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Objective Agonism of protease-activated receptor (PAR) 1 by activated protein C (APC) provides neuro- and vasculoprotection in experimental neuroinjury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurological injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients. Methods The NeuroNEXT trial, RHAPSODY, used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360, and 540 μg/kg of 3K3A-APC. After intravenous tissue plasminogen activator, intra-arterial mechanical thrombectomy, or both, patients were randomized to 1 of the 4 doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates. Results Between January 2015 and July 2017, we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest-dose 3K3A-APC tested, 540 μg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 ± 5.8 ml in placebo to 0.8 ± 2.1 ml in the combined treatment arms (p = 0.066). Interpretation RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540 μg/kg for the PAR1 active cytoprotectant, 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation. Clinical trial registration Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. ANN NEUROL 2019;85:125-136.

Background and Purpose: To assess the effect of optimal medical management including atherosclerotic risk factor control on ischemic stroke (IS), transient ischemic attack (TIA), carotid revascularization (CRV), and progression of severity of carotid stenosis (PSCS) in patients with asymptomatic carotid artery stenosis (ACAS). Methods: We conducted a retrospective analysis of patients with ACAS (who had at least 3 serial carotid duplex ultrasounds) for incidence of IS, TIA, and PSCS. Results: Eight hundred sixty-four patients with a mean follow-up duration of 79 ± 36 months were included. IS/TIA and CRV occurred in 12.2% of the patients and PCSS was observed in 21.5% vessels. On univariate analysis it was found that low-density lipoprotein (LDL) levels >100 mg/dL, no statin or low-potency statins, average systolic blood pressure (SBP) ≥140 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg and history of smoking were predictors of the combined endpoint of IS/TIA/CRV and PSCS. On multivariate analysis, it was found that LDL >100 mg/dL, no statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, and Hx of smoking were independent predictors of PSCS. Similarly no statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, Hx of atrial fibrillation/flutter, Hx of chronic kidney disease, and PSCS were independent predictors of IS/TIA. No statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, diabetes mellitus, baseline carotid artery stenosis ≥70%, and PSCS were found to be independent predictors of combined endpoint IS/TIA and CRV. Conclusion: Intensive medical therapy in the patients with ACAS results in lower incidence of IS/TIA, CRV, and PSCS with a significant incremental beneficial effect.

Introduction: Trials are underway to evaluate the prophylactic use of novel oral anticoagulants (NOAC) in patients with embolic strokes of undetermined source (ESUS). It is uncertain whether the bleeding risks associated with prophylactic NOAC use will outweigh any stroke prevention benefit in ESUS patients who lack underlying atrial fibrillation (AF). Methods: We determined the proportion of patients in the CRYSTAL AF study who met ESUS trial criteria and had AF (≥2 minutes) detected within 3 years via an insertable cardiac monitor (ICM). Cryptogenic stroke patients ≥50 years old with a modified Rankin score ≤3 and no evidence of lacunar infarcts after an extensive stroke work up were included. Age ≥60 years and CHA 2 DS 2 VASc score ≥3 were required for patients whose index stroke occurred 3-6 months before randomization. We also compared AF detection rates between the ICM and standard monitoring arms using Kaplan-Meier estimates and computed the percentage of patients with AF detected within the initial 30 days of ICM monitoring. Results: Among the 441 patients enrolled in CRYSTAL AF, 246 (55.8%) met inclusion criteria for the ongoing ESUS trials. AF detection rates at 3 years reached 38.5% in the ICM arm vs. 2.7% in the control arm (HR 12.1 [3.7-39.3], p Conclusions: Among the subset of CRYSTAL AF patients who met the ESUS trial criteria, >60% did not have AF detected via ICMs within 3 years of their index stroke event. Prophylactic NOAC use in the absence of AF may therefore increase bleeding risks without providing protection against AF-related stroke in the majority of ESUS patients. Furthermore, ICMs were superior to standard monitoring for AF detection in this ESUS population. Monitoring continuously for only the initial 30 days would have failed to identify AF in >80% of patients ultimately found to have AF via an ICM.

Background and Purpose— On the basis of phase II trials, we considered that transcranial laser therapy could have neuroprotective effects in patients with acute ischemic stroke. Methods— We studied transcranial laser therapy in a double-blind, sham-controlled randomized clinical trial intended to enroll 1000 patients with acute ischemic stroke treated ≤24 hours after stroke onset and who did not undergo thrombolytic therapy. The primary efficacy measure was the 90-day functional outcome as assessed by the modified Rankin Scale, with hierarchical Bayesian analysis incorporating relevant previous data. Interim analyses were planned after 300 and 600 patients included. Results— The study was terminated on recommendation by the Data Monitoring Committee after a futility analysis of 566 completed patients found no difference in the primary end point (transcranial laser therapy 140/282 [49.6%] versus sham 140/284 [49.3%] for good functional outcome; modified Rankin Scale, 0–2). The results remained stable after inclusion of all 630 randomized patients (adjusted odds ratio, 1.024; 95% confidence interval, 0.705–1.488). Conclusions— Once the results of the interim futility analysis became available, all study support was immediately withdrawn by the capital firms behind PhotoThera, and the company was dissolved. Proper termination of the trial was difficult but was finally achieved through special efforts by former employees of PhotoThera, the CRO Parexel and members of the steering and the safety committees. We conclude that transcranial laser therapy does not have a measurable neuroprotective effect in patients with acute ischemic stroke when applied within 24 hours after stroke onset. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01120301.

