Stroke RSS : Gourt

Statins for Acute Ischemic Stroke [Cochrane Corner]

Virtual Reality for Stroke Rehabilitation [Cochrane Corner]

Letter by Coutinho et al Regarding Article, "Mortality of Cerebral Venous-Sinus Thrombosis in a Large National Sample" [Letters to the Editor]

Response to Letter by Coutinho et al Regarding Article, "Mortality of Cerebral Venous-Sinus Thrombosis in a Large National Sample" [Letters to the Editor]

Letter by Moll Regarding Article, "Hemostatic Therapy in Experimental Intracerebral Hemorrhage Associated With the Direct Thrombin Inhibitor Dabigatran" [Letters to the Editor]

Response to Letter by Moll Regarding Article, "Hemostatic Therapy in Experimental Intracerebral Hemorrhage Associated With the Direct Thrombin Inhibitor Dabigatran" [Letters to the Editor]

Letter by Urra et al Regarding Article, "Autoimmune Responses to the Brain After Stroke Are Associated With Worse Outcome" [Letters to the Editor]

Response to Letter by Urra et al Regarding Article, "Autoimmune Responses to the Brain After Stroke Are Associated With Worse Outcome" [Letters to the Editor]

Low-Molecular-Weight Heparin in Atherosclerotic Stroke: A Surprising Resurrection of Anticoagulants? [Editorials]

Improving Outcome After Stroke: Time to Treat New Targets [Editorials]

Introduction for Advances in Stroke 2011 [Advances in Stroke]

Advances in Prevention and Health Services Delivery 2010-2011 [Advances in Stroke]

Advances in Health Policy and Outcome 2010-2011 [Advances in Stroke]

Advances in Stroke: Imaging [Advances in Stroke]

Advances in Stroke: Population Studies [Advances in Stroke]

Advances in Stroke: Critical Care and Emergency Medicine [Advances in Stroke]

Advances in Stroke: Advances in Interventional Neuroradiology [Advances in Stroke]

Stroke: Highlights of Selected Articles [Stroke: Highlights of Selected Articles]

Genome-Wide Association Study of Vascular Dementia [Original Contributions; Clinical Sciences]

Background and Purpose— Most studies investigating the genetics of dementia have focused on Alzheimer disease, but little is known about the genetics of vascular dementia. The aim of our study was to identify new loci associated with vascular dementia. Methods— We performed a genome-wide association study in the Rotterdam Study, a large prospective population-based cohort study in the Netherlands. We sought to replicate genome-wide significant loci in 2 independent replication samples. Results— In the discovery analysis of 5700 dementia-free individuals, 67 patients developed incident vascular dementia over a mean follow-up time of 9.3±3.2 years. We showed genome-wide significance for rs12007229, which is located on the X chromosome near the androgen receptor gene (OR, 3.7; 95% CI, 2.3–5.8, per copy of the minor allele; P=1.3x10–8). This association was further confirmed in 2 independent populations (probability value of combined replication samples=0.024). Conclusions— Our study shows a novel genetic locus for vascular dementia on the X chromosome. Further replication of this finding is required.

Stroke and Long-Term Exposure to Outdoor Air Pollution From Nitrogen Dioxide: A Cohort Study [Original Contributions; Clinical Sciences]

Background and Purpose— Years of exposure to tobacco smoke substantially increase the risk for stroke. Whether long-term exposure to outdoor air pollution can lead to stroke is not yet established. We examined the association between long-term exposure to traffic-related air pollution and incident and fatal stroke in a prospective cohort study. Methods— We followed 57 053 participants of the Danish Diet, Cancer and Health cohort in the Hospital Discharge Register for the first-ever hospital admission for stroke (incident stroke) between baseline (1993–1997) and 2006 and defined fatal strokes as death within 30 days of admission. We associated the estimated mean levels of nitrogen dioxide at residential addresses since 1971 to incident and fatal stroke by Cox regression analyses and examined the effects by stroke subtypes: ischemic, hemorrhagic, and nonspecified stroke. Results— Over a mean follow-up of 9.8 years of 52 215 eligible subjects, there were 1984 (3.8%) first-ever (incident) hospital admissions for stroke of whom 142 (7.2%) died within 30 days. We detected borderline significant associations between mean nitrogen dioxide levels at residence since 1971 and incident stroke (hazard ratio, 1.05; 95% CI, 0.99–1.11, per interquartile range increase) and stroke hospitalization followed by death within 30 days (1.22; 1.00–1.50). The associations were strongest for nonspecified and ischemic strokes, whereas no association was detected with hemorrhagic stroke. Conclusions— Long-term exposure to traffic-related air pollution may contribute to the development of ischemic but not hemorrhagic stroke, especially severe ischemic strokes leading to death within 30 days.

The X-Chromosome Has a Different Pattern of Gene Expression in Women Compared With Men With Ischemic Stroke [Original Contributions; Clinical Sciences]

Background and Purpose— Differences in ischemic stroke between men and women have been mainly attributed to hormonal effects. However, sex differences in immune response to ischemia may exist. We hypothesized that differential expression of X-chromosome genes in blood immune cells contribute to differences between men and women with ischemic stroke. Methods— RNA levels of 683 X-chromosome genes were measured on Affymetrix U133 Plus2.0 microarrays. Blood samples from patients with ischemic stroke were obtained at ≤3 hours, 5 hours, and 24 hours (n=61; 183 samples) after onset and compared with control subjects without symptomatic vascular diseases (n=109). Sex difference in X-chromosome gene expression was determined using analysis of covariance (false discovery rate ≤0.05, fold change ≥1.2). Results— At ≤3, 5, and 24 hours after stroke, there were 37, 140, and 61 X-chromosome genes, respectively, that changed in women; and 23, 18, and 31 X-chromosome genes that changed in men. Female-specific genes were associated with post-translational modification, small-molecule biochemistry, and cell–cell signaling. Male-specific genes were associated with cellular movement, development, cell-trafficking, and cell death. Altered sex specific X-chromosome gene expression occurred in 2 genes known to be associated with human stroke, including galactosidase A and IDS, mutations of which result in Fabry disease and Hunter syndrome, respectively. Conclusions— There are differences in X-chromosome gene expression between men and women with ischemic stroke. Future studies are needed to decipher whether these differences are associated with sexually dimorphic immune response, repair or other mechanisms after stroke, or whether some of them represent risk determinants.

Total Antioxidant Capacity of Diet and Risk of Stroke: A Population-Based Prospective Cohort of Women [Original Contributions; Clinical Sciences]

Background and Purpose— Consumption of antioxidant-rich foods may reduce the risk of stroke by inhibition of oxidative stress and inflammation. Total antioxidant capacity (TAC) takes into account all antioxidants and the synergistic effects between them. We examined the association between dietary TAC and stroke incidence in cardiovascular disease (CVD)-free women and in women with CVD history at baseline. Methods— The study included women (31 035 CVD-free and 5680 with CVD history at baseline), aged 49 to 83 years, from the Swedish Mammography Cohort. Diet was assessed with a food frequency questionnaire. Dietary TAC was calculated using oxygen radical absorbance capacity values. Stroke cases were ascertained by linkage with the Swedish Hospital Discharge Registry. Results— During follow-up (September 1997 to December 2009), we identified 1322 stroke cases (988 cerebral infarctions, 226 hemorrhagic strokes, and 108 unspecified strokes) among CVD-free women and 1007 stroke cases (796 cerebral infarctions, 100 hemorrhagic strokes, and 111 unspecified strokes) among women with a CVD history. The multivariable hazard ratio of total stroke comparing the highest with the lowest quintile of dietary TAC was 0.83 (95% CI, 0.70–0.99; P for trend=0.04) in CVD-free women. Among women with a CVD history, the hazard ratios for the highest versus lowest quartile of TAC were 0.90 (95% CI, 0.75–1.07; P for trend=0.30) for total stroke and 0.55 (95% CI, 0.32–0.95; P for trend=0.03) for hemorrhagic stroke. Conclusions— These findings suggest that dietary TAC is inversely associated with total stroke among CVD-free women and hemorrhagic stroke among women with CVD history.

Concurrent Validity and Reliability of Retrospective Scoring of the Pediatric National Institutes of Health Stroke Scale [Original Contributions; Clinical Sciences]

Background and Purpose— The Pediatric National Institutes of Health Stroke Scale (PedNIHSS), an adaptation of the adult National Institutes of Health Stroke Scale, is a quantitative measure of stroke severity shown to be reliable when scored prospectively. The ability to calculate the PedNIHSS score retrospectively would be invaluable in the conduct of observational pediatric stroke studies. The study objective was to assess the concurrent validity and reliability of estimating the PedNIHSS score retrospectively from medical records. Methods— Neurological examinations from medical records of 75 children enrolled in a prospective PedNIHSS validation study were photocopied. Four neurologists of varying training levels blinded to the prospective PedNIHSS scores reviewed the records and retrospectively assigned PedNIHSS scores. Retrospective scores were compared among raters and to the prospective scores. Results— Total retrospective PedNIHSS scores correlated highly with total prospective scores (R2=0.76). Interrater reliability for the total scores was "excellent" (intraclass correlation coefficient, 0.95; 95% CI, 0.94–0.97). Interrater reliability for individual test items was "substantial" or "excellent" for 14 of 15 items. Conclusions— The PedNIHSS score can be scored retrospectively from medical records with a high degree of concurrent validity and reliability. This tool can be used to improve the quality of retrospective pediatric stroke studies.

