Influence of Time to Achieve Target Systolic Blood Pressure on Outcome After Intracerebral Hemorrhage: The Blood Pressure in Acute Stroke Collaboration.

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.

Time Course of Early Hematoma Expansion in Acute Spot-Sign Positive Intracerebral Hemorrhage: Prespecified Analysis of the SPOTLIGHT Randomized Clinical Trial.

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.

Quantitative susceptibility-weighted imaging in presence of strong susceptibility sources: Application to hemorrhage.

PURPOSE: To optimize quantitative susceptibility-weighted imaging also known as true susceptibility-weighted imaging (tSWI) for strong susceptibility sources like hemorrhage and compare to standard susceptibility-weighted imaging (SWI) and quantitative susceptibility mapping (QSM). METHODS: Ten patients with known intracerebral hemorrhage (ICH) were scanned using a 3D SWI sequence. The magnitude and phase images were utilized to compute QSM, tSWI and SWI images. tSWI parameters including the upper threshold for creating susceptibility-weighted masks and the multiplication factor were optimized for hemorrhage depiction. Combined tSWI was also computed with independent optimized parameters for both veins and hemorrhagic regions. tSWI results were compared to SWI and QSM utilizing region-of-interest measurements, Pearson's correlation and Kruskal-Wallis test. RESULTS: Fifteen hemorrhages were found, with mean susceptibility 0.81 ± 0.37 ppm. Unlike SWI which utilizes a phase mask, tSWI uses a mask computed from QSM. In tSWI, the weighted mask required an extended upper threshold far beyond the standard level for more effective visualization of hemorrhage texture. The upper threshold was set to the mean maximum susceptibility in the hemorrhagic region (3.24 ppm) with a multiplication factor of 2. The blooming effect, seen in SWI, was observed to be larger in hemorrhages with higher susceptibility values (r = 0.78, p < 0.001) with reduced blooming on tSWI. On SWI, 4 out of 15 hemorrhages showed phase wrap artifacts in the hemorrhagic region and all patients showed some phase wraps in the air-tissue interface near the auditory and frontal sinuses. These phase wrap artifacts were absent on tSWI. In hemorrhagic regions, a higher correlation was observed between the actual susceptibility values and mean gray value for tSWI (r = -0.93, p < 0.001) than SWI (r = -0.87, p < 0.001). CONCLUSION: In hemorrhage, tSWI minimizes both blooming effects and phase wrap artifacts observed in SWI. However, unlike SWI, tSWI requires an altered upper threshold for best hemorrhage depiction that greatly differs from the standard value. tSWI can be used as a complementary technique for visualizing hemorrhage along with SWI.

Early lowering of blood pressure after acute intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.

OBJECTIVE: To summarise evidence of the effects of blood pressure (BP)-lowering interventions after acute spontaneous intracerebral haemorrhage (ICH). METHODS: A prespecified systematic review of the Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE databases from inception to 23 June 2020 to identify randomised controlled trials that compared active BP-lowering agents versus placebo or intensive versus guideline BP-lowering targets for adults <7 days after ICH onset. The primary outcome was function (distribution of scores on the modified Rankin scale) 90 days after randomisation. Radiological outcomes were absolute (>6 mL) and proportional (>33%) haematoma growth at 24 hours. Meta-analysis used a one-stage approach, adjusted using generalised linear mixed models with prespecified covariables and trial as a random effect. RESULTS: Of 7094 studies identified, 50 trials involving 11 494 patients were eligible and 16 (32.0%) shared patient-level data from 6221 (54.1%) patients (mean age 64.2 [SD 12.9], 2266 [36.4%] females) with a median time from symptom onset to randomisation of 3.8 hours (IQR 2.6-5.3). Active/intensive BP-lowering interventions had no effect on the primary outcome compared with placebo/guideline treatment (adjusted OR for unfavourable shift in modified Rankin scale scores: 0.97, 95% CI 0.88 to 1.06; p=0.50), but there was significant heterogeneity by strategy (pinteraction=0.031) and agent (pinteraction<0.0001). Active/intensive BP-lowering interventions clearly reduced absolute (>6 ml, adjusted OR 0.75, 95%CI 0.60 to 0.92; p=0.0077) and relative (≥33%, adjusted OR 0.82, 95%CI 0.68 to 0.99; p=0.034) haematoma growth. INTERPRETATION: Overall, a broad range of interventions to lower BP within 7 days of ICH onset had no overall benefit on functional recovery, despite reducing bleeding. The treatment effect appeared to vary according to strategy and agent. PROSPERO REGISTRATION NUMBER: CRD42019141136.

