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Introduction: Medium vessel occlusion (MeVO) accounts for 30% of acute ischemic stroke cases. The risk/benefit profile of endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT) or the combination of the two (bridging therapy (BT)) is still unclear in MeVO. Here, we compare reperfusion strategies in MeVO for clinical and radiological outcomes., Methods: This prospective single center study enrolled consecutive patients with AIS due to primary MeVO undergoing IVT, EVT, or BT at a comprehensive stroke center. Primary outcome was good functional status, defined as modified Rankin Scale (mRS) 0-2 at 3-month follow-up. Additional outcomes included mortality, successful recanalization, defined as mTICI ≥ 2b, stroke severity at discharge, and symptomatic intracerebral hemorrhage (sICH) according to SITS-MOST criteria. Logistic regression was modeled to define independent predictors of the primary outcome., Results: Overall, 180 consecutive people were enrolled (IVT = 59, EVT = 38, BT = 83), mean age 75. BT emerged as independent predictor of primary outcome (OR = 2.76, 95% CI = 1.08-7.07) together with age (OR = 0.94, 95% CI = 0.9-0.97) and baseline NIHSS (OR = 0.88, 95% CI = 0.81-0.95). BT associated with a 20% relative increase in successful recanalization compared to EVT (74.4 vs 56.4%, p = 0.049). Rates of sICH (1.1%) and procedural complications (vasospasm 4.1%, SAH in 1.7%) were very low, with no difference across groups., Discussion: BT may carry a higher chance of good functional outcome compared to EVT/IVT only in people with AIS due to MeVO, with marginally higher rates of successful recanalization. Randomized trials are needed to define optimal treatment tailoring for MeVO., (© 2023. Fondazione Società Italiana di Neurologia.)

Ethnopharmacological Relevant: YangXueQingNaoWan (YXQNW), a compound Chinese medicine, has been widely used for dizziness, irritability, insomnia, and dreaminess caused by blood deficiency and liver hyperactivity in China. However, whether YXQNW can inhibit cerebral microvascular exudation and cerebral hemorrhage (CH) caused by blood brain barrier (BBB) damage after tissue plasminogen activator (tPA) still unknown., Aim of the Research: To observe the effect of YXQNW on cerebral microvascular exudation and CH after tPA and investigate its mechanism in protecting BBB., Materials and Methods: Male C57BL/6 N mice suffered from ischemia stroke by mechanical detachment of carotid artery thrombi with the stimulation of ferric chloride. Then mice were treated with tPA (10 mg/kg) and/or YXQNW (0.72 g/kg) at 4.5 h. Cerebral blood flow (CBF), infarct size, survival rate, neurological scores, gait analysis, Evans blue extravasation, cerebral water content, fluorescein isothiocyanate-labeled albumin leakage, hemorrhage, junction and basement membrane proteins expression, leukocyte adhesion and matrix metalloproteinases (MMPs) expression were evaluated 24 h after tPA. Proteomics was used to identify target proteins., Results: YXQNW inhibited cerebral infarction, neurobehavioral deficits, decreased survival, Evans blue leakage, albumin leakage, cerebral water content and CH after tPA thrombolysis; improved CBF, low-expression and degradation of junction proteins, basement membrane proteins, Arhgap21 and its downstream α-catenin and β-catenin proteins expression; and suppressed the increase of adherent leukocytes and the release of MMP-9 derived from macrophage., Conclusion: YXQNW relieved BBB damage and attenuated cerebral microvascular exudation and CH after tPA thrombolysis. The effect of YXQNW on cerebral microvascular exudation was associated with the inhibition of the low-expression of junction proteins, especially AJs mediated by Rho GTPase-activating protein 21 (Arhgap21), while the effect on CH was associated with the inhibition of leukocyte adhesion, the release of MMP-9 derived from macrophage, and low-expression and degradation of collagen IV and laminin in the vascular basement membrane., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Ischemic stroke is a major cause of disability and death worldwide. A narrow therapeutic window profoundly constrained the utilization of alteplase., Objectives: To investigate therapeutic effects and safety of intravenous recombinant human prourokinase (rhPro-UK) in patients with acute ischemic stroke (AIS) in the 4.5-6 h therapeutic time windows., Methods: We conducted a phase IIa, randomized, and open-label multicenter clinical trial. Between 4.5 and 6 h after the onset of AIS, patients were randomly administrated to receive intravenous rhPro-UK at a 50 mg or 35 mg dose. The primary endpoint was excellent functional outcome defined as modified Rankin scale (mRS) score of 1 or less at 90 days. The secondary outcome was the treatment response, which was based on an at least 4-point improvement from baseline National Institutes of Health stroke scale (NIHSS) score at 24 h after drug administration. Safety endpoints included death, symptomatic intracerebral hemorrhage (sICH), and other serious adverse events., Results: We enrolled 80 patients in the 4.5-6 h therapeutic time windows at 17 medical centers in China from December 2016 to November 2017. A total of 39 patients were treated with 50 mg rhPro-UK, and 39 were treated with 35 mg rhPro-UK. Compared with the baseline, the NIHSS score at 24 h and days 7, 14, 30, and 90 was decreased significantly among patients treated with either rhPro-UK 50 mg or 35 mg. The mean reduction in the NIHSS from baseline to 90 days after the onset was 3.56 and 5.79 in the rhPro-UK 50 mg group and the rhPro-UK 35 mg group, respectively. The rates of functional independence at 90 days of rhPro-UK 50 mg and 35 mg were 61.54% and 69.23%, respectively (P = 0.475), and the proportion of patients with functional response to treatment at 24 h were 28.21% and 33.33% (P = 0.624). No sICH occurred in the two groups, and death occurred in only one patient in the rhPro-UK 50 mg group. There was no significant difference in mortality at 90 days and the rate of other serious adverse events between two groups., Conclusion: In the 4.5-6 h time window, more than 60% of patients at either dose of rhPro-UK (50 mg or 35 mg) achieved functional independence at 90 days without increased mortality and sICH risk. Thus, intravenous rhPro-UK was effective and safe for patients with AIS within 4.5-6 h after stroke onset. While no significant differences were identified between different dosages of rhPro-UK regarding clinical outcomes, it is a logical step to further test the safety and efficacy of the low dose of rhPro-UK in a well-powered phase III study., Trial Registration: http://www.chictr.org.cn . Identifier: ChiCTR1800016519. Date of registration: 6 June 2018., (© 2023. The Author(s).)

