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Rationale Whether treatment with intravenous alteplase prior to mechanical thrombectomy (MT) in acute ischemic stroke patients with large vessel occlusion is beneficial remains unclear. Aim To determine whether patients experiencing acute ischemic stroke due to occlusion of the intracranial internal carotid artery or the M1 segment of the middle cerebral artery who are referred to an endovascular stroke center and who are candidates for intravenous alteplase will have non-inferior functional outcome at 90 days when treated with MT alone (direct MT) with stent retrievers compared to patients treated with combined intravenous thrombolysis (IVT) with alteplase plus MT (IVT + MT) with stent retrievers. Sample size To randomize 404 patients 1:1 to direct MT or combined IVT+MT. Methods and design A multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) trial utilizing an adaptive statistical design. Outcomes The primary efficacy endpoint is functional independence (modified Rankin Scale 0–2) at 90 days. Secondary clinical efficacy outcomes include change in National Institutes of Health Stroke Scale score from baseline to day 1 and health-related quality of life at 90 days. Secondary technical efficacy outcomes include successful reperfusion prior to start of MT and time from randomization to successful reperfusion. Safety outcomes include all serious adverse events, symptomatic intracranial hemorrhage, and mortality up to 90 days. Discussion SWIFT DIRECT will inform physicians whether direct MT in acute ischemic stroke patients with large vessel occlusion is equally or more efficacious than combined treatment with intravenous alteplase and MT. Trial registration ClinicalTrials.gov Identifier: NCT03192332

Introduction Stroke remains a global concern due to increasing lifespan, patterns of industrialization, adoption of harmful western diets, and an increasing prevalence of risk factors such as hypertension, obesity, and diabetes. We investigated an adopted novel self-management intervention, TargetEd mAnageMent Intervention (TEAM) to reduce modifiable stroke risk factors in Uganda. Methods A six-month, uncontrolled, prospective pilot study to establish feasibility, acceptability and preliminary efficacy of TEAM in Ugandans at high risk for stroke was conducted. The primary outcome was change in systolic BP from baseline to 24-week follow-up. Secondary outcomes included change in diastolic BP, serum cholesterol, high and low density lipoprotein (HDL, LDL) and triglycerides. Results Mean (SD) baseline systolic BP was 162.9 (± 25.6) mmHg while mean (SD) baseline diastolic BP was 99.1 (± 13.8) mmHg. There was a significant reduction in mean baseline blood pressure of 163/98.8 mmHg to blood pressure of 147.8/88.0 mmHg at 24 weeks, P = 0.023. There were also significant reductions in the serum total cholesterol levels at 24 weeks with P = 0.001. Conclusion Targeted training in self-management (TEAM) adapted to the Ugandan setting is feasible, highly acceptable to participants and appears to be associated with reduced blood pressure, improved lipid profiles and improved glucose control in diabetics.

BACKGROUND The effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy. METHODS We enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (= 80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating more severe disability) at 90 days. RESULTS A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P = 0.50), nor did 90-day mortality (19% and 18%, respectively; P = 1.00). CONCLUSIONS Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone. (Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283.)

Background and Purpose— The visual analogue scale is a self-reported, validated tool to measure quality of life (QoL). Our purpose was to determine whether baseline QoL predicted strokes in the ALLHAT study (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial) and evaluate determinants of poststroke change in QoL. In the ALLHAT study, among the 33 357 patients randomized to treatment arms, 1525 experienced strokes; 1202 (79%) strokes were nonfatal. This study cohort includes 32 318 (97%) subjects who completed the baseline visual analogue scale QoL estimate. Methods— QoL was measured on a visual analogue scale and adjusted using a Torrance transformation (transformed QoL [TQoL]). Kaplan–Meier curves and adjusted proportional hazards analyses were used to estimate the effect of TQoL on the risk of stroke, on a continuous scale (0–1) and by quartiles (≤0.81, >0.81≤0.89, >0.89≤0.95, >0.95). We analyzed the change from baseline to first poststroke TQoL using adjusted linear regression. Results— After adjusting for multiple stroke risk factors, the hazard ratio for stroke events for baseline TQoL was 0.93 (95% confidence interval, 0.89–0.98) per 0.1 U increase. The lowest baseline TQoL quartile had a 20% increased stroke risk (hazard ratio=1.20 [95% confidence interval, 1.00–1.44]) compared with the reference highest quartile TQoL. Poststroke TQoL change was significant within all treatment groups ( P ≤0.001). Multivariate regression analysis revealed that baseline TQoL was the strongest predictor of poststroke TQoL with similar results for the untransformed QoL. Conclusions— The lowest baseline TQoL quartile had a 20% higher stroke risk than the highest quartile. Baseline TQoL was the only factor that predicted poststroke change in TQoL. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00000542.

Intravenous thrombolysis (IVT) with recombinant intravenous (IV) tPA (tissue-type plasminogen activator) significantly improves the odds of good outcome after ischemic stroke when delivered within 4.5 hours of stroke onset, irrespective of age and over a broad range of stroke severity, and despite an increased risk of intracranial hemorrhage (ICH).1 Therefore, in the absence of contraindications, IVT is the standard therapy for all patients presenting with an acute ischemic stroke (AIS) within 4.5 hours after symptom onset.2 However, IVT has some important limitations, such as a narrow time window with a rapidly decreasing efficacy and a rapidly increasing number needed to treat,1 the overall increase of fatal ICH compared with placebo,1 a poor recanalization rate in patients with large thrombus burden,3 and various contraindications, such as pretreatment with oral anticoagulants and unclear time of symptom onset. Endovascular stroke treatment (EVT) in combination with IVT (ie, bridging thrombolysis) has the potential to overcome some limitations of IVT, especially the poor recanalization rate of patients with large vessel occlusions (LVOs). Three randomized controlled trials (RCTs) published in 2013 failed to demonstrate superior clinical outcomes of EVT.4–6 However, since December 2014, 8 RCTs testing newer devices have consistently shown that mechanical thrombectomy (MT) in addition to best medical treatment (with and without IV tPA) improves outcome in anterior circulation (AC) ischemic stroke patients with LVO compared with best medical treatment alone.7–14 These later trials used second-generation devices, required imaging confirmation of LVO, emphasized rapid time to reperfusion, and excluded patients with a priori high chance of futile recanalization (ie, patients with large areas of brain tissue who had already undergone infraction or patients with poor collaterals). MT with stent retriever in addition to IVT is now the recommended treatment for AIS patients with …

Approximately 795 000 strokes occur annually in the United States, and stroke remains a leading cause of major disability.1 Ischemic stroke accounts for ≈85% of cases, whereas the remaining 15% are attributable to hemorrhagic pathogeneses. Despite increased public awareness, improved prehospital triage and a greater focus on systems of care, intravenous tissue-type plasminogen activator, and endovascular intervention remain underutilized.2 Recent advances in endovascular technology, coupled with the positive results of at least 5 major clinical trials, support the efficacy of mechanical thrombectomy as a treatment of ischemic stroke.3–6 These studies emphasize that interventional capabilities are an essential element of stroke care. Before the completion of these interventional trials, several simultaneous efforts arose to provide a method of certifying institutions as being optimized for advanced cerebrovascular care, and these efforts were inclusive of ischemic and hemorrhagic disease. It is in the spirit of constant iterative improvement that the authors of this article call for a refinement of the requirements for the certification of hospitals as comprehensive stroke centers (CSCs). The certification process has the potential to serve an important function in improving the quality of care and patient outcomes by establishing criteria for certification of stroke centers. The Cerebrovascular Coalition (CVC), which represents all neuroscience-based physician professional societies in the United States (CVC member organizations include the American Academy of Neurology, American Association of Neurological Surgeons, Congress of Neurological Surgeons, Society of Vascular and Interventional Neurology, American Society of Neuroradiology, and the Society of NeuroInterventional Surgery) involved in the care of patients with acute stroke, embraces and applauds the need for greater access to acute stroke therapy. The CVC thinks that, in principle, a certification process for stroke centers can have a positive impact on patient care and outcomes. The Joint Commission (TJC), in partnership with the …

Rationale Efficacy of mechanical thrombectomy for acute stroke due to large vessel occlusion initiated beyond 6 h of time last seen well has not been demonstrated in randomized trials. Aim To establish whether subjects considered to have substantial areas of salvageable brain based on age-adjusted clinical core mismatch who can undergo endovascular treatment within 6–24 h from time last seen well (TLSW) have better outcomes at three months compared to subjects treated with standard medical therapy alone. Age-adjusted clinical core mismatch is defined by age (≤80 or >80 years), baseline National Institutes of Health Stroke Scale (NIHSS) (10–20 or ≥21), and core size (0–20 cm3 in subjects older than 80 and, in subjects younger than 80, 0–30 cm3 with NIHSS 10–20 and 31–50 cm3 with NIHSS ≥21). Design Prospective, randomized, multicenter, Bayesian adaptive-enrichment, open label trial with blinded endpoint assessment. For the purpose of enrolment, ischemic core size will be evaluated by CT perfusion or magnetic resonance imaging-diffusion-weighted imaging measured by automated software (RAPID). Procedures Subjects with acute ischemic stroke due to computed tomography angiography- or magnetic resonance angiogram-proven arterial occlusion of the intracranial internal carotid and/or proximal middle cerebral artery (M1) with age-adjusted clinical core mismatch in whom treatment can be initiated between 6 and 24 h from TSLW are randomized in a 1:1 ratio to receive mechanical embolectomy with the Trevo device or medical management alone. Sequential interim analyses allowing adaptation of enrolment criteria or stopping new enrolment for futility or predicted success will occur in every 50 randomized patients starting at 150 to a maximum of 500 patients. Study outcomes The primary endpoint is the modified Rankin Scale score at 90 days. The primary safety outcome is stroke-related mortality at 90 days. Analysis The primary endpoint, expressed as a utility-weighted modified Rankin Scale score is analyzed using a Bayesian posterior probability with adjustment for ischemic core size. For regulatory reasons, a nested co-primary endpoint analysis was added consisting of the proportion of subjects with modified Rankin Scale 0–2 between the active and control groups also analyzed using a Bayesian model.

