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Predictors of In-Hospital Death After Aneurysmal Subarachnoid Hemorrhage [Original Contributions]


Background and Purpose—To identify predictors of in-hospital mortality in patients with aneurysmal subarachnoid hemorrhage and to estimate their impact.Methods—Retrospective analysis of prospective data from a nationwide multicenter registry on all aneurysmal subarachnoid hemorrhage cases admitted to a tertiary neurosurgical department in Switzerland (Swiss SOS [Swiss Study on Aneurysmal Subarachnoid Hemorrhage]; 2009–2015). Both clinical and radiological independent predictors of in-hospital mortality were identified, and their effect size was determined by calculating adjusted odds ratios (aORs) using multivariate logistic regression. Survival was displayed using Kaplan–Meier curves.Results—Data of n=1866 aneurysmal subarachnoid hemorrhage patients in the Swiss SOS database were available. In-hospital mortality was 20% (n=373). In n=197 patients (10.6%), active treatment was discontinued after hospital admission (no aneurysm occlusion attempted), and this cohort was excluded from analysis of the main statistical model. In the remaining n=1669 patients, the rate of in-hospital mortality was 13.9% (n=232). Strong independent predictors of in-hospital mortality were rebleeding (aOR, 7.69; 95% confidence interval, 3.00–19.71; P<0.001), cerebral infarction attributable to delayed cerebral ischemia (aOR, 3.66; 95% confidence interval, 1.94–6.89; P<0.001), intraventricular hemorrhage (aOR, 2.65; 95% confidence interval, 1.38–5.09; P=0.003), and new infarction post-treatment (aOR, 2.57; 95% confidence interval, 1.43–4.62; P=0.002).Conclusions—Several—and among them modifiable—factors seem to be associated with in-hospital mortality after aneurysmal subarachnoid hemorrhage. Our data suggest that strategies aiming to reduce the risk of rebleeding are most promising in patients where active treatment is initially pursued.Clinical Trial Registration—URL: Unique identifier: NCT03245866.

Geographic Modeling to Quantify the Impact of Primary and Comprehensive Stroke Center Destination Policies [Brief Reports]


Background and Purpose—We evaluated the impact of a primary stroke center (PSC) destination policy in a major metropolitan city and used geographic modeling to evaluate expected changes for a comprehensive stroke center policy.Methods—We identified suspected stroke emergency medical services encounters from 1/1/2004 to 12/31/2013 in Philadelphia, PA. Transport times were compared before and after initiation of a PSC destination policy on 10/3/2011. Geographic modeling estimated the impact of bypassing the closest hospital for the closest PSC and for the closest comprehensive stroke center.Results—There were 2 326 943 emergency medical services runs during the study period, of which 15 099 had a provider diagnosis of stroke. Bypassing the closest hospital for a PSC was common before the official policy and increased steadily over time. Geographic modeling suggested that bypassing the closest hospital in favor of the closest PSC adds a median of 3.1 minutes to transport time. Bypassing to the closest comprehensive stroke center would add a median of 8.3 minutes.Conclusions—Within a large metropolitan area, the time cost of routing patients preferentially to PSCs and comprehensive stroke centers is low.

Correction for Delay and Dispersion Results in More Accurate Cerebral Blood Flow Ischemic Core Measurement in Acute Stroke [Original Contributions]


Background and Purpose—This study aimed to assess how the ischemic core measured by perfusion computed tomography (CTP) was affected by the delay and dispersion effect.Methods—Ischemic stroke patients having CTP performed within 6 hours of onset were included. The CTP data were processed twice, generating standard cerebral blood flow (sCBF) and delay- and dispersion-corrected CBF (ddCBF), respectively. Ischemic core measured by the sCBF and ddCBF was then compared at the relative threshold <30% of normal tissue. Two references for ischemic core were used: acute diffusion-weighted imaging or 24-hour diffusion-weighted imaging in patients with complete recanalization. Difference of core volume between CTP and diffusion-weighted imaging was estimated by Mann–Whitney U test and limits of agreement. Patients were also classified into favorable and unfavorable CTP patterns. The imaging pattern classification by sCBF and ddCBF was compared by the χ2 test; their respective ability to predict good clinical outcome (3-month modified Rankin Scale score) was tested in logistic regression.Results—Fifty-five patients were included in this study. Median sCBF ischemic core volume was 38.5 mL (12.4–61.9 mL), much larger than the median core volume of 17.2 mL measured by ddCBF (interquartile range, 5.5–38.8; P<0.001). Moreover, compared with sCBF <30%, ddCBF <30% measured the ischemic core much closer to diffusion-weighted imaging core references, with the mean volume difference of −0.1 mL (95% limits of agreement, −25.4 to 25.2; P=0.97) and 16.7 mL (95% limits of agreement, −21.7 to 55.2; P<0.001), respectively. Imaging patterns defined by sCBF showed a difference to that defined by ddCBF (P<0.001), with 12 patients classified as favorable imaging patterns by ddCBF but as unfavorable by sCBF. The favorable imaging pattern classified by ddCBF, compared with sCBF classification, had higher predictive power for good clinical outcome (odds ratio, 7.8 [2–30.5] and 3.1 [0.9–11], respectively).Conclusions—Delay and dispersion correction increases the accuracy of ischemic core measurement on CTP.

Minocycline Effects on Intracerebral Hemorrhage-Induced Iron Overload in Aged Rats [Original Contributions]


Background and Purpose—Brain iron overload is a key factor causing brain injury after intracerebral hemorrhage (ICH). This study quantified brain iron levels after ICH with magnetic resonance imaging R2* mapping. The effect of minocycline on iron overload and ICH-induced brain injury in aged rats was also determined.Methods—Aged (18 months old) male Fischer 344 rats had an intracerebral injection of autologous blood or saline, and brain iron levels were measured by magnetic resonance imaging R2* mapping. Some ICH rats were treated with minocycline or vehicle. The rats were euthanized at days 7 and 28 after ICH, and brains were used for immunohistochemistry and Western blot analyses. Magnetic resonance imaging (T2-weighted, T2* gradient-echo, and R2* mapping) sequences were performed at different time points.Results—ICH-induced brain iron overload in the perihematomal area could be quantified by R2* mapping. Minocycline treatment reduced brain iron accumulation, T2* lesion volume, iron-handling protein upregulation, neuronal cell death, and neurological deficits (P<0.05).Conclusions—Magnetic resonance imaging R2* mapping is a reliable and noninvasive method, which can quantitatively measure brain iron levels after ICH. Minocycline reduced ICH-related perihematomal iron accumulation and brain injury in aged rats.