Tenecteplase (TNK), a newer fibrinolytic agent with greater fibrin specificity and longer half-life than alteplase, may has practical advantages over alteplase in acute ischemic stroke (AIS) thrombolysis. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare different doses of TNK (0.1, 0.25, 0.4 mg/kg) and alteplase in acute ischemic stroke patients. We systematically searched PubMed, Embase and https://clinicaltrials.gov/ for RCTs comparing TNK with alteplase in this population eligible for thrombolysis. The Cochrane Risk of Bias Tool was used to assess study quality. Random-effects or fixed-effects meta-analysis models were used for evaluating all outcomes. Total 10 RCTs with 5097 patients were included. Compared with alteplase, TNK at doses of 0.25 mg/kg may associated with the greatest odds to achieve 90-day excellent independence (mRS score ≤1), but there were no significant differences between other doses of TNK (0.1 mg/kg and 0.4 mg/kg) and alteplase. Among secondary outcomes, no significant differences were found in functional outcome (mRS score ≤2) and mortality at 90 days between any dose of TNK and alteplase. Compared with alteplase, TNK was effective at doses of 0.1 mg/kg and 0.25 mg/kg without increased risk of symptomatic intracerebral hemorrhage (sICH), but patients treated with TNK 0.4 mg/kg showed increased odds of sICH. In conclusion, compared with alteplase, intravenous thrombolysis with TNK at dose of 0.25 mg/kg has a better efficacy and similar safety profile and is a reasonable option for patients with AIS.

Background: There has been concern that statin therapy may be associated with an increased risk of intracerebral hemorrhage (ICH). We investigated whether the intensity and type of statin therapy instituted after ischemic stroke (IS) were associated with risk of future ICH in a region of northern China with a high incidence of stroke., Methods: Newly diagnosed IS patients who were not treated with lipid-lowering drugs in the Beijing Employee Medical Claims Data database from 2010 to 2017 were included. The primary exposure variable was any statin prescription within 1 month of the first documented stroke diagnosis. High-intensity statin therapy was defined as atorvastatin ⩾ 80 mg, simvastatin ⩾ 80 mg, pravastatin ⩾ 40 mg, and rosuvastatin ⩾ 20 mg per day or equivalent combination. An adjusted Cox proportional hazards model was used to estimate the hazard ratio (HR) for ICH during follow-up in groups exposed and not exposed to statins., Results: Of 62,252 participants with IS and 628 ICH readmissions were recorded during a median follow-up of 3.17 years. The risk of ICH among statin users (N = 43,434) was similar to that among nonusers (N = 18,818) with an adjusted HR and 95% confidence interval (CI) of 0.86 (0.73, 1.02). Compared with non-statin therapy, patients with low/moderate-intensity therapy had a lower risk of ICH (0.62: 0.52, 0.75), while patients with high-intensity therapy had a substantially higher risk (2.12: 1.72, 2.62). For patients with different types of statin therapy, adherence to rosuvastatin had the lowest risk of ICH compared to adherence to atorvastatin (0.46: 0.34, 0.63), followed by simvastatin (0.60: 0.45, 0.81)., Conclusion: In patients with IS, any statin therapy was not associated with an increased risk of ICH. However there appeared to be differential risk according to the dose of statin with high-intensity statin therapy being associated with an increased risk of ICH, while low/moderate-intensity therapy was associated with a lower risk.