Association of Reperfusion After Thrombolysis With Clinical Outcome Across the 4.5- to 9-Hours and Wake-up Stroke Time Window: A Meta-Analysis of the EXTEND and EPITHET Randomized Clinical Trials.

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.

Rapid quantitative susceptibility mapping of intracerebral hemorrhage.

BACKGROUND: Quantitative susceptibility mapping (QSM) offers a means to track iron evolution in hemorrhage. However, standard QSM sequences have long acquisition times and are prone to motion artifact in hemorrhagic patients. PURPOSE: To minimize motion artifact and acquisition time by performing rapid QSM in intracerebral hemorrhage (ICH) using single-shot echo planar imaging (EPI). STUDY TYPE: Prospective method evaluation. POPULATION/SUBJECTS: Forty-five hemorrhages were analyzed from 35 MRI exams obtained between February 2016 and March 2019 from 27 patients (14 male / 13 female, age: 71 ± 12 years) with confirmed primary ICH. FIELD STRENGTH/SEQUENCE: 3T; susceptibility-weighted imaging (SWI) with 4.54-minute acquisition and 2D single-shot gradient EPI with 0.45-minute acquisition. ASSESSMENT: Susceptibility maps were constructed from both methods. Measurement of ICH area and mean magnetic susceptibility were made manually by three independent observers. Motion artifacts were quantified using the magnitude signal ratio of artifact-to-brain tissue to classify into three categories: mild or no artifact, moderate artifact, or severe artifact. The cutoff for each category was determined by four observers. STATISTICAL TESTS: Pearson's correlation coefficient and paired t-test using α = 0.05 were used to compare results. Inter- and intraclass correlation was used to assess observer variability. RESULTS: Using 45 hemorrhages, the ICH regions measured on susceptibility maps obtained from EPI and SWI sequences had high correlation coefficients for area (R2 ≥ 0.97) and mean magnetic susceptibility (R2 ≥ 0.93) for all observers. The artifact-to-tissue ratio was significantly higher (P < 0.01) for SWI vs. EPI, and the standard deviation for the SWI method (SD = 0.05) was much larger than EPI (SD = 0.01). All observers' measurements showed high agreement. DATA CONCLUSION: Single-shot EPI-QSM enabled rapid measurement of ICH area and mean magnetic susceptibility, with reduced motion as compared with more standard SWI. EPI-QSM requires minimal additional acquisition time and could be incorporated into iron tracking studies in ICH. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2020;51:712-718.

One-Year Healthcare Utilization for Patients That Received Endovascular Treatment Compared With Control.

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.

Influence of occlusion site and baseline ischemic core on outcome in patients with ischemic 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.

Lower Blood Pressure Is Not Associated With Decreased Arterial Spin Labeling Estimates of Perfusion in Intracerebral Hemorrhage.

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.

Extending thrombolysis to 4·5-9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data.

BACKGROUND: Stroke thrombolysis with alteplase is currently recommended 0-4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis. METHODS: In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. FINDINGS: We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15-2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23-76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81-2·96, p=0·66). INTERPRETATION: Patients with ischaemic stroke 4·5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis. FUNDING: None.

Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data.

BACKGROUND: CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome. METHODS: In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 µm2/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered. FINDINGS: We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0·47 [95% CI 0·30-0·72], p=0·0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0·77 [0·69-0·86] per 10 mL, pinteraction=0·29; diffusion MRI OR 0·87 [0·81-0·94] per 10 mL, pinteraction=0·94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low. INTERPRETATION: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. FUNDING: Medtronic.

The Multiple Causes of Stroke in Atrial Fibrillation: Thinking Broadly.

Atrial fibrillation (AF) is numerically the most important risk factor for stroke. It is well established that patients with AF have a 5-fold increased risk of stroke relative to those without and that anticoagulation reduces the risk of stroke by approximately two-thirds. Definitively attributing the mechanism of an individual stroke to AF is more problematic, however. In fact, there is no way to reliably establish the etiology of any ischemic infarction. This necessitates screening for all potential stroke risk factors and treating accordingly. The pattern of infarction is often used to classify the presumed mechanism of infarction as thrombotic or embolic, although even this is approach is based on association and increasingly is recognized as not completely reliable. Furthermore, it should not dictate management-patients with perforating arterial territory infarcts with AF also require and benefit from anticoagulation. Likewise, if other potential embolic sources beyond AF are identified, anticoagulation remains the standard of care. The traditional conceptual model of the mechanistic link between AF and cardioembolic infarction is likely oversimplified. Long-term cardiac rhythm recording studies indicate an inconsistent temporal relationship between AF and infarction. This suggests that cardioembolic stroke in patients with AF may result from the underlying atrial cardiopathy, rather than the rhythm disturbance leading to atrial stasis and thromboembolism. We reviewed traditional and current concepts, as well as evidence for the role of AF in ischemic stroke.

Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.

BACKGROUND: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography. METHODS: In a systematic review of OVID MEDLINE-with additional hand-searching of relevant studies' bibliographies- from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5-24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known. FINDINGS: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56-76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36-0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46-11·60; p<0·0001), antiplatelet use (1·68, 1·06-2·66; p=0·026), and anticoagulant use (3·48, 1·96-6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75-0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95-6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03-0·07). INTERPRETATION: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials. FUNDING: UK Medical Research Council and British Heart Foundation.

Quantitative Susceptibility Mapping for Following Intracranial Hemorrhage.

Purpose To follow the evolution of intracranial hemorrhage (ICH) by using quantitative susceptibility mapping (QSM). Materials and Methods Thirty-six patients with ICH confirmed at CT were enrolled to follow ICH evolution on day 2, 7, and 30 after symptom onset between August 2013 and April 2017. QSM was reconstructed from MRI gradient-echo phase images acquired at 1.5 T or 3.0 T. ICH regions were manually drawn on two-dimensional sections of co-registered CT and MR images independently by two raters. The ICH areas and mean values were compared between CT and MRI by using Bland-Altman plots and Pearson correlation. QSM time evolution of ICH was assessed by using paired t tests and was compared with conventional T2-weighted fluid-attenuated inversion recovery, or T1-weighted or T2*-weighted magnitude intensities. Results Significant reductions in ICH susceptibility were found between day 2 and day 7 (P < .001) and between day 7 and day 30 (P = .003), corresponding to different disease stages. The ICH areas measured at CT and QSM were linearly correlated (r2 = 0.98). The mean CT attenuation and mean susceptibility of ICH were linearly correlated (r2 = 0.29). Excellent intra- and interobserver reproducibility were found for QSM (intraclass correlation coefficient, 0.987 and 0.966, respectively). Conclusion Longitudinal evolution of intracranial hemorrhage (ICH) by using quantitative susceptibility mapping (QSM) demonstrated susceptibility differences in different disease stages, which was not found at conventional MRI; therefore, QSM may assist in quantitatively following ICH iron content.

Intravenous Thrombolysis May Not Improve Clinical Outcome of Acute Ischemic Stroke Patients Without a Baseline Vessel Occlusion.

Background and Purpose: The benefit of thrombolysis in ischemic stroke patients without a visible vessel occlusion still requires investigation. This study tested the hypothesis that non-lacunar stroke patients with no visible vessel occlusion on baseline imaging would have a favorable outcome regardless of treatment with alteplase. Methods: We utilized a prospectively collected registry of ischemic stroke patients [the International Stroke Perfusion Imaging Registry (INSPIRE)] who had baseline computed tomographic perfusion and computed tomographic angiography. The rates of patients achieving modified Rankin Scale (mRS) 0-1 were compared between alteplase treated and untreated patients using logistic regression to generate odds ratios. Results: Of 1569 patients in the INSPIRE registry, 1,277 were eligible for inclusion. Of these, 306 (24%) had no identifiable occlusion and were eligible for alteplase, with 141 (46%) of these patients receiving thrombolysis. The treated and untreated groups had significantly different median baseline National Institutes of Health Stroke Scale (NIHSS) [alteplase 8, interquartile range (IQR) 5-10, untreated 6, IQR 4-8, P < 0.001] and median volume of baseline perfusion lesion [alteplase 5.6 mL, IQR 1.3-17.7 mL, untreated 2.6 mL, IQR 0-6.7 mL, P < 0.001]. After propensity analysis, alteplase treated patients without a vessel occlusion were less likely to have an excellent outcome (mRS 0-1; 56%) than untreated (78.8%, OR, 0.42, 95% confidence interval, 0.24-0.75, P = 0.003). Conclusions: In this non-randomized comparison, alteplase treatment in patients without an identifiable vessel occlusion did not result in higher rates of favorable outcome compared to untreated. However, treated patients displayed less favorable baseline prognostic factors than the untreated group. Further studies may be required to confirm this data.

