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Direct oral anticoagulants are the primary stroke prevention option in patients with atrial fibrillation. Anticoagulant use before stroke, however, might inhibit clinician comfort with thrombolysis if a stroke does occur. Resuming anticoagulants after ischemic stroke is also problematic for fear of hemorrhage. We describe extensive literature showing that thrombolysis is safe after stroke with direct anticoagulant use. Early reinstitution of direct anticoagulant treatment is associated with lower risk of embolic recurrence and lower hemorrhage risk. The use of direct anticoagulants before, during, and after thrombolysis appears to be safe and is likely to promote improved outcomes after ischemic stroke. ANN NEUROL 2024;96:871-886., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Purpose: Post thrombolytic intracerebral hemorrhage (ICH) is associated with higher rate of death or disability in acute ischemic stroke patients. We investigated the relationship between post thrombolytic ICH volume and change in volume and death or disability at 90 days in acute ischemic stroke patients., Methods: We analyzed 110 patents recruited in the Safety Evaluation of 3K3A-APC in Ischemic Stroke (RHAPSODY) trial who received intravenous tissue plasminogen activator (tPA) followed by mechanical thrombectomy (if indicated) and 3K3A-APC or placebo. ICH volume was measured at Day 2 and Day 7 using susceptibility weighted sequence (SWI) on magnetic resonance imaging (MRI). We also calculated the post thrombolytic ICH volume change between Day 2 and Day 7. Outcomes were determined by using utility weighted modified Rankin scale (UW-mRs) at 90-days, Outcomes were determined by using utility weighted modified Rankin scale (UW-mRS) at 90 days. To minimize interpretation bias, outcome assessors were blinded to the treatment allocation and clinical data.We adjusted for age, gender, National Institutes of Health Stroke Scale (NIHSS) score (<10,10-19 and ≥20), location of hemorrhage (single basal ganglia hemorrhage, single lobar, single cerebellum, and multiple sites) in multivariate regression analysis., Results: A total of 88 (80%) of 110 patients had post thrombolytic ICH (mean volume 28.3 ml ± SD 62 ml). The strata of ICH volume were not associated with UW-mRs at 90 days: <20 cc (regression coefficient (RC)-0.05, p= 0.58), 20-39 cc (RC-0.22, p=0.17), or ≥40 cc (RC-0.34, p= 0.083) compared with no ICH after adjusting for potential confounders. Change in ICH mean volume 26.78 ml ±59.68, 52 had increase in volume) between Day 2 and day 7 was not associated with UW-mRS at 90 days (RC -67.71, p= 0.06)., Conclusions: We did not observe any independent effect of post thrombolytic ICH volume on death or disability in acute ischemic stroke patients. Although further studies must be done, our data suggest that strategies to prevent ICH expansion such as antifibrinolytic medications and reduction in ICH volume such as surgical evacuation may not reduce death or disability in acute ischemic stroke patients with post thrombolytic ICH., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

