Analysis of brain edema in RHAPSODY.

BACKGROUND: Cerebral edema is a secondary complication of acute ischemic stroke, but its time course and imaging markers are not fully understood. Recently, net water uptake (NWU) has been proposed as a novel marker of edema. AIMS: Studying the RHAPSODY trial cohort, we sought to characterize the time course of edema and test the hypothesis that NWU provides distinct information when added to traditional markers of cerebral edema after stroke by examining its association with other markers. METHODS: A total of 65 patients had measurable supratentorial ischemic lesions. Patients underwent head computed tomography (CT), brain magnetic resonance imaging (MRI) scans, or both at the baseline visit and after 2, 7, 30, and 90 days following enrollment. CT and MRI scans were used to measure four imaging markers of edema: midline shift (MLS), hemisphere volume ratio (HVR), cerebrospinal fluid (CSF) volume, and NWU using semi-quantitative threshold analysis. Trajectories of the markers were summarized, as available. Correlations of the markers of edema were computed and the markers compared by clinical outcome. Regression models were used to examine the effect of 3K3A-activated protein C (APC) treatment. RESULTS: Two measures of mass effect, MLS and HVR, could be measured on all imaging modalities, and had values available across all time points. Accordingly, mass effect reached a maximum level by day 7, normalized by day 30, and then reversed by day 90 for both measures. In the first 2 days after stroke, the change in CSF volume was associated with MLS (ρ = -0.57, p = 0.0001) and HVR (ρ = -0.66, p < 0.0001). In contrast, the change in NWU was not associated with the other imaging markers (all p ⩾ 0.49). While being directionally consistent, we did not observe a difference in the edema markers by clinical outcome. In addition, baseline stroke volume was associated with all markers (MLS (p < 0.001), HVR (p < 0.001), change in CSF volume (p = 0.003)) with the exception of NWU (p = 0.5). Exploratory analysis did not reveal a difference in cerebral edema markers by treatment arm. CONCLUSIONS: Existing cerebral edema imaging markers potentially describe two distinct processes, including lesional water concentration (i.e. NWU) and mass effect (MLS, HVR, and CSF volume). These two types of imaging markers may represent distinct aspects of cerebral edema, which could be useful for future trials targeting this process.

Digital Scientific Platform for Independent Content in Neurology: Rigorous Quality Guideline Development and Implementation.

BACKGROUND: Digital communication has emerged as a major source of scientific and medical information for health care professionals. There is a need to set up an effective and reliable methodology to assess and monitor the quality of content that is published on the internet. OBJECTIVE: The aim of this project was to develop content quality guidelines for Neurodiem, an independent scientific information platform dedicated to neurology for health care professionals and neuroscientists. These content quality guidelines are intended to be used by (1) content providers as a framework to meet content quality standards and (2) reviewers as a tool for analyzing and scoring quality of content. METHODS: Specific scientific criteria were designed using a 5-point scale to measure the quality of curated and original content published on the website: for Summaries, (1) source reliability and topic relevance for neurologists, (2) structure, and (3) scientific and didactic value; for Congress highlights, (1) relevance of congress selection, (2) congress coverage based on the original program, and (3) scientific and didactic value of individual abstracts; for Expert points of view and talks, (1) credibility (authorship) and topic relevance for neurologists, (2) scientific and didactic value, and (3) reliability (references) and format. The criteria were utilized on a monthly basis and endorsed by an independent scientific committee of widely recognized medical experts in neurology. RESULTS: Summary content quality for the 3 domains (reliability and relevance, structure, and scientific and didactic value) increased in the second month after the implementation of the guidelines. The domain scientific and didactic value had a mean score of 8.20/10. Scores for the domains reliability and relevance (8-9/10) and structure (45-55/60) showed that the maintenance of these 2 quality items over time was more challenging. Talks (either in the format of interviews or slide deck-supported scientific presentations) and expert point of view demonstrated high quality after the implementation of the content quality guidelines that was maintained over time (15-25/25). CONCLUSIONS: Our findings support that content quality guidelines provide both (1) a reliable framework for generating independent high-quality content that addresses the educational needs of neurologists and (2) are an objective evaluation tool for improving and maintaining scientific quality level. The use of these criteria and this scoring system could serve as a standard and reference to build an editorial strategy and review process for any medical news or platforms.