Objective: Although tirofiban and endovascular thrombectomy have been widely used in the treatment of acute ischemic stroke (AIS) patients, the effectiveness of their combined application remains a subject of debate. This study aimed to assess the efficacy and safety of tirofiban in direct thrombectomy for AIS with anterior circulation vessel occlusion., Methods: A total of 204 patients undergoing direct thrombectomy between January 2020 and December 2021 for AIS with anterior circulation vessel occlusion from four hospitals were included in this study. Patients at high risk of reocclusion with severe atherosclerosis, those who achieved successful recanalization for ≥ 3 stent retriever passes, or those who underwent emergency stenting or balloon angioplasty for severe residual stenosis were treated with tirofiban. Following a low-dose intra-arterial bolus (0.25-1 mg) immediately after endovascular treatment, tirofiban was administered continuously through intravenous infusion (0.1 μg/kg/min) for 12-24 hours. The primary efficacy outcome was evaluated using the 90-day modified Rankin Scale score. The safety outcome was assessed using symptomatic intracerebral hemorrhage (sICH) and mortality rates., Results: The tirofiban group and nontirofiban group each included 102 patients. The favorable outcome rate in the tirofiban group was significantly higher than that in the nontirofiban group (53.9% vs 35.3%, p = 0.007). However, the sICH and 90-day mortality rates were lower in the tirofiban group, despite a lack of statistical significance (sICH: 15.7% vs 16.7%, p = 0.849; 90-day mortality: 16.67% vs 24.51%, p = 0.166). Finally, it was found that older patients (> 72 years), male patients, patients with admission National Institutes of Health Stroke Scale scores > 14, patients with a time from onset to reperfusion > 327 minutes, and patients with a medical history of diabetes tend to benefit from tirofiban treatment., Conclusions: This study suggests that tirofiban combined with direct thrombectomy improves functional outcomes of AIS and reduces the 90-day mortality rate. Therefore, it could be considered as a suitable treatment option for AIS patients with anterior circulation vessel occlusion.

Clinical evidence comparing bridging endovascular thrombectomy (bEVT) with intravenous thrombolysis and direct endovascular thrombectomy (dEVT) without thrombolysis for patients with acute ischemic stroke (AIS) presented directly to an EVT-capable center is overwhelming but inconsistent. This study aimed to analyze the progress and controversies in clinical evidence based on current meta-analyses. Three databases, including MEDLINE, EMBASE, and the Cochrane Library, were searched. Relevant data were extracted and reviewed from the pooled studies. The Assessment of Multiple Systematic Review (AMSTAR-2) was used for quality assessment. Twenty-five meta-analyses were finally included. There were 56% (14/25) from Asian countries, 20% (5/25) from North America, and 24% (6/25) from Europe. The majority (72%, 18/25) of evidence arose in a short period from 2020 to 2022 with the serial publication of four randomized controlled trials (RCTs). Among the 25 meta-analyses, 11 pooled at least three RCTs but there is substantial overlap among seven (five recruited the same four RCTs solely and two recruited the same three RCTs solely). Meanwhile, quality rating based on AMSTAR-2 showed 16 'high' rated studies (64%). For functional independence, 40% (10/25) of studies favored bEVT and 60% showed neutral results. For symptomatic intracerebral hemorrhage, most studies (82.6%, 19/23) showed no significant difference. Non-RCT studies contributed to evidence favoring bEVT. Current RCTs provide an update of clinical evidence comparing bEVT and dEVT. However, they simultaneously contribute to an unnecessary overlap among studies. Contemporary observational studies demonstrated different but possibly confounded evidence. Thus, this issue still requires more clinical evidence under standard procedures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Association between stroke and cancer is well-established and has led to a growing literature over the past decades. Risk of ischemic and hemorrhagic stroke is increased among patients with newly diagnosed cancer and 5-10% of stroke patients bear an active cancer. All cancers are concerned, but hematological malignancy in childhood and adenocarcinoma from lung, digestive tract and pancreas in adults are most usually identified. Unique stroke mechanisms are dominated by hypercoagulation, a condition that may lead to both arterial and venous cerebral thromboembolism. Direct tumor effects, infections and therapies may also play some active role in stroke happening. Magnetic Resonance Imaging (MRI) is helpful in: i) detecting typical patterns of ischemic stroke in cancer patients (i.e. concomitant strokes in multiple arterial territories); ii) distinguishing spontaneous intracerebral hemorrhage from tumor bleeding. Recent literature suggests that acute treatment using intravenous