Risk Factors for and Clinical Consequences of Multiple Intracranial Aneurysms [Original Contributions]


Background and Purpose—Multiple intracranial aneurysms (MIAs) are common findings of cerebral angiographies; however, MIA prevalence varies in different patient cohorts. We sought to elucidate risk factors influencing MIA prevalence and the clinical consequences.Methods—We systematically searched PubMed, Scopus, Embase, and Cochrane Library databases for publications before January 15, 2017, reporting MIA prevalence and risk factors. We used random-effects meta-analysis and multivariate regression analysis to assess the impacts of individual, study, and population characteristics.Results—We included 174 studies reporting on MIA (mean overall prevalence, 20.1%; range, 2%–44.9%) in 134 study populations with 86 989 intracranial aneurysm (IA) patients enrolled between 1950 and 2015. Studies from Europe and North America (P<0.001) and more recent enrolment years (P=0.046) were independently associated with higher MIA prevalence. In meta-analysis, MIA correlated with female sex (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.4–1.8), higher patient age (>40 years; OR, 1.6; 95% CI, 1.14–2.25), arterial hypertension (OR, 1.51; 95% CI, 1.17–1.94), smoking (OR, 1.89; 95% CI, 1.37–2.6) and familial IA (OR, 2.02; 95% CI, 1.47–2.77), and formation of de novo (OR, 3.92; 95% CI, 1.95–7.87) and growth of initial IA (OR, 3.47; 95% CI, 1.87–6.45). Risk of subarachnoid hemorrhage in MIA patients was higher only in longitudinal studies from Japan and Korea (OR, 2.08; 95% CI, 1.46–2.96).Conclusions—Female sex, higher age, arterial hypertension, smoking, and familial IA are major risk factors for MIA. In addition, MIA patients are at risk for enhanced IA formation. Further studies are needed to evaluate rupture risk and the role of ethnicity, especially in the context of increased MIA identification with improved neurovascular imaging.

Increased Risk of Pregnancy Complications After Stroke [Original Contributions]


Background and Purpose—The study goal was to investigate the prevalence of pregnancy complications and pregnancy loss in women before, during, and after young ischemic stroke/transient ischemic attack.Methods—In the FUTURE study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation), a prospective young stroke study, we assessed the occurrence of pregnancy, miscarriages, and pregnancy complications in 223 women aged 18 to 50 years with a first-ever ischemic stroke/transient ischemic attack. Pregnancy complications (gestational hypertension, diabetes mellitus, preeclampsia, and hemolysis, elevated liver enzymes, low platelet count syndrome) were assessed before, during, and after stroke using standardized questionnaires. Primary outcome was occurrence of pregnancy complications and the rate of pregnancy loss compared with the Dutch population. Secondary outcome was the risk of recurrent vascular events after stroke, stratified by a history of hypertensive disorder in pregnancy.Results—Data were available for 213 patients. Mean age at event was 39.6 years (SD=7.8) and mean follow-up 9.5 years (SD=8.5). Miscarriages occurred in 35.2% and fetal death in 6.2% versus 13.5% and 0.9% in the Dutch population, respectively (P<0.05). In nulliparous women after stroke (n=22), in comparison with Dutch population, there was a high prevalence of hypertensive disorders in pregnancy (33.3 versus 12.2%; P<0.05), hemolysis, elevated liver enzymes, low platelet count syndrome (9.5 versus 0.5%; P<0.05), and early preterm delivery <32 weeks (9.0 versus 1.4%; P<0.05). In primi/multiparous women (n=141) after stroke, 29 events occurred (20-year cumulative risk 35.2%; 95% confidence interval, 21.3–49.0), none during subsequent pregnancies, and a history of a hypertensive disorder in pregnancy did not modify this risk (log-rank P=0.62).Conclusions—When compared with the general population, women with young stroke show higher rates of pregnancy loss throughout their lives. Also, after stroke, nulliparous women more frequently experienced serious pregnancy complications.

Desirable Low-Density Lipoprotein Cholesterol Levels for Preventing Stroke Recurrence [Original Contributions]


Background and Purpose—To define desirable target low-density lipoprotein (LDL) cholesterol levels for the prevention of stroke recurrence, a post hoc analysis was performed in the J-STARS study (Japan Statin Treatment Against Recurrent Stroke).Methods—Subjects (n=1578) were divided into groups based on mean value of postrandomized LDL cholesterol levels until the last observation in 20 mg/dL increments. Adjusted hazard ratios (HRs) and 95% confidence intervals were analyzed for each group, with adjustments for baseline LDL cholesterol, baseline body mass index, hypertension, diabetes mellitus, and statin usage.Results—The postrandomized LDL cholesterol level until the last observation were 104.1±19.3 mg/dL in the pravastatin group and 126.1±20.6 mg/dL in the control group. The adjusted HRs for stroke and transient ischemic attack and all vascular events decreased in the postrandomized LDL cholesterol level of 80 to 100 mg/dL (P=0.23 and 0.25 for the trend, respectively). The adjusted HR for atherothrombotic infarction significantly reduced with the usage of statin after adjusting baseline LDL cholesterol levels (HR, 0.39; 95% confidence intervals, 0.19–0.83). The adjusted HR for atherothrombotic infarction and intracranial hemorrhage were similar among the postrandomized LDL-cholesterol–level subgroups (P=0.50 and 0.37 for the trend, respectively). The adjusted HR for lacunar infarction decreased in the postrandomized LDL cholesterol level of 100 to 120 mg/dL (HR, 0.45; 95% confidence intervals, 0.20–0.99; P=0.41 for the trend).Conclusions—The composite risk of stroke and transient ischemic attack reduced in the postrandomized LDL cholesterol level of 80 to 100 mg/dL after adjusting for statin usage.Clinical Trial Registration—URL: Unique identifier: NCT00221104.

Endothelial Progenitor Cell Secretome and Oligovascular Repair in a Mouse Model of Prolonged Cerebral Hypoperfusion [Original Contributions]


Background and Purpose—Endothelial progenitor cells (EPCs) have been extensively investigated as a therapeutic approach for repairing the vascular system in cerebrovascular diseases. Beyond vascular regeneration per se, EPCs may also release factors that affect the entire neurovascular unit. Here, we aim to study the effects of the EPC secretome on oligovascular remodeling in a mouse model of white matter injury after prolonged cerebral hypoperfusion.Methods—The secretome of mouse EPCs was analyzed with a proteome array. In vitro, the effects of the EPC secretome and its factor angiogenin were assessed on primary oligodendrocyte precursor cells and mature human cerebral microvascular endothelial cells (hCMED/D3). In vivo, mice were subjected to permanent bilateral common carotid artery stenosis, then treated with EPC secretome at 24 hours and at 1 week, and cognitive outcome was evaluated with the Y maze test together with oligodendrocyte precursor cell proliferation/differentiation and vascular density in white matter at 4 weeks.Results—Multiple growth factors, cytokines, and proteases were identified in the EPC secretome, including angiogenin. In vitro, the EPC secretome significantly enhanced endothelial and oligodendrocyte precursor cell proliferation and potentiated oligodendrocyte precursor cell maturation. Angiogenin was proved to be a key factor since pharmacological blockade of angiogenin signaling negated the positive effects of the EPC secretome. In vivo, treatment with the EPC secretome increased vascular density, myelin, and mature oligodendrocytes in white matter and rescued cognitive function in the mouse hypoperfusion model.Conclusions—Factors secreted by EPCs may ameliorate white matter damage in the brain by boosting oligovascular remodeling.

