of 266 vs 46 [19·3%] of 238) or symptomatic intracerebral haemorrhage (14 [5·3%] of 266 vs eight [3·3%] of 239). No heterogeneity of treatment effect was noted across subgroups defined by age, gender, baseline stroke severity, vessel occlusion site, baseline Alberta Stroke Program Early CT Score, and mode of presentation; treatment effect was stronger in patients randomly assigned within 12-24 h (common OR 5·86 [95% CI 3·14-10·94]) than those randomly assigned within 6-12 h (1·76 [1·18-2·62]; pThese findings strengthen the evidence for benefit of endovascular thrombectomy in patients with evidence of reversible cerebral ischaemia across the 6-24 h time window and are relevant to clinical practice. Our findings suggest that in these patients, thrombectomy should not be withheld on the basis of mode of presentation or of the point in time of presentation within the 6-24 h time window.Stryker Neurovascular.

Background: In acute ischemic stroke (AIS) with large vessel occlusion (LVO), core/perfusion mismatch modifies the effect of mechanical thrombectomy (MT) on clinical outcome, MT appears to have greater benefit in patients with significant mismatch. We aimed to study the prevalence of core/perfusion mismatch according to ASPECT score in a large population of LVO-related AIS imaged either with MRI or CT. Methods: Retrospective study including AIS patients with ICA/M1 occlusion and baseline perfusion imaging (MRI or CT) performed within 24hrs from last seen well. To avoid selection bias, patients were selected from (1) the registries of 3 comprehensive centers with systematic use of MRI- or CT-perfusion imaging and including both MT-treated and untreated patients, and (2) one thrombectomy trial where MT decisions were performed blinded to the results of MRI perfusion imaging. Core/perfusion mismatch was defined as mismatch ratio (Tmax>6s volume/ core volume) >1.8 and volume (Tmax>6s - core volume) >15 mL. ASPECT score was rated on diffusion weighted imaging (DWI) or non-contrast CT blinded from the perfusion imaging. Results: Overall, 580 and 350 patients were included in the MRI and CT cohorts. Last-seen-well to imaging time was 4.8hrs (IQR 3.0-8.7) and 3.2hrs (1.3-8.0) in the MRI and CT cohorts, respectively, median ASPECT score was 7 (5-8) and 8 (7-9), and core/perfusion mismatch was present in 393/580 (68%) and 315/350 (90%) patients. In both cohorts, 75% of patients were treated with MT following imaging. In the MRI cohort, mismatch prevalence was 44% (75/170) and 92% (378/410) for DWI-ASPECTS 0-5 and 6-10, respectively. In the CT cohort, mismatch prevalence was 47% (15/32) and 94% (300/318) for ASPECTS 0-5 and 6-10, respectively. Conclusion: About 90% of patients with ASPECTS 6-10 have a core/perfusion mismatch regardless of imaging type. However, patients with ASPECTS ≤5 are heterogeneous in terms of mismatch status. Therefore, perfusion imaging may be particularly useful to select appropriate MT candidates with low ASPECT scores, regardless of imaging type, which has implications for large core trials.

Objective: We propose a novel measure, the PSI, to evaluate procedural success and prognostication after EVT and compare its prognostic ability with successful reperfusion (mTICI ≥2b). Methods: SELECT EVT patients with adequate follow-up MR DWI imaging were stratified based on PSI [ratio of salvaged tissue volume (Tmax >6s volume at baseline – f/up DWI infarct volume) to the Tmax >6s volume at baseline] into good (PSI≥50%) and poor penumbral salvage (PSI Results: 142/206(69%) had good penumbral salvage, with better CT ASPECTS (Good PSI: 9(7-10) vs Poor PSI: 7(6-9),p6s volume (aOR: 1.01, 95%CI: 1.00-1.02, p=0.003) and mTICI≥2b (aOR: 8.84, 95%CI: 3.16-24.71, p Conclusion: Good penumbral salvage is associated with higher odds of functional independence, and has a better predictive value than successful reperfusion on cerebral angiogram after EVT. Prospective studies are needed to confirm the predictive utility of the PSI.