The purpose of this study is to determine if the common insurance practice of requiring precertification before a medically ready stroke patient can be discharged to a skilled nursing facility (SNF) or inpatient rehabilitation facility (IRF) causes a delay in discharge. Eliminating delays in discharge of stroke patients is important given the increasing demands for health-care efficiency after the passage of the Affordable Health Care Act.A retrospective chart review of 1007 patients who were admitted to our comprehensive stroke center with the primary diagnosis of stroke over a 12-month period was performed. Out of the patient pool, 289 patients met the inclusion criterion of a primary diagnosis of stroke that required discharge to a SNF or IRF. All 289 patients were medically cleared for discharge to a SNF or IRF by a board-certified vascular neurologist.Of the 289 patients who met the inclusion criteria, 118 required insurance precertification and 171 did not require precertification before being discharged to a SNF or IRF. All 118 patients who required precertification had private health insurance. The patients who required insurance precertification had an average delay of discharge (DOD) of 1.5 days, and those patients who did not require precertification had an average DOD of .8 days (P value.0001). After removing the outliers, the difference in the length of stay (LOS) between the 2 groups became statistically significant (P value .04).The results of this study demonstrate that insurance precertification leads to delay in discharge, increased LOS, and increased hospital costs for stroke patients.

Background and Purpose: In patients with cryptogenic stroke and patent foramen ovale (PFO), the Risk of Paradoxical Embolism (RoPE) Score has been proposed as a method to estimate a patient-specific “PFO-attributable fraction”—the probability that a documented PFO is causally-related to the stroke, rather than an incidental finding. The objective of this research is to examine the relationship between this RoPE-estimated PFO-attributable fraction and the effect of closure in 3 randomized trials. Methods: We pooled data from the CLOSURE-I (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale), RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment), and PC (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale [PFO] Using the Amplatzer PFO Occluder With Medical Treatment in Patients With Cryptogenic Embolism) trials. We examine the treatment effect of closure in high RoPE score (≥7) versus low RoPE score ( Results: In the low RoPE score group (P =0.56) compared with 0.30 versus 1.03 (hazard ratio, 0.31 [0.11–0.85] P =0.02) in the high RoPE score group (≥7, n=1221); treatment-by-RoPE score group interaction, P =0.12. The RoPE score estimated attributable fraction anticipated the relative risk reduction across all levels of the RoPE score, in both the 3-trial ( r =0.95, P r =0.92, P Conclusions: The RoPE score estimated attributable fraction is highly correlated to the relative risk reduction of device versus medical therapy. This observation suggests the RoPE score identifies patients with cryptogenic stroke who are likely to have a PFO that is pathogenic rather than incidental.

Background and Purpose— The Stroke Imaging Research (STIR) group, the Imaging Working Group of StrokeNet, the American Society of Neuroradiology, and the Foundation of the American Society of Neuroradiology sponsored an imaging session and workshop during the Stroke Treatment Academy Industry Roundtable (STAIR) IX on October 5 to 6, 2015 in Washington, DC. The purpose of this roadmap was to focus on the role of imaging in future research and clinical trials. Methods— This forum brought together stroke neurologists, neuroradiologists, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke (NINDS), industry representatives, and members of the US Food and Drug Administration to discuss STIR priorities in the light of an unprecedented series of positive acute stroke endovascular therapy clinical trials. Results— The imaging session summarized and compared the imaging components of the recent positive endovascular trials and proposed opportunities for pooled analyses. The imaging workshop developed consensus recommendations for optimal imaging methods for the acquisition and analysis of core, mismatch, and collaterals across multiple modalities, and also a standardized approach for measuring the final infarct volume in prospective clinical trials. Conclusions— Recent positive acute stroke endovascular clinical trials have demonstrated the added value of neurovascular imaging. The optimal imaging profile for endovascular treatment includes large vessel occlusion, smaller core, good collaterals, and large penumbra. However, equivalent definitions for the imaging profile parameters across modalities are needed, and a standardization effort is warranted, potentially leveraging the pooled data resulting from the recent positive endovascular trials.

Background The comparative effectiveness of percutaneous closure of patent foramen ovale (PFO) plus medical therapy versus medical therapy alone for cryptogenic stroke is uncertain. Objectives The authors performed the first pooled analysis of individual participant data from completed randomized trials comparing PFO closure versus medical therapy in patients with cryptogenic stroke. Methods The analysis included data on 2 devices (STARFlex [umbrella occluder] [NMT Medical, Inc., Boston, Massachusetts] and Amplatzer PFO Occluder [disc occluder] [AGA Medical/St. Jude Medical, St. Paul, Minnesota]) evaluated in 3 trials. The primary composite outcome was stroke, transient ischemic attack, or death; the secondary outcome was stroke. We used log-rank tests and unadjusted and covariate-adjusted Cox regression models to compare device closure versus medical therapy. Results Among 2,303 patients, closure was not significantly associated with the primary composite outcome. The difference became significant after covariate adjustment (hazard ratio [HR]: 0.68; p = 0.049). For the outcome of stroke, all comparisons were statistically significant, with unadjusted and adjusted HRs of 0.58 (p = 0.043) and 0.58 (p = 0.044), respectively. In analyses limited to the 2 disc occluder device trials, the effect of closure was not significant for the composite outcome, but was for the stroke outcome (unadjusted HR: 0.39; p = 0.013). Subgroup analyses did not identify significant heterogeneity of treatment effects. Atrial fibrillation was more common among closure patients. Conclusions Among patients with PFO and cryptogenic stroke, closure reduced recurrent stroke and had a statistically significant effect on the composite of stroke, transient ischemic attack, and death in adjusted but not unadjusted analyses.

Introduction The lack of adequate knowledge poses a barrier in the provision of appropriate treatment and care of patients with epilepsy within the community. The purpose of this study was to determine the knowledge of and attitude towards epilepsy and its treatment by community dwellers in Uganda. Methods A cross sectional population survey was conducted in urban and rural Mukono district, central Uganda. Adult respondents through multistage stratified sampling were interviewed about selected aspects of epilepsy knowledge, attitudes, and perception using a pretested structured questionnaire. Results Ninety-one percent of the study respondents had heard or read about epilepsy or knew someone who had epilepsy and had seen someone having a seizure. Thirty-seven percent of the respondents did not know the cause of epilepsy, while 29% cited genetic causes. About seventeen percent of the subjects believed that epilepsy is contagious. Only 5.6% (21/377) of the respondents would take a patient with epilepsy to hospital for treatment. Conclusion Adults in Mukono are very acquainted with epilepsy but have many erroneous beliefs about the condition. Negative attitudes are pervasive within communities in Uganda. The national epilepsy awareness programs need to clarify the purported modes of transmission of epilepsy, available treatment options, and care offered during epileptic seizures during community sensitizations in our settings.

Objective: Many examine patient outcomes following endovascular therapy for acute ischemic stroke, but we wanted to better understand why patients presenting within the window for this therapy did not receive it and their outcomes. Methods: We retrospectively examined a cohort of 275 patients with a discharge diagnosis of ischemic stroke, NIHSS≥6 and last known normal (LKN) time Results: Reasons patients did not receive intervention were patent major intracranial vessels (32%), no penumbra on CT or MRI (11.7%), large core infarct (16%), low NIHSS or significant improvement (8%), cerebral ischemia not suspected at admission (6.6%), poor baseline (6.2%) and advanced age (4.4%). Mean decision time for patients without penumbra or large core infarcts was not different from other patients in the cohort. Inability to treat patients within 6 hours was associated with a longer decision time (119 minutes longer, CI 54-185, p value =0.0004), but the time increase was due to transfer, not decision time relative to arrival at the tertiary care center. Patients for whom ischemic stroke was not considered at admission were most likely to present with seizure (33%) or posterior circulation symptoms (22%). Patients not receiving endovascular therapy due to mild/improving symptoms had significant deficits at discharge (mean mRS of 3; 18% discharged to a skilled nursing facility; 41% to an acute rehabilitation facility). At 3 months the mean mRS was 2. Conclusion: The most common reasons patients did not receive endovascular therapy were patent major intracranial vessels, no penumbra and large core infarct. These patients would be unlikely to benefit and might be harmed by intervention. Conversely, patients not treated due to mild/improving symptoms had significant deficits at discharge and 3 months and may have benefited from intervention.