Projected Temperature-Related Years of Life Lost From Stroke Due To Global Warming in a Temperate Climate City, Asia [Original Contributions]


Background and Purpose—Global warming has attracted worldwide attention. Numerous studies have indicated that stroke is associated with temperature; however, few studies are available on the projections of the burden of stroke attributable to future climate change. We aimed to investigate the future trends of stroke years of life lost (YLL) associated with global warming.Methods—We collected death records to examine YLL in Tianjin, China, from 2006 to 2011. We fitted a standard time-series Poisson regression model after controlling for trends, day of the week, relative humidity, and air pollution. We estimated temperature–YLL associations with a distributed lag nonlinear model. These models were then applied to the local climate projections to estimate temperature-related YLL in the 2050s and 2070s. We projected temperature-related YLL from stroke in Tianjin under 19 global-scale climate models and 3 different greenhouse gas emission scenarios.Results—The results showed a slight decrease in YLL with percent decreases of 0.85%, 0.97%, and 1.02% in the 2050s and 0.94%, 1.02%, and 0.91% in the 2070s for the 3 scenarios, respectively. The increases in heat-related annual YLL and the decreases in cold-related YLL under the high emission scenario were the strongest. The monthly analysis showed that the most significant increase occurred in the summer months, particularly in August, with percent changes >150% in the 2050s and up to 300% in the 2070s.Conclusions—Future changes in climate are likely to lead to an increase in heat-related YLL, and this increase will not be offset by adaptation under both medium emission and high emission scenarios. Health protections from hot weather will become increasingly necessary, and measures to reduce cold effects will also remain important.

Thalamic Diaschisis in Acute Ischemic Stroke [Original Contributions]


Background and Purpose—Ipsilateral thalamic diaschisis (ITD) describes the reduction of thalamic function, metabolism, and perfusion resulting from a distant lesion of the ipsilateral hemisphere. Our aim was to evaluate the perfusion characteristics and clinical impact of ITD in acute middle cerebral artery stroke, which does not directly affect the thalamus.Methods—One hundred twenty-four patients with middle cerebral artery infarction were selected from a prospectively acquired cohort of 1644 patients who underwent multiparametric computed tomography (CT), including CT perfusion for suspected stroke. Two blinded readers evaluated the occurrence of ITD, defined as ipsilateral thalamic hypoperfusion present on ≥2 CT perfusion maps. Perfusion alterations were defined according to the Alberta Stroke Program Early CT Score regions. Final infarction volume and subacute complications were assessed on follow-up imaging. Clinical outcome was quantified using the modified Rankin Scale. Multivariable linear and ordinal logistic regression analysis were applied to identify independent associations.Results—ITD was present in 25/124 subjects (20.2%, ITD+). In ITD+ subjects, perfusion of the caudate nucleus, internal capsule, and lentiform nucleus was more frequently affected than in ITD− patients (each with P<0.001). In the ITD+ group, larger cerebral blood flow (P=0.002) and cerebral blood volume (P<0.001) deficit volumes, as well as smaller cerebral blood flow–cerebral blood volume mismatch (P=0.021) were observed. There was no independent association of ITD with final infarction volume or clinical outcome at discharge in treatment subgroups (each with P>0.05). ITD had no influence on the development of subacute stroke complications.Conclusions—ITD in the form of thalamic hypoperfusion is a frequent CT perfusion finding in the acute phase in middle cerebral artery stroke patients with marked involvement of subcortical areas. ITD does not result in thalamic infarction and had no independent impact on patient outcome. Notably, ITD was misclassified as part of the ischemic core by automated software, which might affect patient selection in CT perfusion–based trials.

Transcranial Direct Current Stimulation Does Not Improve Language Outcome in Subacute Poststroke Aphasia [Brief Reports]


Background and Purpose—The aim of the present study is to investigate the effect of transcranial direct current stimulation on word-finding treatment outcome in subacute poststroke aphasia.Methods—In this multi-center, double-blind, randomized controlled trial with 6-month follow-up, we included 58 patients with subacute aphasia (<3 months poststroke), who were enrolled in a stroke rehabilitation program. Patients participated in 2 separate intervention weeks. Each intervention week included 5 daily sessions of 45-minute word-finding therapy combined with either anodal transcranial direct current stimulation (1 mA, 20 minutes; experimental group) or sham transcranial direct current stimulation (control group) over the left inferior frontal gyrus. The primary outcome measure was the Boston Naming Test. Secondary outcome measures included naming performance for trained/untrained picture items and verbal communication.Results—Both the experimental (n=26) and the control group (n=32) improved on the Boston Naming Test over the intervention period and 6-month follow-up; however, there were no significant differences between groups. Also for the secondary outcome measures, no significant differences were found.Conclusions—The results of the present study do not support an effect of transcranial direct current stimulation as an adjuvant treatment in subacute poststroke aphasia.Clinical Trial Registration—URL: Unique identifier: NTR4364.

Age-Specific Associations of Renal Impairment With Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease in Transient Ischemic Attack and Stroke [Original Contributions]


Background and Purpose—It has been hypothesized that cerebral small vessel disease (SVD) and chronic renal impairment may be part of a multisystem small-vessel disorder, but their association may simply be as a result of shared risk factors (eg, hypertension) rather than to a systemic susceptibility to premature SVD. However, most previous studies were hospital based, most had inadequate adjustment for hypertension, many were confined to patients with lacunar stroke, and none stratified by age.Methods—In a population-based study of TIA and ischemic stroke (OXVASC [Oxford Vascular Study]), we evaluated the magnetic resonance imaging markers of cerebral SVD, including lacunes, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular space. We studied the age-specific associations of renal impairment (estimated glomerular filtration rate <60 mL/min per 1.73 m2) and total SVD burden (total SVD score) adjusting for age, sex, vascular risk factors, and premorbid blood pressure (mean blood pressure during 15 years preevent).Results—Of 1080 consecutive patients, 1028 (95.2%) had complete magnetic resonance imaging protocol and creatinine measured at baseline. Renal impairment was associated with total SVD score (odds ratio [OR], 2.16; 95% confidence interval [CI], 1.69–2.75; P<0.001), but only at age <60 years (<60 years: OR, 3.97; 95% CI, 1.69–9.32; P=0.002; 60–79 years: OR, 1.01; 95% CI, 0.72–1.41; P=0.963; ≥80 years: OR, 0.95; 95% CI, 0.59–1.54; P=0.832). The overall association of renal impairment and total SVD score was also attenuated after adjustment for age, sex, history of hypertension, diabetes mellitus, and premorbid average systolic blood pressure (adjusted OR, 0.76; 95% CI, 0.56–1.02; P=0.067), but the independent association of renal impairment and total SVD score at age <60 years was maintained (adjusted OR, 3.11; 95% CI, 1.21–7.98; P=0.018). Associations of renal impairment and SVD were consistent for each SVD marker at age <60 years but were strongest for cerebral microbleeds (OR, 5.84; 95% CI, 1.45–23.53; P=0.013) and moderate–severe periventricular white matter hyperintensities (OR, 6.28; 95% CI, 1.54–25.63; P=0.010).Conclusions—The association of renal impairment and cerebral SVD was attenuated with adjustment for shared risk factors at older ages, but remained at younger ages, consistent with a shared susceptibility to premature disease.