Hyperdense middle cerebral artery sign and response to combination of mechanical Thrombectomy plus intravenous thrombolysis in acute stroke patients.

BACKGROUND AND PURPOSE: Combining intra-arterial mechanical thrombectomy (IAMT) and intravenous thrombolysis (IVT) has shown to have an excellent recanalization rate and better clinical outcome in acute ischemic stroke (AIS) patients. Hyperdense middle cerebral artery sign (HMCAS) on pretreatment non-contrast head CT scan of AIS patients is one of the early ischemic radiological findings in middle cerebral artery territory AIS. We aimed to evaluate whether the presence of HMCAS predicts the outcome of AIS patients receiving combination therapy with IAMT and IVT. METHODS: We retrospectively reviewed medical records and cerebrovascular images of the patients treated with IAMT and IVT for AIS in our center. Patients with occlusion in the terminal internal carotid artery or middle cerebral artery on pretreatment CT angiogram of the head were included. Clinical outcome was compared between subjects with HMCAS and those without. Modified Rankin Score (mRS) and symptomatic intracranial hemorrhage (sICH) were used as measures of efficacy and safety, respectively. RESULTS: Of 93 patients, 46 (49%) had HMCAS on their initial head CT scan. Both groups had comparable baseline characteristics and stroke severity. After adjusting for age, NIHSS score, time from symptom onset to starting IVT, and history of diabetes mellitus in multivariate logistic regression analysis, there was no difference in terms of a poor outcome (mRS >2) (OR = 0.5 [CI 0.2-1.4], p = 0.188) or rate of sICH (OR = 3.3 [CI 0.6-19.0], p = 0.190) between the two groups. CONCLUSIONS: HMCAS is not a predictor of poor outcome in AIS patients receiving combination therapy with IAMT and IVT and does not affect treatment safety.

Thrombolysis for stroke in elderly in the late window period.

OBJECTIVES: Safety of intravenous thrombolysis (IVT) within 3-4.5 hours of stroke onset in patients ≥80 years is still disputable. We evaluated the association of symptom onset-to-treatment time (SOTT) with the symptomatic intracranial hemorrhage (sICH), poor outcome, and mortality in patients≥80 years. MATERIALS AND METHODS: In a retrospective study, patients treated with IVT following stroke were registered. Outcomes were poor outcome (mRS>2), sICH/ECASS-2, and in-hospital mortality. We compared the patients≥80 years who received IVT within 3 hours with those receiving IVT within 3-4.5 hours. We further compared the patients who were <80 years with those ≥80 years and SOTT of 3-4.5 hours. RESULTS: Of 834 patients, 265 aged over 80. In those above 80 and in multivariable analysis, the associations of SOTT with poor outcome (aOR: 1.401, CI: 0.503-3.903, p=0.519), sICH (aOR=2.50, CI=0.76-8.26, p= 0.132) and mortality (aOR=1.12, CI=0.39-3.25, p= 0.833) were not significant. 106 patients received IVT within 3-4.5 hours. In multivariable analysis, the associations of age (≥80 versus <80) with poor outcome (aOR=1.87, CI=0.65-5.37, p=0.246), sICH (aOR=0.65, CI=0.14-3.11, p=0.590), and mortality (aOR=0.87, 95% CI=0.16-4.57, p=0.867) were not significant in patients with SOTT of 3-4.5 hours. CONCLUSION: IVT within 3-4.5 hours in patients ≥80 years is not associated with increased sICH, poor outcome, and mortality compared to the early time window, and also compared to the younger patients in 3-4.5 hours window period. The decision of IVT administration in this age group should not be made solely on the basis of stroke onset timing.

Transesophageal echocardiogram in the evaluation of acute ischemic stroke of young adults.