STAIR XII (12th Stroke Treatment Academy Industry Roundtable) included a workshop to discuss the priorities for advancements in neuroimaging in the diagnostic workup of acute ischemic stroke. The workshop brought together representatives from academia, industry, and government. The participants identified 10 critical areas of priority for the advancement of acute stroke imaging. These include enhancing imaging capabilities at primary and comprehensive stroke centers, refining the analysis and characterization of clots, establishing imaging criteria that can predict the response to reperfusion, optimizing the Thrombolysis in Cerebral Infarction scale, predicting first-pass reperfusion outcomes, improving imaging techniques post-reperfusion therapy, detecting early ischemia on noncontrast computed tomography, enhancing cone beam computed tomography, advancing mobile stroke units, and leveraging high-resolution vessel wall imaging to gain deeper insights into pathology. Imaging in acute ischemic stroke treatment has advanced significantly, but important challenges remain that need to be addressed. A combined effort from academic investigators, industry, and regulators is needed to improve imaging technologies and, ultimately, patient outcomes., Competing Interests: Disclosures Dr Samaniego reports compensation from Rapid Medical for consultant services; compensation from Medtronic for consultant services; compensation from iSchemaView for consultant services; compensation from MicroVention, Inc, for consultant services; and compensation from Cerenovus for consultant services. Dr Boltze reports compensation from Targed Biopharmaceuticals B.V. for consultant services; employment by the University of Warwick; and compensation from Astrocyte Pharmaceuticals for consultant services. Dr Lyden reports compensation from the NIH Clinical Center for other services; compensation from Apex Innovations for consultant services; and employment by the University of Southern California. Dr Hill reports grants from Medtronic; compensation from Brainsgate, Ltd, for consultant services; grants from Boehringer Ingelheim; grants from Medtronic; grants from NoNO, Inc; a patent issued for Systems and Methods for Assisting in Decision-Making and Triaging for Acute Stroke Patients licensed to Circle NVI; grants from Medtronic; grants from the Canadian Institutes of Health Research; grants from MicroVention, Inc; and employment by the University of Calgary. Dr Campbell reports employment by the University of Melbourne. Dr Nguyen reports compensation from Brainomix for consultant services and compensation from Idorsia for other services. Dr Silva reports compensation from Boehringer Ingelheim for consultant services; employment by UNIFESP; compensation from Bayer for consultant services; compensation from iSchemaView for consultant services; employment by Sociedade Beneficente Israelita Brasileira Albert Einstein; and compensation from Pfizer for other services. Dr Sheth reports stock holdings in Verve Therapeutics; compensation from Rhaeos for consultant services; compensation from Sense for data and safety monitoring services; compensation from Astrocyte for consultant services; compensation from Cerevasc for consultant services; grants from Hyperfine; employment by Yale School of Medicine; a patent pending for Stroke wearables licensed to Alva Health; stock holdings in AbbVie; grants from Biogen; compensation from CSL Behring for consultant services; and compensation from ZOLL Medical Corporation for data and safety monitoring services. Dr Fisher reports compensation from Simcere USA for consultant services; employment by Beth Israel Deaconess Medical Center; compensation from Lumosa for consultant services; and employment by Beth Israel Deaconess Medical Center. Dr Hillis reports employment by the Johns Hopkins University School of Medicine; compensation from Elsevier Publishing for other services; compensation from the National Institute on Deafness and Other Communication Disorders for other services; and compensation from the American Heart Association for other services. Dr Carone reports stock options in Brainomix, Ltd, and employment by Brainomix, Ltd. Dr Deljkich reports employment by Imperative Care, Inc. Dr Albers reports compensation from Genentech for consultant services; stock holdings in iSchemaView; and compensation from iSchemaView for consultant services. Dr Heit reports compensation from Medtronic for consultant services; compensation from iSchemaView for consultant services; and compensation from MicroVention, Inc, for consultant services. The other authors report no conflicts.

Human diseases may be modeled in animals to allow preclinical assessment of putative new clinical interventions. Recent, highly publicized failures of large clinical trials called into question the rigor, design, and value of preclinical assessment. We established the Stroke Preclinical Assessment Network (SPAN) to design and implement a randomized, controlled, blinded, multi-laboratory trial for the rigorous assessment of candidate stroke treatments combined with intravascular thrombectomy. Efficacy and futility boundaries in a multi-arm multi-stage statistical design aimed to exclude from further study highly effective or futile interventions after each of four sequential stages. Six independent research laboratories performed a standard focal cerebral ischemic insult in five animal models that included equal numbers of males and females: young mice, young rats, aging mice, mice with diet-induced obesity, and spontaneously hypertensive rats. The laboratories adhered to a common protocol and efficiently enrolled 2615 animals with full data completion and comprehensive animal tracking. SPAN successfully implemented treatment masking, randomization, prerandomization inclusion and exclusion criteria, and blinded assessment of outcomes. The SPAN design and infrastructure provide an effective approach that could be used in similar preclinical, multi-laboratory studies in other disease areas and should help improve reproducibility in translational science.