Object The role of endovascular therapy in patients with acute ischemic stroke and a solitary M2 occlusion remains unclear. Through a pooled analysis of 3 interventional stroke trials, the authors sought to analyze the impact of successful early reperfusion of M2 occlusions on patient outcome. Methods Patients with a solitary M2 occlusion were identified from the Prolyse in Acute Cerebral Thromboembolism (PROACT) II, Interventional Management of Stroke (IMS), and IMS II trial databases and were divided into 2 groups: successful reperfusion (thrombolysis in cerebral infarction [TICI] 2–3) at 2 hours and failed reperfusion (TICI 0–1) at 2 hours. Baseline characteristics and clinical outcomes were compared. Results Sixty-three patients, 40 from PROACT II and 23 from IMS and IMS II, were identified. Successful early angiographic reperfusion (TICI 2–3) was observed in 31 patients (49.2%). No statistically significant difference in the rates of intracerebral hemorrhage (60.9% vs 47.6%, p = 0.55) or mortality (19.4% vs 15.6%, p = 0.75) was observed. However, there was a trend toward higher incidence of symptomatic hemorrhage in the TICI 2–3 group (17.4% vs 0%, p = 0.11). There was also a trend toward higher baseline glucose levels in this group (151.5 mg/dl vs 129.6 mg/ dl, p = 0.09). Despite these differences, the rate of functional independence (modified Rankin Scale Score 0–2) at 3 months was similar (TICI 2–3, 58.1% vs TICI 0–1, 53.1%; p = 0.80). Conclusions A positive correlation between successful early reperfusion and clinical outcome could not be demonstrated for patients with M2 occlusion. Irrespective of reperfusion status, such patients have better outcomes than those with more proximal occlusions, with more than 50% achieving functional independence at 3 months.

Background and Purpose— Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) has been used to estimate diffusion-weighted imaging (DWI) lesion volume in acute stroke. We aimed to assess correlations of DWI-ASPECTS with lesion volume in different middle cerebral artery (MCA) subregions and reproduce existing ASPECTS thresholds of a malignant profile defined by lesion volume ≥100 mL. Methods— We analyzed data of patients with MCA stroke from a prospective observational study of DWI and fluid-attenuated inversion recovery in acute stroke. DWI-ASPECTS and lesion volume were calculated. The population was divided into subgroups based on lesion localization (superficial MCA territory, deep MCA territory, or both). Correlation of ASPECTS and infarct volume was calculated, and receiver-operating characteristics curve analysis was performed to identify the optimal ASPECTS threshold for ≥100-mL lesion volume. Results— A total of 496 patients were included. There was a significant negative correlation between ASPECTS and DWI lesion volume ( r =–0.78; P r =–0.19; P =0.038) when compared with superficial ( r =–0.72; P r =–0.72; P Conclusions— ASPECTS has limitations when lesion location is not considered. Identification of patients with malignant profile by DWI-ASPECTS may be unreliable. ASPECTS may be a useful tool for the evaluation of noncontrast computed tomography. However, if MRI is used, ASPECTS seems dispensable because lesion volume can easily be quantified on DWI maps.

Objectives This study sought to identify predictors of recurrent ischemic neurologic events within the CLOSURE I (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale) trial. Background The CLOSURE I trial found that transcatheter patent foramen ovale (PFO) closure using the STARFlex device was not superior to medical therapy in patients with cryptogenic stroke or transient ischemic attack (TIA) and PFO. Methods The CLOSURE I trial is a multicenter, randomized trial of transcatheter PFO closure compared with medical therapy in patients who presented with cryptogenic stroke or TIA and had a PFO. We identified clinical predictors of recurrent ischemic stroke or TIA during 2 years of follow-up using Cox proportional hazards regression within the pooled intention-to-treat cohort. Results In 909 patients, the incidence of recurrent events was 5.7% with 25 patients suffering a recurrent stroke and 30 a TIA. Patients who had a recurrent event had higher body mass index (30.2 ± 6.2 vs. 28.3 ± 5.8%; p = 0.03) and more frequently had diabetes (19.2% vs. 7.1%; p = 0.0016), hypertension (46.2% vs. 30.1%; p = 0.015), and ischemic heart disease (3.8% vs. 0.9%; p = 0.05). Diabetes (hazard ratio [HR]: 3.39; 95% confidence interval [CI]: 1.69 to 6.84; p = 0.0007), index TIA (HR vs. stroke: 2.13; 95% CI: 1.20 to 3.80; p = 0.01), and the detection of atrial fibrillation after study enrollment (HR: 4.85; 95% CI: 2.05 to 11.47; p = 0.0003) independently predicted recurrent ischemic neurologic events. Recurrent neurologic events were more frequent in subjects with RoPE (Risk of Paradoxical Embolism) score ≤5 than those with >5 (14.5% vs. 4.2%; p Conclusions These findings suggest an alternative etiology to paradoxical embolism was frequently responsible for recurrent events within the CLOSURE I trial. (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke or TIA Due to the Possible Passage of a Clot of Unknown Origin Through a Patent Foramen Ovale (PFO) [CLOSURE I]; NCT00201461 )

Background and Purpose— Early blood–brain barrier damage after acute ischemic stroke has previously been qualitatively linked to subsequent intracranial hemorrhage (ICH). In this quantitative study, it was investigated whether the amount of blood–brain barrier damage evident on pre–tissue-type plasminogen activator MRI scans was related to the degree of post–tissue-type plasminogen activator ICH in patients with acute ischemic stroke. Methods— Analysis was performed on a database of patients with acute ischemic stroke provided by the Stroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA) Imaging Investigators. Patients with perfusion-weighted imaging lesions >10 mL and negative gradient-recalled echo imaging before intravenous tissue-type plasminogen activator were included. Postprocessing of the perfusion-weighted imaging source images was performed to estimate changes in blood–brain barrier permeability within the perfusion deficit relative to the unaffected hemisphere. Follow-up gradient-recalled echo images were reviewed for evidence of ICH and divided into 3 groups according to European Cooperative Acute Stroke Study (ECASS) criteria: no hemorrhage, hemorrhagic infarction, and parenchymal hematoma. Results— Seventy-five patients from the database met the inclusion criteria, 28 of whom experienced ICH, of which 19 were classified as hemorrhagic infarction and 9 were classified as parenchymal hematoma. The mean permeability (±SDs), expressed as an index of contrast leakage, was 17.0±8.8% in the no hemorrhage group, 19.4±4.0% in the hemorrhagic infarction group, and 24.6±4.5% in the parenchymal hematoma group. Permeability was significantly correlated with ICH grade in univariate ( P= 0.007) and multivariate ( P= 0.008) linear regression modeling. Conclusions— A perfusion-weighted imaging–derived index of blood–brain barrier damage measured before intravenous tissue-type plasminogen activator is given is associated with the severity of ICH after treatment in patients with acute ischemic stroke.

Objective Primary CNS Vasculitis (PCNSV) is a rare disease that is often challenging to diagnose. Cerebral angiography and biopsy have been utilized in the diagnostic workup for several decades but limited literature reports on the concordance of findings of angiography and biopsy. The primary objective of this work was to examine how cerebral angiography corresponded with biopsy findings in patients with suspected PCNSV. Patients and methods A total of 128 patients who underwent workup for PCNSV between years 2005–2016 were identified by query of existing neurological surgery and angiography databases at University Hospitals Cleveland Medical Center (UHCMC) and the Cleveland Clinic Foundation (CCF). The primary outcome was to examine the concordance of results between angiography and cerebral biopsy. Secondary outcomes included examining concordance between results of biopsy and other commonly performed tests for diagnosis of PCNSV including Magnetic Resonance Imaging (MRI), cerebrospinal fluid white blood cell count (CSF WBC), Erythrocyte Sedimentation Rate (ESR), C-reactive protein (CRP). Results 128 patients underwent cerebral biopsy for diagnosis of suspected PCNSV. 93 (73%) of these patients also underwent angiography. Of the 34 patients with positive biopsy findings, only 5 also had positive angiography. Positive angiography was not found to be correlated with positive biopsy in our analysis. The only test that was significantly associated with biopsy proven vasculitis was increased CSF WBC count (P = 0.0114). Conclusions PCNSV is a rare disease and often requires multiple tests or procedures to obtain definitive diagnosis. These results suggest that cerebral angiography findings are not associated with biopsy findings and should be used cautiously in the diagnostic work-up of PCNSV.