Introduction: Improvement in NIH stroke scale scores on 24h follow-up is considered a key prognostic element after endovascular thrombectomy (EVT). We aimed to evaluate the proportion of effect of 24h NIHSS improvement on mRS 0-2 at 90d mediated through improvement in motor and language domains. Methods: From SELECT study, EVT patients with detailed NIHSS components on presentation and 24h follow-up as well as complete mRS on discharge and 90d were selected. Motor improvement was defined as ≥2 point in cumulative arms and legs score or 0 score at 24h and language improvement was defined as ≥1 point in cumulative aphasia and dysarthria scores at 24h. Mediation analysis framework using 4-step method (Figure 1a) was used to evaluate the effect of 24h NIHSS improvement mediated through improvement in motor and language scores. Results: Of 192 eligible EVT patients, 176 demonstrated motor deficits and 187 demonstrated language deficits. 24h NIHSS improvement was significantly associated with mRS 0-2 (aOR:1.15[1.07-1.23], p Conclusions: Almost all (~95%) of the effect of 24h NIHSS improvement on functional independence (mRS 0-2) was mediated through specific improvement in motor and language domains, suggesting a large role of improvement in motor and language domains in achieving better functional independence. Further studies are needed to confirm the findings.

Background: The benefit of mechanical thrombectomy (MT) in acute ischemic stroke (AIS) patients with M2 occlusion is uncertain. Observational studies suggest that perfusion imaging may help select optimal M2 candidates for MT. We aimed to study the prevalence and factors associated with core/perfusion mismatch, as assessed by both CT and MRI, in an unselected population of AIS with M2 occlusion. Methods: Retrospective observational study including AIS patients with M2 occlusion and baseline perfusion imaging (MRI or CT) performed within 24hrs from last seen well. To avoid selection bias, patients were selected from the prospective registries of 3 centers with systematic use of perfusion imaging, including both MT-treated and untreated patients. Core/perfusion mismatch was defined as mismatch ratio (Tmax>6s/ core volume) >1.8 and mismatch volume (Tmax>6s - core volume) >15mL. Results: Overall, 156 and 196 patients were included in the MRI and CT cohorts, respectively. Last-seen-well to imaging time was 5.6hrs (IQR 3.9-9.7) and 3.5hrs (1.5-9.8) in the MRI and CT cohorts, and 103/156 (66%) and 134/196 (68%) had proximal M2 occlusions (the remainder had distal M2 occlusions). Median ASPECT score was 7 (5-8) and 8 (7-9), and core/perfusion mismatch was present in 70/156 (45%) and 167/196 (85%) patients. In both cohorts, mismatch was less frequent in distal M2 occlusions and among patients with lower ASPECTS (Figure). Multivariable analysis showed higher ASPECT scores (OR=3.09, 95%CI=2.11-4.52, P P P =0.002 and OR=32.78, 95%CI 8.36-128.47, P Conclusion: Perfusion imaging may be useful in triaging M2 patients, particularly for those with ASPECT score

Introduction: Reduced left ventricular ejection fraction (EF) is associated with worse outcomes after stroke. CT perfusion (CTP) is widely used in acute stroke evaluation; its reliability in patients with reduced EF is unknown. We hypothesized that patients with reduced EF would have abnormal dose-time curves that may impair standard perfusion maps and reduce their quality. Methods: A retrospective database of all patients presenting to Stanford University for large vessel occlusion (LVO) stroke between 2010-2019 was used. CTPs were post-processed using RAPID software. Concentration-time curve metrics—width of the venous output function (VOF) at half maximum amplitude and VOF peak amplitude—were assessed automatically for each case. A reader blinded to EF visually evaluated the VOF curve for evidence of truncation (yes/no) and graded the quality of the time to maximum (Tmax) map on a scale from 0 (excellent) to 3 (poor), based on the degree of “speckling” present on the map. Continuous parameters were compared using the t-test or Mann-Whitney test and dichotomous parameters with the Fisher’s exact or Chi-square test, where appropriate. Results: 160 patients with sufficient quality baseline CTP and in-hospital echocardiogram were evaluated; 34 had EF Conclusion: Patients with reduced EF have dispersion of the contrast bolus as evidenced by a VOF curve that is wider and has a lower peak. Consequently, the quality of the Tmax map in patients with low EF is reduced, which may render automated CTP results unreliable. Additional studies are needed to determine to what extent poor CTP image quality in patients with low EF affects treatment decisions.