Importance: Current guidelines recommend against use of intravenous alteplase in patients with acute ischemic stroke who are taking non-vitamin K antagonist oral anticoagulants (NOACs)., Objective: To evaluate the safety and functional outcomes of intravenous alteplase among patients who were taking NOACs prior to stroke and compare outcomes with patients who were not taking long-term anticoagulants., Design, Setting, and Participants: A retrospective cohort study of 163 038 patients with acute ischemic stroke either taking NOACs or not taking anticoagulants prior to stroke and treated with intravenous alteplase within 4.5 hours of symptom onset at 1752 US hospitals participating in the Get With The Guidelines-Stroke program between April 2015 and March 2020, with complementary data from the Addressing Real-world Anticoagulant Management Issues in Stroke registry., Exposures: Prestroke treatment with NOACs within 7 days prior to alteplase treatment., Main Outcomes and Measures: The primary outcome was symptomatic intracranial hemorrhage occurring within 36 hours after intravenous alteplase administration. There were 4 secondary safety outcomes, including inpatient mortality, and 7 secondary functional outcomes assessed at hospital discharge, including the proportion of patients discharged home., Results: Of 163 038 patients treated with intravenous alteplase (median age, 70 [IQR, 59 to 81] years; 49.1% women), 2207 (1.4%) were taking NOACs and 160 831 (98.6%) were not taking anticoagulants prior to their stroke. Patients taking NOACs were older (median age, 75 [IQR, 64 to 82] years vs 70 [IQR, 58 to 81] years for those not taking anticoagulants), had a higher prevalence of cardiovascular comorbidities, and experienced more severe strokes (median National Institutes of Health Stroke Scale score, 10 [IQR, 5 to 17] vs 7 [IQR, 4 to 14]) (all standardized differences >10). The unadjusted rate of symptomatic intracranial hemorrhage was 3.7% (95% CI, 2.9% to 4.5%) for patients taking NOACs vs 3.2% (95% CI, 3.1% to 3.3%) for patients not taking anticoagulants. After adjusting for baseline clinical factors, the risk of symptomatic intracranial hemorrhage was not significantly different between groups (adjusted odds ratio [OR], 0.88 [95% CI, 0.70 to 1.10]; adjusted risk difference [RD], -0.51% [95% CI, -1.36% to 0.34%]). There were no significant differences in the secondary safety outcomes, including inpatient mortality (6.3% for patients taking NOACs vs 4.9% for patients not taking anticoagulants; adjusted OR, 0.84 [95% CI, 0.69 to 1.01]; adjusted RD, -1.20% [95% CI, -2.39% to -0%]). Of the secondary functional outcomes, 4 of 7 showed significant differences in favor of the NOAC group after adjustment, including the proportion of patients discharged home (45.9% vs 53.6% for patients not taking anticoagulants; adjusted OR, 1.17 [95% CI, 1.06 to 1.29]; adjusted RD, 3.84% [95% CI, 1.46% to 6.22%])., Conclusions and Relevance: Among patients with acute ischemic stroke treated with intravenous alteplase, use of NOACs within the preceding 7 days, compared with no use of anticoagulants, was not associated with a significantly increased risk of intracranial hemorrhage.

We search for ischemic stroke treatment knowing we have failed-intensely and often-to translate mechanistic knowledge into treatments that alleviate our patients' functional impairments. Lessons can be derived from our shared failures that may point to new directions and new strategies. First, the principle criticisms of both preclinical and clinical assessments are summarized. Next, previous efforts to develop single-mechanism treatments are reviewed. Finally, new definitions, novel approaches, and different directions are presented. In previous development efforts, the basic science and preclinical assessment of candidate treatments often lacked rigor and sufficiency; the clinical trials may have lacked power, rigor, or rectitude; or most likely both preclinical and clinical investigations were flawed. Single-target agents directed against specific molecular mechanisms proved unsuccessful. The term neuroprotection should be replaced as it has become ambiguous: protection of the entire neurovascular unit may be called cerebral cytoprotection or cerebroprotection. Success in developing cerebroprotection-either as an adjunct to recanalization or as stand-alone treatment-will require new definitions that recognize the importance of differential vulnerability in the neurovascular unit. Recent focus on pleiotropic multi-target agents that act via multiple mechanisms of action to interrupt ischemia at multiple steps may be more fruitful. Examples of pleiotropic treatments include therapeutic hypothermia and 3K3A-APC (activated protein C). Alternatively, the single-target drug NA-1 triggers multiple downstream signaling events. Renewed commitment to scientific rigor is essential, and funding agencies and journals may enforce quality principles of rigor in preclinical science. Appropriate animal models should be selected that are suited to the purpose of the investigation. Before clinical trials, preclinical assessment could include subjects that are aged, of both sexes, and harbor comorbid conditions such as diabetes or hypertension. With these new definitions, novel approaches, and renewed attention to rigor, the prospect for successful cerebroprotective therapy should improve.