Although many stroke centers worldwide have performed endovascular stroke therapy since the results of the Prolyse in Acute Cerebral Thromboembolism (PROACT) II trial were published in 1999,1 lingering uncertainties about efficacy and the selection of patients created an uneasy equipoise. Especially nettlesome was the uncertain benefit of endovascular therapy as compared with intravenous tissue plasminogen activator (t-PA). The controversy over endovascular therapy was heightened in 2013 when the results of the Interventional Management of Stroke (IMS) III,2 Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE),3 and Local versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS Expansion)4 clinical . . .

Introduction: The Risk of Paradoxical Embolism (RoPE) Score can disaggregate patients with cryptogenic stroke (CS) and patent foramen ovale (PFO) into those who are more likely to have a pathogenic PFO (high RoPE score) than an incidental PFO (low RoPE score). Those with higher RoPE scores have a lower risk of recurrent stroke and different recurrence predictors compared to those with low RoPE scores. Hypotheses: Patients with high RoPE scores benefit more from PFO closure than patients with low RoPE scores. Patients with high RoPE scores and risk factors for recurrence should benefit even more. Methods: The RoPE score was created from a database of CS patients with known PFO status to estimate stratum-specific PFO-attributable fraction and recurrence rates. Variables that predict stroke recurrence in high RoPE score groups (atrial septal aneurysm, history of stroke/TIA prior to index event) were added – the “RoPE Recurrence Score.” Using pooled individual patient data from all 3 RCTs of PFO closure vs. medical therapy (ITT populations; stroke outcome) we tested the ability of the scores to predict the heterogeneity of response to assigned treatment. Results: The mean RoPE score was significantly higher (6.8 vs. 6.3) with smaller variance (Stdev 1.5 vs. 1.9) in the pooled RCT population than in the original RoPE cohort (p Conclusion: As expected, the HR favoring closure trended lower in the high RoPE score group in the RCTs but missed statistical significance. The RoPE Recurrence score did not improve the prediction. This may be due to the narrow distribution of relatively high RoPE scores amongst RCT patients and so a low power to detect heterogeneity of treatment effect. Given that PFO closure can only prevent PFO-related recurrences, the treatment effect may also have been obscured by including recurrent strokes with non-PFO-related mechanisms.

Background Integrated care pathways (ICP) in stroke management are increasingly being implemented to improve outcomes of acute stroke patients. We evaluated the effect of implementing a 72 hour stroke care bundle on early outcomes among patients admitted within seven days post stroke to the national referral hospital in Uganda. Methods In a one year non-randomised controlled study, 127 stroke patients who had ‘usual care’ (control group) were compared to 127 stroke patients who received selected elements from an ICP (intervention group). Patients were consecutively enrolled (controls first, intervention group second) into each group over 5 month periods and followed to 30-days post stroke. Incidence outcomes (mortality and functional ability) were compared using chi square test and adjusted for potential confounders. Kaplan Meier survival estimates and log rank test for comparison were used for time to death analysis for all strokes and by stroke severity categories. Secondary outcomes were in-hospital mortality, median survival time and median length of hospital stay. Results Mortality within 7 days was higher in the intervention group compared to controls (RR 13.1, 95% CI 3.3–52.9). There was no difference in 30-day mortality between the two groups (RR 1.2, 95% CI 0.5–2.6). There was better 30-day survival in patients with severe stroke in the intervention group compared to controls (P = 0.018). The median survival time was 30 days (IQR 29–30 days) in the control group and 30 days (IQR 7–30 days) in the intervention group. In the intervention group, 41patients (32.3%) died in hospital compared to 23 (18.1%) in controls (P < 0.001). The median length of hospital stay was 8 days (IQR 5–12 days) in the controls and 4 days (IQR 2–7 days) in the intervention group. There was no difference in functional outcomes between the groups (RR 0.9, 95% CI 0.4–2.2). Conclusions While implementing elements of a stroke-focused ICP in a Ugandan national referral hospital appeared to have little overall benefit in mortality and functioning, patients with severe stroke may benefit on selected outcomes. More research is needed to better understand how and when stroke protocols should be implemented in sub-Saharan African settings. Trial Registration Pan African Clinical Trials Registry PACTR201510001272347

Background and Purpose— The DIAS-2 study was the only large, randomized, intravenous, thrombolytic trial that selected patients based on the presence of ischemic penumbra. However, DIAS-2 did not confirm the positive findings of the smaller DEDAS and DIAS trials, which also used penumbral selection. Therefore, a reevaluation of the penumbra selection strategy is warranted. Methods— In post hoc analyses we assessed the relationships of magnetic resonance imaging–measured lesion volumes with clinical measures in DIAS-2, and the relationships of the presence and size of the diffusion-perfusion mismatch with the clinical effect of desmoteplase in DIAS-2 and in pooled data from DIAS, DEDAS, and DIAS-2. Results— In DIAS-2, lesion volumes correlated with National Institutes of Health Stroke Scale (NIHSS) at both baseline and final time points ( P P =0.004). In the pooled analysis, desmoteplase was associated with 47% clinical response rate (n=143) vs 34% in placebo (n=73; P =0.08). For both the pooled sample and for DIAS-2, increasing the minimum baseline mismatch volume (MMV) for inclusion increased the desmoteplase effect size. The odds ratio for good clinical response between desmoteplase and placebo treatment was 2.83 (95% confidence interval, 1.16–6.94; P =0.023) for MMV >60 mL. Increasing the minimum NIHSS score for inclusion did not affect treatment effect size. Conclusions— Pooled across all desmoteplase trials, desmoteplase appears beneficial in patients with large MMV and ineffective in patients with small MMV. These results support a modified diffusion-perfusion mismatch hypothesis for patient selection in later time-window thrombolytic trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique Identifiers: NCT00638781, NCT00638248, NCT00111852.

There have been only 3 positive Phase III randomized clinical trials in acute ischemic stroke, all reperfusion therapies (NINDS; PROACT II; ECASS III). The only approved acute stroke therapy is

The foundation of thrombolytic therapy for acute stroke rests on the NINDS IV tPA trial published in 1995 [1] and the PROACT II intra-arterial trial published in 1999 [2]. Based on NINDS and PROACT II, virtually all major stroke centers now routinely perform IV and IA thrombolysis in patients with acute ischemic stroke. The early road to thrombolytic stroke therapy had many twists and turns, some of which I now retravel with you in my strokemobile (fig. ​(fig.1,1, ​,22). Fig. 1 Strokemobile, 1986. Artist's conception (Furlan). Fig. 2 Strokemobile, 2012 [17]. Homburg, Germany. a Mobile stroke unit. b Point-of-care laboratory system and telemedicine. c Portable CT scan. In 1990 there were 2 major groups in the world working on stroke thrombolysis: the angiography-based group, spearheaded by Gregory Del Zoppo and funded by Burroughs Wellcome (BW), and the NINDS group led by Tom Brott and supported by Genentech. The angiographic group, of which I was a charter member, argued (sometimes vehemently) that all thrombolysis candidates must first undergo angiography to determine the site of occlusion and whether recanalization had occurred. Our seminal angiographic dose escalation study published in 1992 [3] established that the site of vascular occlusion in acute stroke was highly variable and could not be reliably determined by the clinical neurological examination. Moreover, recanalization varied by site of occlusion with only distal M3 MCA occlusion reliably opening with IV tPA. The NINDS group made the seminal insight that time is brain (prior to 1990 almost all stroke trials used up to a 48-hour window). For the first time NINDS established a very aggressive treatment window of 700 hospitals were JC-certified primary stroke centers) [11]. Following the (quiet) collapse of TTATTS, our splinter US group decided to approach Abbott laboratories for support of a radical new idea. At that time Abbott laboratories, manufacturer of urokinase, the world's leading thrombolytic in sales but requiring large volumes of human urine, was looking to convert to genetically engineered prourokinase. Our group successfully argued that the fastest way to FDA approval was a small homogeneous intra-arterial stroke trial, i.e. PROACT [12]. We argued that to demonstrate efficacy of stroke thrombolysis beyond 3 h (and therefore increase market potential) a more homogeneous patient population would need to be studied in order to eliminate acute stroke ‘noise.’ PROACT established the recanalization efficacy of IA prourokinase through a double blind sham control (IA saline into the MCA; never to be repeated). In 1999 I reported the results of PROACT II which demonstrated the clinical efficacy of IA prourokinase out to 6 h and remains the foundation of IA stroke thrombolysis in selected patients. Unfortunately, and although IA thrombolysis is now performed routinely in every stroke center in the world, neither prourokinase nor IA stroke thrombolysis is FDA approved. In fact Abbott, at one time the world's leading manufacturer of thrombolytics and the sponsor of PROACT II, has now completely abandoned its thrombolytic venture. In the meantime, and despite a Europe-wide training program on how to read early CT signs of infarction, ECASS II was also negative using the NINDS outcome of Rankin 0–1 (unless the analysis was performed using PROACT Rankin 0–2) [13]. It was not until ECASS III in 2008 that my old friend Werner Hacke finally got his positive IV tPA result [14]. ECASS III managed to expand the IV treatment window from 3 to 4.5 h – 18 years of work for an hour and a half; stroke thrombolysis was not proving easy. There have been several unanticipated outcomes from the PROACT II trial. One is the development of device-based IA thrombolysis. Shortly after PROACT II was presented I was called by POSSIS Medical claiming their device could remove clots in the MCA faster than drug. POSSIS subsequently sponsored the first stroke device clinical trial, the TIME study, which used the PROACT II protocol and a modified AngioJet® device. TIME was stopped due to excess fatalities and never published (and therefore forgotten). Ironically the first approved stroke thrombectomy device, the MERCI retriever, relied on the PROACT II control data to obtain not only FDA approval but also CMS reimbursement – endorsements denied prourokinase [15]. Another unanticipated result of PROACT II, and of particular relevance for this inaugural issue, was interventional neurology. Interventional neurology was born at the Wild Boar restaurant in Nashville, Tenn., USA, in February, 1999. On the evening of the PROACT II presentation at the AHA Stroke Conference I learned that neuroradiology and neurosurgery were actively negotiating joint interventional training guidelines. Randy Higashida, a co-investigator in PROACT II, leaned over at dinner and asked me if neurology would like to get involved. Larry Wechsler and I subsequently approached Fran Kittredge and the American Academy of Neurology (AAN) which formed an Interventional Neurology Task Force consisting of Larry Wechsler, Camillo Gomez, and myself. Many difficult negotiations ensued. The AAN threatened legal action if neurology was not included in the ACGME interventional negotiations. The ACGME agreed with the AAN, the radiology and neurosurgery Residency Review Committees (RRCs) acquiesced, and the ACGME approved an interventional neurology training pathway in 2001 (the official but clumsy ACGME designation endovascular surgical neuroradiology is seldom used) [16]. One final irony: as a prerequisite to interventional training, neurologists had to complete an ACGME-approved vascular neurology residency which did not exist at that time (i.e. stroke fellowships were not ACGME approved). In a classic example of the tail wagging the dog, a second AAN task force under Harold Adams was formed which completed the ACGME requirements for board certification in vascular neurology. I was told by Jasper Daube, head of the neurology RRC, that obtaining 2 new ACGME-approved residencies (vascular neurology and interventional neurology) within 2 years was a world record. The rest is history.