INTRODUCTION: Acute ischemic stroke (AIS) in the young age (≤50 years) is a major cause of disability. The underlying mechanism of AIS in this age group is usually different from elderly. Transthoracic echocardiography (TTE) is used to detect the potential cardiac sources of embolism in AIS patients. Transthoracic echocardiogram (TEE) is superior to detect specific underlying cardio-aortic source of embolism when compared to TTE. We aim to evaluate the diagnostic yield and therapeutic impact of TEE in AIS of young adults. METHODS: We retrospectively reviewed the consecutive patients with AIS in our comprehensive center in a 5-year period from our prospectively collected registry. We selected patients with age ≤50 years who had acute infarcts on brain magnetic resonance imaging or head computed tomography and underwent TEE as part of their diagnostic workup. Demographic details including, age, gender, body mass index, cardiovascular risk factors profile, and TEE findings were collected. RESULTS: Among a total 7,930 patients, 876 (11.04%) were found to be ≤50 years old. Among those, TEE was done in 113 patients (12.8%) in addition to TTE. Those who underwent TEE had a mean age of 40.4 ± 7.9 years, 60 were male (53%), 7 (6.2%) had a history of coronary artery disease, 38 (33%) had a history of diabetes, and 45 (40%) had a history of smoking. TEE showed new abnormal findings in a total of 15 patients (13.2%) that were not reported in their TTEs. Out of these, left atrial appendage thrombus was found in 5, infective endocarditis in 4, atrial septal aneurysms associated with patent foramen ovale (PFO) in 3, and spontaneous mobile echo density in three patients. Overall, new findings from TEE resulted in change in the secondary stroke prevention strategy in 14 patients of those who underwent TEE (12.3%). TEE also confirmed the presence of PFO, which was present on TTE with bubble study in 20 (17.6%) patients. CONCLUSION: TEE may provide additional information in the evaluation of the AIS in young adults, which could lead to change of the secondary stroke prevention strategy.

Safety and efficacy of antiplatelet use before intravenous thrombolysis for acute Ischemic stroke.

AIM: To study the effects of pretreatment with Antiplatelet (AP) before IV thrombolysis (IVT) on the rate of symptomatic intracranial hemorrhage (sICH) and functional outcome in patients with Acute Ischemic stroke (AIS). METHOD: In this retrospective study, the medical records and cerebrovascular images of all the patients who received IVT for AIS in our center in a 9.6-year period were reviewed. Patients who took at least one dose of any APs in the last 24 h prior to IVT were identified. They were categorized according to the type of AP, single versus dual AP therapy (DAPT), and dose of AP. Rate of sICH and functional outcome at discharge were compared between the AP users and non-users. RESULTS: A total of 834 patients received IVT for AIS in our center during a 9.6- year period. Multivariate models were adjusted for age, NIHSS on admission, history of atrial fibrillation, history of hypertension, INR on admission, history of stroke and diabetes mellitus. In multivariate regression analyses and after adjusting for the variables mentioned above, the use of any AP was not associated with an increased rate of sICH (OR = 1.28 [0.70-2.34], p = 0.425). Furthermore, the use of DAPT did not significantly increase the rate of sICH in multivariate regression analyses. (OR = 0.663 [0.15-2.84], p = 0.580). The patients on any AP had a lower chance of having good functional outcome in univariate analysis (OR = 0.735 [0.552-0.979], p = 0.035). However, when adjusted for age, baseline NIHSS, history of diabetes, hypertension and prior stroke, AP use was not associated with a decreased chance of having a good functional outcome at discharge. (OR = 0.967 [0.690-1.357], p = 0.848). In addition, no significant difference was noted in the rate of good functional outcome between patients on DAPT and no AP users in multivariate regression analyses. (OR = 1.174 [0.612-2.253], p = 0.629). CONCLUSION: Our study did not show any significant association between the risk of sICH and good functional outcome after IVT for AIS patients on AP therapy (dual or single) in comparison with AP naïve patients.

Outcomes and resource use of patients with large hemispheric infarction and cerebral edema: analysis of real-world data.