thrombolysis is safe in non-metastatic cancer patients. First results from endovascular procedures are reassuring, although arterial reobstruction is more frequent than in cancer-free patients. Prognosis is worse in patients with compared to those without cancer and mostly depends upon several predictors such as the initial stroke severity and the presence of metastasis. In the present review, we aim to provide some practical responses to neurologists about the stroke-cancer association, including prevalence, stroke mechanisms, biomarkers indicative for an occult cancer, influence of neoplasia on acute and long-term stroke treatments, and prognosis., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Aim: Our study aimed to explore the effectiveness and safety of intravenous t-PA compared with dual antiplatelet therapy (DAPT) and aspirin alone for minor stroke with National Institutes of Health Stroke Scale (NIHSS) score ≤5 and large vessel occlusion (LVO)., Methods: Patients with minor stroke harboring LVO within 4.5-h time window were included from the Third China National Stroke Registry (CNSR-III) between August 2015 and March 2018 in China. Clinical outcomes including modified Rankin scale (mRS) score, recurrent stroke, and all-cause mortality at 90 days and 36-h symptomatic intracerebral hemorrhage (sICH) were collected. Multivariable logistic regression models and propensity score matching analyses were used to determine the association between treatment groups and clinical outcomes., Results: A total of 1401 minor stroke patients with LVO were included. Overall 251 patients (17.9%) received intravenous t-PA, 722 patients (51.5%) received DAPT, and 428 patients (30.5%) received aspirin alone. The intravenous t-PA was associated with greater proportions of mRS 0-1 (aspirin versus t-PA: adjusted odds ratio [aOR], 0.50; 95% confidence interval [CI], 0.32 to 0.80; p = 0.004; DAPT versus t-PA: aOR, 0.76; 95% CI, 0.49 to 1.19; p = 0.23). Using propensity score matching analyses, the results were similar. There was no difference in 90-day recurrent stroke among the groups. The rates of all-cause mortality in intravenous t-PA, DAPT, and aspirin groups were 0%, 0.55%, 2.34%, respectively. No patient developed sICH within 36 h of intravenous t-PA., Conclusion: In patients with minor stroke harboring LVO within 4.5-h time window, intravenous t-PA was associated with higher odds for the excellent functional outcome, as compared with the aspirin alone. Further randomized controlled trials are warranted., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: This study aims to investigate the risk factors of hemorrhagic transformation (HT) after thrombolysis with recombinant tissue plasminogen activator (rt-PA) in patients with acute cerebral infarction (ACI) and establish a logistic regression equation and the risk prediction model., Patients and Methods: One hundred and ninety patients with ACI were divided into the HT group (n=20) and non-HT group (n=170) according to whether HT occurred within 24 hours after rt-PA thrombolysis. The clinical data were collected for analyzing the influencing factors, and a logistic regression analysis model was then established. Besides, patients in the HT group were further grouped into symptomatic hemorrhage (n=7) and non-symptomatic hemorrhage (n=13) according to the type of hemorrhage. The clinical diagnostic value of risk factors in symptomatic hemorrhage after thrombolysis in ACI was analyzed using the ROC curve., Results: We found that history of atrial fibrillation, time from onset to thrombolysis, pre-thrombolytic glucose, pre-thrombolytic National Institute of Health Stroke Scale (NIHSS) score, 24-hour post-thrombolytic NIHSS score, and proportion of patients with large cerebral infarction were all the influencing factors of HT risk after rt-PA thrombolysis in patients with ACI (p<0.05). Logistic regression analysis model was established with an accuracy of 88.42% (168/190), a sensitivity of 75.00% (15/20), and a specificity of 90.00% (153/170). The time from onset to thrombolysis, pre-thrombolytic glucose, and 24-hour post-thrombolytic NIHSS score had higher clinical value in predicting the risk of HT after rt-PA thrombolysis, with the AUCs of 0.874, 0.815 and 0.881, respectively. Blood glucose and pre-thrombolytic NIHSS score were independent risk factors related to symptomatic hemorrhage after thrombolysis in ACI (p<0.05). The AUCs for predicting symptomatic hemorrhage alone and in combination were 0.813, 0.835, and 0.907, respectively, with sensitivities of 85.70%, 87.50% and 90.00%, and specificities of 62.50%, 60.00%, and 75.42% respectively., Conclusions: The establishment of a prediction model based on the risk factors of HT after rt-PA thrombolysis had a good predictive value in patients with ACI. This model was helpful in guiding clinical judgment and improving the safety of intravenous thrombolysis. Early identification of symptomatic bleeding risk factors provided a reference for clinical treatment and prognostic measures of patients with ACI.