Low-Molecular-Weight Heparin Versus Aspirin for Acute Ischemic Stroke With Large Artery Occlusive Disease: Subgroup Analyses From the Fraxiparin in Stroke Study for the Treatment of Ischemic Stroke (FISS-tris) Study [Original Contributions; Clinical Sciences]

Background and Purpose— The Fraxiparin in Stroke Study for the treatment of ischemic stroke (FISS-tris) study showed no superiority of low-molecular-weight heparin (LMWH) over aspirin for the primary end point (Barthel Index) in acute ischemic stroke due to large artery occlusive disease. This study aims to evaluate the efficacy of LMWH and aspirin in selected subgroups so as to generate hypotheses for further studies. Methods— The FISS-tris study was a multicenter, randomized trial to investigate the efficacy and safety of LMWH (nadroparin calcium 3800 antifactor Xa IU/0.4 mL subcutaneously twice daily) or aspirin (160 mg once daily) for the treatment of patients with acute ischemic stroke and large artery occlusive disease. The primary outcome was the Barthel Index score dichotomized at 85 6 months poststroke. Exploratory subgroup analysis was performed using different levels of baseline characteristics and the distribution of symptomatic arteries. Results— Compared with aspirin, LMWH improved outcome among older patients >68 years (P=0.043; OR, 1.86; 95% CI, 1.02–3.41) without ongoing antiplatelet treatment on admission (P=0.029; OR, 1.85; 95% CI, 1.06–3.21) and with symptomatic posterior circulation arterial disease (P=0.001; OR, 5.76; 95% CI, 2.00–16.56). Conclusions— Our findings suggest that LMWH may be of benefit in certain subgroups of patients with acute cerebral infarct and large artery occlusive disease. Hence, further investigation of LMWH may be justified in subgroups such as the elderly, nonusers of antiplatelet agents, and patients with posterior circulation stenosis. Clinical Trial Registration— URL: www.strokecenter.org/trials. Unique identifier: registration no. 493.

Risk of Recurrent Stroke in Patients With Silent Brain Infarction in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) Imaging Substudy [Original Contributions; Clinical Sciences]

Background and Purpose— Silent brain infarctions are associated with an increased risk of stroke in healthy individuals. Risk of recurrent stroke in patients with both symptomatic and silent brain infarction (SBI) has only been investigated in patients with cardioembolic stroke in the European Atrial Fibrillation Trial. We assessed whether patients with recent noncardioembolic stroke and SBI detected on MRI are at increased risk for recurrent stroke, other cardiovascular events, and mortality. Methods— The prevalence of SBI detected on MRI was assessed in 1014 patients enrolled in the imaging substudy of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial. The primary outcome was first recurrence of stroke in patients with both symptomatic stroke and SBI in comparison with age- and sex-matched patients with stroke without SBI. Secondary outcomes were a combined vascular end point, other vascular events, and mortality. The 2 groups were compared using conditional logistic regression. Results— Silent brain infarction was detected in 207 (20.4%) of the 1014 patients. Twenty-seven (13.0%) patients with SBI and 19 (9.2%) without SBI had a recurrent stroke (OR, 1.42; 95% CI, 0.79–2.56; P=0.24) during a mean follow-up of 2.5 years. Similarly, there was no statistically significant difference for all secondary outcome parameters between patients with SBI and matched patients without SBI. Conclusions— The presence of SBI in patients with recent mild noncardioembolic ischemic stroke could not be shown to be an independent risk factor for recurrent stroke, other vascular events, or a higher mortality rate. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT00153062.

How Does Number of Risk Factors Affect Prognosis in Young Patients With Ischemic Stroke? [Original Contributions; Clinical Sciences]

Background and Purpose— We aimed to explore clinical features of young patients with ischemic stroke with no traditional vascular risk factors and to assess the impact of risk factor counts on outcomes. Methods— We included 990 patients aged 15 to 49 years with first-ever ischemic stroke followed for a mean of 9.0±3.8 years (survivors). Risk factors were categorized as well-documented and less well-documented. Outcome measures were unfavorable functional outcome (3-month modified Rankin Scale 2–6); recurrent ischemic stroke; myocardial infarction or other arterial noncerebrovascular event; and death from any cause. Results— Compared with those with at least 1 well-documented risk factor, the 127 (12.8%) patients without risk factors were younger (median age, 37 versus 44 years; P<0.001), likely to be females (54.3% versus 34.9%; P<0.001), and they had more frequently a low-risk source of cardioembolism (21.3% versus 8.1%; P<0.001), internal carotid artery dissection (12.6% versus 6.4%; P=0.011), or vertebral artery dissection (17.3% versus 7.2%; P<0.001). The groups had similar 3-month functional outcomes. Patients without well-documented risk factors had less frequently recurrent ischemic strokes (4.7% versus 13.6%; log rank P=0.014), noncerebrovascular arterial events (0% versus 6.1%; P=0.008), and lower long-term mortality (3.4% versus 14.3%; P=0.003) than did those with at least 1 risk factor. Adjusted for demographics and stroke etiology, the number of well-documented risk factors was associated with higher risk for noncerebrovascular events. Increasing count of less well-documented risk factors was, in turn, independently associated with higher long-term mortality. Conclusions— In young adults with first-ever ischemic stroke, risk factor counts added independent prognostic information regarding noncerebrovascular events and mortality.

Factors Associated With Prehospital Delays in the Presentation of Acute Stroke in Urban China [Original Contributions; Clinical Sciences]

Background and Purpose— Low rates of thrombolysis for ischemic stroke in China have mainly been attributed to delays in presentation to the hospital. This study aimed to evaluate factors associated with these delays. Methods— Data were from a prospective, multicenter, hospital-based registry of patients with acute stroke (ChinaQUEST [Quality Evaluation of Stroke Care and Treatment]), which involved 62 hospitals across a variety of economic and geographic regions in China during 2006. Univariate and multivariate analyses were undertaken to determine associations between variables of interest and delays to hospital presentation. Results— Median time to hospital presentation was 15.0 hours for 6102 cases (interquartile range, 2.8–51.0 hours). A total of 1546 (25%) patients arrived within 3 hours and 2244 (37%) patients arrived within 6 hours after symptom onset. Factors that prolonged time to presentation were: visiting a local doctor before presenting at emergency (OR, 0.48; P<0.001), symptom onset at home (OR, 0.62; P<0.001), transfer to a large (Level III) hospital for management (OR, 0.70; P=0.04), and history of diabetes (OR, 0.78; P=0.01). In contrast, factors that accelerated presentation to the hospital were hemorrhagic stroke (OR, 2.25; P<0.001), history of atrial fibrillation (OR, 1.94; P<0.001), unconsciousness at presentation (OR, 1.91; P<0.001), transfer by ambulance (OR, 1.91; P<0.001), and history of coronary artery disease (OR, 1.20; P=0.04). Conclusions— Health promotion strategies to improve community awareness of early symptoms of stroke, establishment of an alert system to cater for patients likely to experience stroke at home, and wider availability and use of ambulance services are promising methods to help expedite presentation to hospital poststroke and thereby improve the management of stroke in China.

Towards a Consensus-Based Classification of Childhood Arterial Ischemic Stroke [Original Contributions; Clinical Sciences]

Background and Purpose— The implementation of uniform nomenclature and classification in adult arterial ischemic stroke (AIS) has been critical for defining outcomes and recurrence risks according to etiology and in developing risk-stratified treatments. In contrast, current classification and nomenclature in childhood AIS are often overlapping or contradictory. Our purpose was to develop a comprehensive consensus-based classification system for childhood AIS. Methods— Using a modified-Delphi method, members of the International Pediatric Stroke Study (IPSS) developed the Childhood AIS Standardized Classification And Diagnostic Evaluation (CASCADE) criteria. Two groups of pediatric stroke specialists from the IPSS classified 7 test cases using 2 methods each: (1) classification typical of the individual clinician's current clinical practice; and (2) classification based on the CASCADE criteria. Group 1 underwent in-person training in the utilization of the CASCADE criteria. Group 2 classified the same cases via an online survey, including definitions but without training. Inter-rater reliability (IRR) was assessed via multi-rater unweighted -statistic. Results— In Group 1 (with training), IRR was improved using CASCADE criteria (=0.78, 95% CI=[0.49, 0.94]), compared with typical clinical practice (=0.40, 95% CI=[0.11, 0.60]). In Group 2 (without training), IRR was lower than among trained raters (=0.61, 95% CI=[0.29, 0.77]), but higher than current practice (=0.23, 95% CI=[0.03, 0.36]). Conclusions— A new, consensus-based classification system for childhood AIS, the CASCADE criteria, can be used to classify cases with good IRR. These preliminary findings suggest that the CASCADE criteria may be particularity useful in the setting of prospective multicenter studies in childhood-onset AIS, where standardized training of investigators is feasible.