Background A target mismatch profile can identify good clinical response to recanalization after acute ischemic stroke, but does not consider region specificities. Purpose To test whether location-weighted infarction core and mismatch, determined from diffusion and perfusion MRI performed in patients with acute stroke, could improve prediction of good clinical response to mechanical thrombectomy compared with a target mismatch profile. Materials and Methods In this secondary analysis, two prospectively collected independent stroke data sets (2012-2015 and 2017-2019) were analyzed. From the brain before stroke (BBS) study data (data set 1), an eloquent map was computed through voxel-wise associations between the infarction core (based on diffusion MRI on days 1-3 following stroke) and National Institutes of Health Stroke Scale (NIHSS) score. The French acute multimodal imaging to select patients for mechanical thrombectomy (FRAME) data (data set 2) consisted of large vessel occlusion-related acute ischemic stroke successfully recanalized. From acute MRI studies (performed on arrival, prior to thrombectomy) in data set 2, target mismatch and eloquent (vs noneloquent) infarction core and mismatch were computed from the intersection of diffusion- and perfusion-detected lesions with the coregistered eloquent map. Associations of these imaging metrics with early neurologic improvement were tested in multivariable regression models, and areas under the receiver operating characteristic curve (AUCs) were compared. Results Data sets 1 and 2 included 321 (median age, 69 years [IQR, 58-80 years]; 207 men) and 173 (median age, 74 years [IQR, 65-82 years]; 90 women) patients, respectively. Eloquent mismatch was positively and independently associated with good clinical response (odds ratio [OR], 1.14; 95% CI: 1.02, 1.27

Background: Predicting infarct growth rate (IGR) in acute stroke with large vessel occlusion (LVO) is important for treatment decision-making. IGR has typically been studied in patients treated with thrombectomy, which likely has underestimated the prevalence of ‘fast progressors’, as large core patients are less frequently treated. We aimed to study IGR in an unselected LVO population and study the association between Hypoperfusion Intensity Ratio (HIR, a surrogate marker of collaterals) and IGR as assessed by both CT and MRI. Methods: Retrospective study including ICA/M1 stroke patients with witnessed stroke onset and baseline perfusion imaging (MRI or CT) performed within 24hrs from symptoms onset. To avoid selection bias, patients were selected from (1) the registries of 3 centers with systematic use of MRI- or CT-perfusion and including both MT-treated and untreated patients, and (2) one trial where thrombectomy decisions were performed blinded from perfusion MRI results. IGR was defined as core volume/onset-to-imaging time, and fast progressors as IGR≥10mL/hr. HIR was defined as the proportion of Tmax>6s volume with Tmax>10s. Results: Overall, 423 and 215 patients were included in the MRI and CT cohorts. Median IGR was 6.4mL/hr (IQR 2.2-21.3) and 5.2mL/hr (0-25.2) in the MRI and CT cohorts, and median HIR was 0.44 (0.27-0.59) and 0.45 (0.25-0.60). 174 (41%) MRI patients and 86 (40%) CT patients were fast progressors. IGR was increasing with increase of HIR quartiles in both cohorts ( P P P Conclusion: In this unselected LVO population, 40% of patients were fast progressors regardless of imaging modality. HIR was a strong predictor of IGR in both CT and MRI-assessed patients, and may help for patient triage, e.g . for transfer decision from an outside hospital for thrombectomy.