Background and Purpose— High revascularization rates in large-vessel occlusion strokes treated by mechanical thrombectomy are not always associated with good clinical outcomes. We evaluated predictors of functional dependence despite successful revascularization among patients with acute ischemic stroke treated with thrombectomy. Methods— We analyzed the pooled data from the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI), Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke (TREVO), and TREVO 2 trials. Successful revascularization was defined as thrombolysis in cerebral infarction score 2b or 3. Functional dependence was defined as a score of 3 to 6 on the modified Rankin Scale at 3 months. We assessed relationship of demographic, clinical, angiographic characteristics, and hemorrhage with functional dependence despite successful revascularization. Results— Two hundred and twenty-eight patients with successful revascularization had clinical outcome follow-up. The rates of functional dependence with endovascular success were 48.6% for Trevo thrombectomy and 58.0% for Merci thrombectomy. Age (odds ratio, 1.04; 95% confidence interval, 1.02–1.06 per 1-year increase), National Institutes of Health Stroke Scale score (odds ratio, 1.08; 95% confidence interval, 1.02–1.15 per 1-point increase), and symptom onset to endovascular treatment time (odds ratio, 1.11; 95% confidence interval, 1.01–1.22 per 30-minute delay) were predictors of functional dependence despite successful revascularization. Symptom onset to reperfusion time beyond 5 hours was associated with functional dependence. All subjects with symptomatic intracranial hemorrhage had functional dependence. Conclusions— One half of patients with successful mechanical thrombectomy do not have good outcomes. Age, severe neurological deficits, and delayed endovascular treatment were associated with functional dependence despite successful revascularization. Our data support efforts to minimize delays to endovascular therapy in patients with acute ischemic stroke to improve outcomes. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00318071, NCT01088672, and NCT01270867.

Background and purposeEndovascular techniques are frequently employed to treat large artery occlusion in acute ischemic stroke (AIS). We sought to determine the predictors and clinical impact of intracranial hemorrhage (ICH) after endovascular therapy.MethodsRetrospective analysis of consecutive patients presenting to 13 high volume stroke centers with AIS due to proximal occlusion in the anterior circulation who underwent endovascular treatment within 8 h from symptom onset. Logistic regression was performed to determine the variables associated with ICH, hemorrhagic infarction (HI), and parenchymal hematomas (PHs), as well as 90 day poor outcome (modified Rankin Scale score ≥3) and mortality.ResultsThere were a total of 363 ICHs (overall rate 32.3%; HI=267, 24%; PH=96, 8.5%) among the 1122 study patients (mean age 67±15 years; median National Institutes of Health Stroke Scale score 17 (IQR 13-20)). Independent predictors for HI included diabetes mellitus (OR 2.27, 95% CI (1.58 to 3.26), p

Background and Purpose— Compare access and outcomes in a tertiary care community hospital (Saint Luke’s Neuroscience Institute) and its stroke network to hospitals in 3 national databases. Methods— Retrospective analysis of ischemic stroke patients (2005, 2007, 2010) in Saint Luke’s (n=1576), Get With The Guidelines-Stroke (n=423 809), Premier (n=91 598), and Merci Registry (n=966). Study measures were use of computed tomography scans and tissue plasminogen activator (tPA), symptomatic intracranial hemorrhage, discharge disposition, discharge National Institutes of Health Stroke Scale scores, and 90-day modified Rankin Scores. Results— Saint Luke’s increased access to care with higher tPA use than other hospitals (17.2% received intravenous tPA therapy compared with 5.8% at Get With The Guidelines–Stroke hospitals, P P P =0.001). Saint Luke’s patients also were more likely than those in other hospitals to receive computed tomography scans (99.4% vs 58.6% at Premier hospitals). Embolectomy at Saint Luke’s was associated with better outcomes than peer hospitals, and treatment at Saint Luke’s was independently associated with more discharges to home (odds ratio, 3.92; 95% confidence interval, 1.84–8.32). In 2010, symptomatic intracranial hemorrhages after tPA therapy was similar for Saint Luke’s patients and Premier patients (2.2% vs 1.5%; P =0.590). Conclusions— Regionally coordinated stroke programs can substantially improve access and patient outcomes.

Purpose/Aim: Data from chronic stroke studies have reported reduced blood flow and vascular endothelial function in the stroke-affected limb. It is unclear whether these differences are present early after stroke. First, we investigated whether vascular endothelial function in the stroke-affected limb would be different from healthy adults. Second, we examined whether between-limb differences in vascular endothelial function existed in the stroke-affected arm compared to the non-affected arm. Last, we tested whether reduced vascular endothelial function was related to pro-inflammatory markers that are present early after stroke.Vascular endothelial function was assessed by flow-mediated dilation (FMD) in the brachial artery within 72 h post-stroke. All participants withheld medications from midnight until after the procedure. Ultrasound scans and blood draws for pro-inflammatory markers occurred on the same day between 7:30 am and 9:00 am.People with acute stroke had significantly lower FMD (4.2% ± 4.6%) than control participants (8.5% ± 5.2%, p = 0.037). Stroke participants had between-limb differences in FMD (4.2% ± 4.6% stroke-affected vs. 5.3% ± 4.4% non-affected, p = 0.02), whereas, the control participants did not. Of the pro-inflammatory markers, only vascular cell adhesion molecule-1(VCAM-1) had a significant relationship to FMD (stroke-affected limb, r = -0.62, p = 0.03; non-affected limb, r = -0.75, p = 0.005), but not tumor necrosis factor alpha nor interleukin-6.Vascular endothelial function is reduced starting in the early stage of stroke recovery. People with higher levels of VCAM-1 had a lower FMD response.