OBJECTIVE: Large hemispheric infarction (LHI) is associated with a high likelihood of the evolution of life-threatening edema. Few studies have assessed real-world clinical outcomes and management strategies among patients with LHI. The objective of this study was to describe the management, in-hospital outcomes, and direct healthcare resource burden of patients with LHI, as well as those of patients with subsequent cerebral edema. METHODS: This observational, retrospective cohort study analyzed de-identified data from US adult patients using the IBM MarketScan Hospital Drug Database (Q4-2015 to Q4-2017). Patients were included in the "Possible LHI" or the "Other Ischemic Strokes" cohorts using ICD-10 diagnosis codes. Patients with possible LHI were further categorized into "LHI with Edema" and "LHI without Edema" subgroups using diagnosis and procedure codes. Select clinical and economic outcomes were compared between cohorts and subgroups using multivariable regressions. RESULTS: Of 79,201 eligible encounters with ischemic strokes, 11,772 unique patients were assigned to the Possible LHI cohort while 67,429 were assigned to the Other Ischemic Strokes cohort. Among patients with possible LHI, 869 (7%) were assigned to the LHI with Edema subgroup and 10,903 (93%) were assigned to the LHI without Edema subgroup. Patients in the Possible LHI cohort had longer hospital stays (mean difference [MD] [95%CI] = 2.6 [2.4;2.8] days), higher total facility charges (MD [95%CI] = $28,656 [26,794;30,524]), and higher odds of death (odds ratio [95%CI] = 2.2 [2.0;2.4]) than the Other Ischemic Strokes cohort. Among patients with possible LHI, the incremental clinical and resource burden was further exacerbated in the subgroup of patients with edema (hospital days: MD [95%CI] = 5.0 [3.9;6.2] days; total facility charges: MD [95%CI] = $59,585 [50,816;67,583]; mortality: odds ratio [95%CI] = 10.3 [8.5;12.4]). CONCLUSIONS: Among patients with ischemic strokes, LHI was associated with increased clinical management and direct healthcare resource burden in real-world hospital settings. The burden was substantially increased among patients who developed cerebral edema.

Safety of Intravenous Thrombolysis for Acute Ischemic Stroke in Patients Taking Warfarin with Subtherapeutic INR.

INTRODUCTION: Current guidelines allow the administration of intravenous recombinant tissue plasminogen activator (IV r-tPA) to warfarin-treated patients with acute ischemic stroke (AIS) who have an international normalized ratio (INR) of ≤1.7. However, concerns remain about the safety of using IV r-tPA in this situation due to a conceivable risk of symptomatic intracranial hemorrhage (sICH), lack of dedicated randomized controlled trials and the conflicts in the available data. We aimed to determine the risk of sICH in warfarin-treated patients with subtherapeutic INR who received IV r-tPA for AIS in our large volume comprehensive center. METHODS: Patients who had received IV r-tPA for AIS in a 9.6-year period were retrospectively investigated (n = 834). Patients taking warfarin prior to presentation were identified (n = 55). One patient was excluded due to elevated INR beyond the acceptable range for IV r-tPA treatment. Because of the significant difference in the sample size (54 vs 779), warfarin group was matched with 54 non-warfarin patients adjusted for independent risk factors for sICH (age, admission NIHSS, history of diabetes). Good outcome was defined as mRS of 0-2 on discharge and sICH was defined as an ICH causing increase in NIHSS ≥4 or death. Warfarin-treated group was further dichotomized based on INR (1-1.3 vs 1.3-1.7) and safety and outcome measures were compared between resultant groups. RESULTS: No significant difference was found between warfarin-treated and the non-warfarin groups in terms of chance of good outcome on discharge (27.8% in warfarin group vs 26.4% in non-warfarin group; p-value >0.05), or the rate of occurrence of sICH (3.7% in warfarin group vs 11.1% in non-warfarin group; p-value >0.05). Furthermore, rate of sICH (5.1% in patients with INR <1.3 versus 0.0% in patients with INR 1.3-1.7; p-value >0.05) or chance of good outcome on discharge (28.2% of patients with INR <1.3 versus 26.7% in patients with INR 1.3-1.7; p-value >0.05) were not found to be different after the warfarin-treated group was dichotomized. CONCLUSION: Administration of IV r-tPA for AIS in warfarin-treated patients with subtherapeutic INR <1.7 does not increase the risk of sICH.

Does Body Mass Index Impact the Outcome of Stroke Patients Who Received Intravenous Thrombolysis?