Influence of the Arterial Input Function on Absolute and Relative Perfusion-Weighted Imaging Penumbral Flow Detection: A Validation With 15O-Water Positron Emission Tomography [Original Contributions; Clinical Sciences]

Background and Purpose— Perfusion-weighted imaging maps are used to identify critical hypoperfusion in acute stroke. However, quantification of perfusion may depend on the choice of the arterial input function (AIF). Using quantitative positron emission tomography we evaluated the influence of the AIF location on maps of absolute and relative perfusion-weighted imaging to detect penumbral flow (PF; <20 mL/100 g/min on positron emission tomographyCBF) in acute stroke. Methods— In 22 patients with acute stroke the AIF was placed at 7 sites (M1, M2, M3 ipsi- and contralateral and internal carotid artery–M1 contralateral to the infarct). Comparative 15O-water positron emission tomography and AIF-dependent perfusion-weighted imaging (cerebral blood flow, cerebral blood volume, mean transit time, and time to maximum) were performed. A receiver operating characteristic curve analysis described the threshold independent performance (area under the curve) of the perfusion-weighted maps for all 7 AIF locations and identified the best AIF-dependent absolute and relative thresholds to identify PF. These results were compared with AIF-independent time-to-peak maps. Results— Quantitative perfusion-weighted imaging maps of cerebral blood flow and time to maximum performed best. For PF detection, AIF placement did significantly influence absolute PF thresholds. However, AIF placement did not influence (1) the threshold independent performance; and (2) the relative PF thresholds. AIF placement in the proximal segment of the contralateral middle cerebral artery (cM1) was preferable for quantification. Conclusions— AIF-based maps of cerebral blood flow and time to maximum were most accurate to detect the PF threshold. The AIF placement significantly altered absolute PF thresholds and showed best agreement with positron emission tomography for the cM1 segment. The performance of relative PF thresholds, however, was not AIF location-dependent and might be along with AIF-independent time-to-peak maps, more suitable than absolute PF thresholds in acute stroke if detailed postprocessing is not feasible.

Sulcal Effacement on Fluid Attenuation Inversion Recovery Magnetic Resonance Imaging in Hyperacute Stroke: Association With Collateral Flow and Clinical Outcomes [Original Contributions; Clinical Sciences]

Background and Purpose— The clinical significance of sulcal effacement has been widely investigated in CT studies, but the results are controversial. In this study, we evaluated the presence of perisylvian sulcal effacement (PSE) on fluid attenuation inversion recovery MRI and hypothesized that PSE may be related to collateral flow status together with hyperintense vessels on fluid attenuation inversion recovery in hyperacute stroke. In addition, we investigated whether an association between PSE and clinical outcome could be found in these patients. Methods— Consecutive patients with acute middle cerebral artery infarcts within 6 hours of symptom onset were included. All patients had internal carotid artery or middle cerebral artery occlusion and underwent MRI including FLAIR. The presence of PSE and hyperintense vessels on fluid attenuation inversion recovery and the collateral status and occurrence of early recanalization (ER) on conventional angiography were evaluated. Results— Of 139 patients, 79 (56.8%) had PSE. Multivariate testing revealed PSE was independently associated with collateral status. The association between hyperintense vessels and collaterals was different depending on PSE. Compared to PSE-positive and ER-negative patients, PSE-negative and ER-negative patients (odds ratio, 4.11; 95% confidence interval, 1.12–15.17) and PSE-negative and ER-positive patients (odds ratio, 34.62; 95% confidence interval, 5.75–208.60), but not PSE-positive and ER-positive patients, were more likely to experience favorable clinical outcomes (modified Rankin Scale score ≤2 at 3 months). Conclusions— PSE is independently associated with collateral status in patients with acute middle cerebral artery stroke. Moreover, PSE in conjunction with recanalization status can predict clinical outcomes in these patients.

Assessment of Carotid Plaque Stability Based on the Dynamic Enhancement Pattern in Plaque Components With Multidetector CT Angiography [Original Contributions; Clinical Sciences]

Background and Purpose— Recent studies have investigated plaque morphology to determine patients who are at high risk of carotid atherosclerosis. In this study, we investigated whether a difference in dynamic enhancement pattern in plaque components could be useful to assess plaque stability with multidetector CT angiography. Methods— Fifty-nine lesions with moderate to severe carotid atherosclerosis in 51 patients (33 symptomatic, 18 asymptomatic) were consecutively included. Early- and delayed-phase images were obtained in 3 equivalent axial slices with multidetector CT angiography. Hounsfield units (HU) in the early phase were subtracted from those in the delayed phase in plaques (HU) and compared with clinical features, MRI-based plaque characteristics, and histological findings with 20 surgical specimens acquired from carotid endarterectomy. Results— The HU was significantly higher in asymptomatic than that in symptomatic presentation (P=0.02). With MRI, a higher HU was negatively correlated with signal intensity on T1-weighted imaging (r=–0.56, P<0.0001). Histology confirmed that HU was positively correlated with fibrous tissue (r=0.67, P=0.001) and negatively correlated with a lipid-rich necrotic core with hemorrhage (r=–0.70, P<0.001). Moreover, less neovascularization and inflammation was found in plaques with a higher HU. Conclusions— Delayed-phase images provide information regarding the dynamic change in contrast media from the early arterial phase. An increase in HU from the early phase on multidetector CT angiography indicates plaque stability with more fibrous tissue and a less lipid-rich necrotic core, intraplaque hemorrhage, and neovascularization.

Response of Blood Pressure and Blood Glucose to Treatment With Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke: Evidence From the Virtual International Stroke Trials Archive [Original Contributions; Clinical Sciences]

Background and Purpose— Elevations in blood pressure (BP) and blood glucose are common during stroke and may represent a stress response secondary to the acute neurological deficit. If so, they should settle more completely in recombinant tissue-type plasminogen activator (rtPA)-treated patients in association with improved neurological status. Methods— We performed a controlled comparison of 24-hour declines in BP and glucose in rtPA-treated and control patients from the Virtual Stroke International Stroke Trial Archive (VISTA) database. Twenty-four-hour falls in BP and glucose were compared using multiple regression to account for baseline imbalances. The logarithmic transformation of glucose was used and 24-hour differences expressed as ratios of 24 hours to admission geometric means. Two-way analysis of variance was used to test for interaction between rtPA and early improvement for 24-hour falls in BP and blood glucose. Results— BP analysis included 5406 patients (rtPA=41%) and glucose analysis 4288 (rtPA=37%). rtPA-treated patients were younger, less likely to have a history of hypertension or diabetes, and had more severe strokes on admission. BP and glucose were lower at baseline in rtPA-treated patients than control subjects. On regression, rtPA predicted significantly greater 24-hour falls in systolic BP (β=3.9; 95% CI, 2.8–5.0), diastolic BP (β=3.1; 95% CI, 2.4–3.9), and glucose (β=0.97; 95% CI, 0.95–0.99). rtPA did not interact with early neurological improvement for 24-hour falls in systolic BP (P=0.72), diastolic BP (P=0.79), or blood glucose (P=0.51). Conclusions— A stress response does not appear to be the principal cause of elevations in BP and glucose during stroke.

Granulocyte-Colony Stimulating Factor for Mobilizing Bone Marrow Stem Cells in Subacute Stroke: The Stem Cell Trial of Recovery Enhancement After Stroke 2 Randomized Controlled Trial [Original Contributions; Clinical Sciences]

Background and Purpose— Granulocyte-colony stimulating factor (G-CSF) is neuroprotective in experimental stroke and mobilizes CD34+ peripheral blood stem cells into the circulation. We assessed the safety of G-CSF in recent stroke in a phase IIb single-center randomized, controlled trial. Methods— G-CSF (10 μg/kg) or placebo (ratio 2:1) was given SC for 5 days to 60 patients 3 to 30 days after ischemic or hemorrhagic stroke. The primary outcome was the frequency of serious adverse events. Peripheral blood counts, CD34+ count, and functional outcome were measured. MRI assessed lesion volume, atrophy, and the presence of iron-labeled CD34+ cells reinjected on day 6. Results— Sixty patients were recruited at mean of 8 days (SD ±5) post ictus, with mean age 71 years (±12 years) and 53% men. The groups were well matched for baseline minimization/prognostic factors. There were no significant differences between groups in the number of participants with serious adverse events: G-CSF 15 (37.5%) of 40 versus placebo 7 (35%) of 20, death or dependency (modified Rankin Score: G-CSF 3.3±1.3, placebo 3.0±1.3) at 90 days, or the number of injections received. G-CSF increased CD34+ and total white cell counts of 9.5- and 4.2-fold, respectively. There was a trend toward reduction in MRI ischemic lesion volume with respect to change from baseline in G-CSF–treated patients (P=0.06). In 1 participant, there was suggestion that labeled CD34+ cells had migrated to the ischemic lesion. Conclusions— This randomized, double-blind, placebo-controlled trial suggests that G-CSF is safe when administered subacutely. It is feasible to label and readminister iron-labeled CD34+ cells in patients with ischemic stroke. Clinical Trial Registration— URL: www.controlled-trials.com. Unique identifier: ISRCTN63336619.

The Safety of Intravenous Thrombolysis for Ischemic Stroke in Patients With Pre-Existing Cerebral Aneurysms: A Case Series and Review of the Literature [Original Contributions; Clinical Sciences]

Background and Purpose— Unruptured cerebral aneurysms are currently considered a contraindication to intravenous tissue-type plasminogen activator for acute ischemic stroke. This is due to a theoretical increase in the risk of hemorrhage from aneurysm rupture, although it is unknown whether this risk is a significant one. We sought to determine the safety of intravenous tissue-type plasminogen activator administration in a cohort of patients with pre-existing aneurysms. Methods— We reviewed the medical records of patients treated for acute ischemic stroke with intravenous tissue-type plasminogen activator during an 11-year period at 2 academic medical centers. We identified a subset of patients with unruptured cerebral aneurysms present on prethrombolysis vascular imaging. Our outcomes of interest were any intracranial hemorrhage, symptomatic intracranial hemorrhage, and subarachnoid hemorrhage. Fisher exact test was used to compare the rates of hemorrhage among patients with and without aneurysms. Results— We identified 236 eligible patients, of whom 22 had unruptured cerebral aneurysms. The rate of intracranial hemorrhage among patients with aneurysms (14%; 95% CI, 3%–35%) did not significantly differ from the rate among patients without aneurysms (19%; 95% CI, 14%–25%). None of the patients with aneurysms developed symptomatic intracranial hemorrhage (0%; 95% CI, 0%–15%) compared with 10 of 214 patients without aneurysms (5%; 95% CI, 2%–8%). Similar proportions of patients developed subarachnoid hemorrhage (5%; 95% CI, 0%–23% versus 6%; 95% CI, 3%–10%). Conclusions— Our findings suggest that intravenous tissue-type plasminogen activator for acute ischemic stroke is safe to administer in patients with pre-existing cerebral aneurysms because the risk of aneurysm rupture and symptomatic intracranial hemorrhage is low.