Introduction: Previous studies have failed to show an interaction between known atrial fibrillation (AF) and treatment effect of endovascular thrombectomy (EVT) performed within 6 hours of time last known well. However, it is not known if these findings apply to patients treated beyond 6 hours. The objective of the present study is to determine if a known diagnosis of AF exhibits effect modification on the association between treatment (EVT vs. medical therapy) and outcomes in patients >6 hours from time last known well. Methods: We performed a post hoc analysis of the DEFUSE-3 trial investigating the functional outcomes in study participants stratified by AF status. Our primary endpoint was functional outcome as measured by the modified Rankin Scale (mRS) score. We constructed an ordinal logistic regression model to determine the association between EVT/medical therapy and mRS in subgroups by AF status. Secondary endpoints include functional independence (mRS 0-2 vs. 3-6), final infarct volume, sICH, and mortality, examined via binary logistic or linear regression. We fit treatment modality*AF interaction terms. Results: Among 182 participants, 62 had AF (34 randomized to EVT) and 120 did not have AF (58 randomized to EVT). Patients with AF were older (median: 76.5 vs 66.5), presented with a higher NIHSS (median: 17 vs 16), and received IV tPA less frequently (4.8% vs. 12.5%). In patients with AF, the odds of a one-point improvement in mRS in EVT vs. medical therapy were 4.56 (95% CI: 1.79-12.17), while in patients without AF, the odds were 2.42 (95% CI: 1.27-4.67). We found no significant interaction between AF and EVT for the primary or secondary endpoints. Conclusion: Our study did not show a significant interaction between AF status and EVT, with the caveat that the study may be underpowered to detect such an effect. The trend for greater treatment effect should be evaluated in larger studies.

OBJECTIVE Perfusion imaging identifies anterior circulation stroke patients who respond favorably to endovascular thrombectomy (ET), but its role in basilar artery occlusion (BAO) is unknown. We hypothesized that BAO patients with limited regions of severe hypoperfusion (time to reach maximum concentration in seconds [Tmax] > 10) would have a favorable response to ET compared to patients with more extensive regions involved. METHODS We performed a multicenter retrospective cohort study of BAO patients with perfusion imaging prior to ET. We prespecified a Critical Area Perfusion Score (CAPS; 0-6 points), which quantified severe hypoperfusion (Tmax > 10) in cerebellum (1 point/hemisphere), pons (2 points), and midbrain and/or thalamus (2 points). Patients were dichotomized into favorable (CAPS ≤ 3) and unfavorable (CAPS > 3) groups. The primary outcome was a favorable functional outcome 90 days after ET (modified Rankin Scale = 0-3). RESULTS One hundred three patients were included. CAPS ≤ 3 patients (87%) had a lower median National Institutes of Health Stroke Scale score (NIHSS; 12.5, interquartile range [IQR] = 7-22) compared to CAPS > 3 patients (13%; 23, IQR = 19-36; p = 0.01). Reperfusion was achieved in 84% of all patients, with no difference between CAPS groups (p = 0.42). Sixty-four percent of reperfused CAPS ≤ 3 patients had a favorable outcome compared to 8% of nonreperfused CAPS ≤ 3 patients (odds ratio [OR] = 21.0, 95% confidence interval [CI] = 2.6-170; p 3 patients had a favorable outcome, regardless of reperfusion. In a multivariate regression analysis, CAPS ≤ 3 was a robust independent predictor of favorable outcome after adjustment for reperfusion, age, and pre-ET NIHSS (OR = 39.25, 95% CI = 1.34->999, p = 0.04). INTERPRETATION BAO patients with limited regions of severe hypoperfusion had a favorable response to reperfusion following ET. However, patients with more extensive regions of hypoperfusion in critical brain regions did not benefit from endovascular reperfusion. ANN NEUROL 2021.