BACKGROUND: We sought to investigate the effect of obesity and BMI on functional outcome and rate of symptomatic intracranial hemorrhage (sICH) in a large sample of patients with acute ischemic stroke (AIS) treated with intravenous thrombolysis (IVT). METHODS: In a single-center retrospective, but prospectively collected data, study of patients with AIS treated with IVT in a 10-year period, patients were placed into groups based on their BMI defined as underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), or obese (<30 kg/m2). The rate of sICH and discharge modified Rankin Scale (mRS) were compared between the groups using logistic regression analysis. RESULTS: In a total of 834 patients who received IVT for AIS during a 10-year period, 224 (27.0%) were obese. Obese patients did not have a higher rate of sICH after IVT for AIS on the unadjusted or adjusted analysis (adjusted OR 0.95, 95% CI 0.48-1.88). We did not find an association between obesity and poor functional outcome at discharge (adjusted OR 0.76, 95% CI 0.53-1.09). CONCLUSIONS: After adjusting for confounding factors such as age, baseline National Institute of Health Stroke Scale (NIHSS), and comorbidities, obesity was not associated with an unfavorable functional outcome at discharge nor with a higher risk of sICH in patients with AIS treated with IVT.

Laboratory factors associated with symptomatic hemorrhagic conversion of acute stroke after systemic thrombolysis.

BACKGROUND: Laboratory factors associated with hemorrhagic conversion (HC) after Intravenous thrombolysis with rtPA (IVT) for Acute Ischemic Stroke (AIS) remain nebulous despite advances in our knowledge of AIS. This study aimed to investigate the laboratory factors predisposing to HC in AIS patients receiving IVT. METHODS: We retrospectively reviewed the medical records of patients who received IV tPA for AIS at our comprehensive stroke center over a 9.6-year period. Besides age, gender, NIHSS, history of diabetes mellitus (DM), history of atrial fibrillation (Afib), we gathered their laboratory data including International Normalized Ratio (INR), lipid panel, serum albumin, serum creatinine, hemoglobin A1c (HbA1c), and admission blood glucose. Post-thrombolysis brain imagings were reviewed to evaluate for symptomatic ICH (sICH). The mean values of above mentioned laboratory data were compared between the group with sICH and patients with no sICH. Univariate and multivariate logistic regression were performed to evaluate the association of the laboratory findings with presence of sICH. sICH was defined as ICH causing an increase in NIHSS ≥4. RESULTS: Of the 794 subjects in this study 51 (6.4%) had sICH. In the univariate analysis, patients who developed sICH had significantly higher NIHSS on admission (14.2 ± 5.4 vs 11.2 ± 6.5, p < .001), LDL-cholesterol (113.3 mg/dl ±36.9 vs. 101.8 mg/dl ± 38.2, p = .032), HbA1c (6.9% ± 2.3 vs. 6.1 ± 1.3, p = .003) and lower levels of Albumin (3.5 g/dl ±0.4 vs. 3.9 g/dl ± 0.5, p < .001). Furthermore, a higher prevalence of history of DM (45% vs. 21.6%, p = .020) and Afib (25.4% vs. 10.4%, p = .028) was found in subjects who developed sICH. There were no significant group differences regarding age, sex, total cholesterol, blood glucose on admission, serum creatinine or INR levels (p > .05). After adjusting for multiple covariates, lower Albumin level and and higher HbA1c were significantly associated with an increased risk for sICH development (p < .05). Chances of sICH increased by 33% for every 1 g/dl below a normal albumin level of 4.0 g/dl (p < .05). CONCLUSION: Lower endogenous albumin level and higher HbA1c have shown to predispose to a higher risk of sICH after IVT for AIS and might be good predictors of sICH post IVT.

Strokes occurring in the hospital: Symptom recognition and eligibility for treatment in the intensive care units versus hospital wards.