Background and Purpose: Studies have shown that mild stroke patients with National Institutes of Health Stroke Scale (NIHSS) score 3-5 but not 0-2 may benefit from the intravenous thrombolysis when compared with antiplatelet therapy. We aimed to compare the safety and effectiveness of thrombolysis in mild stroke with NIHSS score of 0-2 vs. 3-5 and identify the predictors of an excellent functional outcome in a real world longitudinal registry., Methods: In a prospective thrombolysis registry, we identified patients with acute ischemic stroke who presented within 4.5 hours of symptom onset and had initial NIHSS scores ≤ 5. Demographic data, medical history, pre-stroke medications, imaging data, and laboratory measures were collected. The outcome of interest was modified Rankin Scale score of 0 to 1 at discharge. Safety outcome was evaluated by syptomatic intracrerebral hemorrhage defined as any decline in neurologic status due to hemorrhage within 36 h. Multivariable regression models were performed to explore the safety and effectiveness in the alteplase-treated patients with admission NIHSS 0-2 vs. 3-5 and identify factors independently associated with an excellent functional outcome., Results: Of a total of 236 eligible patients, those with an admission NIHSS score of 0-2 (n=80) had a better functional outcome at discharge compared with NIHSS 3-5 group (n=156) (81.3% vs. 48.7%, adjusted odds ratio [aOR] 0.40, 95% confidential interval [CI] 0.17 - 0.94, P=0.04) without increasing the rate of symptomatic intracerebral hemorrhage and mortality. Non-disabling stroke (Model 1: aOR 0.06, 95%CI 0.01-0.50, P=0.01; Model 2: aOR 0.06, 95% CI 0.01-0.48, P=0.01) and prior statin therapy (Model 1: aOR 3.46, 95% CI 1.02-11.70, P=0.046; Model 2: aOR 3.30, 95% CI 0.96-11.30, P=0.06) were independent predictors of excellent outcomes., Conclusions: Acute ischemic stroke patients with admission NIHSS 0-2 was associated with better functional outcomes at discharge compared with NIHSS 3-5 within the 4.5-hour time window. Minor stroke severity, non-disabling stroke and prior statin therapy were independent predictors for funcitonal outcomes at discharge. Further studies with large sample size are needed to confirm the findings., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Antiplatelet therapy (APT) plays an important role in the prevention of ischaemic stroke (IS). Our aim was to assess the influence of short-term single APT (SAPT) and dual APT (DAPT) on the prognosis of patients with acute IS with and without cerebral microbleeds (CMBs). We conducted a single-centre, retrospective, observational cohort study of patients with acute IS who underwent susceptibility-weighted imaging (SWI) to determine the presence of CMBs between January 2015 and December 2020. The patients were treated with either DAPT or SAPT and followed up for at least 2 years. The primary endpoint was a composite of recurrent IS and intracerebral haemorrhage (ICH), while either recurrent IS or ICH was considered as other endpoints. We computed weighted Kaplan-Meier curves and identified risk factors using the Cox proportional hazards model. Among the 581 enrolled patients, those with CMBs (n = 225; P = 0.004) had a higher risk of the primary endpoint than those without CMBs (n = 356), especially higher risk of recurrent IS (P = 0.029). In the SAPT group, the presence of CMBs increased the risk of the primary endpoint (P = 0.013), especially that of recurrent IS (P = 0.019). In the DAPT group, the occurrence of ICH was higher in patients with CMBs (P = 0.031). The CMB distribution did not influence the risk of recurrent IS or ICH. In patients with acute IS and CMBs, DAPT may offset the risk of recurrent IS due to CMBs but increase the risk of ICH., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Aim: To compare safety and functional outcomes of intravenous thrombolysis (IVT) between females and males with acute ischaemic stroke (AIS) in relation to preadmission use of antiplatelets., Methods: Multicentre cohort study of patients admitted from 1 January 2014 to 31 January 2020 to hospitals participating in the Swiss Stroke Registry, presenting with AIS and receiving IVT. Primary safety outcome was in-hospital symptomatic intracerebral haemorrhage (sICH). Primary functional outcome was functional independence at 3 months after discharge. Multivariable logistic regression models were fitted to assess the association between sex and each outcome according to preadmission use of antiplatelets., Results: The study included 4996 patients (42.51 % females, older than males, median age 79 vs 71 years, p < 0.0001). Comparable proportions of females (39.92 %) and males (40.39 %) used antiplatelets before admission (p = 0.74). In total, 3.06 % females and 2.47 % males developed in-hospital sICH (p = 0.19), with similar odds (adjusted odds ratio, [AOR] 0.93, 95 % confidence interval, [CI] 0.63-1.39). No interaction was found between sex and preadmission use of either single or dual antiplatelets in relation to in-hospital sICH (p = 0.94 and p = 0.23). Males had higher odds of functional independence at 3 months (AOR 1.34, 95 % CI 1.09-1.65), regardless of preadmission use of antiplatelets (interaction between sex and preadmission use of either single or dual antiplatelets p = 0.41 and p = 0.58)., Conclusion: No sex differences were observed in the safety of IVT regarding preadmission use of antiplatelets. Males showed more favourable 3-month functional independence than females; however, this sex difference was apparently not explained by a sex-specific mechanism related to preadmission use of antiplatelets., (© 2023. The Author(s).)