Background and Aims: Intracranial atherosclerotic disease (ICAD) is a major etiologic cause for acute ischemic stroke (AIS) and transient ischemic attack (TIA). The study was designed to investigate if differential morphological features exist in symptomatic atherosclerotic lesions between AIS and TIA patients., Methods: The culprit plaques from 45 AIS patients and 42 TIA patients were analyzed for the degree of stenosis, vessel wall irregularity, normalized wall index (NWI), remodeling index, plaque-wall contrast ratio (CR), high signal intensity on T1-weighted images, plaque enhancement ratio and enhancement grade. These plaque features along with clinical characteristics were compared between AIS and TIA groups as well as between their stenosis degree-matched subgroups., Results: Overall, grade 2 enhancement (OR 3.85, 95%CI 1.42-10.46, p = 0.006) and hyperlipidemia (OR 3.04, 95%CI 1.13-8.22, p = 0.025) were independent indicators for AIS, whereas high NWI (OR 1.47, 95%CI 0.76-2.86, p = 0.004) was associated with TIA. In the comparison between the subgroups with moderate (30%-69%) stenosis, high plaque-wall CR (OR 5.38, 95%CI 1.39-20.75, p = 0.008) was associated with AIS, whereas high NWI (OR 2.50, 95%CI 0.61-10.00, p = 0.006) was associated with TIA., Conclusions: Our study reveals differential morphological features in symptomatic ICAD lesions between AIS and TIA patients. Probing these features with MR vessel wall imaging may provide insights into the prognosis of patients with ICAD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To describe the impact of COVID-19 on acute cerebrovascular disease care across 9 comprehensive stroke centers throughout Los Angeles County (LAC)., Methods: Volume of emergency stroke code activations, patient characteristics, stroke severity, reperfusion rates, treatment times, and outcomes from February 1 to April 30, 2020, were compared against the same time period in 2019. Demographic data were provided by each participating institution., Results: There was a 17.3% decrease in stroke code activations across LAC in 2020 compared to 2019 (1,786 vs. 2,159, respectively, χ2 goodness of fit test p < 0.0001) across 9 participating comprehensive stroke centers. Patients who did not receive any reperfusion therapy decreased by 16.6% in 2020 (1,527) compared to 2019 (1,832). Patients who received only intravenous thrombolytic (IVT) therapy decreased by 31.8% (107 vs. 157). Patients who received only mechanical thrombectomy (MT) increased by 3% (102 vs. 99). Patients who received both IVT and MT decreased by 31.8% (45 vs. 66). Recanalization treatment times in 2020 were comparable to 2019. CSCs serving a higher proportion of Latinx populations in the eastern parts of LAC experienced a higher incidence of MT in 2020 compared to 2019. Mild increase in stroke severity was seen in 2020 compared to 2019 (8.95 vs. 8.23, p = 0.046). A higher percentage of patients were discharged home in 2020 compared to 2019 (59.5 vs. 56.1%, p = 0.034), a lower percentage of patients were discharged to skilled nursing facility (16.1 vs. 20.7%, p = 0.0004), and a higher percentage of patients expired (8.6 vs. 6.3%, p = 0.008)., Conclusion: LAC saw a decrease in overall stroke code activations in 2020 compared to 2019. Reperfusion treatment times remained comparable to prepandemic metrics. There has been an increase in severe stroke incidence and higher volume of thrombectomy treatments in Latinx communities within LAC during the pandemic of 2020. More patients were discharged home, less patients discharged to skilled nursing facilities, and more patients expired in 2020, compared to the same time frame in 2019., (© 2021 S. Karger AG, Basel.)

Ischemic stroke is the most widespread cause of disability and a leading cause of death in developed countries. To date, the most potent approved treatment for acute stroke is recanalization therapy with thrombolytic drugs such as tissue plasminogen activator (rt-PA or tPA) or endovascular mechanical thrombectomy. Although tPA and thrombectomy are widely available in the United States, it is currently estimated that only 10–20% of stroke patients get tPA treatment, in part due to restrictive selection criteria. Recently, however, tPA and thrombectomy selection criteria have loosened, potentially allowing more patients to qualify. The relatively low rate of treatment may also reflect the perceived risk of brain hemorrhage following treatment with tPA. In translational research and a single patient study, protease activated receptor 1 (PAR-1) targeted therapies given along with thrombolysis and thrombectomy appear to reduce hemorrhagic transformation after recanalization. Such adjuncts may likely enhance the availability of recanalization and encourage more physicians to use the recently expanded selection criteria for applying recanalization therapies. This narrative review discusses stroke therapies, the role of hemorrhagic transformation in producing poor outcomes, and presents the data suggesting that PAR-1 acting agents show promise for decreasing hemorrhagic transformation and improving outcomes. [ABSTRACT FROM AUTHOR]