BACKGROUND: Studies have shown that 4%-17% of acute ischemic strokes (AISs) occur in patients hospitalized for another reason; scanty data are available about the care delivery and outcome of this patient population. MATERIALS AND METHODS: All consecutive inhospital AISs over a 10-year period at our comprehensive stroke center were included in the study. We compared the meantime from last known neurologically intact to symptom detection and also eligibility for acute treatment of patients based on their physical location in the hospital with respect to the level of care when they were found to have the stroke symptoms. RESULTS: Fifty-three patients suffered inhospital AIS during this period (28 in intensive care units/emergency department [ICUs/ED] vs. 25 in regular floors). Only in four patients (7.5%), initial brain imaging was done within 25 min from symptom recognition (as recommended by the American Heart Association/American Society of Anesthesiologists guidelines). Forty-two (79%) underwent brain imaging within 6 h of symptom recognition; of them, 11 (26%) received intravenous thrombolysis (IVT) within the first 4.5 h of symptom onset and 7 (17%) underwent endovascular treatment (EVT). The mean (±standard deviation) time in minutes from last known neurologically intact to symptom detection for floor patients was significantly longer compared to the ICU/ED patients (194 [±149] vs. 74 [±45], P = 0.0003). Patients admitted to the ICU/ED had more chance of being recognized earlier and being eligible for IVT or/and EVT compared to the patients admitted to the regular floors (44% vs. 25%, P = 0.14); however, the difference did not reach statistical significance. CONCLUSIONS: ICU/ED patients had a significantly shorter time to stroke symptom detection from last known neurologically intact when compared to the regular floor patients. Furthermore, they had a trend toward a higher likelihood of being eligible for acute treatment compared to the regular floors, although the result did not reach statistical significance.

Statins Use and Outcome of Acute Ischemic Stroke Patients after Systemic Thrombolysis.

AIM: The aim of this was to study the effects of statins and their intensity on symptomatic intracranial hemorrhage (sICH) and outcome after IV thrombolysis (IVT) for acute ischemic stroke (AIS). METHODS: We retrospectively reviewed the medical records and cerebrovascular images of all the patients treated with IVT for AIS in our center in a 10-year period. Patients were further characterized as any statin users versus non-users on admission to the emergency department. Statins were categorized in high intensity or low intensity statin based on its propensity to reduce lower low-density cholesterol by ≥45% or <45%, respectively. Safety and discharge modified Rankin Score were compared between statin users versus non-users and also between high-intensity versus low-intensity groups. RESULTS: A total of 834 patients received IVT for AIS in our center during a 10-year period. Multivariate models were adjusted for age, NIH Stroke Scale at admission, INR, and history of DM and atrial fibrillation. There was no association between odds of sICH and any statin use (OR = 0.52 [0.26-1.03], p = 0.06). In multivariate model, any statin use was not associated with odds of poor outcome (Table 4: OR = 1.01 [0.79-1.55], p = 0.57). There was no significant association between odds of sICH among patients on high-intensity statin compared to low intensity statin (multivariate model OR = 0.39 [0.11-1.40], p = 0.15). There was 47% reduced odds of poor outcome among patients on high-intensity statin as compared to low-intensity statin (OR = 0.53[0.32-0.88] p = 0.01). However, this significant association was lost in the multivariate model (OR = 0.60 [0.35-1.05], p = 0.07). CONCLUSION: Our study does not show any significant association between risk of sICH and poor outcome after IVT for patients on prior statin therapy. We also did not find significant association between the risk of sICH and poor outcome after IVT and the intensity of the stain used.

Intravenous Tissue Plasminogen Activator for Large Vessel Ischemic Stroke - Is There Still a Role?

While the efficacy of Intravenous tissue plasminogen activator (tPA) is well established, its impact on large vessel occlusion (LVO) is controversial. Whether IV tPA should be bypassed in favor of endovascular thrombectomy (MT) will be addressed. Compelling evidence exists to suggest tPA administration might be bypassed in tPA eligible patients in favor of MT for LVO. A trial of MT with patients randomized for IV tPA within the 4.5-h time window should conducted at comprehensive stroke centers demonstrating equipoise between time to tPA or MT with time to treatment from ED arrival of 45 min. We may do well to consider the systems pathway taken by interventional cardiologists 15 years ago.

Final Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke.

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.

Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The PRISMS Randomized Clinical Trial.