Background and Purpose— Current selection criteria for intra-arterial therapies in the anterior circulation use time windows of 8 hours. Modern neuroimaging techniques have identified individuals with salvageable penumbra who present beyond this timeframe. We sought to assess safety, procedural, and clinical outcomes of MRI or CT perfusion imaging-based endovascular therapy in patients with anterior circulation stroke treated beyond 8 hours from time last seen well. Methods— We conducted a multicenter retrospective review of consecutive patients meeting the following criteria: (1) acute proximal intracranial anterior circulation occlusion; (2) endovascular treatment initiated >8 hours from time last seen well; and (3) treatment selection based on MRI or CT perfusion imaging. Results— Two hundred thirty-seven patients were identified (mean age, 63.8±16 years; mean baseline National Institutes of Health Stroke Scale, 15±5.5; mean time last seen well to treatment, 15±11.2 hours; male gender, 46%). Successful revascularization was achieved in 175 of 237 (73.84%) patients. Parenchymal hematoma occurred in 21 of 237 (8.86%) patients. The 90-day mortality rate was 21.5% (51 of 237). The rate of good outcomes was 45% (100 of 223) in the 223 patients with available modified Rankin Scale data at 90 days or time of hospital discharge. In multivariate analyses, age (OR, 0.96; 95% CI, 0.94 to 0.98; P =0.002), admission National Institutes of Health Stroke Scale (OR, 0.93; 0.87 to 0.98; P =0.016), and successful revascularization (OR, 4.32; 1.99 to 9.39; P Conclusions— Endovascular therapy can be instituted with acceptable safety beyond 8 hours from time last seen well when selection is based on advanced neuroimaging. Successful revascularization is significantly associated with higher rates of good outcomes. The benefit of this approach compared with standard medical therapy should be assessed in a prospective randomized trial.

BACKGROUND: Reperfusion therapy for acute ischemic stroke (AIS) is rapidly evolving, with the development of multiple endovascular modalities that can be used alone or in combination. OBJECTIVE: To determine which pharmacologic or mechanical modality may be associated with increased rates of recanalization. METHODS: A cohort of 1122 patients with AIS involving the anterior circulation treated at 13 stroke centers underwent intra-arterial (IA) therapy within 8 hours of symptom onset. Demographic information, admission National Institutes of Health Stroke Scale (NIHSS), mechanical and pharmacologic treatments used, recanalization grade, and hemorrhagic complications were recorded. RESULTS: The mean age was 6 7 ± 16 years and the median NIHSS was 1 7. The sites of arterial occlusion before treatment were M1 middle cerebral artery (MCA) in 561 (50%) patients, carotid terminus in 214 (19%) patients, M2 MCA in 171 (15%) patients, tandem occlusions in 141 (13%) patients, and isolated extracranial internal carotid artery occlusion in 35 (3%) patients. Therapeutic interventions included multimodal therapy in 584 (52%) patients, pharmacologic therapy only in 264 (24%) patients, and mechanical therapy only in 274 (24%) patients. Patients treated with multimodal therapy had a significantly higher Thrombolysis in Myocardial Infarction 2 or 3 recanalization rate (435 patients [74%]) compared with pharmacologic therapy only (160 patients, [61%]) or mechanical only therapy (173 patients [63%]), P < .001. In binary logistic regression modeling, independent predictors of Thrombolysis in Myocardial Infarction 2 or 3 recanalization were use of IA thrombolytic OR 1.58 (1.21-2.08), P < .001 and stent deployment 1.91 (1.23-2.96), P < .001. CONCLUSION: Multimodal therapy has significantly higher recanalization rates compared with pharmacologic or mechanical therapy. Among the individual treatment modalities, stent deployment or IA thrombolytics increase the chance of recanalization.

Object The authors evaluated the prognostic significance of blood glucose level at admission (BGA) and change in blood glucose at 48 hours from the baseline value (CG48) in nondiabetic and diabetic patients before and after endovascular therapy for acute ischemic stroke (AIS). Methods The BGA and CG48 data were analyzed in 614 patients with AIS who received endovascular therapy at 7 US centers between 2006 and 2009. Data reviewed included demographics, stroke risk factors, diabetic status, National Institutes of Health Stroke Scale (NIHSS) score at presentation, recanalization grade, intracranial hemorrhage (ICH) rate, and 90-day outcomes (mortality rate and modified Rankin Scale score of 3–6 [defined as poor outcome]). Variables with p values < 0.2 in univariate analysis were included in a binary logistic regression model for independent predictors of 90-day outcomes. Results The mean patient age was 67.3 years, the median NIHSS score was 16, and 27% of patients had diabetes. In nondiabetic patients, BGA ≥ 116 mg/dl (≥ 6.4 mmol/L) and failure of glucose level to drop > 30 mg/dl (> 1.7 mmol/L) from the admission value were both significant predictors of 90-day poor outcome and death (p < 0.001). In patients with diabetes, BGA ≥ 116 mg/dl (≥ 6.4 mmol/L) was an independent predictor of poor outcome (p = 0.001). The CG48 was not a predictor of outcome in diabetic patients. A simplified 6-point scale including BGA, Thrombolysis in Myocardial Infarction (TIMI) Grade 2–3 Reperfusion, Age, presentation NIHSS score, CG48, and symptomatic ICH (BRANCH) corresponded with poor outcomes at 90 days; the area under the curve value was > 0.79. Conclusions Failure of blood glucose values to decrease in the first 48 hours after AIS intervention correlated with poor 90-day outcomes in nondiabetic patients. The BRANCH scale shows promise as a simple prognostication tool after endovascular therapy for AIS, and it merits prospective validation.