Background Perfusion imaging is important to identify a target mismatch in stroke but requires contrast agents and postprocessing software. Purpose To use a deep learning model to predict the hypoperfusion lesion in stroke and identify patients with a target mismatch profile from diffusion-weighted imaging (DWI) and clinical information alone, using perfusion MRI as the reference standard. Materials and Methods Imaging data sets of patients with acute ischemic stroke with baseline perfusion MRI and DWI were retrospectively reviewed from multicenter data available from 2008 to 2019 (Imaging Collaterals in Acute Stroke, Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 2, and University of California, Los Angeles stroke registry). For perfusion MRI, rapid processing of perfusion and diffusion software automatically segmented the hypoperfusion lesion (time to maximum, ≥6 seconds) and ischemic core (apparent diffusion coefficient [ADC], ≤620 × 10

Background: Parenchymal hematoma (PH) is a major complication after endovascular treatment (EVT) for ischemic stroke. The hypoperfusion intensity ratio (HIR) represents a perfusion parameter reflecting arterial collateralization and cerebral microperfusion in ischemic brain tissue. We hypothesized that HIR correlates with the risk of PH after EVT. Methods: Retrospective multicenter cohort study of patients with large vessel occlusion who underwent EVT between 2013 and 2021 at one of the 2 comprehensive stroke centers (University Medical Center Hamburg-Eppendorf, Germany and Stanford University School of Medicine, CA). HIR was automatically calculated on computed tomography perfusion studies as the ratio of brain volume with time-to-max (Tmax) delay >10 s over volume with Tmax >6 s. Reperfusion hemorrhages were assessed according to the Heidelberg Bleeding Classification. Primary outcome was PH occurrence (PH+) or absence (PH−) on follow-up imaging. Secondary outcome was good clinical outcome defined as a 90-day modified Rankin Scale score of 0 to 2. Results: A total of 624 patients met the inclusion criteria. We observed PH in 91 (14.6%) patients after EVT. PH+ patients had higher HIR on admission compared with PH− patients (median, 0.6 versus 0.4; P P P =0.002), and higher HIR (aOR, 1.22 [1.09–1.38]; P P P =0.013) were independently associated with lower odds of achieving good clinical outcome. Conclusions: Poorer (higher) HIR on admission perfusion imaging was strongly associated with PH occurrence after EVT. HIR as a surrogate for cerebral microperfusion might reflect tissue vulnerability for reperfusion hemorrhages. This automated and quickly available perfusion parameter might help to assess the need for intensive medical care after EVT.

BackgroundPrevious randomized controlled trials (RCTs) and meta-analyses were underpowered to demonstrate the superiority of endovascular thrombectomy (EVT) over medical therapy (MEDT) in the treatment of acute ischemic stroke due to large vessel occlusion of the posterior circulation (PC-LVO). We performed an updated systematic review and meta-analysis after the publication of the BAOCHE and ATTENTION trials to determine whether EVT can benefit patients presenting with PC-LVO.MethodsUsing Nested Knowledge, we screened literature for RCTs on EVT in PC-LVO. The primary outcome was 90-day modified Rankin Scale (mRS) score 0–3, and secondary outcomes included 90-day mRS score 0–2, 90-day mortality, and rate of symptomatic intracranial hemorrhage (sICH). A random-effects model was used to compute rate ratios (RRs) and their corresponding 95% confidence intervals (CIs).ResultsFour RCTs with 988 patients, 556 patients in the EVT arm and 432 patients in the MEDT arm, were included in the meta-analysis. EVT resulted in significantly higher rates of mRS score 0–3 (RR=1.54; 95% CI 1.16 to 2.04; P=0.002) and functional independence (RR=1.83; 95% CI 1.08 to 3.08; P=0.024), and lower rates of mortality (RR=0.76; 95% CI 0.65 to 0.90; P=0.002) at 90-day follow-up compared with MEDT alone. However, EVT patients had higher rates of sICH (RR=7.48; 95% CI 2.27 to 24.61; PConclusionsEVT conferred significant patient benefit over MEDT alone in the treatment of PC-LVO. Future studies should better define patients for whom EVT is futile and determine factors that contribute to higher rates of sICH.