Influence of Penumbral Reperfusion on Clinical Outcome Depends on Baseline Ischemic Core Volume.

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; R2, 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; R2, 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 (R2, 0.31; P<0.0001). This association was again stronger after adjustment for baseline ischemic core volume (R2, 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.

Blood-brain barrier compromise does not predict perihematoma edema growth in intracerebral hemorrhage.

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 (ß=-0.192 [-0.06 to 0.01]) or SBP change (ß=-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.

Intensive blood pressure reduction in acute intracerebral hemorrhage: a meta-analysis.

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.

The Alberta Stroke Prevention in TIAs and mild strokes (ASPIRE) intervention: rationale and design for evaluating the implementation of a province-wide TIA triaging system.

RATIONALE: Stroke risk after transient ischaemic attack is high and, it is a challenge worldwide to provide urgent assessment and preventive services to entire populations. AIMS: To determine whether a province-wide transient ischaemic attack Triaging algorithm and transient ischaemic attack hotline (the Alberta Stroke Prevention in transient ischaemic attacks and mild strokes intervention) can reduce the rate of stroke recurrence following transient ischaemic attack across the population of Alberta, Canada (population 3·7 million, 90-day rate of post-stroke transient ischaemic attack currently 9·5%). It also seeks to improve upon current transient ischaemic attack triaging rules by incorporating time from symptom onset as a predictive variable. DESIGN: The transient ischaemic attack algorithm and hotline were developed with a broad consensus of clinicians, patients, policy-makers, and researchers and based on local adaptation of the work of others and research and insights developed within the province. Because neither patient-level nor region-level randomization was possible, we conducted a quasi-experimental design examining changes in the post-transient ischaemic attack rate of stroke recurrence before and after the 15-month implementation period using an interrupted time-series regression analysis. The design controls for changes in case-mix, co-interventions, and secular trends. A prospective transient ischaemic attack cohort will also be concurrently created with telephone follow-up at seven-days and 90 days as well as passive follow-up over the longer term using linkages to provincial healthcare administrative databases. STUDY OUTCOMES: The primary outcome measure is the change in recurrence rate of stroke following transient ischaemic attack at seven-days and 90 days, comparing a period of two-years before vs. two-years after the intervention is implemented. All cases of recurrent stroke will be validated. Secondary outcomes include functional status, hospitalizations, morbidity, and mortality. CONCLUSIONS: We are undertaking a rigorous evaluation of a population-based approach to improving quality of transient ischaemic attack care. Whether positive or negative, our work should provide important insights for all potential stakeholders.

Blood pressure reduction does not reduce perihematoma oxygenation: a CT perfusion study.

Blood pressure (BP) reduction after intracerebral hemorrhage (ICH) is controversial, because of concerns that this may cause critical reductions in perihematoma perfusion and thereby precipitate tissue damage. We tested the hypothesis that BP reduction reduces perihematoma tissue oxygenation.Acute ICH patients were randomized to a systolic BP target of <150 or <180 mm Hg. Patients underwent CT perfusion (CTP) imaging 2 hours after randomization. Maps of cerebral blood flow (CBF), maximum oxygen extraction fraction (OEF(max)), and the resulting maximum cerebral metabolic rate of oxygen (CMRO2(max)) permitted by local hemodynamics, were calculated from raw CTP data.Sixty-five patients (median (interquartile range) age 70 (20)) were imaged at a median (interquartile range) time from onset to CTP of 9.8 (13.6) hours. Mean OEF(max) was elevated in the perihematoma region (0.44±0.12) relative to contralateral tissue (0.36±0.11; P<0.001). Perihematoma CMRO2(max) (3.40±1.67 mL/100 g per minute) was slightly lower relative to contralateral tissue (3.63±1.66 mL/100 g per minute; P=0.025). Despite a significant difference in systolic BP between the aggressive (140.5±18.7 mm Hg) and conservative (163.0±10.6 mm Hg; P<0.001) treatment groups, perihematoma CBF was unaffected (37.2±11.9 versus 35.8±9.6 mL/100 g per minute; P=0.307). Similarly, aggressive BP treatment did not affect perihematoma OEF(max) (0.43±0.12 versus 0.45±0.11; P=0.232) or CMRO2(max) (3.16±1.66 versus 3.68±1.85 mL/100 g per minute; P=0.857). Blood pressure reduction does not affect perihematoma oxygen delivery. These data support the safety of early aggressive BP treatment in ICH.