Background and Purpose— Patients undergoing intra-arterial therapy (IAT) for acute ischemic stroke receive either general anesthesia (GA) or conscious sedation. GA may delay time to treatment, whereas conscious sedation may result in patient movement and compromise the safety of the procedure. We sought to determine whether there were differences in safety and outcomes in GA patients before initiation of IAT. Methods— A cohort of 980 patients at 12 stroke centers underwent IAT for acute stroke between 2005 and 2009. Only patients with anterior circulation strokes due to large-vessel occlusion were included in the study. A binary logistic-regression model was used to determine independent predictors of good outcome and death. Results— The mean age was 66±15 years and median National Institutes of Health Stroke Scale score was 17 (interquartile range, 13–20). The overall recanalization rate was 68% and the symptomatic hemorrhage rate was 9.2%. GA was used in 44% of patients with no differences in intracranial hemorrhage rates when compared with the conscious sedation group. The use of GA was associated with poorer neurologic outcome at 90 days (odds ratio=2.33; 95% CI, 1.63–3.44; P P Conclusions— Patients placed under GA during IAT for anterior circulation stroke appear to have a higher chance of poor neurologic outcome and mortality. There do not appear to be differences in hemorrhagic complications between the 2 groups. Future clinical trials with IAT can help elucidate the etiology of the differences in outcomes.

Background and Purpose— We hypothesized that transcranial laser therapy (TLT) can use near-infrared laser technology to treat acute ischemic stroke. The NeuroThera Effectiveness and Safety Trial–2 (NEST-2) tested the safety and efficacy of TLT in acute ischemic stroke. Methods— This double-blind, randomized study compared TLT treatment to sham control. Patients receiving tissue plasminogen activator and patients with evidence of hemorrhagic infarct were excluded. The primary efficacy end point was a favorable 90-day score of 0 to 2 assessed by the modified Rankin Scale. Other 90-day end points included the overall shift in modified Rankin Scale and assessments of change in the National Institutes of Health Stroke Scale score. Results— We randomized 660 patients: 331 received TLT and 327 received sham; 120 (36.3%) in the TLT group achieved favorable outcome versus 101 (30.9%), in the sham group ( P =0.094), odds ratio 1.38 (95% CI, 0.95 to 2.00). Comparable results were seen for the other outcome measures. Although no prespecified test achieved significance, a post hoc analysis of patients with a baseline National Institutes of Health Stroke Scale score of P Conclusions— TLT within 24 hours from stroke onset demonstrated safety but did not meet formal statistical significance for efficacy. However, all predefined analyses showed a favorable trend, consistent with the previous clinical trial (NEST-1). Both studies indicate that mortality and adverse event rates were not adversely affected by TLT. A definitive trial with refined baseline National Institutes of Health Stroke Scale exclusion criteria is planned.

Background and Purpose— Endovascular mechanical thrombectomy may be used during acute ischemic stroke due to large vessel intracranial occlusion. First-generation MERCI devices achieved recanalization rates of 48% and, when coupled with intraarterial thrombolytic drugs, recanalization rates of 60% have been reported. Enhancements in embolectomy device design may improve recanalization rates. Methods— Multi MERCI was an international, multicenter, prospective, single-arm trial of thrombectomy in patients with large vessel stroke treated within 8 hours of symptom onset. Patients with persistent large vessel occlusion after IV tissue plasminogen activator treatment were included. Once the newer generation (L5 Retriever) device became available, investigators were instructed to use the L5 Retriever to open vessels and could subsequently use older generation devices and/or intraarterial tissue plasminogen activator. Primary outcome was recanalization of the target vessel. Results— One hundred sixty-four patients received thrombectomy and 131 were initially treated with the L5 Retriever. Mean age±SD was 68±16 years, and baseline median (interquartile range) National Institutes of Health Stroke Scale score was 19 (15 to 23). Treatment with the L5 Retriever resulted in successful recanalization in 75 of 131 (57.3%) treatable vessels and in 91 of 131 (69.5%) after adjunctive therapy (intraarterial tissue plasminogen activator, mechanical). Overall, favorable clinical outcomes (modified Rankin Scale 0 to 2) occurred in 36% and mortality was 34%; both outcomes were significantly related to vascular recanalization. Symptomatic intracerebral hemorrhage occurred in 16 patients (9.8%); 4 (2.4%) of these were parenchymal hematoma type II. Clinically significant procedural complications occurred in 9 (5.5%) patients. Conclusions— Higher rates of recanalization were associated with a newer generation thrombectomy device compared with first-generation devices, but these differences did not achieve statistical significance. Mortality trended lower and the proportion of good clinical outcomes trended higher, consistent with better recanalization.

We assessed predictors of atrial fibrillation (AF) in cryptogenic stroke (CS) or transient ischemic attack (TIA) patients who received an insertable cardiac monitor (ICM).We studied patients with CS/TIA who were randomized to ICM within the CRYSTAL AF study. We assessed whether age, sex, race, body mass index, type and severity of index ischemic event, CHADS2 score, PR interval, and presence of diabetes, hypertension, congestive heart failure, or patent foramen ovale and premature atrial contractions predicted AF development within the initial 12 and 36 months of follow-up using Cox proportional hazards models.Among 221 patients randomized to ICM (age 61.6 ± 11.4 years, 64% male), AF episodes were detected in 29 patients within 12 months and 42 patients at 36 months. Significant univariate predictors of AF at 12 months included age (hazard ratio [HR] per decade 2.0 [95% confidence interval 1.4-2.8], p = 0.002), CHADS2 score (HR 1.9 per one point [1.3-2.8], p = 0.008), PR interval (HR 1.3 per 10 milliseconds [1.2-1.4], p0.0001), premature atrial contractions (HR 3.9 for123 vs 0 [1.3-12.0], p = 0.009 across quartiles), and diabetes (HR 2.3 [1.0-5.2], p0.05). In multivariate analysis, age (HR per decade 1.9 [1.3-2.8], p = 0.0009) and PR interval (HR 1.3 [1.2-1.4], p0.0001) remained significant and together yielded an area under the receiver operating characteristic curve of 0.78 (0.70-0.85). The same predictors were found at 36 months.Increasing age and a prolonged PR interval at enrollment were independently associated with an increased AF incidence in CS patients. However, they offered only moderate predictive ability in determining which CS patients had AF detected by the ICM.