Shared and Distinct Rupture Discriminants of Small and Large Intracranial Aneurysms [Original Contributions]


Background and Purpose—Many ruptured intracranial aneurysms (IAs) are small. Clinical presentations suggest that small and large IAs could have different phenotypes. It is unknown if small and large IAs have different characteristics that discriminate rupture.Methods—We analyzed morphological, hemodynamic, and clinical parameters of 413 retrospectively collected IAs (training cohort; 102 ruptured IAs). Hierarchal cluster analysis was performed to determine a size cutoff to dichotomize the IA population into small and large IAs. We applied multivariate logistic regression to build rupture discrimination models for small IAs, large IAs, and an aggregation of all IAs. We validated the ability of these 3 models to predict rupture status in a second, independently collected cohort of 129 IAs (testing cohort; 14 ruptured IAs).Results—Hierarchal cluster analysis in the training cohort confirmed that small and large IAs are best separated at 5 mm based on morphological and hemodynamic features (area under the curve=0.81). For small IAs (<5 mm), the resulting rupture discrimination model included undulation index, oscillatory shear index, previous subarachnoid hemorrhage, and absence of multiple IAs (area under the curve=0.84; 95% confidence interval, 0.78–0.88), whereas for large IAs (≥5 mm), the model included undulation index, low wall shear stress, previous subarachnoid hemorrhage, and IA location (area under the curve=0.87; 95% confidence interval, 0.82–0.93). The model for the aggregated training cohort retained all the parameters in the size-dichotomized models. Results in the testing cohort showed that the size-dichotomized rupture discrimination model had higher sensitivity (64% versus 29%) and accuracy (77% versus 74%), marginally higher area under the curve (0.75; 95% confidence interval, 0.61–0.88 versus 0.67; 95% confidence interval, 0.52–0.82), and similar specificity (78% versus 80%) compared with the aggregate-based model.Conclusions—Small (<5 mm) and large (≥5 mm) IAs have different hemodynamic and clinical, but not morphological, rupture discriminants. Size-dichotomized rupture discrimination models performed better than the aggregate model.

Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study) [Original Contributions]


Background and Purpose—Emerging evidence suggests that an underlying atrial cardiopathy may result in thromboembolism before atrial fibrillation (AF) develops. We examined the association between various markers of atrial cardiopathy and the risk of ischemic stroke.Methods—The CHS (Cardiovascular Health Study) prospectively enrolled community-dwelling adults ≥65 years of age. For this study, we excluded participants diagnosed with stroke or AF before baseline. Exposures were several markers of atrial cardiopathy: baseline P-wave terminal force in ECG lead V1, left atrial dimension on echocardiogram, and N terminal pro B type natriuretic peptide (NT-proBNP), as well as incident AF. Incident AF was ascertained from 12-lead electrocardiograms at annual study visits for the first decade after study enrollment and from inpatient and outpatient Medicare data throughout follow-up. The primary outcome was incident ischemic stroke. We used Cox proportional hazards models that included all 4 atrial cardiopathy markers along with adjustment for demographic characteristics and established vascular risk factors.Results—Among 3723 participants who were free of stroke and AF at baseline and who had data on all atrial cardiopathy markers, 585 participants (15.7%) experienced an incident ischemic stroke during a median 12.9 years of follow-up. When all atrial cardiopathy markers were combined in 1 Cox model, we found significant associations with stroke for P-wave terminal force in ECG lead V1 (hazard ratio per 1000 μV*ms 1.04; 95% confidence interval, 1.001–1.08), log-transformed NT-proBNP (hazard ratio per doubling of NT-proBNP, 1.09; 95% confidence interval, 1.03–1.16), and incident AF (hazard ratio, 2.04; 95% confidence interval, 1.67–2.48) but not left atrial dimension (hazard ratio per cm, 0.96; 95% confidence interval, 0.84–1.10).Conclusions—In addition to clinically apparent AF, other evidence of abnormal atrial substrate is associated with subsequent ischemic stroke. This finding is consistent with the hypothesis that thromboembolism from the left atrium may occur in the setting of several different manifestations of atrial disease.

Posttreatment National Institutes of Health Stroke Scale Is Superior to the Initial Score or Thrombolysis in Cerebral Ischemia for 3-Month Outcome [Original Contributions]


Background and Purpose—The majority of ischemic stroke patients receiving endovascular recanalization therapy (EVT) experience variable changes of neurological severities during the hyperacute period. We hypothesized that the National Institutes of Health Stroke Scale (NIHSS) score after EVT is a better prognostic factor compared with the initial NIHSS score or revascularization status.Methods—We identified 566 stroke patients who received EVT at Seoul National University Bundang Hospital between April 2008 and December 2015. We prospectively collected post-EVT NIHSS score, which was measured in the angiography suite by on-duty physicians after completion of EVT. Model 1 included baseline predictors including an initial NIHSS score. In model 2, 3, and 4, revascularization status, post-EVT NIHSS score, or both were additionally included. The discrimination powers for modified Rankin Scale score of 0 to 2 at 3 months were assessed using C statistic, integrated discrimination index, and category-free net reclassification index.Results—The median of initial and post-EVT NIHSS score were 14 (9–19) and 11 (5–17) points, respectively (an improvement, 58.8%; no change, 20.7%; deterioration, 20.5%). A modified Rankin Scale score 0 to 2 at 3 months was achieved in 47%. Based on the results of differences among the C statistics, both model 3 and model 4 (C statistics: 0.896 and 0.906) showed significantly increased discrimination power for modified Rankin Scale score 0 to 2 at 3 months than the model 1 or 2 (C statistics: 0.802 and 0.834, P values<0.001 for all comparisons). Model 4 showed significant improvement of both integrated discrimination index and net reclassification index as compared with all other models, but the magnitude of improvement from model 3 to model 4 (integrated discrimination index, 0.021; net reclassification index, 0.322) was modest.Conclusions—Incorporation of post-EVT NIHSS score conferred better discrimination power to the statistical models for functional recovery. Post-EVT NIHSS score may be an appropriate baseline factor when evaluating an intervention after hyperacute period.

Utility-Weighted Modified Rankin Scale as Primary Outcome in Stroke Trials [Original Contributions]


Background and Purpose—The utility-weighted modified Rankin Scale (UW-mRS) has been proposed as a new patient-centered primary outcome in stroke trials. We aimed to describe utility weights for the mRS health states and to evaluate the statistical efficiency of the UW-mRS to detect treatment effects in stroke intervention trials.Methods—We used data of the 500 patients enrolled in the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). Utility values were elicited from the EuroQol Group 5-Dimension Self-Report Questionnaire assessed at 90 days after inclusion, simultaneously with the mRS. Utility weights were determined by averaging the utilities of all patients within each mRS category. We performed simulations to evaluate statistical efficiency. The simulated treatment effect was an odds ratio of 1.65 in favor of the treatment arm, similar for all mRS cutoffs. This treatment effect was analyzed using 3 approaches: linear regression with the UW-mRS as outcome, binary logistic regression with a dichotomized mRS (0–1/2–6, 0–2/3–6, and 0–4/5–6), and proportional odds logistic regression with the ordinal mRS. The statistical power of the 3 approaches was expressed as the proportion of 10 000 simulations that resulted in a statistically significant treatment effect (P≤0.05).Results—The mean utility values (SD) for mRS categories 0 to 6 were: 0.95 (0.08), 0.93 (0.13), 0.83 (0.21), 0.62 (0.27), 0.42 (0.28), 0.11 (0.28), and 0 (0), respectively, but varied substantially between individual patients within each category. The UW-mRS approach was more efficient than the dichotomous approach (power 85% versus 71%) but less efficient than the ordinal approach (power 85% versus 87%).Conclusions—The UW-mRS as primary outcome does not capture individual variation in utility values and may reduce the statistical power of a randomized trial.