Stroke is the third leading cause of death in the USA, Canada, Europe, and Japan. According to the American Heart Association and the American Stroke Association, there are now 750,000 new strokes that occur each year, resulting in 200,000 deaths, or 1 of every 16 deaths, per year in the USA alone. Endovascular therapy for patients with acute ischemic stroke is an area of intense investigation. The American Stroke Association has given a qualified endorsement of intraarterial thrombolysis in selected patients. Intraarterial thrombolysis has been studied in two randomized trials and numerous case series. Although two devices have been granted FDA approval with an indication for mechanical stroke thrombectomy, none of these thrombectomy devices has demonstrated efficacy for the improvement of patient outcomes. The purpose of the present document is to define what constitutes adequate training to perform neuroendovascular procedures in patients with acute ischemic stroke and what performance standards should be adopted to assess outcomes. These guidelines have been written and approved by multiple neuroscience societies which historically have been directly involved in the medical, surgical and endovascular care of patients with acute stroke. The participating member organizations of the Neurovascular Coalition involved in the writing and endorsement of this document are the Society of NeuroInterventional Surgery, the American Academy of Neurology, the American Association of Neurological Surgeons/Congress of Neurological Surgeons Cerebrovascular Section, and the Society of Vascular & Interventional Neurology.

Background and Purpose— Recanalization of occluded vessels in acute ischemic stroke is associated with improved outcome. Devices that can quickly and safely remove thrombus and promote recanalization are useful in the management of these patients. The Alligator retrieval device, developed for endovascular foreign body retrieval, may also be useful for thrombus removal. Methods— Seven patients with acute ischemic stroke (aged 31 to 88 years) who underwent intra-arterial therapy with the Alligator retrieval device at our center are presented. Results— The Alligator retrieval device was able to retrieve the thrombus in 5 of 7 cases with good to excellent recanalization seen and was unsuccessful in 2 of 7 patients. Complete recanalization was obtained in one of 7 patients and near complete recanalization obtained in 4 of 7 patients. Three of the 7 patients had good outcome at 3 months and 3 of 7 patients died within 30 days of treatment. Conclusion— The Alligator retrieval device was successfully able to remove thrombus in the majority of cases. It appears to have increased success in proximal occlusions in relatively straight segments. In properly selected cases, it may be a useful device in intra-arterial stroke management.

Background Acute ischemic stroke (AIS) is common cause of hospital admission. The objective of this study was to determine the impact of the new Accreditation Council for Graduate Medical Education (ACGME) duty hour regulations on AIS outcomes including inhospital mortality. Methods Hospitalized patients with AIS were selected from the National Inpatient Sample database. Patients with AIS with a known mortality and hospital teaching status were included for the years 2000 through 2005. Inhospital mortality and predictors of mortality were stratified by the hospital teaching status. To determine the variability of mortality around the month of July (July phenomenon) the trend of mortality was determined in teaching hospitals stratified by the calendar month of each year. Results In all, 377,266 patients were included in this analysis; 43.0% were admitted to teaching hospitals. Overall inhospital mortality was 10.8%, slightly higher in teaching hospitals (11.4% v 10.3%, P < .0001). The trend in AIS mortality showed a decline during the 6 years included in this study in both hospital types (P < .0001). Adjusted analysis showed decline in mortality in both hospital types after July 1, 2003: odds ratio (OR) 0.91 (95% confidence interval [CI] 0.87, 0.94) in teaching hospitals and OR 0.81 (95% CI 0.78, 0.84) in nonteaching hospitals. Predictors of AIS-associated hospital mortality were similar in both hospital types except for sepsis, which was another independent predictor of death in nonteaching hospitals (OR 1.58, 95% CI 1.30, 1.94). There was no significant change in AIS mortality when stratified by each calendar month within the years included in this study (P value = .25-.93). Conclusion There was no difference in AIS mortality after the implementation of the new ACGME duty hour standards. In addition, data support the lack of July phenomenon in neurology residency programs in regard to AIS mortality.

Background and Purpose— Although self-expanding intracranial microstents have been used to treat acute middle cerebral artery (MCA) stroke, there are disadvantages associated with placing a permanent endovascular implant. We describe a technique in which a reconstrainable stent was used to provide a temporary endovascular bypass to achieve MCA recanalization without permanent stent implantation. Methods— A 55-year-old male presented with acute onset left hemiplegia (National Institutes of Health Stroke Score (NIHSS) of 20. Angiography showed an occluded right cervical internal carotid artery (ICA), a patent anterior communicating artery (ACOMM), and embolic occlusion of the right middle cerebral artery (MCA), M1 segment. Results— Working through a 6F guide-catheter positioned in the left cervical ICA, an SL-10 microcatheter, and 0.014-inch Synchro-2 microwire were manipulated across the anterior communicating artery and into the right M1 segment occlusion. 5 mg of abciximab and 3 mg tPA were infused directly into the thrombus through the microcatheter. Mechanical thrombolysis using the microwire and microcatheter was ineffective in achieving any recanalization. An Enterprise stent (4×22 mm) was delivered across the occlusion site and partially unconstrained. The unconstrained portion of the stent expanded and acted as a temporary bypass, to circumferentially displace and structurally disrupt the M1 thrombus, producing immediate revascularization of the right territory MCA. After approximately 20 minutes, the Enterprise stent was reconstrained and removed. Final angiography demonstrated excellent filling of the right M1 and distal MCA branches. The patient improved to an NIHSS of 7, regaining movement of his left upper and lower extremities. Conclusions— The temporary endovascular bypass technique yielded immediate and durable revascularization of an acutely occluded middle cerebral artery without the disadvantages associated with the placement of a permanent endovascular stent.

Pooled analysis of individual patient data from stroke trials can deliver more precise estimates of treatment effect, enhance power to examine prespecified subgroups, and facilitate exploration of treatment-modifying influences. Analysis plans should be declared, and preferably published, before trial results are known. For pooling trials that used diverse analytic approaches, an ordinal analysis is favored, with justification for considering deaths and severe disability jointly. Because trial pooling is an incremental process, analyses should follow a sequential approach, with statistical adjustment for iterations. Updated analyses should be published when revised conclusions have a clinical implication. However, caution is recommended in declaring pooled findings that may prejudice ongoing trials, unless clinical implications are compelling. All contributing trial teams should contribute to leadership, data verification, and authorship of pooled analyses. Development work is needed to enable reliable inferences to be drawn about individual drug or device effects that contribute to a pooled analysis, versus a class effect, if the treatment strategy combines ≥2 such drugs or devices. Despite the practical challenges, pooled analyses are powerful and essential tools in interpreting clinical trial findings and advancing clinical care.