Background— National guidelines endorse recombinant tissue-type plasminogen activator (r-tPA) in eligible patients with acute ischemic stroke to improve patients’ functional recovery. However, 23% to 40% of ideal candidates with acute ischemic stroke for reperfusion are not treated, perhaps because of the difficulty in explaining the benefits and risks of r-tPA within the frenetic pace of emergency department care. To support better knowledge transfer and creation of a shared decision-making tool, we conducted qualitative interviews to define the information needs and preferred presentation format for stroke survivors, caregivers, and clinicians considering r-tPA treatment. Methods and Results— A multidisciplinary team used qualitative research methods to identify informational needs and strategies for describing the benefits and risks of r-tPA in a clinical setting. Through focus groups (n=10) of stroke survivors (n=39) and caregivers (n=24) and individual interviews with emergency physicians (n=23) and advanced practice nurses (n=20), several themes emerged. Survivors and caregivers preferred a broader definition of a good outcome (independence, rather than no significant disability), simpler graphs as compared with detailed pictographs, and presentation of both population and individualized benefits (framed positively) and risk of receiving r-tPA. Some physicians expressed skepticism with the data and the ability to present risk/benefit information emergently, whereas other physicians and most advanced practice nurses thought such information would improve care. Physicians stressed the importance of presenting the risk of thrombolytic-related intracranial hemorrhage. Conclusions— This study suggests that a positively framed risk–benefit tool with graphical presentations of general and patient-specific risk estimates could support patients and providers in considering r-tPA for acute ischemic stroke. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01864928.

Observational studies demonstrate low levels of physical activity during inpatient stroke rehabilitation. There are no prior studies that have objectively measured sedentary time on the acute stroke unit and whether sedentary time is related to functional outcomes. The purpose of this study was to characterize sedentary time after acute stroke and determine whether there is a relationship to functional performance at discharge.Thirty-two individuals (18 men; 56.5 ± 12.7 years) with acute stroke were enrolled within 48 hours of hospital admission. An accelerometer was placed on the stroke-affected ankle to measure 24-hour activity and was worn for 4 days or until discharge from the hospital. Performance of activities of daily living, walking endurance, and functional mobility were assessed using the Physical Performance Test, Six-Minute Walk Test, and Timed Up and Go, respectively.Mean percent time spent sedentary was 93.9 ± 4.1% and percent time in light activity was 5.1 ± 2.4%. When controlling for baseline performance, the mean time spent sedentary per day was significantly related to Physical Performance Test performance at discharge (r = -0.37; P = .05), but not the Six-Minute Walk Test or Timed Up and Go.Patients with acute stroke were sedentary most of their hospital stay. To minimize the potential negative effects of inactivity, our data suggest that there should be greater emphasis on increasing physical activity during the hospital stay.Video Abstract Available for more insights from the authors (Supplemental Digital Content 1, http://links.lww.com/JNPT/A101).

Background: Insertable cardiac monitors (ICM) have been shown to detect atrial fibrillation (AF) at a higher rate than routine monitoring methods in patients with cryptogenic stroke (CS). However, it is unknown whether there are topographic patterns of brain infarction in patients with CS that are particularly associated with underlying AF. If such patterns exist, these could be used to help decide whether or not CS patients would benefit from long-term monitoring with an ICM. Methods: In this retrospective analysis, a neuro-radiologist blinded to clinical details reviewed brain images from 212 patients with CS who were enrolled in the ICM arm of the CRYptogenic STroke And underLying AF (CRYSTAL AF) trial. Kaplan-Meier estimates were used to describe rates of AF detection at 12 months in patients with and without pre-specified imaging characteristics. Hazard ratios (HRs), 95% confidence intervals (CIs), and p values were calculated using Cox regression. Results: We did not find any pattern of acute brain infarction that was significantly associated with AF detection after CS. However, the presence of chronic brain infarctions (15.8 vs. 7.0%, HR 2.84, 95% CI 1.13-7.15, p = 0.02) or leukoaraiosis (18.2 vs. 7.9%, HR 2.94, 95% CI 1.28-6.71, p < 0.01) was associated with AF detection. There was a borderline significant association of AF detection with the presence of chronic territorial (defined as within the territory of a first or second degree branch of the circle of Willis) infarcts (20.9 vs. 10.0%, HR 2.37, 95% CI 0.98-5.72, p = 0.05). Conclusions: We found no evidence for an association between brain infarction pattern and AF detection using an ICM in patients with CS, although patients with coexisting chronic, as well as acute, brain infarcts had a higher rate of AF detection. Acute brain infarction topography does not reliably predict or exclude detection of underlying AF in patients with CS and should not be used to select patients for ICM after cryptogenic stroke.