Distribution and Temporal Trends From 1993 to 2015 of Ischemic Stroke Subtypes [Original Contributions]


Background and Purpose—Preventive strategies, together with demographic and socioeconomic changes, might have modified the worldwide distribution of ischemic stroke (IS) subtypes. We investigated those changes by means of a systematic review and meta-analysis.Methods—We evaluated all population- and hospital-based studies reporting the distribution of IS etiologic subtypes according to the TOAST criteria (Trial of ORG 10172 in Acute Stroke Treatment). Studies were identified by searching articles indexed on PubMed and Scopus from January 1, 1993, to June 30, 2017. Two independent investigators extracted data and checked them for accuracy. Proportions of each etiologic subtype were pooled according to a random effect meta-analytic model weighted by study size; temporal trends were assessed using a mixed-effect meta-regression model.Results—Sixty-five studies including patients from 1993 to 2015 were finally included. Overall, ISs were attributed to cardioembolism (22%; 95% confidence interval [CI], 20–23); large artery atherosclerosis (23%; 95% CI, 21–25); small artery occlusion (22%; 95% CI, 21–24); other determined cause (3%; 95% CI, 3–3); and undetermined cause (26%; 95% CI, 24–28). Cardioembolism was the leading IS etiologic subtype in whites (28%; 95% CI, 26–29) and large artery atherosclerosis in Asians (33%; 95% CI, 31–36). Meta-regression showed an increasing temporal trend for cardioembolism in whites (2.4% annually, P=0.008) and large artery atherosclerosis in Asians (5.7% annually, P<0.001), and a decrease for small artery occlusion in whites (−4.7% annually, P=0.001); there was considerable heterogeneity across all the analyses.Conclusions—According to our systematic review and meta-analysis, cardioembolism in whites and large artery atherosclerosis in Asians are the leading causes of IS. The heterogeneous distribution of etiologic subtypes of IS may depend on the demographic and socioeconomic characteristics of the different populations. More extensive protocols should be adopted to reduce the persistently relevant proportion of undetermined cause IS.

Quantitative Arterial Tortuosity Suggests Arteriopathy in Children With Cryptogenic Stroke [Brief Reports]


Background and Purpose—Quantitative arterial tortuosity (QAT) is a ratio of vessel length between 2 points to the shortest linear distance between same points. QAT has been reported as an imaging biomarker of arteriopathy in pediatric arterial ischemic stroke (AIS) because of dissection and transient cerebral arteriopathy. We sought to determine whether QAT abnormalities are present in other subtypes of pediatric AIS.Methods—Children with AIS-absent conventional biomarkers of arteriopathy and case–controls who underwent magnetic resonance angiography were classified by stroke mechanism. The primary study population consisted of cryptogenic AIS cases. AIS with bow hunter physiology and cardiogenic emboli were also evaluated. AIS because of nontraumatic dissection served as positive controls. Patients without vascular risk factors served as negative controls. Segmental QAT of cervicocerebral arteries were measured using automated image processing and differences between groups analyzed.Results—In negative controls, QAT showed significant age-related variability for most arterial segments. Positive controls showed significantly increased QAT of the distal extracranial vertebral arteries (VAs) and decreased QAT of the intracranial VA relative to negative controls. Cryptogenic stroke and bow hunter physiology cases were similar to positive controls showing increased QAT of the distal extracranial VA and decreased QAT of the intracranial VA relative to negative controls. Cardioembolic stroke cases were similar to negative controls showing decreased QAT of the distal extracranial VA and increased QAT of the intracranial VA relative to positive controls.Conclusions—Pediatric cryptogenic stroke is frequently associated with cervicocerebral arteriopathies expressing altered QAT. QAT may be a diagnostic biomarker of arteriopathy in pediatric AIS.

Hyperintense Plaque on Intracranial Vessel Wall Magnetic Resonance Imaging as a Predictor of Artery-to-Artery Embolic Infarction [Original Contributions]


Background and Purpose—The aim of the present study was to investigate atherosclerotic plaque characteristics in patients with artery-to-artery (A-to-A) embolic infarction by whole-brain high-resolution magnetic resonance imaging.Methods—Seventy-four patients (mean age, 54.7±12.1 years; 59 men) with recent stroke in the territory of middle cerebral artery because of intracranial atherosclerotic disease were prospectively enrolled. Whole-brain high-resolution magnetic resonance imaging was performed in all the patients both precontrast and postcontrast administration by using a 3-dimensional T1-weighted vessel wall magnetic resonance imaging technique known as inversion-recovery prepared sampling perfection with application-optimized contrast using different flip angle evolutions. Patients were divided into A-to-A embolic infarction and non–A-to-A embolic infarction groups based on diffusion-weighted imaging findings. The characteristics of the intracranial atherosclerotic plaques were compared between groups.Results—A total of 74 intracranial atherosclerotic plaques were analyzed (36 in A-to-A embolism group and 38 in non–A-to-A embolism group). Hyperintense plaques (HIPs) were more frequently observed in A-to-A embolism group (75.0% versus 21.1%; P<0.001). Eighteen of the 27 HIPs (66.7%) demonstrated hyperintense spots or areas located adjacent to the lumen versus 9 HIPs (33.3%) located within the plaque in A-to-A embolism group. Furthermore, a higher prevalence of plaque surface irregularity was also observed in A-to-A embolism group (41.7% versus 18.4%; P=0.029). Logistic regression analysis showed that HIP was the most powerful independent predictor of A-to-A embolic infarction (P<0.001), with the odds ratio of 11.2 (95% confidence interval, 3.5–36.2).Conclusions—A-to-A embolic infarction has distinct vulnerable plaque characteristics compared with non–A-to-A embolic infarction. HIP and plaque surface irregularity may predict A-to-A embolic infarction.

Rates and Risk Factors for Arterial Ischemic Stroke Recurrence in Children [Original Contributions]


Background and Purpose—Recurrent ischemic events are common in children with arterial ischemic stroke (AIS) and put patients at risk for further neurological impairment. This study sought to identify rates and risk factors for recurrent AIS or transient ischemic attack in a cohort of children seen after index AIS and uniformly investigated and managed using contemporary clinical guidelines.Methods—Case note and radiology review of children >28 days and <18 years of age who presented to Great Ormond Street Hospital from 2005 to 2015 with index AIS. Demographic characteristics, medical history, index AIS features, radiological findings, and neurological outcome were examined. Recurrence was identified from clinical records and coded as AIS (if there was associated new cerebral infarction) or transient ischemic attack.Results—Eighty-four children (43 girls; median age at index AIS, 4.1 years) were identified. Cumulative AIS recurrence was 5% at 1 month, 10% at 3 months, 12% at 6 months, 12% at 12 months, and 15% at 60 months after index event. Factors that independently predicted AIS recurrence were referral to Great Ormond Street Hospital from outside the catchment area, a prior relevant diagnosis, bilateral arteriopathy, and AIS CASCADE category 3A or 3B (Childhood AIS Standardized Classification and Diagnostic Evaluation). Multiple infarcts and evidence of mature, as well as acute, infarcts on first brain imaging, although independently associated with AIS recurrence, were also associated with bilateral arteriopathy. Only CASCADE categories 3A and 3B (bilateral cerebral arteriopathy with or without collaterals) remained significant in multivariate analysis. AIS recurrence was not associated with poor neurological outcome.Conclusions—AIS recurrence remains a significant problem, despite the wide use of antithrombotic medications. AIS subtypes should direct clinicians and future trials to use stratified management strategies and durations of treatment. Bilateral cerebral arteriopathies are especially sinister, and consensus criteria should be developed to improve consistency of management.