BACKGROUND AND PURPOSE Arterial clot localization affects collateral flow to ischemic brain in patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO). We determined the association between vessel occlusion locations, tissue-level collaterals (TLC), and venous outflow (VO) profiles and their impact on good functional outcomes. METHODS We conducted a multicenter retrospective cohort study of consecutive AIS-LVO patients who underwent thrombectomy triage. Baseline computed tomographic angiography (CTA) was used to localize vessel occlusion, which was dichotomized into proximal vessel occlusion (PVO; internal carotid artery and proximal first segment of the middle cerebral artery [M1]) and distal vessel occlusion (DVO; distal M1 and M2), and to assess collateral scores. TLC were assessed on computed tomographic perfusion data using the hypoperfusion intensity ratio. VO was determined on baseline CTA by the cortical vein opacification score. Primary outcomes were favorable VO and TLC; secondary outcome was the modified Rankin Scale after 90 days. RESULTS A total of 649 patients met inclusion criteria. Of these, 376 patients (58%) had a PVO and 273 patients (42%) had a DVO. Multivariate ordinal logistic regression showed that DVO predicted favorable TLC (odds ratio [OR] = 1.77, 95% confidence interval [CI] = 1.24-2.52, p = 0.002) and favorable VO (OR = 7.2, 95% CI = 5.2-11.9, p < 0.001). DVO (OR = 3.4, 95% CI = 2.1-5.6, p < 0.001), favorable VO (OR = 6.4, 95% CI = 3.8-10.6, p < 0.001), and favorable TLC (OR = 3.2, 95% CI = 2-5.3, p < 0.001), but not CTA collaterals (OR = 1.07, 95% CI = 0.60-1.91, p = 0.813), were predictors of good functional outcome. CONCLUSIONS DVO in AIS-LVO patients correlates with favorable TLC and VO profiles, which are associated with good functional outcome.

Background and Purpose: In patients with acute large vessel occlusion, the natural history of penumbral tissue based on perfusion time-to-maximum (T max ) delay is not well established in relation to late-window endovascular thrombectomy. In this study, we sought to evaluate penumbra consumption rates for T max delays in patients with large vessel occlusion evaluated between 6 and 16 hours from last known normal. Methods: This is a post hoc analysis of the DEFUSE 3 trial (The Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke), which included patients with an acute ischemic stroke due to anterior circulation occlusion within 6 to 16 hours of last known normal. The primary outcome is percentage penumbra consumption, defined as (24-hour magnetic resonance imaging infarct volume–baseline core infarct volume)/(T max 6 or 10 s volume–baseline core volume). We stratified the cohort into 4 categories based on treatment modality and Thrombolysis in Cerebral Infarction (TICI score; untreated, TICI 0-2a, TICI 2b, and TICI3) and calculated penumbral consumption rates in each category. Results: We included 141 patients, among whom 68 were untreated. In the untreated versus TICI 3 patients, a median (interquartile range) of 53.7% (21.2%–87.7%) versus 5.3% (1.1%–14.6%) of penumbral tissue was consumed based on T max >6 s ( P max >10 s, we saw a difference of 165.4% (interquartile range, 56.1%–479.8%) versus 25.7% (interquartile range, 3.2%–72.1%; P max >6 s ( P =0.52) or T max >10 s ( P =0.92). Conclusions: Among extended window endovascular thrombectomy patients, T max >10-s mismatch volume may comprise large volumes of salvageable tissue, whereas nearly half the T max >6-s mismatch volume may remain viable in untreated patients at 24 hours.