Purpose— Our goal is to provide an overview of the current evidence about components of the evaluation and treatment of adults with acute ischemic stroke. The intended audience is physicians and other emergency healthcare providers who treat patients within the first 48 hours after stroke. In addition, information for healthcare policy makers is included. Methods— Members of the panel were appointed by the American Heart Association Stroke Council’s Scientific Statement Oversight Committee and represented different areas of expertise. The panel reviewed the relevant literature with an emphasis on reports published since 2003 and used the American Heart Association Stroke Council’s Levels of Evidence grading algorithm to rate the evidence and to make recommendations. After approval of the statement by the panel, it underwent peer review and approval by the American Heart Association Science Advisory and Coordinating Committee. It is intended that this guideline be fully updated in 3 years. Results— Management of patients with acute ischemic stroke remains multifaceted and includes several aspects of care that have not been tested in clinical trials. This statement includes recommendations for management from the first contact by emergency medical services personnel through initial admission to the hospital. Intravenous administration of recombinant tissue plasminogen activator remains the most beneficial proven intervention for emergency treatment of stroke. Several interventions, including intra-arterial administration of thrombolytic agents and mechanical interventions, show promise. Because many of the recommendations are based on limited data, additional research on treatment of acute ischemic stroke is needed.

Studies of stroke in adults under age 50 emphasize nonatherosclerotic causes. We examined the risk factor profile in 41 patients under age 45 who underwent carotid endarterectomy for severe atherosclerotic stenosis at the Cleveland Clinic Foundation from 1975 to 1990. Smoking was the strongest risk factor. Hyperlipidemia, family history, and associated coronary atherosclerosis were also major risk factors. In contradistinction to older patients with carotid disease, hypertension was a less important risk factor.

The control of blood pressure in acute ischemic cerebrovascular disease has received little critical analysis. Most physicians are aware that precipitous drops in mean arterial blood pressure (MABP)should be avoided in patients with acute focalbrain ischemia, even if they are unfamiliar with the physiologic principle of cerebral blood flow (CBF) autoregulatory paralysis. However, specific antihypertensive regimens and guidelines for blood pressure regulation in acute stroke have not been critically evaluated. Autoregulation, or the ability to maintain blood flow over a wide range of perfusion pressures, is welldeveloped in the cerebral circulation. Normally, CBF is maintained at normal levels (approximately 50 mll min/lOO g) with mean arterial pressures between 50 and 150 mm Hg. In this range of arterial pressures, cerebral vessels constrict in response to elevations in pressure and dilate during decreases in pressure, and the vascular response is adequate to maintain blood flow. Autoregulation is not instantaneous and may require a few seconds for initiation. During gradual changes in perfusion pressure, blood flow is maintained, but during sudden changes in pressure, a substantial period of time occurs before blood flow returns to the basal level. Experimental studies in several species indicate that autoregulation of blood flow in the cerebrum results from vascular responses of both arteries and microvessels. In contrast, in the brainstem, large arteries apparently have little involvement in autoregulation. Microvascular pressure, therefore, is higher in the brainstem, and small arteries and arterioles must respond with greater changes in resistance to maintain blood flow.

Although it is a well-recognized sequela, the clinical course of fever following intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) with or without ICH has not been well-studied. Patients with fever following either ICH or IVH routinely undergo extensive testing only to conclude that the fever is "central" in origin. We performed a retrospective analysis of the clinical course of fever following isolated IVH, ICH, or IVH associated with ICH. Records of 49 patients with ICH and/or IVH who were admitted to the Cleveland Clinical Foundation from 1987 to 1991 were studied for the onset, duration and degree of temperature following the hemorrhage. The incidence of fever was 83.3% in 6 patients with isolated IVH, 52% in 25 patients with isolated ICH, and 88.8% in 18 patients with both ICH and IVH. The highest temperature reached was 40.6°C in a patient with basal ganglia, third, and fourth ventricular hemorrhage. The fever lasted from 1 to 40 days. The fever could be attributed to infection in only 4 patients, and none of the patients with fever had proven deep vein thrombosis.

The natural history of large-vessel extracranial and intracranial arterial occlusion has played a major role in the evolution of endovascular stroke therapy. Basilar artery occlusion was felt to have the worst prognosis, and this drove Zeumer et al1 to first perform basilar thrombolysis via catheter and report excellent outcomes based on historical controls. However, early stroke thrombolysis clinical trials focused on intravenous (IV) and not intraarterial (IA) delivery. Gregory del Zoppo—a hematologist by training—led international angiography-based, dose escalation trials of double-stranded tissue-type plasminogen activator (tPA) given IV. This Burroughs Wellcome–sponsored research trial showed that distal M3 middle cerebral artery (MCA) occlusions often recanalized with IV tPA, but recanalization rates were low with more proximal large-vessel occlusions. Furthermore, the site of arterial occlusion could not be reliably predicted by clinical phenotype or National Institutes of Health Stroke Scale (NIHSS). Concurrent with this angiography-based effort, the National Institute of Neurological Disorders and Stroke (NINDS) investigators downplayed the need for angiography and instead focused on time to treatment with IV tPA. The NINDS Genentech IV tPA stroke trial established the critical importance of time to treatment and led to Food and Drug Administration (FDA) approval of IV tPA to treat acute ischemic stroke in 1996 but within a small window of 3 hours. The major drivers for the development of endovascular stroke therapy were the desire to expand the 3-hour treatment window and the relatively low recanalization rates for large-vessel occlusions with IV tPA (which often caused the most severe strokes). Toward this end, Gregory Del Zoppo, Anthony Furlan, Randall Higashida, and Michael Pessin convinced Abbott Laboratories that the quickest way to FDA approval of their new thrombolytic agent recombinant prourokinase (r-proUK) was an IA trial focused only on MCA occlusion. Accordingly, Del Zoppo, Furlan, Higashida, and Pessin designed the Prolyse in …

As compared with carotid endarterectomy, carotid-artery stenting has uncertain efficacy and safety in patients at risk for stroke from atherosclerotic stenosis of the internal carotid artery. The benefits of carotid endarterectomy for both symptomatic and asymptomatic patients have been established in several randomized trials comparing surgery with medical therapy. The benefits of surgery in reducing the long-term risk of stroke need to be weighed against the immediate risk of death or stroke as a complication of the surgery. For symptomatic patients with stenosis of the internal carotid artery of 70% or more, carotid endarterectomy is superior to medical therapy alone, . . .

Background and Purpose— Sex influences outcome after intravenous thrombolysis. In a combined analysis of the tissue plasminogen activator clinical trials, a sex-by-treatment interaction was observed. We sought to confirm that observation in an independent data set. Methods— Data were from the Pro-Urokinase for Acute Cerebral Thromboembolism-2 (PROACT-2) trial. Baseline factors were compared by sex. The primary outcome was an assessment of a sex-by-treatment interaction term within a logistic regression model, using a modified Rankin Scale score ≤2 at 90 days as the binary outcome. We also assessed whether there were differences in CT-scan appearance and recanalization at 2 hours post-treatment. Results— In the PROACT-2 study of intra-arterial stroke thrombolysis, in both women and men, prourokinase resulted in better outcomes than control. A sex by prourokinase treatment interaction was observed, with women showing a larger treatment effect (20% absolute benefit) compared with men (10% absolute benefit). The reason for this interaction is that thrombolytic treatment nullifies the worse outcome for untreated women compared with men. The reasons for effect modification do not include improved recanalization at 2 hours among women. Conclusions— Women with middle cerebral artery ischemic stroke benefit more from intra-arterial therapy. Further study of how sex affects stroke outcome is needed.

Background: It is unclear why atherosclerosis remains restricted to one arterial tree in some patients whereas it is more generalized in others. Few studies have addressed the role that systemic risk factors play in the progression of atherosclerosis from one arterial tree to another. Methods: We studied 344 consecutive patients with suggested coronary artery disease (CAD) who underwent combined coronary and carotid angiography during a 7-month period. Coronary and carotid disease was graded as absent-mild or moderate-severe based on the degree of stenosis of these vessels. Traditional vascular risk factors were compared for patients with moderate-severe CAD alone versus patients with moderate-severe CAD and carotid disease. Results: Moderate-severe CAD alone was found in 162 patients and moderate-severe CAD and carotid disease was found in 100 patients. Multivariate analysis showed that hypertension ( P = .007, odds ratio 2.2, 95% confidence interval 1.2–3.9), history of smoking ( P = .06, odds ratio 1.8, 95% confidence interval 1.0–3.4), and diabetes ( P = .09, odds ratio 1.6, 95% confidence interval 0.9–2.8) were associated with combined moderate-severe CAD and carotid disease. Patients with combined moderate-severe CAD and carotid disease were significantly more likely to have at least 2 of these 3 risk factors ( P Conclusion: An accumulating burden of hypertension, diabetes, and smoking are important in the progression of atherosclerosis from the coronary to the carotid circulation.