Boosted Tree Model Reforms Multimodal Magnetic Resonance Imaging Infarct Prediction in Acute Stroke [Original Contributions]


Background and Purpose—Stroke imaging is pivotal for diagnosis and stratification of patients with acute ischemic stroke to treatment. The potential of combining multimodal information into reliable estimates of outcome learning calls for robust machine learning techniques with high flexibility and accuracy. We applied the novel extreme gradient boosting algorithm for multimodal magnetic resonance imaging–based infarct prediction.Methods—In a retrospective analysis of 195 patients with acute ischemic stroke, fluid-attenuated inversion recovery, diffusion-weighted imaging, and 10 perfusion parameters were derived from acute magnetic resonance imaging scans. They were integrated to predict final infarct as seen on follow-up T2-fluid-attenuated inversion recovery using the extreme gradient boosting and compared with a standard generalized linear model approach using cross-validation. Submodels for recanalization and persistent occlusion were calculated and were used to identify the important imaging markers. Performance in infarct prediction was analyzed with receiver operating characteristics. Resulting areas under the curve and accuracy rates were compared using Wilcoxon signed-rank test.Results—The extreme gradient boosting model demonstrated significantly higher performance in infarct prediction compared with generalized linear model in both cross-validation approaches: 5-folds (P<10e-16) and leave-one-out (P<0.015). The imaging parameters time-to-peak, mean transit time, time-to-maximum, and diffusion-weighted imaging were indicated as most valuable for infarct prediction by the systematic algorithm rating. Notably, the performance improvement was higher with 5-folds cross-validation approach than leave-one-out.Conclusions—We demonstrate extreme gradient boosting as a state-of-the-art method for clinically applicable multimodal magnetic resonance imaging infarct prediction in acute ischemic stroke. Our findings emphasize the role of perfusion parameters as important biomarkers for infarct prediction. The effect of cross-validation techniques on performance indicates that the intrapatient variability is expressed in nonlinear dynamics of the imaging modalities.

Residential Proximity to Major Roadways and Risk of Incident Ischemic Stroke in NOMAS (The Northern Manhattan Study) [Original Contributions]


Background and Purpose—The evidence supporting the deleterious cardiovascular health effects of living near a major roadway is growing, although this association is not universal. In primary analyses, we hypothesized that residential proximity to a major roadway would be associated with incident ischemic stroke and that cardiovascular risk factors would modify that association.Methods—NOMAS (The Northern Manhattan Study) is an ongoing, population-based cohort study designed to measure cardiovascular risk factors, stroke incidence, and other outcomes in a multiethnic urban population. Recruitment occurred from 1993 to 2001 and participants are followed-up annually by telephone. Residential addresses at baseline were geocoded and Euclidean distance to nearest major roadway was estimated and categorized as in prior studies. We used Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals for the association of this distance to incidence of stroke and other outcomes, adjusting for sociodemographic and cardiovascular risk factors, year at baseline, and neighborhood socioeconomic status. We assessed whether these associations varied by age, sex, smoking status, diabetes mellitus, and hypertension.Results—During a median follow-up period of 15 years (n=3287), 11% of participants were diagnosed with ischemic stroke. Participants living <100 m from a roadway had a 42% (95% confidence interval, 1.01–2.02) higher rate of ischemic stroke versus those living >400 m away. This association was more pronounced among noncurrent smokers (hazard ratio, 1.54; 95% confidence interval, 1.05–2.26) and not evident among smokers (hazard ratio, 0.69; 95% confidence interval, 0.23–2.06). There was no clear pattern of association between proximity to major roadways and other cardiovascular events including myocardial infarction, all-cause death, or vascular death.Conclusions—In this urban multiethnic cohort, we found evidence supporting that within-city variation in residential proximity to major roadway is associated with higher risk of ischemic stroke. An individual’s smoking history modified this association, with the association remaining only among participants not currently smokers.

Ambulance Clinical Triage for Acute Stroke Treatment [Original Contributions]


Background and Purpose—Clinical triage scales for prehospital recognition of large vessel occlusion (LVO) are limited by low specificity when applied by paramedics. We created the 3-step ambulance clinical triage for acute stroke treatment (ACT-FAST) as the first algorithmic LVO identification tool, designed to improve specificity by recognizing only severe clinical syndromes and optimizing paramedic usability and reliability.Methods—The ACT-FAST algorithm consists of (1) unilateral arm drift to stretcher <10 seconds, (2) severe language deficit (if right arm is weak) or gaze deviation/hemineglect assessed by simple shoulder tap test (if left arm is weak), and (3) eligibility and stroke mimic screen. ACT-FAST examination steps were retrospectively validated, and then prospectively validated by paramedics transporting culturally and linguistically diverse patients with suspected stroke in the emergency department, for the identification of internal carotid or proximal middle cerebral artery occlusion. The diagnostic performance of the full ACT-FAST algorithm was then validated for patients accepted for thrombectomy.Results—In retrospective (n=565) and prospective paramedic (n=104) validation, ACT-FAST displayed higher overall accuracy and specificity, when compared with existing LVO triage scales. Agreement of ACT-FAST between paramedics and doctors was excellent (κ=0.91; 95% confidence interval, 0.79–1.0). The full ACT-FAST algorithm (n=60) assessed by paramedics showed high overall accuracy (91.7%), sensitivity (85.7%), specificity (93.5%), and positive predictive value (80%) for recognition of endovascular-eligible LVO.Conclusions—The 3-step ACT-FAST algorithm shows higher specificity and reliability than existing scales for clinical LVO recognition, despite requiring just 2 examination steps. The inclusion of an eligibility step allowed recognition of endovascular-eligible patients with high accuracy. Using a sequential algorithmic approach eliminates scoring confusion and reduces assessment time. Future studies will test whether field application of ACT-FAST by paramedics to bypass suspected patients with LVO directly to endovascular-capable centers can reduce delays to endovascular thrombectomy.

Association of White Matter Hyperintensities With Short-Term Outcomes in Patients With Minor Cerebrovascular Events [Original Contributions]


Background and Purpose—White matter lesions (WML) are associated with cognitive decline, increased stroke risk, and disability in old age. We hypothesized that superimposed acute cerebrovascular occlusion on chronic preexisting injury (leukoaraiosis) leads to worse outcome after minor cerebrovascular event, both using quantitative (volumetric) and qualitative (Fazekas scale) assessment, as well as relative total brain volume.Methods—WML volume assessment was performed in 425 patients with high-risk transient ischemic attack (TIA; motor/speech deficits >5 minutes) or minor strokes from the CATCH study (CT and MRI in the Triage of TIA and Minor Cerebrovascular Events to Identify High Risk Patients). Complete baseline characteristics and outcome assessment were available in 412 patients. Primary outcome was disability at 90 days, defined as modified Rankin Scale score of >1. Secondary outcomes were stroke progression, TIA recurrence, and stroke recurrence. Analysis was performed using descriptive statistics and regression models including interaction terms.Results—Median age was 69 years, 39.8% were female. Sixty-two patients (15%) had unfavorable outcome with disability at 90 days (modified Rankin Scale score >1). Higher Fazekas scores were strongly correlated with higher WML volume (r=0.79). Both higher Fazekas score and higher WMH volume were associated with disability at 90 days in univariate regression (odds ratio 1.22; 95% confidence interval, 1.04–1.43 and odds ratio, 1.25 per milliliter increase; 95% confidence interval, 1.02–1.54, respectively) but not with stroke progression, TIA recurrence, or stroke recurrence. In multivariable-adjusted analyses, additive interaction terms were associated with unfavorable outcome (adjusted odds ratio 3.99, 95% confidence interval, 1.87–8.49).Conclusions—Our data suggest that quantitative and qualitative WML assessments are highly correlated and comparable in TIA/minor stroke patients. WML burden is associated with short-term outcome of patients with good prestroke function in the presence of intracranial stenosis/occlusion.