Circadian biology modulates almost all aspects of mammalian physiology, disease, and response to therapies. Emerging data suggest that circadian biology may significantly affect the mechanisms of susceptibility, injury, recovery, and the response to therapy in stroke. In this review/perspective, we survey the accumulating literature and attempt to connect molecular, cellular, and physiological pathways in circadian biology to clinical consequences in stroke. Accounting for the complex and multifactorial effects of circadian rhythm may improve translational opportunities for stroke diagnostics and therapeutics.

Background Ischemic lesion net water uptake (NWU) at noncontrast head CT enables quantification of cerebral edema in patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). Purpose To assess whether favorable venous outflow (VO) profiles at CT angiography are associated with reduced NWU and good functional outcomes in patients with AIS due to LVO. Materials and Methods This multicenter retrospective cohort study evaluated consecutive patients with AIS due to LVO who underwent thrombectomy triage between January 2013 and December 2019. Arterial collateral vessel status (Tan scale) and venous output were measured at CT angiography. Venous outflow was graded with use of the cortical vein opacification score, which quantifies opacification of the vein of Labbé, sphenoparietal sinus, and superficial middle cerebral vein. Favorable VO was regarded as a score of 3-6 and unfavorable VO as a score of 0-2. NWU was determined at follow-up noncontrast CT. Multivariable regression analyses were performed to determine the association between favorable VO profiles and NWU after treatment and good functional outcome (modified Rankin Scale, ≤2). Results A total of 580 patients were included. Of the 580 patients, 231 had favorable VO (104 women; median age, 73 years [interquartile range {IQR}, 62-81 years]) and 349 had unfavorable VO (190 women; median age, 77 years [IQR, 66-84 years]). Compared with patients with unfavorable VO, those with favorable VO exhibited lower baseline National Institutes of Health Stroke Scale score (median, 12.5 [IQR, 7-17] vs 17 [IQR, 13-21]), higher Alberta Stroke Program Early CT Score (median, 9 [IQR, 7-10] vs 7 [IQR, 6-8]), and less NWU after treatment (median, 7% [IQR, 4.6%-11.5%] vs 17.9% [IQR, 12.3%-22.2%]). In a multivariable regression analysis, NWU mean difference between patients with unfavorable VO and those with favorable VO was 6.1% (95% CI: 4.9, 7.3

Background/ImportanceDelayed cerebral ischemia (DCI) is the second-leading cause of death and disability in patients with aneurysmal subarachnoid hemorrhage (aSAH), and is associated with cerebral arterial vasospasm (CAV). Current treatments for CAV are expensive, invasive, and have limited efficacy. Cervical sympathetic block (CSB) is an underappreciated, but potentially highly effective therapy for CAV.ObjectiveTo provide a comprehensive review of the preclinical and human literature pertinent to CSB in the context of CAV.Evidence reviewThis study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. We conducted a literature search using Embase, PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Scopus and Web of Science until February 2022, to identify abstracts, conference proceedings, and full-text papers pertinent to cervical sympathectomy and CAV in animal/adult patients.FindingsWe included six human and six experimental studies. Human studies were mostly prospective observational, except one retrospective and one randomized clinical trial, and used various imaging modalities to measure changes in arterial diameter after the block. Studies that used digital subtraction angiography showed an improvement in cerebral perfusion without change in vessel diameter. Transcranial Doppler studies found an approximately 15% statistically significant decrease in velocities consistent with arterial vasodilatation. Overall, the results suggest an increase in cerebral arterial diameter and neurological improvement in patients receiving a CSB. Animal studies demonstrate that sympathetic system ablation vasodilates cerebral vasculature and decreases the incidence of symptomatic vasospasm.ConclusionsThis scoping review suggests that CSB may be a viable option for treatment and prevention of CAV/DCI in patients with aSAH, although the included studies were heterogeneous, mostly observational, and with a small sample size. Further research is needed to standardize the technique and prove its effectiveness to treat patients suffering of CAV/DCI after aSAH.