Background and Purpose— Most acute ischemic stroke patients arrive after the 3-hour time window for recombinant tissue plasminogen activator (rtPA) administration. The Desmoteplase In Acute Ischemic Stroke trial (DIAS) was a dose-finding randomized trial designed to evaluate the safety and efficacy of intravenous desmoteplase, a highly fibrin-specific and nonneurotoxic thrombolytic agent, administered within 3 to 9 hours of ischemic stroke onset in patients with perfusion/diffusion mismatch on MRI. Methods— DIAS was a placebo-controlled, double-blind, randomized, dose-finding phase II trial. Patients with National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch were eligible. Of 104 patients, the first 47 (referred to as Part 1) were randomized to fixed doses of desmoteplase (25 mg, 37.5 mg, or 50 mg) or placebo. Because of an excessive rate of symptomatic intracranial hemorrhage (sICH), lower weight-adjusted doses escalating through 62.5 μg/kg, 90 μg/kg, and 125 μg/kg were subsequently investigated in 57 patients (referred to as Part 2). The safety endpoint was the rate of sICH. Efficacy endpoints were the rate of reperfusion on MRI after 4 to 8 hours and clinical outcome as assessed by NIHSS, modified Rankin scale, and Barthel Index at 90 days. Results— Part 1 was terminated prematurely because of high rates of sICH with desmoteplase (26.7%). In Part 2, the sICH rate was 2.2%. No sICH occurred with placebo in either part. Reperfusion rates up to 71.4% ( P =0.0012) were observed with desmoteplase (125 μg/kg) compared with 19.2% with placebo. Favorable 90-day clinical outcome was found in 22.2% of placebo-treated patients and between 13.3% (62.5 μg/kg; P =0.757) and 60.0% (125 μg/kg; P =0.0090) of desmoteplase-treated patients. Early reperfusion correlated favorably with clinical outcome ( P =0.0028). Favorable outcome occurred in 52.5% of patients experiencing reperfusion versus 24.6% of patients without reperfusion. Conclusions— Intravenous desmoteplase administered 3 to 9 hours after acute ischemic stroke in patients selected with perfusion/diffusion mismatch is associated with a higher rate of reperfusion and better clinical outcome compared with placebo. The sICH rate with desmoteplase was low, using doses up to 125 μg/kg.

Appropriate and adequate cognitive and technical training, proficiency and experience are essential for the safe performance of procedures that confer significant risk to patient well-being. This principle is the foundation of all medical education and is especially important when considering the cerebral vasculature, for which stroke is a defined risk for every endovascular procedure. Despite recent advances in noninvasive diagnostic neuroimaging, diagnostic cervicocerebral angiography remains the cornerstone and “gold standard” for the evaluation and treatment of patients with cerebrovascular disease.1 In addition to a high level of technical expertise, performance and interpretation of diagnostic cervicocerebral angiography requires in-depth cognitive knowledge of related neurological pathophysiology, neurovascular anatomy and pathology, and an understanding of the full range of neurodiagnostic possibilities. Expert diagnostic cervicocerebral angiography is the foundation for safe and successful cervicocerebral endovascular intervention, including carotid artery angioplasty and stenting for atherosclerosis, interventional stroke therapy, intracranial angioplasty and stenting, and embolization of cerebral aneurysms, epistaxis and vascular malformations. All of these procedures are increasing in volume and complexity with recent technological advances that further mandate the need for adequate cognitive acumen and technical skills. To ensure proper outcomes, formal neuroscience training, adequate procedural training and sufficient experience are all essential for competency in diagnostic cervicocerebral angiography and interventional procedures, including carotid stenting. These concepts have been delineated in training requirements by the Accreditation Council for Graduate Medical Education (ACGME) and by previously published official society statements. The purpose of this document is to define the minimum training and experience necessary to provide adequate quality of patient care for extracranial cerebrovascular interventions, particularly carotid artery stenting. Hospital credentialing is the mechanism by which competence is ensured. ### Risks of diagnostic cervicocerebral angiography. Stroke is recognized as the most disabling and costly of all medical conditions.2 Stroke is also the most feared of all iatrogenic medical and procedural …

Background and Purpose— The role of endovascular therapy for acute M2 trunk occlusions is debatable. Through a subgroup analysis of Prolyse in Acute Cerebral Thromboembolism-II, we compared outcomes of M2 occlusions in treatment and control arms. Methods— Solitary M2 occlusions were identified from the Prolyse in Acute Cerebral Thromboembolism-II database. Primary endpoints were successful angiographic reperfusion (TICI 2–3) at 120 minutes and functional independence (mRS 0–2) at 90 days. Results— Forty-four patients with solitary M2 occlusions, 30 in the treatment arm and 14 in the control arm, were identified. Successful reperfusion (TICI 2–3) was achieved in 53.6% and 16.7% of patients in the treatment and control arms, respectively ( P =0.04). A favorable clinical outcome (mRS 0–2) was observed in 53.3% and 28.6%, respectively ( P =0.19). Baseline characteristics were similar between the 2 groups. Conclusions— Intra-arterial thrombolysis may lead to a 3-fold increase in the rate of early reperfusion of solitary M2 occlusions and could potentially double the chance of a favorable functional outcome at 90 days. Clinical Trial Registration— This trial was not registered because enrollment began before July 1, 2005.

The use of intravenous thrombolytic therapy for the treatment of patients with acute ischemic stroke is now approved in the United States, Canada, Germany, and the European Union. Guidelines published in 1996 from the American Heart Association and American Academy of Neurology committees recommended intravenous administration of recombinant tissue-plasminogen activator (rt-PA) (0.9 mg/kg; maximum of 90 mg) given in a 10% bolus, followed by an infusion lasting 60 minutes, to patients within 3 hours of onset of ischemic stroke. The recommendations stipulate that a computed tomography scan before the infusion should not show major infarction, mass effect, edema, or hemorrhage. Yet, only a small fraction of eligible patients (< 5%) have received rt-PA during the 7 years since its approval in the United States. Although effective, thrombolysis carries an important risk (5% to 10%) of brain hemorrhage and edema that can prove fatal. Many physicians and medical centers are not presently equipped or willing to give thrombolytic drugs for stroke treatment.

Background and Purpose— The PROACT II study demonstrated a significant benefit from treatment with intra-arterial pro-urokinase (r-proUK) in patients with middle cerebral artery occlusion treated within 6 hours of stroke onset. The purpose of the current study was to examine baseline factors to determine predictors of good outcome and response to treatment. Methods— We selected from the baseline clinical, radiologic, and angiographic data variables that considered possibly related to outcome. A univariate analysis was performed to examine the association between these baseline factors and good outcome, defined as a modified Rankin scale score ≤2. A multivariate model then selected the most important variables independently influencing prognosis. A risk score for each patient was constructed on the basis of the patient’s individual values for each independent variable. Patients were stratified into risk quartiles based on their risk scores, and an odds ratio for each risk quartile was calculated. The treatment effects of each quartile were compared. Results— In the univariate analysis, screening National Institutes of Health stroke scale (NIHSS) score and age were strongly associated with good outcome. The multivariate model selected age, NIHSS score, and CT hypodensity as the most important prognostic variables. Dividing patients into quartiles based on risk scores achieved a uniform gradient of probability of good outcomes. A trend toward benefit of r-proUK treatment was seen in all risk quartiles, and no differential treatment effect was observed across risk groups. Conclusions— There was no evidence of differential effect of r-proUK across subgroups of patients stratified by risk.

Background and Relevance: Atherosclerotic stenosis of the major intracranial arteries is an important cause of transient ischemic attack (TIA) or stroke. Of the 900,000 patients who suffer a TIA or stroke each year in the USA, intracranial stenosis is responsible for approximately 10%, i.e. 90,000 patients. There have been no prospective trials evaluating antithrombotic therapies for preventing recurrent vascular events in these patients. The main objective of this trial is to compare warfarin [International Normalized Ratio (INR) 2–3] with aspirin (1,300 mg/day) for preventing stroke (ischemic and hemorrhagic) and vascular death in patients presenting with TIA or stroke caused by stenosis of a major intracranial artery. Study Design: Prospective, randomized, double-blind, multicenter trial. The sample sizerequired will be 403 patients per group, based on stroke and vascular death rates of 33% per 3 years in the aspirin group vs. 22% per 3 years in the warfarin group, a p value of 0.05, power of 80%, a 24% rate of ‘withdrawal of therapy’, and a 1% rate of ‘lost to follow-up’. Conduct of Trial: Patients with TIA or nondisabling stroke caused by ≧50% stenosis of a major intracranial artery documented by catheter angiography are randomized to warfarin or aspirin. Patients are contacted monthly by phone and examined every 4 months until a common termination date. Mean follow-up in the study is expected to be 3 years. Conclusion: This study will determine whether warfarin or aspirin is superior for patients with symptomatic intracranial arterial stenosis. Furthermore, it will identify patients whose rate of ischemic stroke in the territory of the stenotic intracranial artery on best medical therapy is sufficiently high to justify a subsequent trial comparing intracranial angioplasty/stenting with best medical therapy in this subset of patients.