Importance: More than half of patients with acute ischemic stroke have minor neurologic deficits (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) at presentation. Although prior major trials of alteplase included patients with low NIHSS scores, few without clearly disabling deficits were enrolled. Objective: To evaluate the efficacy and safety of alteplase in patients with NIHSS scores of 0 to 5 whose deficits are not clearly disabling. Design, Setting, and Participants: The PRISMS trial was designed as a 948-patient, phase 3b, double-blind, double-placebo, multicenter randomized clinical trial of alteplase compared with aspirin for emergent stroke at 75 stroke hospital networks in the United States. Patients with acute ischemic stroke whose deficits were scored as 0 to 5 on the NIHSS and judged not clearly disabling and in whom study treatment could be initiated within 3 hours of onset were eligible and enrolled from May 30, 2014, to December 20, 2016, with final follow-up on March 22, 2017. Interventions: Participants were randomized to receive intravenous alteplase at the standard dose (0.9 mg/kg) with oral placebo (n = 156) or oral aspirin, 325 mg, with intravenous placebo (n = 157). Main Outcomes and Measures: The primary outcome was the difference in favorable functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days via Cochran-Mantel-Haenszel test stratified by pretreatment NIHSS score, age, and time from onset to treatment. Because of early termination of the trial, prior to unblinding or interim analyses, the plan was revised to examine the risk difference of the primary outcome by a linear model adjusted for the same factors. The primary safety end point was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous study treatment. Results: Among 313 patients enrolled at 53 stroke networks (mean age, 62 [SD, 13] years; 144 [46%] women; median NIHSS score, 2 [interquartile range {IQR}, 1-3]; median time to treatment, 2.7 hours [IQR, 2.1-2.9]), 281 (89.8%) completed the trial. At 90 days, 122 patients (78.2%) in the alteplase group vs 128 (81.5%) in the aspirin group achieved a favorable outcome (adjusted risk difference, -1.1%; 95% CI, -9.4% to 7.3%). Five alteplase-treated patients (3.2%) vs 0 aspirin-treated patients had sICH (risk difference, 3.3%; 95% CI, 0.8%-7.4%). Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke, treatment with alteplase vs aspirin did not increase the likelihood of favorable functional outcome at 90 days. However, the very early study termination precludes any definitive conclusions, and additional research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02072226.

Delays in door-to-needle time for acute ischemic stroke in the emergency department: A comprehensive stroke center experience.

BACKGROUND: Current American Stroke Association guidelines recommend initiating intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) within 60min of patient arrival, given the benefits of IVT for AIS are time dependent. This study aimed to identify the delaying factors in door-to-needle time (DTN) in the emergency department of one of the largest comprehensive stroke centers in New York State. We also recommended measures to reduce the delays. METHODS: We retrospectively reviewed the medical charts of all AIS patients who received IVT in our emergency department patients between April 1, 2012 and December 31, 2015 to identify those with a DTN time of >60min. We categorized the factors causing the delay into different groups. For each group, we recommended measures to reduce the treatment delays. RESULTS: A total of 487 patients received IVT for AIS during the 3.7-year period. Of these, 96 patients (20.4%) met our DTN time delay criteria. Delays for obtaining stroke imaging and hypertension control were the most common factors. Thirty eight patients (39.5%) had delay in obtaining CT-based stroke imaging. Twenty-two patients (22.9%) required control of elevated blood pressure prior to IVT. Other causes for delay in DTN time included delay in stroke triage and paging (11.4%), fluctuating neurological symptoms (7.2%), uncertainty about diagnosis (12.5%), delays associated with obtaining consent (9.3%), and uncertainty about the time of symptom onset (5.2%). CONCLUSION: Important and common causes of delay in IVT for AIS were identified in a review of charts at our comprehensive stroke center. The authors recommend strategies to achieve faster DTN time for each of the delaying factor categories including faster acquisition and interpretation of stroke imaging, more effective triage protocols and faster blood pressure control for AIS patients who are eligible for IVT.

Intravenous Thrombolysis for Acute Ischemic Stroke in Patients with Thrombocytopenia.