Background: Neutrophil serine proteinases (NSPs), released by activated neutrophils, are key proteins involved in the pathophysiologic processes of stroke. NSPs are also implicated in the process and response of thrombolysis. This study aimed to analyze three NSPs (neutrophil elastase, cathepsin G, and proteinase 3) in relation to acute ischemic stroke (AIS) outcomes and in relation to the outcomes of patients treated with intravenous recombinant tissue plasminogen activator (IV-rtPA)., Methods: Among 736 patients prospectively recruited at the stroke center from 2018 to 2019, 342 patients diagnosed with confirmed AIS were included. Plasma neutrophil elastase (NE), cathepsin G (CTSG), and proteinase 3 (PR3) concentrations were measured on admission. The primary endpoint was unfavorable outcome defined as modified Rankin Scale score 3-6 at 3 months, and the secondary endpoints were symptomatic intracerebral hemorrhage (sICH) within 48 h, and mortality within 3 months. In the subgroup of patients who received IV-rtPA, post-thrombolysis early neurological improvement (ENI) (defined as National Institutes of Health Stroke Scale score = 0 or decrease of ≥ 4 within 24 h after thrombolysis) was also included as the secondary endpoint. Univariate and multivariate logistic regression analyses were performed to evaluate the association between NSPs levels and AIS outcomes., Results: Higher NE and PR3 plasma levels were associated with the 3-month mortality and 3-month unfavorable outcome. Higher NE plasma levels were also associated with the risk of sICH after AIS. After adjusting for potential confounders, plasma NE level > 229.56 ng/mL (odds ratio [OR] = 4.478 [2.344-8.554]) and PR3 > 388.77 ng/mL (OR = 2.805 [1.504-5.231]) independently predicted the 3-month unfavorable outcome. Regarding rtPA treatment, patients with NE plasma concentration > 177.22 ng/mL (OR = 8.931 [2.330-34.238]) or PR3 > 388.77 ng/mL (OR = 4.275 [1.045-17.491]) were over 4 times more likely to suffer unfavorable outcomes after rtPA treatment. The addition of NE and PR3 to clinical predictors of unfavorable functional outcome after AIS and the outcome after rtPA treatment improved discrimination as well as reclassification (integrated discrimination improvement = 8.2% and 18.1%, continuous net reclassification improvement = 100.0% and 91.8%, respectively)., Conclusions: Plasma NE and PR3 are novel and independent predictors of 3-month functional outcomes after AIS. Plasma NE and PR3 also possess predictive value to identify patients with unfavorable outcomes after rtPA treatment. NE is probably an important mediator of the effects of neutrophils on stroke outcomes, which worth further investigation., (© 2023. The Author(s).)

Cerebral amyloid angiopathy and atrial fibrillation are two frequent comorbidities in older patients, leading to a therapeutic dilemma on the risk-benefit ratio of long-term anticoagulation. These patients both have a risk of cardioembolic complications due to atrial fibrillation, and a risk of cerebral haemorrhage from cerebral amyloid angiopathy. Since there is no therapeutic consensus, the best therapeutic strategy should be discussed during a multidisciplinary staff, based on four risk estimations: 1) the baseline risk of intracerebral haemorrhage without anticoagulation; 2) the risk of ischaemic stroke without anticoagulation; 3) the expected increase of intracerebral haemorrhage with anticoagulation; 4) the expected reduction in ischaemic stroke risk with anticoagulation. The risk of intracerebral haemorrhage varies according to the cerebral amyloid angiopathy phenotype. Patients with transient neurological episode or cortical superficial siderosis have the highest risk of intracerebral haemorrhage. Direct oral anticoagulant should be preferred to vitamin K antagonists, as the risk of intracerebral haemorrhage is lower with direct oral anticoagulants. If anticoagulation is introduced, a close clinical and radiological monitoring should be performed every 6-12 months minimum. If it has been decided not to anticoagulate, left atrial appendage occlusion should be proposed. In all situations, close blood pressure control is essential to reduce the risk of intracerebral haemorrhage.

Purpose: To investigate whether preceding intravenous thrombolysis combined with tirofiban in patients with acute ischemic stroke undergoing endovascular treatment is safe and effective., Materials and Methods: Consecutive data were identified for patients who experienced acute ischemic stroke and were admitted to 2 comprehensive stroke centers from January 2015 to August 2021. All patients were divided into 2 groups-a thrombolytic with tirofiban group and a tirofiban-alone group-on the basis of whether intravenous thrombolysis before emergency endovascular angioplasty was used. Multivariate regression and propensity adjustment analyses were performed to characterize differences in safety and clinical outcomes between the 2 groups., Results: Of 373 eligible patients, 111 (29.7%) were treated with thrombolysis with tirofiban. There was a significant difference in the rate of any intracerebral hemorrhage (35.1% vs 24.8%; P = .04) but not in the rates of symptomatic intracerebral hemorrhage (16.2% vs 11.5%; P = .23) and reocclusion at 24 hours (5.4% vs 7.6%; P = .51) between the 2 groups. Multivariate regression analysis revealed that intravenous thrombolysis was not associated with any or symptomatic intracerebral hemorrhage, artery occlusion, functional outcome, or death at the 3-month follow-up (all adjusted P > .05). After propensity adjustment, the thrombolytic with tirofiban group showed nonsignificant rates of clinical and safety outcomes compared with those of the tirofiban-alone group (all P > .05)., Conclusions: Tirofiban may be used without increasing the risk of adverse events in selected patients who experienced ischemic stroke and were treated with intravenous thrombolysis and endovascular therapy., (Copyright © 2022 SIR. Published by Elsevier Inc. All rights reserved.)