Acute ischemic stroke is the second leading cause of death worldwide and the leading cause of adult disability in the United States (US). Thrombolytic therapy was proved effective, and approved for use, in the US by the Food and Drug Administration in 1996, yet 8 years later just 3-4% of stroke victims in the US are treated with tissue plasminogen activator. In order to understand how this figure can be substantially improved, it is important to evaluate the available therapies and systems of care, delineate the critical steps and the existing barriers in the process for successful intervention, and thoroughly understand the key components in the highly successful interventional stroke programs, especially regionalization of care.A review of the available literature was carried out and interventional stroke data from the Mid America Brain and Stroke Institute at Saint Luke's Hospital (SLH) in Kansas City, Missouri, was analysed.There are several treatment strategies available for acute stroke intervention and more are likely to be developed. There is increasing interest in organizing and standardizing care for stroke. The steps in the process for successful intervention are understood and progress is being made in several areas of the country, but challenges remain in public education, directing emergency transport to 'stroke ready' hospitals and linking stroke experts to primary care providers. The Kansas City regional network linking primary care hospitals to the stroke team at SLH has been highly successful in substantially increasing the number of patients receiving acute stroke intervention.The stage is set for many more stroke victims to receive acute interventional therapy. However, these patients must present to hospitals equipped and staffed to render this therapy. Most stroke victims will go or be taken to the closest medical facility. Organizing regional networks linking primary care hospitals and physicians to comprehensive stroke centers staffed, and capable of providing the entire spectrum of acute stroke intervention will be essential in substantially increasing the number of stroke victims who actually receive acute interventional therapy. This article summarizes the evolving solutions to this challenge with specific data from the successful regional network developed around the Mid America Brain and Stroke Institute at Saint Luke's Hospital in Kansas City, Missouri, USA.

Background: Posterior circulation strokes (PCS) can be more difficult to diagnose than anterior circulation strokes (ACS). Ambiguous symptoms such as isolated vertigo, non-lateralizing signs and low National Institute of Health Stroke Scale (NIHSS) scores have been shown to delay treatment with intravenous (IV) tissue plasminogen activator (tPA) and prolong Door-to-needle (DTN) times. In 2006, this institution implemented the use of Code Neuro Nurses 24/7 as part of a highly developed stroke response system of care, to expedite diagnosis and treatment of all stroke patients. As part of this program, all patients in the Emergency Department (ED) with suspected stroke are evaluated by a Code Neuro Nurse. Anecdotal evidence suggested that overall DTN times improved as a result of the Code Neuro Nurse. But were DTN times still prolonged in PCS patients compared to ACS patients? Purpose: The purpose of this project was to determine if DTN times in PCS were longer than times for ACS, in patients who received IV tPA. Methods: An IRB approved retrospective chart review of ischemic stroke cases in 2011 and 2012 found 145 patients who received IV tPA. Data analysis was performed on data elements contained in the table. Results: Of the 145 patients who received tPA, 15.8% (n=23) had PCS. Age and gender were similar between the two groups. Mean admission NIHSS scores in patients with PCS were lower than scores in ACS patients. There were no differences in mean DTN times for PCS compared to ACS. Mortality and disposition to home were not different between the groups. Conclusion: As expected, the admission NIHSS scores for PCS tended to be lower than for ACS, which can contribute to delays in DTN times. However, there was no statistical difference in DTN times between the two groups. Utilizing the expertise of the Code Neuro Nurse in the ED may be a key factor in accurately and efficiently diagnosing PCS strokes, leading to DTN times comparable to ACS cases.

OBJECTIVE: To provide recovery rates after stroke for specific functions using the Orpington Prognostic Scale (OPS). DESIGN: Prospective cohort. SETTING: Hospital and community. PARTICIPANTS: 413 stroke survivors entered the study 3 to 14 days after suffering a stroke. MEASUREMENTS: A cohort of hospitalized stroke survivors were recruited 3 to 14 days after stroke and assessed at 1, 3, and 6 months poststroke for neurological, functional, and health status. Baseline OPS score was used to predict five functional outcomes at 3 and 6 months using development and validation datasets and receiver operating characteristic (ROC) curves. RESULTS: In 413 stroke survivors, functional recovery rates at 3 and 6 months were similar. Baseline OPS predicted significant differences in recovery rates for all five outcomes (P < .0001 for all five outcomes at 3 and 6 months). Personal care dependence was present at 3 months in only 3% of persons with baseline OPS scores of 3.2 or less compared with over 50% with OPS of 4.8 or higher. Independent personal care, meal preparation, and self administration of medication were achieved by 80% who had baseline OPS scores of 2.4 or lower compared with less than 20% when OPS scores were 4.4 or higher. Independent community mobility was achieved in 50% of those who had OPS scores of 2.4 or lower but only 3% of those with OPS scores of 4.4 or higher. The area under ROC curves assessing OPS scores against each of the five outcomes ranged from 0.805 to 0.863 at 3 months and 0.74 to 0.806 at 6 months. CONCLUSION: OPS scores can predict widely differing rates of functional recovery in five important functional abilities. These estimates can be useful to survivors, families, providers, and healthcare systems who need to plan for the future.

Clinical pathways for stroke are important tools for improved case management and outcome assessment. The clinical path created at St. Luke's Hospital in Kansas City is described here. It evolved through the collaboration of a multidisciplinary team of clinical experts and is still evolving. Ideally, a clinical path should be used as a guide rather than a standard of care, which is to be individualized for each patient. This article describes the methods for writing the pathways and how they are used for documentation. It also summarizes how the pathway data support stroke outcome assessment.

Current knowledge of antithrombotic therapy based on controlled clinical trials has revolutionized the way clinicians approach stroke prevention and treatment. This review article addresses the pathogenesis of stroke and summarizes information from clinical trials regarding the use of antiplatelet agents, heparin, warfarin (particularly in nonvalvular atrial fibrillation), and thrombolytics in stroke prevention and treatment.