Predictors of Tissue-Type Plasminogen Activator Nonresponders According to Location of Vessel Occlusion [Original Contributions; Clinical Sciences]

Background and Purpose— Information on the clinical and hemodynamic profile of intravenous tissue-type plasminogen activator nonresponders, at different locations of arterial occlusion, may improve the selection of candidates for rescue reperfusion therapies. Therefore, we aim to investigate predictors of failing intravenous tissue-type plasminogen activator therapy according to occluded vessel and location of the clot. Methods— We prospectively evaluated consecutive patients with an acute ischemic stroke admitted within the first 6 hours of onset. Five hundred forty-eight patients with documented intracranial occlusion were included. Patients were categorized according to site of vessel occlusion into 4 distinct groups: proximal middle cerebral artery occlusion (n=251), distal middle cerebral artery occlusion (n=194), internal carotid artery bifurcation occlusion (n=61), and basilar artery occlusion (n=42). Recanalization was assessed on transcranial Doppler at 1 hour of tissue-type plasminogen activator bolus. Results— Among patients with proximal middle cerebral artery occlusion, the presence of severe extracranial internal carotid artery stenosis or occlusion (OR, 2.36; 95% CI, 1.15–4.84; P=0.02) and age >74 years (OR, 1.84; 95% CI, 1.02–3.31; P=0.04) independently predicted no recanalization. No independent predictors of no recanalization were identified in patients with distal middle cerebral artery occlusion. In patients with internal carotid artery bifurcation occlusion, a previous diagnosis of hypertension (OR, 12.77; 95% CI, 2.12–76.88; P=0.05), and absence of atrial fibrillation (OR, 8.15; 95% CI, 1.40–47.44; P=0.02) emerged as independent predictors of no recanalization. Similarly, among patients with basilar artery occlusion, absence of atrial fibrillation was as an independent predictor of no recanalization (OR, 7.50; 95% CI, 1.40–40.35; P=0.02). Conclusions— The use of relevant predictors of no recanalization and a rapid neurovascular evaluation may improve the selection of patients for more aggressive rescue strategies.

Patent Foramen Ovale Closure and Medical Treatments for Secondary Stroke Prevention: A Systematic Review of Observational and Randomized Evidence [Original Contributions; Clinical Sciences]

Background and Purpose— Patients discovered to have a patent foramen ovale in the setting of a cryptogenic stroke may be treated with percutaneous closure, antiplatelet therapy, or anticoagulants. A recent randomized trial (CLOSURE I) did not detect any benefit of closure over medical treatment alone; the optimal medical therapy is also unknown. We synthesized the available evidence on secondary stroke prevention in patients with patent foramen ovale and cryptogenic stroke. Methods— A MEDLINE search was performed for finding longitudinal studies investigating medical treatment or closure, meta-analysis of incidence rates (IR), and IR ratios of recurrent cerebrovascular events. Results— Fifty-two single-arm studies and 7 comparative nonrandomized studies and the CLOSURE I trial were reviewed. The summary IR of recurrent stroke was 0.36 events (95% confidence interval [CI], 0.24–0.56) per 100 person-years with closure versus 2.53 events (95% CI, 1.91–3.35) per 100 person-years with medical therapy. In comparative observational studies, closure was superior to medical therapy (IR ratio=0.19; 95% CI, 0.07–0.54). The IR for the closure arm of the CLOSURE I trial was higher than the summary estimate from observational studies; there was no significant benefit of closure over medical treatment (P=0.002 comparing efficacy estimates between observational studies and the trial). Observational and randomized data (9 studies) comparing medical therapies were consistent and suggested that anticoagulants are superior to antiplatelets for preventing stroke recurrence (IR ratio=0.42; 95% CI, 0.18–0.98). Conclusions— Although further randomized trial data are needed to precisely determine the effects of closure on stroke recurrence, the results of CLOSURE I challenge the credibility of a substantial body of observational evidence strongly favoring mechanical closure over medical therapy.

Effect of Antihypertensive Therapy on Incident Stroke in Cohorts With Prehypertensive Blood Pressure Levels: A Meta-Analysis of Randomized Controlled Trials [Original Contributions; Clinical Sciences]

Background and Purpose— Compared with normotensive individuals, there is a higher incidence of stroke in patients with hypertensive, as well as prehypertensive, blood pressure levels (ie, 120–139/80–89 mm Hg). Although several studies have shown that blood pressure reduction in hypertensive patients reduces the incidence of cardiovascular events, including stroke, it is still unknown whether treatment of prehypertensive blood pressure levels has a similar effect. We sought to determine whether reduction in blood pressure in the prehypertensive range reduces the incidence of stroke by performing a meta-analysis of randomized trials comparing an antihypertensive drug against placebo in cohorts with prehypertensive baseline blood pressure levels. Methods— Randomized controlled trials performed with the 95 different antihypertensive agents available in the market were identified using MEDLINE, returning a total of 2852 results. Exclusion criteria included: average blood pressure of ≥140/90 mm Hg at baseline, crossover studies, and lack of a control group receiving placebo. Results— A total of 16 trials involving 70 664 patients were included. Patients randomized to the active treatment arm had a statistically significant 22% reduction in the risk of stroke compared with placebo, with little heterogeneity among the trials (I2, 18.0%; RR, 0.78 [95% CI, 0.71–0.86]; P<0.000001). To prevent 1 stroke, 169 patients had to be treated with a blood-pressure-lowering medication for an average of 4.3 years. Conclusions— The risk of stroke is significantly reduced with antihypertensive therapy in cohorts with prehypertensive blood pressure levels. These findings can have important clinical implications.

Brain Natriuretic Peptide Predicts Functional Outcome in Ischemic Stroke [Original Contributions; Clinical Sciences]

Background and Purpose— Elevated serum levels of brain natriuretic peptide (BNP) have been associated with cardioembolic stroke and increased poststroke mortality. We sought to determine whether BNP levels were associated with functional outcome after ischemic stroke. Methods— We measured BNP in consecutive patients aged ≥18 years admitted to our stroke unit between 2002 to 2005. BNP quintiles were used for analysis. Stroke subtypes were assigned using Trial of ORG 10172 in Acute Stroke Treatment criteria. Outcomes were measured as 6-month modified Rankin Scale score ("good outcome"=0–2 versus "poor") as well as mortality. Multivariate logistic regression was used to assess association between the quintiles of BNP and outcomes. Predictive performance of BNP as compared with clinical model alone was assessed by comparing receiver operating characteristic curves. Results— Of 569 patients with ischemic stroke, 46% were female; mean age was 67.9±15 years. In age- and gender-adjusted analysis, elevated BNP was associated with lower ejection fraction (P<0.0001) and left atrial dilatation (P<0.001). In multivariate analysis, elevated BNP decreased the odds of good functional outcome (OR, 0.64; 95% CI, 0.41–0.98) and increased the odds of death (OR, 1.75; 95% CI, 1.36–2.24) in these patients. Addition of BNP to multivariate models increased their predictive performance for functional outcome (P=0.013) and mortality (P<0.03) after cardioembolic stroke. Conclusions— Serum BNP levels are strongly associated with cardioembolic stroke and functional outcome at 6 months after ischemic stroke. Inclusion of BNP improved prediction of mortality in patients with cardioembolic stroke.

Characterizing and Identifying Risk for Falls in the LEAPS Study: A Randomized Clinical Trial of Interventions to Improve Walking Poststroke [Original Contributions; Clinical Sciences]

Background and Purpose— Better understanding of fall risk poststroke is required for developing screening and prevention programs. This study characterizes falls in the Locomotor Experience Applied Post-Stroke (LEAPS) randomized clinical trial, describes the impact of 2 walking recovery interventions on falls, and examines the value of clinical assessments for predicting falls. Methods— Community-dwelling ambulatory stroke survivors enrolled in LEAPS were assessed 2 months poststroke. Falls were monitored until 12 months poststroke and participants were characterized as multiple or injurious (M/I); single, noninjurious; or nonfallers. Incidence and time to M/I falls were compared across interventions (home exercise and locomotor training initiated 2 months [early-LTP] or 6 months [late-LTP] poststroke). Predictive value of 2-month clinical assessments for falls outcome was assessed. Results— Among the 408 participants, 36.0% were M/I, 21.6% were single, noninjurious, and 42.4% were nonfallers. Most falls occurred at home in the first 3 months after assessment. Falls incidence was highest for those with severe walking impairment who received early-LTP (P=0.025). Berg Balance Scale score ≤42/56 was the single best predictor of M/I falls. Conclusions— As individuals with stroke improve in walking capacity, risk for M/I falls remains high. Individuals walking <0.4 m/s are at higher risk for M/I falls if they receive early-LTP training. Berg Balance Scale score at 2 months poststroke is useful for informing falls risk, but it cannot account for the multifactorial nature of the problem. Falls prevention in stroke will require multifactorial risk assessment and management provided concomitantly with exercise interventions to improve mobility. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00243919.