OBJECTIVE: To determine the safety of intravenous (IV) recombinant tissue plasminogen activator (rtPA) in patients with acute ischemic stroke (AIS) who had a platelet count <100,000 /mm3. METHODS: We reviewed the charts of all patients who received IV rtPA for AIS during a 9.6-year period at our stroke center. Those with platelets <100,000/mm3 were identified. Head computed tomography scans performed in 24-36 hours postthrombolysis were reviewed to evaluate the rate of symptomatic intracranial hemorrhage (sICH). RESULTS: A total of 835 patients received IV rtPA for AIS during this period. A total of 5 patients were identified to have a platelet count <100,000/mm3. One of them (20%) developed sICH post-IV tPA administration .The mean platelet count of those 5 patients was 63,000 ± 19,000/mm3. To the best of our knowledge, only 21 thrombocytopenic patients have been reported to receive IV rtPA for AIS in the medical literature. Combining our 5 cases with 21 patients previously reported, we have 26 AIS patients who had a platelet count <100,000/mm3 and received IV rtPA, with 2 of them developing sICH (7.7 %). Comparing the rate of sICH among this group with the patients with normal platelet count in our cohort, there was no statistically significant difference (7.7% versus 6.04%, P value = .73). CONCLUSION: IV rtPA for AIS might be safe in patients with platelet count <100,000/mm3 and it is reasonable not to delay IV rtPA administration while waiting for the platelet count result, unless there is strong suspicion for abnormal platelet count.

Is acute reperfusion therapy safe in acute ischemic stroke patients who harbor unruptured intracranial aneurysm?

BACKGROUND: Intracranial aneurysms are currently considered as contraindication for intravenous thrombolysis in acute ischemic stroke, very likely due to a possible increase in the risk of bleeding from aneurysm rupture; however, there is limited data available on whether intravenous thrombolysis is safe for acute ischemic stroke patients with pre-existing intracranial aneurysms. AIMS AND/OR HYPOTHESIS: To find out the safety of intravenous thrombolysis in acute ischemic stroke patients who harbor unruptured intracranial aneurysms. METHODS: We retrospectively reviewed the medical records and cerebrovascular images of all the patients treated with intravenous thrombolysis for acute ischemic stroke in our center from the beginning of 2006 till the end of April 2014. Those with unruptured intracranial aneurysm present on cerebrovascular images prior to acute reperfusion therapy were identified. Post-thrombolysis brain imaging was reviewed to evaluate for any intraparenchymal or subarachnoid hemorrhage related or unrelated to the aneurysm. RESULTS: A total of 637 patients received intravenous thrombolysis for acute ischemic stroke in our center during an 8·3-year period. Thirty-three (5·2%) were found to have at least one intracranial aneurysms. Twenty-three (70%) of those received only intravenous thrombolysis, and 10 patients received combination of intravenous and intra-arterial thrombolysis. The size of the largest aneurysm was 10 mm in maximum diameter (range: 2-10 mm). The mean size of aneurysms was 4·8 mm. No symptomatic intracranial hemorrhage occurred among the 23 patients receiving only intravenous thrombolysis. Out of those who received a combination of intravenous and intra-arterial thrombolysis, one developed symptomatic intracranial hemorrhage in the location of acute infarct, distant to the aneurysm location. CONCLUSION: Our findings suggest that neither intravenous thrombolysis nor combination of intravenous and intra-arterial thrombolysis increases the risk of aneurysmal hemorrhage in acute ischemic stroke patients who harbor unruptured intracranial aneurysms less than 10 mm in diameter. Their listing in exclusion criteria for intravenous thrombolysis should be reconsidered to assure appropriate use of acute reperfusion therapy in this group of patients.

Third nerve palsy following carotid artery dissection and posterior cerebral artery thrombectomy: Case report and review of the literature.

BACKGROUND: Common causes of oculomotor nerve palsy are diabetes, aneurysmal compression, and uncal herniation. A lesser-known cause of third nerve dysfunction is ischemia, often due to carotid artery dissection. CASE DESCRIPTION: An 80-year-old man presented with an acute ischemic stroke with a National Institutes of Health Stroke Scale score of >20 from a high cervical internal carotid artery (ICA) dissection and a tandem ICA terminus embolic occlusion with extension of clot into the adjacent fetal posterior cerebral artery (PCA). We used a stentriever to perform selective PCA thrombectomy, with immediate postthrombectomy development of ipsilateral anisocoria. The anisocoria progressed into complete oculomotor nerve palsy over 8 h after the procedure. CONCLUSIONS: The clinical course described in this case is consistent with injury to the third nerve due to mechanical injury or occlusion of perforator supply to the nerve during thrombectomy. Oculomotor nerve palsy is a rare but known complication after ischemia; however, to our knowledge, this is the first case after thrombectomy for a PCA embolus.