Objective Mortality of 40% to 86% and good outcomes in only 13% to 21% of patients beg for treatment options for basilar occlusion. This study determined outcomes of patients with vertebrobasilar occlusion treated with mechanical embolus removal in cerebral ischemia (MERCI) retriever mechanical thrombectomy. Methods Patients with vertebrobasilar occlusion in the MERCI and Multi-MERCI trials received treatment up to 8 hours after symptom onset. Recanalization was determined after retriever use and adjunctive therapy. Mortality and good outcomes, modified Rankin scale score 0-3, were determined at 90 days in patients who were recanalized and not recanalized. Results Recanalization occurred in 21 of 27 (78%) patients. Mortality was 44% and good outcomes were seen in 41%. Patients with recanalization tended to have better outcomes than those without. Conclusions Outcomes in patients with vertebrobasilar occlusions treated with the MERCI retriever compared favorably with natural history reports and tended to be better in those patients with recanalization.

The primary therapeutic strategy for ischemic stroke, as for MI patients, is early reperfusion. Improvement in stroke treatment will require dedicated stroke centers to emulate MI quality indicators such as minimizing the "door-to-balloon time". A critical element in achieving this goal will be organizing the existing multidisciplinary pool of carotid interventionalists to provide the endovascular component of the acute care for ischemic stroke patients.

Background and Purpose— The only Food and Drug Administration (FDA)-approved treatment for acute ischemic stroke is tissue plasminogen activator (tPA) given intravenously within 3 hours of symptom onset. An alternative strategy for opening intracranial vessels during stroke is mechanical embolectomy, especially for patients ineligible for intravenous tPA. Methods— We investigated the safety and efficacy of a novel embolectomy device (Merci Retriever) to open occluded intracranial large vessels within 8 hours of the onset of stroke symptoms in a prospective, nonrandomized, multicenter trial. All patients were ineligible for intravenous tPA. Primary outcomes were recanalization and safety, and secondary outcomes were neurological outcome at 90 days in recanalized versus nonrecanalized patients. Results— Recanalization was achieved in 46% (69/151) of patients on intention to treat analysis, and in 48% (68/141) of patients in whom the device was deployed. This rate is significantly higher than that expected using an historical control of 18% ( P P P =0.01). Conclusions— A novel endovascular embolectomy device can significantly restore vascular patency during acute ischemic stroke within 8 hours of stroke symptom onset and provides an alternative intervention for patients who are otherwise ineligible for thrombolytics.

Background: In the Heart Outcomes Prevention Evaluation (HOPE) Study, the angiotensin-converting enzyme (ACE) inhibitor ramipril was shown to significantly reduce the relative risk of stroke by 32% in high-risk cardiovascular patients ( P Objective: The purpose of this economic analysis was to estimate the potential economic benefits of the differences in direct health care costs attributable to the prevention of first and recurrent strokes in the HOPE Study patient population through the use of ramipril. Methods: The epidemiologic component of the model examined the incidence of first and recurrent strokes in the HOPE Study population, assessed at annual increments, for the years 1995 through 1997. An economic decision model was constructed by the application of costs to the epidemiologic foundation. Direct costs for stroke hospitalization and follow-up were calculated based on estimates provided by Samsa et al (1999). The estimated cost of ramipril treatment was based on the average wholesale price for the corresponding year of the analysis. The Samsa index costs are given in 1991 US $; they were converted to study-year US $ using the Consumer Price Index for the corresponding year. Results: The mean age of the patient population was 69 years, with >70% of patients aged ≥65 years. When ACE-inhibitor treatment costs were included in the calculation of treatment costs, the expense to avert 1 stroke was estimated at $13,766 for years 1 to 2 after randomization and $12,281 for years 2 to 3. By years 3 to 4, ramipril treatment resulted in 21 fewer strokes and produced an estimated savings of $52,861. Conclusion: Ramipril 10 mg/d was a cost-effective means of preventing first and recurrent ischemic strokes in the HOPE Study patient population.

Background and Purpose— We sought to evaluate whether a comprehensive stroke center could work with regional hospitals to increase the use of tissue plasminogen activator (tPA) in acute stroke. Methods— In 30 months, 142 patients seen at the Mid America Brain and Stroke Institute received tPA. Site of presentation, protocol selection, and outcomes were analyzed. Results— We found that 18.2% (142 of 781) of all ischemic strokes received tPA. Of those, 70% (99 of 142) were transferred from hospitals within 100 miles of Kansas City (Mo). Mortality rate was 12.7% (18 of 142). Symptomatic hemorrhage rate was 9.2%. Conclusions— A comprehensive stroke center can serve as a hub for a regional network and increase the number of stroke interventions with acceptable outcomes.

Two patients underwent gastric bypasses and had uneventful hospital courses. In the early postoperative periods, both developed severe, protracted vomiting, weakness, and hyporeflexia. After thorough laboratory and clinical evaluations by neurologists, the patients were diagnosed with Guillain-Barre syndrome, although there were many atypical features. The clinical presentations of these patients are very similar to case reports of nutritional polyneuropathy associated with gastric partitioning. This paper addresses the difficulties of differentiating these two diagnoses.