Atrophy of Spared Gray Matter Tissue Predicts Poorer Motor Recovery and Rehabilitation Response in Chronic Stroke [Original Contributions; Clinical Sciences]

Background and Purpose— Although the motor deficit after stroke is clearly due to the structural brain damage that has been sustained, this relationship is attenuated from the acute to chronic phases. We investigated the possibility that motor impairment and response to constraint-induced movement therapy in patients with chronic stroke may relate more strongly to the structural integrity of brain structures remote from the lesion than to measures of overt tissue damage. Methods— Voxel-based morphometry analysis was performed on MRI scans from 80 patients with chronic stroke to investigate whether variations in gray matter density were correlated with extent of residual motor impairment or with constraint-induced movement therapy-induced motor recovery. Results— Decreased gray matter density in noninfarcted motor regions was significantly correlated with magnitude of residual motor deficit. In addition, reduced gray matter density in multiple remote brain regions predicted a lesser extent of motor improvement from constraint-induced movement therapy. Conclusions— Atrophy in seemingly healthy parts of the brain that are distant from the infarct accounts for at least a portion of the sustained motor deficit in chronic stroke.

Variations in Quality Indicators of Acute Stroke Care in 6 European Countries: The European Implementation Score (EIS) Collaboration [Original Contributions; Clinical Sciences]

Background and Purpose— Quality indicators serve as standards of care by which performance of individual hospitals is measured. Although several audits for monitoring quality of stroke care have been established in Europe, there is currently no consensus on quality indicators for acute stroke care or for methodology for collecting information on these measures. Methods— An up-to-date inventory on European stroke audits in place in 2006 was performed in the course of a project funded by the European Union (European Implementation Score Collaboration [EIS]). Two regional (Flanders, Belgium; Catalonia, Spain) and 4 national (Germany, Scotland, Sweden, England/Wales/Northern Ireland) stroke audits took part. Between November 2009 and July 2010, 2 standardized surveys and a series of interviews were performed to determine characteristics, methods, and content of these quality initiatives. For quality purposes, all summarized information was validated by representatives of the respective audits. Results— Overall, 123 quality indicators (91 process, 24 outcome, and 8 structural indicators) were identified. Anticoagulants in patients with atrial fibrillation and brain imaging were the only quality indicators used in all, whereas another 13 indicators were used in at least 2 of the quality initiatives. Substantial variations were found across the audits in terms of the development process of quality indicators, inclusion criteria, participation, population coverage, data documentation, follow-ups, benchmarking, and feedback of results to participants. Conclusions— There is a huge variety in measuring performance of acute stroke care in Europe, hampering valid comparisons of acute stroke care. Common standards for defining quality indicators and collecting information required for these measures should be defined in Europe.

MoCA, ACE-R, and MMSE Versus the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards Neuropsychological Battery After TIA and Stroke [Original Contributions; Clinical Sciences]

Background and Purpose— The Montreal Cognitive Assessment (MoCA) and Addenbrooke's Cognitive Examination–Revised (ACE-R) are proposed as short cognitive tests for use after stroke, but there are few published validations against a neuropsychological battery. We studied the relationship between MoCA, ACE-R, Mini-Mental State Examination (MMSE) and mild cognitive impairment (MCI) in patients with cerebrovascular disease and mild cognitive impairment (MCI). Methods— One hundred consecutive non-institutionalized patients had the MMSE, MoCA, ACE-R, and National Institute of Neurological Disorders and Stroke–Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards Neuropsychological Battery ≥1 year after transient ischemic attack or stroke in a population-based study. MCI was diagnosed using modified Petersen criteria in which subjective cognitive complaint is not required (equivalent to cognitive impairment–no dementia) and subtyped by number and type of cognitive domains affected. Results— Among 91 nondemented subjects completing neuropsychological testing (mean/SD age, 73.4/11.6 years; 44% female; 56% stroke), 39 (42%) had MCI (amnestic multiple domain=10, nonamnestic multiple domain=9, nonamnestic single domain=19, amnestic single domain=1). Sensitivity and specificity for MCI were optimal with MoCA <25 (sensitivity=77%, specificity=83%) and ACE-R <94 (sensitivity=83%, specificity=73%). Both tests detected amnestic MCI better than nonamnestic single-domain impairment. MMSE only achieved sensitivity >70% at a cutoff of <29, mainly due to relative insensitivity to single-domain impairment. Conclusions— The MoCA and ACE-R had good sensitivity and specificity for MCI defined using the Neurological Disorders and Stroke–Canadian Stroke Network Vascular Cognitive Impairment Battery ≥1 year after transient ischemic attack and stroke, whereas the MMSE showed a ceiling effect. However, optimal cutoffs will depend on use for screening (high sensitivity) or diagnosis (high specificity). Lack of timed measures of processing speed may explain the relative insensitivity of the MoCA and ACE-R to single nonmemory domain impairment.

Delay of Stroke Onset by Milk Proteins in Stroke-Prone Spontaneously Hypertensive Rats [Original Contributions; Basic Sciences]

Background and Purpose— There is an inverse association between dairy food consumption and the incidence of stroke in observational studies. However, it is unknown whether the relationship is causal or, if so, what components in milk are responsible for reducing the incidence of stroke. Methods— Stroke-prone spontaneously hypertensive rats were fed diets comprising amino acids, proteins from different sources (casein, whey, soybean, or egg white), or fats from different sources (butter, beef tallow, or cocoa butter) and the onset of stroke and lifespan were examined. Results— Increasing the amount of dietary casein (5% to 55% of caloric intake) markedly delayed the onset of stroke. However, when stroke-prone spontaneously hypertensive rats were fed diets containing 55% of caloric intake as protein, rats fed casein or whey protein, a major component of milk, displayed a delayed onset of stroke compared with rats fed soybean or egg white protein. Rats fed an amino acids diet containing the same amino acids composition as casein did not have a delay in the onset of stroke. Increasing dietary fats, including butter as well as beef tallow and cocoa butter, did not affect the onset of stroke. All diets did not affect blood pressure in the early stage. Conclusions— These data suggest that the inverse association between dairy food consumption and incidence of stroke in epidemiological studies is causal and that peptides in milk protein, but not fat, might be responsible for this effect.

Activation of Signal Transducer and Activator of Transcription-3 by a Peroxisome Proliferator-Activated Receptor Gamma Agonist Contributes to Neuroprotection in the Peri-Infarct Region After Ischemia in Oophorectomized Rats [Original Contributions; Basic Sciences]

Background and Purpose— The role of the phosphorylated signal transducer and activator of transcription-3 (p-STAT3) after cerebral ischemia by the peroxisome proliferator-activated receptor (PPAR) agonist pioglitazone (PGZ) remains controversial. Whether the increase in p-STAT3 by estrogen is mediated by the estrogen receptor α is also obscure. We examined the role of p-STAT3, PPAR, and estrogen receptor α against ischemic brain damage after PGZ treatment. Methods— Female Wistar rats subjected or not subjected to bilateral oophorectomy were injected with 1.0 or 2.5 mg/kg PGZ 2 days, 1 day, and 1 hour before 90-minute middle cerebral artery occlusion–reperfusion and compared with vehicle-control rats. Results— The cortical infarct size was larger in ovariectomized than in nonovarietomized rats; it was reduced by PGZ treatment. Inversely with the reduction of the infarct size, PPAR, and p-STAT3 but not estrogen receptor α in the peri-infarct area were increased in PGZ-treated compared with vehicle-control rats. The increase in PPAR and p-STAT3 was associated with the transactivation of antiapoptotic and survival genes and the reduction of caspase-3 in this area. Inhibitors of PPAR or STAT3 abolished the PGZ-induced neuroprotection and the increase in p-STAT3. More importantly, p-STAT3 increased by PGZ was bound to PPAR and the complex translocated to the nucleus to dock to the response element through p-STAT3. Conclusions— Our findings suggest that the activation in the peri-infarct region of p-STAT3 and PPAR by PGZ is essential for neuroprotection after ischemia and that PGZ may be of benefit even in postmenopausal stroke patients.

CHOP Silencing Reduces Acute Brain Injury in the Rat Model of Subarachnoid Hemorrhage [Original Contributions; Basic Sciences]

Background and Purpose— Endoplasmic reticulum stress triggers apoptotic cascades in neurons of the central nervous system after subarachnoid hemorrhage. The aim of this work was to study the mechanism of neuroprotection conferred by targeting cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the acute brain injury following subarachnoid hemorrhage. Methods— A total of 172 rats were used. Endovascular perforation induced subarachnoid hemorrhage. Two small interfering RNAs for CHOP were injected 24 hours before hemorrhage induction. At 24 or 72 hours, rats were neurologically evaluated and euthanized. The brains were recovered for molecular biology and histology studies. Results— Western blot analysis revealed effective silencing of CHOP associated with suppression of Bim-Caspase-3 apoptotic pathway. Moreover, the antiapoptotic Bcl2 was found upregulated with CHOP siRNA treatment. A reduced number of TUNEL-positive cells in the subcortex and in the hippocampus reflected histological protection. CHOP siRNA treatment ameliorated intracranial sequelae of and improved functional performance. Conclusions— We conclude that CHOP silencing alleviates early brain injury following subarachnoid hemorrhage via inhibiting apoptosis and that CHOP siRNA treatment has a clinical potential for patients with this type of hemorrhagic stroke.