Background: To determine the predictive value of retinal microvascular abnormalities for cerebrovascular ischemic diseases (CVDs), we aimed to investigate the quantitative association between retinal microvascular changes and CVD subcategories: white matter hyperintensities (WMHIs), lacunar infarcts (LIs), and cerebral infarctions (CIs).Methods: Using Meta-analyses Of Observational Studies in Epidemiology guidelines, we searched 6 databases through September 2016 for studies evaluating the linkage between retinal microvascular abnormalities and WMHI, and LI and CI. Studies were included if they reported odds ratios (ORs) and 95% confidence intervals or raw patient level data (that were computed into ORs). Unadjusted and vascular risk-factor adjusted ORs were pooled into meta-analysis using DerSimonian Laird random effects model. Study quality and dissemination biases were assessed and integrated.Results: From 24,444 search-identified records, 28 prospective studies encompassing 56,379 patients were eligible for the meta-analysis. After vascular risk-factor adjustment, focal arteriolar narrowing was associated with WMHI (OR, 1.24 [1.01-1.79]), LI (OR, 1.77 [1.14-2.74]), and CI (OR, 1.75 [1.14-2.69]). Venular dilation was associated with LI (OR, 1.46 [1.10-1.93]), and retinal hemorrhages with WMHI (OR, 2.23 [1.34-3.70]). Any retinopathy exhibited significant association with CI (OR, 1.96 [1.65-2.50]). Heterogeneity was significant (I2>50%) for all syntheses except retinal hemorrhages and WMHI, and retinopathy and CI (I2=0 ⋅ 0%). Associations remained significant after adjustments for quality and publication bias.Conclusions: We found the most significant association between retinal hemorrhages and WMHI. Focal arteriolar narrowing and retinopathy predicted CVD subtypes after risk-factor adjustment, suggesting that features different than traditional vascular risk factors, are involved in CVD pathophysiology. [ABSTRACT FROM AUTHOR]

Cerebral postischemic reperfusion injury is defined as deterioration of ischemic brain tissue that parallels and antagonizes the benefits of restoring cerebral circulation after therapeutic thrombolysis for acute ischemic stroke. To understand the paradox of injury caused by treatment, we first emphasize the phenomenon in which recanalization of an occluded artery does not lead to tissue reperfusion. Additionally, no-reflow after recanalization may be due to injury of the neurovascular unit, distal microthrombosis, or both, and certainly worsens outcome. We examine the mechanism of molecular and subcellular damage in the neurovascular unit, notably oxidative stress, mitochondrial dysfunction, and apoptosis. At the level of the neurovascular unit, which mediates crosstalk between the damaged brain and systemic responses in blood, we summarize emerging evidence demonstrating that individual cell components play unique and cumulative roles that lead to damage of the blood-brain barrier and neurons. Furthermore, we review the latest developments in establishing a link between the immune system and microvascular dysfunction during ischemic reperfusion. Progress in assessing reperfusion injury has also been made, and we review imaging studies using various magnetic resonance imaging modalities. Lastly, we explore potential treatment approaches, including ischemic preconditioning, postconditioning, pharmacologic agents, and hypothermia. [ABSTRACT FROM AUTHOR]

Introduction The National Institutes of Health Stroke Scale (NIHSS), the most commonly used tool to quantify neurological deficit in acute stroke, was initially developed in English. We present our experience in developing and validating an Arabic version of the NIHSS (arNIHSS). Methods A) Scale development phase: 6 bilingual neurologists translated the scale to Arabic. Items 9 and 10 were modified to suit the Arabic language and culture. A panel of 11 Arab neurologists reviewed the final product and an Arabic language expert did final editing. B) Scale validation phase: 10 examiners (four neurology residents and six nurses), who had no experience with the NIHSS, were trained to use the arNIHSS. Patients with acute stroke were recruited at two academic institutions in Egypt. Each patient was examined on admission by 3 examiners using the arNIHSS and at 24 hours by one of the three examiners. The agreement between the first three examinations was used to calculate the interrater agreement. The agreement between the admission and the 24-hour arNIHSS performed by the same examiner was used to calculate the intrarater agreement. Construct validity was evaluated by correlating the arNIHSS on admission with the infarct volume on initial the diffusion weighted imaging (DWI) using the Alberta Stroke Program Early CT score (DWI-ASPECTS) and the functional outcome at 3 months assessed by the modified Rankin Scale (mRS). Results In 6 months, 137 patients were recruited (mean age ± standard deviation 62 ± 12 years; 48 women). For interrater agreement, weighted kappa value ranged from 0.36 to 0.66 and intraclass correlation coefficient (ICC) for the whole scale was excellent at 0.95 (95% confidence interval [CI] 0.94–0.97). For intrarater agreement, weighted kappa ranged from 0.52 to 1.0 and the ICC was 0.94 (95% CI 0.87–0.98). The construct validity of the arNIHSS is demonstrated by its correlation with the DWI-ASPECT and the 3 months mRS score (Spearman correlation − 0.46 and 0.58 respectively; P < 0.001 for both). Conclusion We developed and validated a culturally adapted Arabic version of the NIHSS. Further validation in other Arab countries is recommended. [ABSTRACT FROM AUTHOR]