Plasma A{beta} (Amyloid-{beta}) Levels and Severity and Progression of Small Vessel Disease [Original Contributions]


Background and Purpose—Cerebral small vessel disease (SVD) is a frequent pathology in aging and contributor to the development of dementia. Plasma Aβ (amyloid β) levels may be useful as early biomarker, but the role of plasma Aβ in SVD remains to be elucidated. We investigated the association of plasma Aβ levels with severity and progression of SVD markers.Methods—We studied 487 participants from the RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort) of whom 258 participants underwent 3 MRI assessments during 9 years. We determined baseline plasma Aβ38, Aβ40, and Aβ42 levels using ELISAs. We longitudinally assessed volume of white matter hyperintensities semiautomatically and manually rated lacunes and microbleeds. We analyzed associations between plasma Aβ and SVD markers by ANCOVA adjusted for age, sex, and hypertension.Results—Cross-sectionally, plasma Aβ40 levels were elevated in participants with microbleeds (mean, 205.4 versus 186.4 pg/mL; P<0.01) and lacunes (mean, 194.8 versus 181.2 pg/mL; P<0.05). Both Aβ38 and Aβ40 were elevated in participants with severe white matter hyperintensities (Aβ38, 25.3 versus 22.7 pg/mL; P<0.01; Aβ40, 201.8 versus 183.3 pg/mL; P<0.05). Longitudinally, plasma Aβ40 levels were elevated in participants with white matter hyperintensity progression (mean, 194.6 versus 182.9 pg/mL; P<0.05). Both Aβ38 and Aβ40 were elevated in participants with incident lacunes (Aβ38, 24.5 versus 22.5 pg/mL; P<0.05; Aβ40, 194.9 versus 181.2 pg/mL; P<0.01) and Aβ42 in participants with incident microbleeds (62.8 versus 60.4 pg/mL; P<0.05).Conclusions—Plasma Aβ levels are associated with both presence and progression of SVD markers, suggesting that Aβ pathology might contribute to the development and progression of SVD. Plasma Aβ levels might thereby serve as inexpensive and noninvasive measure for identifying individuals with increased risk for progression of SVD.

Rescue Stenting for Failed Mechanical Thrombectomy in Acute Ischemic Stroke [Original Contributions]


Background and Purpose—Effective rescue treatment has not yet been suggested in patients with mechanical thrombectomy (MT) failure. This study aimed to test whether rescue stenting (RS) improved clinical outcomes in MT-failed patients.Methods—This is a retrospective analysis of the cohorts of the 16 comprehensive stroke centers between September 2010 and December 2015. We identified the patients who underwent MT but failed to recanalize intracranial internal carotid artery or middle cerebral artery M1 occlusion. Patients were dichotomized into 2 groups: patients with RS and without RS after MT failure. Clinical and laboratory findings and outcomes were compared between the 2 groups. It was tested whether RS is associated with functional outcome.Results—MT failed in 148 (25.0%) of the 591 patients with internal carotid artery or middle cerebral artery M1 occlusion. Of these 148 patients, 48 received RS (RS group) and 100 were left without further treatment (no stenting group). Recanalization was successful in 64.6% (31 of 48 patients) of RS group. Compared with no stenting group, RS group showed a significantly higher rate of good outcome (modified Rankin Scale score, 0–2; 39.6% versus 22.0%; P=0.031) without increasing symptomatic intracranial hemorrhage (16.7% versus 20.0%; P=0.823) or mortality (12.5% versus 19.0%; P=0.360). Of the RS group, patients who had recanalization success had 54.8% of good outcome, which is comparable to that (55.4%) of recanalization success group with MT. RS remained independently associated with good outcome after adjustment of other factors (odds ratio, 3.393; 95% confidence interval, 1.192–9.655; P=0.022). Follow-up vascular imaging was available in the 23 (74.2%) of 31 patients with recanalization success with RS. The stent was patent in 20 (87.0%) of the 23 patients. Glycoprotein IIb/IIIa inhibitor was significantly associated with stent patency but not with symptomatic intracranial hemorrhage.Conclusions—RS was independently associated with good outcomes without increasing symptomatic intracranial hemorrhage or mortality. RS seemed considered in MT-failed internal carotid artery or middle cerebral artery M1 occlusion.

Arterial Wall Imaging in Pediatric Stroke [Original Contributions]


Background and Purpose—Arteriopathy is common in childhood arterial ischemic stroke (AIS) and predicts stroke recurrence. Currently available vascular imaging techniques mainly image the arterial lumen rather than the vessel wall and have a limited ability to differentiate among common arteriopathies. We aimed to investigate the value of a magnetic resonance imaging-based technique, namely noninvasive arterial wall imaging (AWI), for distinguishing among arteriopathy subtypes in a consecutive cohort of children presenting with AIS.Methods—Children with confirmed AIS and magnetic resonance angiography underwent 3-Tesla AWI including T1-weighted 2-dimensional fluid-attenuated inversion recovery fast spin echo sequences pre- and post-gadolinium contrast. AWI characteristics, including wall enhancement, wall thickening, and luminal stenosis, were documented for all.Results—Twenty-six children with AIS had AWI. Of these, 9 (35%) had AWI enhancement. AWI enhancement was associated with anterior circulation magnetic resonance angiography abnormality and cortical infarction in 8 of 9 (89%) children and normal magnetic resonance angiography with posterior circulation subcortical infarction in 1 (1 of 9; 11%) child. AWI enhancement was not seen in 17 (65%), 10 (59%) of whom had an abnormal magnetic resonance angiography. Distinct patterns of pre- and postcontrast signal abnormality were demonstrated in the vessel wall in the region of interest in children with transient cerebral arteriopathy, arterial dissection, primary central nervous system angiitis, dissecting aneurysm, and cardioembolic stroke.Conclusions—AWI is a noninvasive, high-resolution magnetic resonance AWI technique, which can be successfully used in children presenting with AIS. Patterns of AWI enhancement are recognizable and associated with specific AIS pathogeneses. Further studies are required to assess the additional diagnostic utility of AWI over routine vascular imaging techniques, in childhood AIS.