Moderate Dietary Restriction Reduces p53-Mediated Neurovascular Damage and Microglia Activation After Hypoxic Ischemia in Neonatal Brain [Original Contributions; Basic Sciences]

Background and Purpose— Neurovascular damage, including neuronal apoptosis and blood–brain barrier (BBB) damage, and microglia activation account for the hypoxic-ischemia (HI) susceptibility in neonatal brain. The p53 upregulation is involved in apoptosis, endothelial cell damage, and microglia activation. We hypothesized that underweight induced by dietary restriction (DR) protects against HI in rat pups by attenuating p53-mediated neurovascular damage. Methods— Male rat pups were grouped as normal litter (NL) size (12 pups/dam), DR (18 pups/dam), and extreme DR (24 pups/dam) from postnatal day 1 and subjected to HI on postnatal day 7. Immunohistochemistry and immunoblotting were used to determine p53, phospho-murine double minute-2, caspases, BBB damage and microglia activation, and immunofluorescence to determine the cellular distribution of p53. Pharmacological approaches were used to regulate p53. Results— The NL, DR, and extreme DR pups had similar TUNEL-positive cells and caspases on postnatal day 7 and comparable learning performance at adulthood. After HI, the DR-HI, but not extreme DR-HI, pups had significantly lower p53, higher phospho-murine double minute-2, lower cleaved caspases, less BBB damage and microglia activation, and less brain volume loss than NL-HI pups. In NL-HI pups, p53 expression was located mainly in the neurons, endothelial cells, and microglia. The p53 blockage by pifithrin-α in NL-HI pups decreased apoptosis, BBB damage, and microglia activation, and was neuroprotective. In contrast, upregulating p53 by nutlin-3 in DR-HI pups increased apoptosis, BBB damage, and microglia activation, and worsened brain damage. Conclusions— Moderate DR, but not extreme DR, reduces p53-mediated neurovascular damage after HI and confers long-term protection in neonatal brain.

Cilostazol Reduces the Risk of Hemorrhagic Infarction After Administration of Tissue-Type Plasminogen Activator in a Murine Stroke Model [Original Contributions; Basic Sciences]

Background and Purpose— Prior use of antiplatelet agents improves stroke outcome in patients undergoing thrombolytic therapy as shown by reduced arterial reocclusion, although the risk of cerebral hemorrhage can be increased. Methods— The effect of cilostazol, an antiplatelet drug that improves endothelial function through upregulation of intracellular cAMP, on cerebral hemorrhage after thrombolytic therapy was investigated using a highly reproducible transient ischemia model. Results— Treatment with cilostazol for 7 days before ischemia significantly suppressed the risk and severity of cerebral hemorrhage after injection of tissue-type plasminogen activator, although treatment with aspirin had no such protective effect compared with nontreated mice. Immunohistological analysis revealed that treatment with cilostazol suppressed disruption of the microvasculature in the ischemic area associated with reduced matrix metalloproteinase-9 activity. Conclusions— Our results suggest that patients treated with cilostazol before onset of stroke could have a lower risk of cerebral hemorrhage after thrombolytic therapy and might also have a longer therapeutic time window for thrombolysis. Furthermore, the risk of cerebral hemorrhage can be significantly altered by prestroke therapies, and analysis of the effects of multiple drugs on tissue-type plasminogen activator-induced cerebral hemorrhage in animal models is essential for the extending safe and effective thrombolytic therapy to a wider group of patients.

Levodopa Treatment Improves Functional Recovery After Experimental Stroke [Original Contributions; Basic Sciences]

Background and Purpose— Delayed treatment of patients with stroke with levodopa/benserazide contributes to enhanced functional recovery, but the mechanisms involved are poorly understood. The present study was designed to investigate if levodopa/benserazide treatment improves recovery of lost neurological function and contributes to tissue reorganization in the rat brain after stroke. Methods— Male Wistar rats were subjected to transient occlusion of the middle cerebral artery (120 minutes) and treated with levodopa (1, 5, and 20 mg/kg)/benserazide (15 mg/kg) or saline for 12 consecutive days starting on Day 2 after transient occlusion of the middle cerebral artery. Infarct volume was determined and sensorimotor function was assessed using the rotating pole test, a 28-point neuroscore, and a cylinder test on Days 2, 7, and 14 after transient occlusion of the middle cerebral artery. The spatiotemporal expression pattern of dopamine-1 and dopamine-2 receptors and the dopamine- and cAMP-regulated neuronal phosphoprotein in reactive astrocytes were analyzed in the ischemic hemisphere as well as in cultured astrocytes. Results— Treatment with levodopa/benserazide significantly improved the recovery of sensorimotor function after transient occlusion of the middle cerebral artery without affecting the infarct volume. In addition, we found that different subpopulations of glial fibrillary acidic protein-positive astrocytes in the peri-infarct area express dopamine-1 receptors and dopamine-2 receptors as well as dopamine- and cAMP-regulated neuronal phosphoprotein. Conclusions— Our results strongly corroborate the concept of recovery enhancing actions of levodopa treatment after stroke. Also, astrocytes in the peri-infarct area may contribute to the dopamine enhanced recovery mechanisms.

Amyloid-{beta} Contributes to Blood-Brain Barrier Leakage in Transgenic Human Amyloid Precursor Protein Mice and in Humans With Cerebral Amyloid Angiopathy [Original Contributions; Basic Sciences]

Background and Purpose— Cerebral amyloid angiopathy (CAA) is a degenerative disorder characterized by amyloid-β (Aβ) deposition in the blood–brain barrier (BBB). CAA contributes to injuries of the neurovasculature including lobar hemorrhages, cortical microbleeds, ischemia, and superficial hemosiderosis. We postulate that CAA pathology is partially due to Aβ compromising the BBB. Methods— We characterized 19 patients with acute stroke with "probable CAA" for neurovascular pathology based on MRI and clinical findings. Also, we studied the effect of Aβ on the expression of tight junction proteins and matrix metalloproteases (MMPs) in isolated rat brain microvessels. Results— Two of 19 patients with CAA had asymptomatic BBB leakage and posterior reversible encephalopathic syndrome indicating increased BBB permeability. In addition to white matter changes, diffusion abnormality suggesting lacunar ischemia was found in 4 of 19 patients with CAA; superficial hemosiderosis was observed in 7 of 9 patients. Aβ40 decreased expression of the tight junction proteins claudin-1 and claudin-5 and increased expression of MMP-2 and MMP-9. Analysis of brain microvessels from transgenic mice overexpressing human amyloid precursor protein revealed the same expression pattern for tight junction and MMP proteins. Consistent with reduced tight junction and increased MMP expression and activity, permeability was increased in brain microvessels from human amyloid precursor protein mice compared with microvessels from wild-type controls. Conclusions— Our findings indicate that Aβ contributes to changes in brain microvessel tight junction and MMP expression, which compromises BBB integrity. We conclude that Aβ causes BBB leakage and that assessing BBB permeability could potentially help characterize CAA progression and be a surrogate marker for treatment response.

Plasmalemma Permeability and Necrotic Cell Death Phenotypes After Intracerebral Hemorrhage in Mice [Original Contributions; Basic Sciences]

Background and Purpose— Traumatic and ischemic brain injury induce plasmalemma permeability and necrosis; however, no studies have examined these aspects of cellular injury in intracerebral hemorrhage models. Methods— In vivo propidium iodide (PI) and YOYO-1 were used to assess plasmalemma damage after collagenase-induced intracerebral hemorrhage in mice. Ex vivo aspartylglutamylvalylaspartic acid, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, and electron microscopy were used to assess the relationship between plasmalemma permeability and mode of cell death. Cell types vulnerable to plasmalemma damage were determined by immunohistochemistry. Results— Plasmalemma permeability was first detected in the lesion at 1 to 3 hours and peaked at 48 to 72 hours. Neurons and IBA-1-positive cells with morphological features of monocytes were sensitive, whereas resident microglia and astrocytes were resistant to plasmalemma permeability. PI+ cells colocalized with fluorescent-labeled caspase substrates and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling beginning at 3 to 6 hours. At 48 hours, greater than half of injured cells were PI+/aspartylglutamylvalylaspartic acid– or PI+/terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling– suggesting necrosis, and <5% were PI–/terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling+ or PI–/aspartylglutamylvalylaspartic acid+. Electron microscopy confirmed ultrastructural features of necrosis at 24 hours after intracerebral hemorrhage, high mobility group box protein-1 was released from permeable cells, and mice deficient in receptor interacting protein kinase (RIPK) 3, a known necrosis trigger, had 50% less PI+ cells at 24 hours. Permeable cells remained in the brain for at least 24 hours with <10% spontaneous resealing. Conclusions— Necrosis contributes to cell demise after intracerebral hemorrhage. Programmed necrosis and plasmalemma damage may represent novel therapeutic targets to prevent cell death or rescue injured cells after intracerebral hemorrhage.

Restricted Diffusion in Spinal Cord Infarction Demonstrated by Magnetic Resonance Line Scan Diffusion Imaging [Original Contributions; Brief Reports]

Background and Purpose— We report on the use of line scan diffusion magnetic resonance imaging in the evaluation of spinal cord infarctions. Methods— Data on 19 patients with clinical findings consistent with spinal cord infarctions and abnormal findings on line scan diffusion imaging were reviewed. The Apparent Diffusion Coefficient (ADC) measurements for the normal spinal cord and for the areas of abnormality were calculated from trace ADC maps. Results— Restricted diffusion was found in all 19 patients. Absolute ADC values in the ischemic area ranged between 395.4 and 575.8x10–6 mm2/s, with ADC ratios ranging between 39.4% and 57.4%. Conclusions— Line scan diffusion imaging is technically feasible and appears to be a reliable method to diagnose spinal cord infarction in the acute setting.