Treatment of acute ischemic stroke with the recombinant tissue plasminogen activator (rtPA) is associated with increased blood-brain barrier (BBB) disruption and hemorrhagic transformation. Remote ischemic conditioning (RIC) has demonstrated neuroprotective effects against acute ischemic stroke. However, whether and how RIC regulates rtPA-associated BBB disruption remains unclear. Here, a rodent model of thromboembolic stroke followed by rtPA thrombolysis at different time points was performed with or without RIC. Brain infarction, neurological outcomes, BBB permeability, and intracerebral hemorrhage were assessed. The platelet-derived growth factor CC (PDGF-CC)/PDGFRα pathway in the brain tissue, PDGF-CC levels in the skeletal muscle and peripheral blood were also measured. Furthermore, impact of RIC on serum PDGF-CC levels were measured in healthy subjects and AIS patients. Our results showed that RIC substantially reduced BBB injury, intracerebral hemorrhage, cerebral infarction, and neurological deficits after stroke, even when rtPA was administrated in a delayed therapeutic time window. Mechanistically, RIC significantly decreased PDGFRα activation in ischemic brain tissue and reduced blood PDGF-CC levels, which partially resulted from PDGF-CC reduction in the skeletal muscle of RIC-applied hindlimbs and platelets. Intravenous or intraventricular recombinant PDGF-CC supplementation abolished RIC protective effects on BBB integrity. Moreover, similar changes of PDGF-CC in serum by RIC were also observed in healthy humans and acute ischemic stroke patients. Together, our study demonstrates that RIC can attenuate rtPA-aggravated BBB disruption after ischemic stroke via reducing the PDGF-CC/PDGFRα pathway and thus supports RIC as a potential approach for BBB disruption prevention or treatment following thrombolysis., Competing Interests: Conflict of interest The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Intravenous thrombolysis (IVT) use for acute ischemic stroke (AIS) varies among countries, partly due to guidelines and product labeling changes. The study aim was to identify the characteristics of patients with AIS treated with off-label IVT and to determine its safety when performed in a primary stroke center (PSC)., Methods: This observational, single-center study included all consecutive patients admitted to Perpignan PSC for AIS and treated with IVT and patients transferred for EVT, between January 1, 2015 and December 31, 2019. Data of patients treated with IVT according to ("in-label group") or outside ("off-label") the initial guidelines and manufacturer's product specification were compared. Safety was assessed using symptomatic intracerebral hemorrhage (SIH) as the main adverse event., Results: Among the 892 patients in the database (834 screened by MRI, 93.5%), 746 were treated by IVT: 185 (24.8%) "in-label" and 561 (75.2%) "off-label". In the "off-label" group, 316 (42.4% of the cohort) had a single criterion for "off-label" use, 197 (26.4%) had two, and 48 (6.4%) had three or more criteria, without any difference in IVT safety pattern among them. SIH rates were comparable between the "off-label" and "in-label" groups (2.7% vs. 1.1%, P=0.21); early neurological deterioration and systematic adverse event due to IVT treatment were similar in the 2 groups. "Off-label" patients had higher in-hospital (8.7% vs. 3.8%, P=0.05) and 3-month mortality rates (12.1% vs 5.4%, P<0.01), but this is explained by confounding factors as they were older (76 vs 67 years, P<0.0001) and more dependent (median modified Rankin scale score 0.4 vs 0.1, P<0.0001) at admission., Conclusions: "Off-label" thrombolysis for AIS seems to be safe and effective in the routine setting of a primary stroke center., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Whether direct endovascular thrombectomy (EVT) is non-inferior to bridging therapy (intravenous thrombolysis [IVT] followed by EVT) in minor acute ischemic stroke due to large vessel occlusions (AIS-LVO) is not clear. Therefore, this study aimed to assess whether direct EVT is non-inferior to bridging therapy in minor AIS-LVO., Methods: 903 patients with acute ischemic stroke due to large vessel occlusion and National Institutes of Health Stroke Scale (NIHSS) score <6 receiving EVT treatment were enrolled at Bigdata Observatory Platform for Stroke of China in China from January 1, 2019, to December 31, 2020, with final follow-up on March 31, 2021. The primary efficacy endpoint was a favorable outcome defined as a modified Rankin Scale score of 0 to 2 at three months. In addition, there were three prespecified secondary efficacy endpoints, including symptomatic intracerebral hemorrhage (ICH), in-hospital mortality, and mortality by month 3., Results: A total of 662 patients treated with direct EVT (age 65.9 ± 10.5 years, 71.5 % male, NIHSS score 2.4 [standard deviation {SD}. 