Eligibility for Endovascular Trial Enrollment in the 6- to 24-Hour Time Window [Brief Reports]


Background and Purpose—The results of the DAWN trial (Diffusion-Weighted Imaging or Computerized Tomography Perfusion Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) support the benefit of endovascular therapy in patients presenting beyond the 6-hour time window with anterior circulation large vessel occlusions. The impact of these results with respect to additional number of eligible patients in clinical practice remains unknown.Methods—A retrospective review of ischemic stroke admissions to a single DAWN trial-participating comprehensive stroke center was performed during the DAWN enrollment period (November 2014 to February 2017) to identify patients meeting criteria for DAWN and DEFUSE-3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke-3) eligibility. Patients presenting beyond 6 hours were further investigated to clarify reasons for trial exclusion.Results—Of the 2667 patients with acute ischemic stroke admitted within the study period, 30% (n=792) presented within the 6- to 24-hour time window, and 47% (n=1242) had a National Institutes of Health Stroke Scale ≥6. Further clinical trial-specific selection criteria were applied based on the presence of large vessel occlusion, baseline modified Rankin Scale score, core infarct, and perfusion imaging (when available). There were 45 patients who met all DAWN trial criteria and 47 to 58 patients who would meet DEFUSE-3 trial criteria. Thirty-three percent of DAWN-eligible patients are DEFUSE-3 ineligible.Conclusions—Of all patients with acute ischemic stroke presenting to a single comprehensive stroke center, 1.7% of patients qualified for DAWN clinical trial enrollment with an additional 0.6% to 1% qualifying for the DEFUSE-3 trial. These data predict an increase in thrombectomy utilization with important implications for comprehensive stroke center resource optimization and stroke systems of care.

Time From Imaging to Endovascular Reperfusion Predicts Outcome in Acute Stroke [Original Contributions]


Background and Purpose—This study aims to describe the relationship between computed tomographic (CT) perfusion (CTP)-to-reperfusion time and clinical and radiological outcomes, in a cohort of patients who achieve successful reperfusion for acute ischemic stroke.Methods—We included data from the CRISP (Computed Tomographic Perfusion to Predict Response in Ischemic Stroke Project) in which all patients underwent a baseline CTP scan before endovascular therapy. Patients were included if they had a mismatch on their baseline CTP scan and achieved successful endovascular reperfusion. Patients with mismatch were categorized into target mismatch and malignant mismatch profiles, according to the volume of their Tmax >10s lesion volume (target mismatch, <100 mL; malignant mismatch, >100 mL). We investigated the impact of CTP-to-reperfusion times on probability of achieving functional independence (modified Rankin Scale, 0–2) at day 90 and radiographic outcomes at day 5.Results—Of 156 included patients, 108 (59%) had the target mismatch profile, and 48 (26%) had the malignant mismatch profile. In patients with the target mismatch profile, CTP-to-reperfusion time showed no association with functional independence (P=0.84), whereas in patients with malignant mismatch profile, CTP-to-reperfusion time was strongly associated with lower probability of functional independence (odds ratio, 0.08; P=0.003). Compared with patients with target mismatch, those with the malignant mismatch profile had significantly more infarct growth (90 [49–166] versus 43 [18–81] mL; P=0.006) and larger final infarct volumes (110 [61–155] versus 48 [21–99] mL; P=0.001).Conclusions—Compared with target mismatch patients, those with the malignant profile experience faster infarct growth and a steeper decline in the odds of functional independence, with longer delays between baseline imaging and reperfusion. However, this does not exclude the possibility of treatment benefit in patients with a malignant profile.

Ischemic Stroke Alters the Expression of the Transcribed Ultraconserved Regions of the Genome in Rat Brain [Brief Reports]


Background and Purpose—Human and rodent genomes diverged ≈75 million years ago. However, 481 regions of their genomes (200–779 nucleotide each) remained absolutely conserved and form noncoding RNAs known as transcribed ultraconserved regions (T-UCRs). The functional significance of T-UCRs is not apparent, but their altered expression is associated with many diseases, and thus thought to be critical for life. We presently investigated the poststroke temporal changes in the expression of T-UCRs with potential functional significance.Methods—Male, spontaneously hypertensive rats were subjected to transient middle cerebral artery occlusion. Expression profile of T-UCRs was determined at 3, 6, and 12 hours of reperfusion using microarrays and real-time polymerase chain reaction in the peri-infarct cortex. The putative functional significance of stroke-responsive T-UCRs was identified by bioinformatics.Results—Ischemia altered expression of 69 T-UCRs at ≥1 time points of reperfusion compared with sham. Poststroke expression of the intragenic T-UCRs is independent of the expression of their parent gene mRNAs. Bioinformatics showed that the upstream/downstream and the parent genes of the T-UCRs modulate several biological and molecular functions, including metabolism, response to stimuli, cell communication, protein and nucleic acid binding.Conclusions—This first report shows that ischemic stroke temporally alters the noncoding ultraconserved RNAs in spontaneously hypertensive rats, but their functional significance is yet to be evaluated.

Risk Factors for Poststroke Cognitive Decline [Original Contributions]


Background and Purpose—Poststroke cognitive decline causes disability. Risk factors for poststroke cognitive decline independent of survivors’ prestroke cognitive trajectories are uncertain.Methods—Among 22 875 participants aged ≥45 years without baseline cognitive impairment from the REGARDS cohort (Reasons for Geographic and Racial Differences in Stroke), enrolled from 2003 to 2007 and followed through September 2015, we measured the effect of incident stroke (n=694) on changes in cognitive functions and cognitive impairment (Six-Item Screener score <5) and tested whether patient factors modified the effect. Median follow-up was 8.2 years.Results—Incident stroke was associated with acute declines in global cognition, new learning, verbal memory, and executive function. Acute declines in global cognition after stroke were greater in survivors who were black (P=0.04), men (P=0.04), and had cardioembolic (P=0.001) or large artery stroke (P=0.001). Acute declines in executive function after stroke were greater in survivors who had

Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes [Original Contributions]


Background and Purpose—Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR).Methods—Summary data on 185 genome-wide lipids-associated single nucleotide polymorphisms were obtained from the Global Lipids Genetics Consortium and the Stroke Genetics Network for their association with ischemic stroke (n=16 851 cases and 32 473 controls) and its subtypes, including large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. Inverse-variance–weighted MR was used to obtain the causal estimates. Inverse-variance–weighted multivariable MR, MR-Egger, and sensitivity exclusion of pleiotropic single nucleotide polymorphisms after Steiger filtering and MR-Pleiotropy Residual Sum and Outlier test were used to adjust for pleiotropic bias.Results—A 1-SD genetically elevated LDL cholesterol was associated with an increased risk of ischemic stroke (odds ratio: 1.12; 95% confidence interval: 1.04–1.20) and large artery atherosclerosis stroke (odds ratio: 1.28; 95% confidence interval: 1.10–1.49) but not with small artery occlusion or cardioembolic stroke in multivariable MR. A 1-SD genetically elevated high-density lipoprotein cholesterol was associated with a decreased risk of small artery occlusion stroke (odds ratio: 0.79; 95% confidence interval: 0.67–0.90) in multivariable MR. MR-Egger indicated no pleiotropic bias, and results did not markedly change after sensitivity exclusion of pleiotropic single nucleotide polymorphisms. Genetically elevated triglycerides did not associate with ischemic stroke or its subtypes.Conclusions—LDL cholesterol lowering is likely to prevent large artery atherosclerosis but may not prevent small artery occlusion nor cardioembolic strokes. High-density lipoprotein cholesterol elevation may lead to benefits in small artery disease prevention. Finally, triglyceride lowering may not yield benefits in ischemic stroke and its subtypes.