Thrombolytic Therapy Rates and Stroke Severity: An Analysis of Data From the Swedish Stroke Register (Riks-Stroke) 2007-2010 [Original Contributions; Brief Reports]

Background and Purpose— We tested the hypothesis that higher proportions of patients with minor stroke being treated with thrombolysis contribute to increasing overall rates of thrombolysis. Methods— We included 1743 ischemic stroke patients (age 18–80 years) treated with thrombolysis, recorded in the Swedish stroke register Riks-Stroke between 2007 and 2010. Minor stroke was defined as National Institutes of Health Stroke Scale score ≤5. Results— The proportion with minor stroke among patients treated with thrombolysis increased from 22.1% in 2007 to 28.7% in 2010 (P=0.021). The rate of increase did not differ significantly between men and women, age groups, or hospital types (university hospitals, other large hospitals, or community hospitals). Hospitals with high proportions of thrombolysis patients with minor stroke were more likely to have high thrombolysis frequencies (R=0.55; P<0.001). Conclusions— In recent years, an increase in the proportion of patients with minor stroke treated with thrombolysis has contributed to rising overall thrombolysis rates in Sweden. At the hospital level, high rates of thrombolysis are associated with a high proportion of minor stroke being treated.

Fluid-Attenuated Inversion Recovery Images and Stroke Outcome After Thrombolysis [Original Contributions; Brief Reports]

Background and Purpose— We investigated if hyperintensities on fluid-attenuated inversion recovery (FLAIR) sequences in arteries and parenchyma are associated with poor outcome 3 months after thrombolysis. Methods— Consecutive acute stroke patients with known time of symptom onset who had an MRI before and 1 day after thrombolysis were included in this study. Blinded to follow-up imaging and outcome, 2 raters independently judged the presence or absence of arterial and parenchymal FLAIR hyperintensities. Functional outcome (modified Rankin Scale) was assessed after 3 months. Results— Out of 90 patients, 22 had parenchymal FLAIR hyperintensities and 42 had hyperintense vessels. The combination of FLAIR hyperintensities in arteries and parenchyma occurred in 15 patients. Stepwise forward regression analysis revealed an adjusted odds ratio of 14.5 for a worse outcome (modified Rankin Scale score >2) in patients with FLAIR hyperintensities in arteries and parenchyma (95% confidence interval, 1.3–158.5; P=0.03). Conclusions— FLAIR hyperintensities in arteries and parenchyma are an easy-to-use MRI feature in acute ischemic stroke associated with poor outcome 3 months after thrombolysis.

Aortic Stiffness Predicts Functional Outcome in Patients After Ischemic Stroke [Original Contributions; Brief Reports]

Background and Purpose— Increased aortic stiffness (measured by carotid–femoral pulse wave velocity) and central augmentation index have been shown to independently predict cardiovascular events, including stroke. We studied whether pulse wave velocity and central augmentation index predict functional outcome after ischemic stroke. Methods— In a prospective study, we enrolled 99 patients with acute ischemic stroke (age 63.7±12.4 years, admission National Institutes of Health Stroke Scale score 6.6±6.6, mean±SD). Carotid–femoral pulse wave velocity and central augmentation index (SphygmoCor) were measured 1 week after stroke onset. Functional outcome was evaluated 90 days after stroke using the modified Rankin Scale with modified Rankin Scale score of 0 to 1 considered an excellent outcome. Results— In univariate analysis, low carotid–femoral pulse wave velocity (P=0.000001) and low central augmentation index (P=0.028) were significantly associated with excellent stroke outcome. Age, severity of stroke, presence of previous stroke, diabetes, heart rate, and peripheral pressures also predicted stroke functional outcome. In multivariate analysis, the predictive value of carotid–femoral pulse wave velocity (<9.4 m/s) remained significant (OR, 0.21; 95% CI, 0.06–0.79; P=0.02) after adjustment for age, National Institutes of Health Stroke Scale score on admission, and presence of previous stroke. By contrast, central augmentation index had no significant predictive value after adjustment. Conclusions— This study indicates that aortic stiffness is an independent predictor of functional outcome in patients with acute ischemic stroke.

Effects of Public Education by Television on Knowledge of Early Stroke Symptoms Among a Japanese Population Aged 40 to 74 Years: A Controlled Study [Original Contributions; Brief Reports]

Background and Purpose— An educational campaign by mass media has been associated with great increases in the knowledge about early symptoms of stroke. However, few studies were conducted with a controlled community intervention study. Methods— To clarify the effects of a 1-year television campaign for the whole population on improvement of knowledge about stroke symptoms in 2 cities, a campaign area and a control area in Japan were selected. Before and after the campaign, 1960 randomly selected residents aged 40 to 74 years answered a telephone survey regarding knowledge of early stroke symptoms. We calculated the percentage and 95% CIs of participants who correctly chose all 5 early symptoms of stroke in each area and in each year. Results— Before the campaign, 53% of participants (95% CI, 50%–55%) in the campaign area and 46% (95% CI, 44%–49%) in the control area correctly chose 5 early symptoms. After the 1-year television campaign, knowledge was significantly improved only in the campaign area (campaign area, 63%; 95% CI, 60%–66%; control area, 51%; 95% CI, 48%–54%). After sex stratification, only women showed improved knowledge of early symptoms. The audience rate for the campaign television programs was found to be higher in women than in men. Conclusions– A 1-year stroke educational television campaign effectively improved knowledge about early stroke symptoms among Japanese women aged 40 to 74 years. No impact was found among men in this age group. Future studies should examine the impact of this approach on stroke knowledge among younger individuals and whether there are any behavioral changes that contribute to earlier presentation for treatment.

How Often Are Patients With Ischemic Stroke Eligible for Decompressive Hemicraniectomy? [Original Contributions; Brief Reports]

Background and Purpose— Malignant middle cerebral artery infarction is estimated to occur in 10% of ischemic strokes, but few patients undergo decompressive hemicraniectomy, a proven therapy. We determined the proportion of patients with ischemic stroke without significant baseline disability with large middle cerebral artery infarction who would have been potentially eligible for hemicraniectomy in an era before publication of recent hemicraniectomy trials. Methods— Ischemic stroke cases that occurred in 2005 among residents of the 5-county Greater Cincinnati/Northern Kentucky area were ascertained. Two study physicians reviewed all clinical and neuroimaging data for patients with baseline modified Rankin Scale score <2, age ≥18 years with National Institutes of Health Stroke Scale score ≥10. Large middle cerebral artery infarction was defined as >50% of the middle cerebral artery territory or >145 mL on diffusion-weighted MRI. Other eligibility criteria for hemicraniectomy, based on the pooled analysis of recent clinical trials, were age 18 to 60 years and National Institutes of Health Stroke Scale score >15. Results— Of 2227 ischemic strokes, 39 (1.8%) with baseline modified Rankin Scale score <2 had large middle cerebral artery infarction. None underwent hemicraniectomy, and 16 (41.0%) died within 30 days. Six patients (0.3% of all ischemic strokes) were potentially eligible for hemicraniectomy; 1 died within 30 days. Conclusions— Based on criteria from clinical trials, only 0.3% of cases were eligible for hemicraniectomy. Given the survival and functional outcome benefit in treated patients, future studies should determine whether additional subgroups of patients with ischemic stroke may benefit from hemicraniectomy.

Time Course of Vascular Reactivity Using Repeated Phase-Contrast MR Angiography in Patients With Carotid Artery Stenosis [Original Contributions; Brief Reports]

Background and Purpose— Cerebral vascular reactivity assessment is typically performed with 2 perfusion measurements before and after a vasodilatory challenge. The aim of this study was to assess the time course of the vasodilatory effect in the brain-feeding arteries after a challenge with acetazolamide in patients with a stenosis of the internal carotid artery (ICA). Methods— Twenty-one patients with a symptomatic ICA stenosis and 18 healthy control subjects underwent 2-dimensional phase-contrast MR angiography to repeatedly measure the blood flow (mL/min) in both ICAs at baseline and in 5-minute intervals for 30 minutes after intravenous administration of acetazolamide. Results— At baseline, the blood flow was significantly lower in the stenosed ICAs of patients (155±17 mL/min) than in the contralateral ICAs (237±21 mL/min, P<0.05) and the ICAs of healthy control subjects (249±15 mL/min, P<0.05) and remained lower throughout the time course. The maximum vasodilatory effect in the stenosed ICAs was observed after 15.3±0.9 minutes, which was significantly later than in the contralateral ICAs (within 12.9±0.7 minutes, P<0.05) and healthy ICAs (within 12.8±0.8 minutes, P<0.05). Conclusions— The onset of the maximum vasodilatory effect after administration of acetazolamide is delayed in patients with a symptomatic ICA stenosis.

Emergency Department Adherence to American Heart Association Guidelines for Blood Pressure Management in Acute Ischemic Stroke [Original Contributions; Brief Reports]

Background and Purpose— Severely elevated blood pressure (BP) and aggressive BP reduction are both associated with poor outcome in acute ischemic stroke (AIS). In nontissue-type plasminogen activator patients, the American Heart Association recommends antihypertensive therapy only if BP is ≥220/120 mm Hg with a goal of 15% to 25% reduction in the first 24 hours. We hypothesized that patients with AIS often receive antihypertensives in the emergency department below the recommended threshold and that BP reduction is often >20%. Methods— In 2005, AIS cases were ascertained at all 16 hospitals in Greater Cincinnati. BP was recorded at emergency department presentation and before and after antihypertensive treatment. Hypertension was defined as BP ≥220/120 mm Hg. Chi-square and Mann-Whitney U tests were used for comparisons. Results— A total of 1739 patients with AIS met inclusion criteria. Median age was 72 years with 43% male and 25% black. Of 218 treated with antihypertensives, 65 (30.0%) met treatment criteria immediately before treatment. Treated patients were younger (66 versus 73 years, P<0.001) with greater stroke severity than untreated patients (National Institutes of Health Stroke Scale score 4 versus 3, P=0.028). Median change in systolic BP was –25 mm Hg (range, –96 to 25 mm Hg). Median percentage change in systolic BP was –12.3% (range, –49.2% to 16.1%). Systolic BP decreased >20% in 52 treated patients (23.7%). Conclusions— Only one third of patients with AIS treated with antihypertensives met American Heart Association-recommended treatment criteria, and the rate of change of BP was frequently greater than recommended. Further studies are warranted to determine the impact of practice patterns on AIS outcomes.