Identification of early outcomes post stroke and their predictors is important in stroke management strategies. We prospectively analysed 30-day outcomes (mortality and functional ability) after stroke and their predictors among patients admitted within 7 days post event to a national referral hospital in Uganda. This was a prospective study of acute stroke patients consecutively enrolled between February and July 2014. Social demographics, clinical, laboratory, imaging characteristics, outcomes (all through 30 days), time of death were assessed using standardised questionnaires. Multiple regression was used to analyse the independent influence of factors on outcomes. Of 127 patients, 88 (69.3 %) had ischemic stroke and 39 (30.7 %) had hemorrhagic stroke. Eight (6.3 %) died within 7 days, 34 (26.8 %) died within 30 days, with 2/3 of deaths occurring in hospital. Two were lost to follow up. Of 91 survivors, 49 (53.9 %) had satisfactory outcome, 42 (46.1 %) had poor functional outcome. At multivariate analysis, independent predictors of mortality at 30 days were unconsciousness (GCS

Lechat is usually credited with first calling attention to patent foramen ovale (PFO) and stroke in 1988.1 Previous studies of the role of echocardiography in stroke rarely, if ever, mentioned PFO and focused on now-almost-forgotten disorders, such as mitral valve prolapse.2 Interest in PFO has emerged for 3 main reasons: (1) renewed interest in cryptogenic stroke especially in younger patients; (2) technical advances, including bubble contrast transthoracic echocardiography, transesophageal echocardiography, and saline contrast transcranial doppler; and (3) perhaps most importantly, the emergence of endovascular device closure as a treatment option. Cryptogenic stroke is highly prevalent in stroke populations under the age of 55 years. Many of these patients have circumstantial evidence for embolism on MR, such as cortical infarct location or multiple silent infarcts in different vascular territories. Large PFO with a substantial shunt and atrial septal aneurysm has been identified in many (although not all) studies as anatomic comorbidities associated with stroke. However, as with PFO detection, new technology, including implantable cardiac monitors and MR plaque morphological analysis, has identified occult atrial fibrillation and acute rupture of benign atherosclerotic plaques as underdiagnosed causes of crytpogenic stroke.3 This suggests that in many patients with cryptogenic stroke, a PFO may be coincidental. The explosion of device technology has played a central role in the PFO renaissance. Reimbursement policies and an inherent bias in young patients with stroke to close the hole bolstered by numerous observational case series provided a strong incentive for endovascular device closure.4 With this background, 3 randomized clinical trials of the management of patients with cryptogenic stroke and PFO have recently been completed. Given the lingering controversy, it is important to review why the Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical …

Background: Socioeconomic transition is changing stroke risk factors in Sub-Saharan Africa. This study assessed stroke-risk factors and their associated characteristics in urban and rural Uganda. Methods: We surveyed 5,420 urban and rural participants and assessed the stroke-risk factor prevalence and socio-behavioural characteristics associated with risk factors. Results: Rural participants were older with higher proportions of men and fewer poor compared to urban areas. The most prevalent modifiable stroke-risk factors in all areas were hypertension (27.1% rural and 22.4% urban, p = 0.004), overweight and obesity (22.0% rural and 42% urban, p < 0.0001), and elevated waist hip ratio (25.8% rural and 24.1% urban, p = 0.045). Diabetes, smoking, physical inactivity, harmful alcohol consumption were found in ≤5%. Age, family history of hypertension, and waist hip ratio were associated with hypertension in all, while BMI, HIV were associated with hypertension only in urban dwellers. Sex and family history of hypertension were associated with BMI in all, while age, socio-economic status and diabetes were associated with BMI only in urban dwellers. Conclusions: The prevalence of stroke-risk factors of diabetes, smoking, inactivity and harmful alcohol consumption was rare in Uganda. Rural dwellers belonging to a higher age group tended to be with hypertension and elevated waist hip ratio. Unlike high-income countries, higher socioeconomic status was associated with overweight and obesity.

AIMS The preferred antithrombotic strategy for secondary prevention in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO) is unknown. We pooled multiple observational studies and used propensity score-based methods to estimate the comparative effectiveness of oral anticoagulation (OAC) compared with antiplatelet therapy (APT). METHODS AND RESULTS Individual participant data from 12 databases of medically treated patients with CS and PFO were analysed with Cox regression models, to estimate database-specific hazard ratios (HRs) comparing OAC with APT, for both the primary composite outcome [recurrent stroke, transient ischaemic attack (TIA), or death] and stroke alone. Propensity scores were applied via inverse probability of treatment weighting to control for confounding. We synthesized database-specific HRs using random-effects meta-analysis models. This analysis included 2385 (OAC = 804 and APT = 1581) patients with 227 composite endpoints (stroke/TIA/death). The difference between OAC and APT was not statistically significant for the primary composite outcome [adjusted HR = 0.76, 95% confidence interval (CI) 0.52-1.12] or for the secondary outcome of stroke alone (adjusted HR = 0.75, 95% CI 0.44-1.27). Results were consistent in analyses applying alternative weighting schemes, with the exception that OAC had a statistically significant beneficial effect on the composite outcome in analyses standardized to the patient population who actually received APT (adjusted HR = 0.64, 95% CI 0.42-0.99). Subgroup analyses did not detect statistically significant heterogeneity of treatment effects across clinically important patient groups. CONCLUSION We did not find a statistically significant difference comparing OAC with APT; our results justify randomized trials comparing different antithrombotic approaches in these patients.

Objective Benign angiopathy of the central nervous system (BACNS) is a subset of primary angiitis of the central nervous system (PACNS) with favorable outcome, not requiring prolonged immunosuppression. We retrospectively studied the clinical characteristics and prospectively assessed long-term outcome in a cohort of BACNS patients. Methods Patients meeting the clinical description for BACNS, evaluated and treated by a single investigator, were included. Data on demographics, signs and symptoms, laboratory studies, neuroimaging, brain biopsy, treatment, and complications were recorded. The long-term assessment included a phone interview utilizing the Barthel index and a specifically designed cognitive index. Results Sixteen cases met the inclusion criteria. Mean age was 40 years (range 10–66 years) with female:male ratio of 4.3:1 and a mean followup period of 35 months (0–128 months). Headache was the most common presenting symptom, seen in 88% of the cases, followed by focal symptoms (63%), and diffuse symptoms (44%). All patients had highly abnormal cerebral angiography, and magnetic resonance imaging abnormalities were present in 77% (10 of 13). Severe cerebral spinal fluid (CSF) abnormalities were present in 1 patient (7%). All followup cerebral angiography showed marked improvement. Recovery was demonstrated in 94% of the patients, 6% relapsed, and there were no deaths. Of patients assessed by the Barthel index, 71% showed no disability and 29% had mild disability. Conclusion There is a PACNS subset characterized by acute presentation (most commonly headache), normal to mildly abnormal CSF findings, female predominance, and highly abnormal cerebral angiography (reversible after treatment), requiring less intensive treatment than has been traditionally used.

Background and Purpose — The purpose of this study was to evaluate the role of noncontrast CT in the selection of patients to receive thrombolytic therapy for acute ischemic stroke and to predict radiological and clinical outcomes. Methods — One hundred eighty patients with stroke due to middle cerebral artery (MCA) occlusion were randomized 2:1 within 6 hours of onset to receive intra-arterial recombinant prourokinase plus intravenous heparin or intravenous heparin only. Four hundred fifty-four CT examinations were digitized to calculate early infarct changes, infarct volumes, and hemorrhagic changes among the 162 patients treated as randomized (108 recombinant prourokinase–treated patients and 54 control patients). CT changes were correlated with baseline stroke severity, angiographic clot location, collateral vessels, and outcome at 90 days. Results — Baseline CT scans, 120 (75%) of 159, showed early infarct–related abnormalities. The baseline CT abnormality volume was not correlated with the baseline National Institutes of Health Stroke Scale (NIHSS) score ( r =−0.11) but was correlated weakly with the outcome ( r =0.17, P P P Conclusions — Noncontrast CT is not correlated with baseline stroke severity and does not predict outcome in patients with stroke due to MCA occlusion. However, baseline CT changes, clinical presentation, and the evolution of CT changes are influenced by clot location and the presence of a collateral supply.

By delivering a higher concentration of drug directly into a clot, intra-arterial (IA) thrombolysis may be more effective than intravenous therapy at opening a blocked artery. The clinical efficacy and safety of IA thrombolysis with the selective thrombolytic r-pro-urokinase (r-pro-UK) has been demonstrated in two randomized acute stroke treatment trials, PROACT I and PROACT II. However, IA pro-UK is not yet FDA approved, and it is not known if IA thrombolysis with other agents would have the same results. However the American Heart Association has deemed IA thrombolysis an 'acceptable alternative therapy' and many stroke centres are offering it to patients with a major acute stroke presenting within 6 h.