Introduction The relationship between the two angiographic parameters, recanalization and reperfusion, as they relate to clinical outcome of acute stroke patients undergoing endovascular intervention is not well defined. We sought to determine the relationship of recanalization of the primary arterial occlusive lesion (AOL) and global reperfusion of the distal vascular bed in patients treated with endovascular stroke rescue at our institution. Hypothesis We assessed the hypothesis that recanalization and reperfusion scores would comparably predict outcome. Methods 96 angiograms were reanalyzed using recanalization and reperfusion scores by neurointerventionalists blinded to clinical outcome. The AOL score was defined as follows: 0=no recanalization of the primary occlusion; I=incomplete or partial recanalization of the primary occlusion with no distal flow; II=incomplete or partial recanalization of the primary occlusion with distal flow; or III=complete recanalization of the primary occlusion with distal flow. The Thrombolysis in Cerebral Infarction (TICI) Score was defined as follows: 0=no perfusion; 1= penetration, but no distal branch filling; 2a= perfusion with incomplete ( 50%) distal branch filling; and 3=full perfusion with filling of all distal branches. We compared these methods of assessment to one another and with good clinical outcome (modified Rankin Score 0 to 2). Results AOL and TICI scores showed moderate to substantial agreement (κ=0.660, 95% CI (0.518 to 0.801). Good clinical outcome was seen in 60% of patients with AOL II/III scores (p=0.462) and in 71% with TICI 2/3 scores (p=0.854). The two methods did not significantly differ in predicting outcome (p=0.52). Conclusion In conclusion, TICI reperfusion scores and AOL recanalization scores comparably predicted clinical outcome in our patient population. However, further investigation should be performed, possibly with the aid of other imaging modalities, to further differentiate between these parameters and their relationship to clinical outcome.

Background and purpose The use of endovascular techniques to treat large artery occlusion in acute ischemic stroke has become more frequently employed as a treatment option. We sought to determine the predictors of intracranial hemorrhage after these procedures were performed. Methods This is a retrospective review of data from 13 high volume stroke centers that perform endovascular treatments for acute ischemic stroke. Patients with anterior circulation strokes treated under 8 h from symptom onset with endovascular therapy were included. Hemorrhages were classified as parenchymal hematoma (PH) types 1 and 2 and hemorrhagic infarction (HI) types 1 and 2. Patients with PH bleeds were considered symptomatic and HI bleeds were asymptomatic. Binary logistic regression modeling was performed to determine the variables associated with symptomatic and asymptomatic hemorrhages after correcting for multiple comparisons. Results A total of 1122 patients met the inclusion criterion for this study. Mean age for the cohort was 67±15 years with a median National Institutes of Health Stroke Scale (NIHSS) of 17 (IQR 13–20). The distribution for thrombus location at the initiation of endovascular therapy was as follows: M1 segment of the middle cerebral artery (MCA) 561 (50%), carotid terminus 214 (19%), M2 MCA 171 (15%), tandem occlusions 141 (13%) and isolated extracranial internal carotid artery occlusion 35 (3%). Parenchymal hematomas occurred in 96 (8.5%) patients and HI in 265 (24%) patients. There were no variables associated with symptomatic hemorrhages while the following variables were predictors of asymptomatic hemorrhage: diabetes mellitus (OR 2.02; 95% CI 1.46 to 2.79; p Conclusions Diabetic patients and those who have been treated with intravenous tPA prior to the procedure or intraprocedural use of thrombolytics or the Merci device appear to be at a higher risk for asymptomatic hemorrhage. Moreover, patients with asymptomatic hemorrhage appear to be at a higher risk for a worse clinical outcome at the 90 day follow-up.

An animal model of inappropriate antidiuretic hormone secretion was used to study changes in water and electrolytes in water intoxication. As the serum became hypotonic, brain and muscle initially reacted by swelling and decreasing sodium content. Subsequently, muscle continued to swell and maintained normal potassium levels. Brain decreased its dry weight potassium content by 20% and swelled half as much as muscle. The critical factor in determination of consciousness was the level of brain water, not the level of sodium or potassium. Grey and white matter were affected equally. Permeability to mannitol was normal in the experimental model. Corticosteroids were found to have no effect on the syndrome. The drop in brain potassium level is interpreted as a protective adaptation to prevent massive swelling as occurred in muscle.

Ischemic stroke cause remains undetermined in 30% of cases, leading to a diagnosis of cryptogenic stroke. Paroxysmal atrial fibrillation (AF) is a major cause of ischemic stroke but may go undetected with short periods of ECG monitoring. The Cryptogenic Stroke and Underlying Atrial Fibrillation trial (CRYSTAL AF) demonstrated that long-term electrocardiographic monitoring with insertable cardiac monitors (ICM) is superior to conventional follow-up in detecting AF in the population with cryptogenic stroke. We evaluated the sensitivity and negative predictive value (NPV) of various external monitoring techniques within a cryptogenic stroke cohort. Simulated intermittent monitoring strategies were compared to continuous rhythm monitoring in 168 ICM patients of the CRYSTAL AF trial. Short-term monitoring included a single 24-hour, 48-hour, and 7-day Holter and 21-day and 30-day event recorders. Periodic monitoring consisted of quarterly monitoring through 24-hour, 48-hour, and 7-day Holters and monthly 24-hour Holters. For a single monitoring period, the sensitivity for AF diagnosis was lowest with a 24-hour Holter (1.3%) and highest with a 30-day event recorder (22.8%). The NPV ranged from 82.3% to 85.6% for all single external monitoring strategies. Quarterly monitoring with 24-hour Holters had a sensitivity of 3.1%, whereas quarterly 7-day monitors increased the sensitivity to 20.8%. The NPVs for repetitive periodic monitoring strategies were similar at 82.6% to 85.3%. Long-term continuous monitoring was superior in detecting AF compared to all intermittent monitoring strategies evaluated (p