Ninety-Day Outcome Rates of a Prospective Cohort of Consecutive Patients With Mild Ischemic Stroke [Original Contributions; Brief Reports]

Background and Purpose— Prior studies have shown that patients with mild ischemic stroke have substantial disability rates at hospital discharge. We sought to determine disability rates at 90 days among patients not treated with thrombolytic therapy and explore the role of early neurological worsening. Methods— We reviewed a prospective cohort of 136 consecutive patients with mild deficits (National Institutes of Health Stroke Scale score ≤5) presenting within 24 hours of onset and no baseline disability. Baseline MRIs were performed on all subjects. Five-day MRIs were performed on a prespecified subcohort. Results— Among 136 patients, 40 (29%; 95% CI, 22%–38%) had poor outcomes (modified Rankin Scale score 2–6) at 90 days. Early worsening (4-point National Institutes of Health Stroke Scale increase; 25% versus 1%, P<0.001) and acute infarct growth (>10% on MRI–diffusion-weighted imaging; 79% versus 53%, P=0.02) from baseline to 5 days were more common among those with poor outcome. Conclusions— Patients with mild ischemic stroke have substantial rates (29%) of disability at 90 days.

Systematic Review of Perfusion Imaging With Computed Tomography and Magnetic Resonance in Acute Ischemic Stroke: Heterogeneity of Acquisition and Postprocessing Parameters: A Translational Medicine Research Collaboration Multicentre Acute Stroke Imaging Study [Original Contributions; Brief Reports]

Background and Purpose— Heterogeneity of acquisition and postprocessing parameters for magnetic resonance– and computed tomography–based perfusion imaging in acute stroke may limit comparisons between studies, but the current degree of heterogeneity in the literature has not been precisely defined. Methods— We examined articles published before August 30, 2009 that reported perfusion thresholds, average lesion perfusion values, or correlations of perfusion deficit volumes from acute stroke patients <24 hours postictus. We compared acquisition parameters from published studies with guidance from the Acute Stroke Imaging Research Roadmap1. In addition, we assessed the consistency of postprocessing parameters. Results— Twenty computed tomography perfusion and 49 perfusion-weighted imaging studies were included from 7152 articles. Although certain parameters were reported frequently, consistently, and in line with the Roadmap proposals, we found substantial heterogeneity in other parameters, and there was considerable variation and underreporting of postprocessing methodology. Conclusions— There is substantial scope to increase homogeneity in future studies, eg, through reporting standards.

A Rat Model of Studying Tissue-Type Plasminogen Activator Thrombolysis in Ischemic Stroke With Diabetes [Original Contributions; Brief Reports]

Background and Purpose— Poststroke hyperglycemia and diabetes mellitus are associated with lower thrombolytic efficacy and an increased risk of postischemic cerebral hemorrhage. We aimed to develop a rodent model of thrombolysis in diabetic stroke that mimics the clinical situation. Method— Male 6-week Type I diabetic rats (14 weeks old) were subjected to embolic focal stroke and treated with tissue-type plasminogen activator at 1.5 hours. Reperfusion and 24-hour neurological outcomes were measured and compared with nondiabetic control rats. Results— Diabetic rats exhibited resistance to thrombolytic reperfusion, larger infarction volumes, and increased intracerebral hemorrhage. Conclusions— This animal model would be relevant to future studies investigating pathophysiological mechanisms and in developing new therapeutic approaches to enhance the efficacy of tissue-type plasminogen activator thrombolysis in stroke patients with diabetes or poststroke hyperglycemia.

Fasudil Decreases Lesion Burden in a Murine Model of Cerebral Cavernous Malformation Disease [Original Contributions; Brief Reports]

Background and Purpose— Cerebral cavernous malformations (CCMs) are characterized by grossly dilated capillaries, associated with vascular leak and hemorrhage, and occur in sporadic or inherited (autosomal-dominant) forms with mutations in 1 of 3 gene loci (CCM 1, 2 or 3). We previously reported that the CCM1 protein (KRIT1) localizes to endothelial cell–cell junctions and loss of KRIT1 leads to junctional instability associated with activation of RhoA and its effector Rho kinase. Although Rho kinase inhibition has been proposed as potential therapy for CCM, there has been no demonstration of a therapeutic effect on CCM lesion genesis in vivo. Methods— Our recently generated a model of CCM1 disease (Ccm1+/–Msh2–/–) was treated with the Rho kinase inhibitor fasudil (100 mg/kg/day administered in drinking water from weaning to 5 months of age), or placebo, and blindly assessed CCM lesion burden by systematic survey of animals' brains. For comparison, we also assessed therapeutic effect in previously described Ccm2+/–Trp53–/– mice treated with the same dose and duration of fasudil and placebo. Results— Fasudil-treated Ccm1+/–Msh2–/– mice had a significantly decreased prevalence of CCM lesions compared with placebo controls. Lesions in treated animals were smaller and less likely associated with hemorrhage, inflammation, and endothelial proliferation and exhibited decreased expression of Rho kinase activation biomarkers. A therapeutic effect was also documented in Ccm2+/–Trp53–/– mice. Conclusions— This represents the first report of therapeutic benefit of pharmacological therapy in development and progression of CCMs and indicates that Rho kinase activation is a critical step in CCM lesion genesis and maturation.

Transition to Collateral Flow After Arterial Occlusion Predisposes to Cerebral Venous Steal [Comments and Opinions]

Background and Purpose— Stroke-related tissue pressure increase in the core and penumbra determines regional cerebral perfusion pressure (rCPP) defined as a difference between local inflow pressure and venous or tissue pressure, whichever is higher. We previously showed that venous pressure reduction below the pressure in the core causes blood flow diversion–cerebral venous steal. Now we investigated how transition to collateral circulation after complete arterial occlusion affects rCPP distribution. Methods— We modified parallel Starling resistor model to simulate transition to collateral inflow after complete main stem occlusion. We decreased venous pressure from the arterial pressure to zero and investigated how arterial and venous pressure elevation augments rCPP. Results— When core pressure exceeded venous, rCPP=inflow pressure in the core. Venous pressure decrease from arterial pressure to pressure in the core caused smaller inflow pressure to drop augmenting rCPP. Further drop of venous pressure decreased rCPP in the core but augmented rCPP in penumbra. After transition to collateral circulation, lowering venous pressure below pressure in the penumbra further decreased rCPP and collaterals themselves became a pathway for steal. Venous pressure level at which rCPP in the core becomes zero we termed the "point of no reflow." Transition from direct to collateral circulation resulted in decreased inflow pressure, decreased rCPP, and a shift of point of no reflow to higher venous loading values. Arterial pressure augmentation increased rCPP, but only after venous pressure exceeded point of no reflow. Conclusions— In the presence of tissue pressure gradients, transition to collateral flow predisposes to venous steal (collateral failure), which may be reversed by venous pressure augmentation.

Is There a Future for Endovascular Treatment of Intracranial Atherosclerotic Disease After Stenting and Aggressive Medical Management for Preventing Recurrent Stroke and Intracranial Stenosis (SAMMPRIS)? [Comments and Opinions]

The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke and Intracranial Stenosis (SAMMPRIS) trial, a randomized clinical trial comparing aggressive medical management to stenting with aggressive medical management for symptomatic intracranial stenosis, was prematurely halted when a high rate of periprocedural events was found in the stent arm. The trial also demonstrated a high rate of stroke with medical management. This article explores possible reasons for these outcomes and discusses some weaknesses of the trial. Against this background endovascular therapy should continue to be explored in the treatment of this disease.

Tracks of a Non-Main Path Traveler: 2011 Thomas Willis Lecture [Special Reports]

After an unconventional beginning in stroke research, I veered off the main path repeatedly to view problems from a different perspective. In this lecture summary, I would like to return to several points along the byways that led to research with some continuity.

Adjunctive and Alternative Approaches to Current Reperfusion Therapy [Topical Reviews]

Background and Purpose— Current ischemic stroke reperfusion therapy consists of intravenous thrombolysis given in eligible patients after review of a noncontrast CT scan and a time-based window of opportunity. Rapid clot lysis has a strong association with clinical improvement but remains incomplete in many patients. This review appraises novel adjunctive or alternative approaches to current reperfusion strategies being tested in all trial phases. Summary of Review— Alternative approaches to current reperfusion therapy can be separated into 4 main categories: (1) combinatory approaches with other drugs or devices; (2) novel systemic thrombolytic agents; (3) endovascular medical or mechanical reperfusion treatments; and (4) noninvasive or minimally invasive methods to augment cerebral blood flow and alleviate intracranial blood flow steal. Conclusions— Reperfusion treatments must be provided as fast as possible in patients most likely to benefit. Patients who fail to rapidly reperfuse may benefit from other strategies that maintain collateral flow or protect tissue at risk.