1.8]) were compared to 241 bridging-treated patients (age 65.7 ± 10.8, 75.9 % female, NIHSS score 2.5 [1.8]). The rate of symptomatic ICH in the EVT group was lower than in the bridging group (4.2 % vs. 8.3 %; P = 0.02). The in-hospital mortality was not different between the two groups (EVT vs. bridging group: adjusted hazard ratio {HR}, 0.9 [95 % confidence interval {CI}, 0.5 to 1.9]; P = 0.93). There was no significant difference in 3-month poor functional outcome rate (EVT vs. bridging group: 17.1 % vs. 16.2 % [absolute difference, 0.9 % {95 % CI, -0.8 % to 2.4 %}, P = 0.75; adjusted hazard ratio {HR}, 1.0 {95 % CI, 0.6 to 1.7}, P = 0.83]) and mortality rate (13.0 % vs. 11.2 % [absolute difference, 1.5 % {95 % CI, -3.9 % to 6.8 %}, P = 0.47; adjusted HR, 1.1 {95 % CI, 0.8 to 1.9}, P = 0.55]) between those two groups., Conclusion: Among patients with minor AIS-LVO, direct EVT, compared with bridging therapy, met the prespecified statistical threshold for noninferiority for the 3-month prognosis., Competing Interests: Declaration of competing interest The corresponding author states that there is no conflict of interest on behalf of all authors., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Pooled analyses of previous randomised studies have suggested that very early treatment with glyceryl trinitrate (also known as nitroglycerin) improves functional outcome in patients with acute ischaemic stroke or intracerebral haemorrhage, but this finding was not confirmed in a more recent trial (RIGHT-2). We aimed to assess whether patients with presumed acute stroke benefit from glyceryl tr initrate started within 3 h after symptom onset., Methods: MR ASAP was a phase 3, randomised, open-label, blinded endpoint trial done at six ambulance services serving 18 hospitals in the Netherlands. Eligible participants (aged ≥18 years) had a probable diagnosis of acute stroke (as assessed by a paramedic), a face-arm-speech-time test score of 2 or 3, systolic blood pressure of at least 140 mm Hg, and could start treatment within 3 h of symptom onset. Participants were randomly assigned (1:1) by ambulance personnel, using a secure web-based electronic application with random block sizes stratified by ambulance service, to receive either transdermal glyceryl trinitrate 5 mg/day for 24 h plus standard care (glyceryl trinitrate group) or to standard care alone (control group) in the prehospital setting. Informed consent was deferred until after arrival at the hospital. The primary outcome was functional outcome assessed with the modified Rankin Scale (mRS) at 90 days. Safety outcomes included death within 7 days, death within 90 days, and serious adverse events. Analyses were based on modified intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. We separately analysed the total population and the target population (ie, patients with intracerebral haemorrhage, ischaemic stroke, or transient ischaemic attack). The target sample size was 1400 patients. The trial is registered as ISRCTN99503308., Findings: On June 24, 2021, the MR ASAP trial was prematurely terminated on the advice of the data and safety monitoring board, with recruitment stopped because of safety concerns in patients with intracerebral haemorrhage. Between April 4, 2018, and Feb 12, 2021, 380 patients were randomly allocated to a study group. 325 provided informed consent or died before consent could be obtained, of whom 170 were assigned to the glyceryl trinitrate group and 155 to the control group. These patients were included in the total population. 201 patients (62%) had ischaemic stroke, 34 (10%) transient ischaemic attack, 56 (17%) intracerebral haemorrhage, and 34 (10%) a stroke-mimicking condition. In the total population (n=325), the median mRS score at 90 days was 2 (IQR 1-4) in both the glyceryl trinitrate and control groups (adjusted common OR 0·97 [95% CI 0·65-1·47]). In the target population (n=291), the 90-day mRS score was 2 (2-4) in the glyceryl trinitrate group and 3 (1-4) in the control group (0·92 [0·59-1·43]). In the total population, there were no differences between the two study groups with respect to death within 90 days (adjusted OR 1·07 [0·53-2·14]) or serious adverse events (unadjusted OR 1·23 [0·76-1·99]). In patients with intracerebral haemorrhage, 12 (34%) of 35 patients allocated to glyceryl trinitrate versus two (10%) of 21 allocated to the control group died within 7 days (adjusted OR 5·91 [0·78-44·81]); death within 90 days occurred in 16 (46%) of 35 in the glyceryl trinitrate group and 11 (55%) of 20 in the control group (adjusted OR 0·87 [0·18-4·17])., Interpretation: We found no sign of benefit of transdermal glyceryl trinitrate started within 3 h of symptom onset in the prehospital setting in patients with presumed acute stroke. The signal of potential early harm of glyceryl trinitrate in patients with intracerebral haemorrhage suggests that glyceryl trinitrate should be avoided in this setting., Funding: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation., Competing Interests: Declaration of interests HR reports financial support from the European Union's Horizon 2020 research and innovation program, paid to his institution. BJE reports financial support from Health Holland Top Sector Life Sciences & Health (via the Top Consortia for Knowledge and Innovation's public–private partnership), paid to his institution; and unpaid board membership of UEMS Neuroradiology and the Dutch Society of Radiology, Division of Neuroradiology. CBLMM, DWJD, PJN and HBvdW report funding from the Dutch Heart Foundation and Stryker, all paid to their institutions or the CONTRAST consortium. CBLMM reports financial support from the TWIN Foundation and Health Evaluation Netherlands, all paid to his institution. CBLMM and HBvdW report financial support from the European Commission, all paid to their institutions. CBLMM and YBWEMR are minor shareholders of Nicolab. DWJD reports grants from Medtronic, Cerenovus, Penumbra, Brain Foundation Netherlands, ZON MW–The Netherlands Organisation for Health Research and Development, and Health Holland Top Sector Life Sciences & Health, all paid to his institution. HBvdW reports honoraria for consultancy from Bayer and LivaNova, all paid to his institution. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Factors for the utilization of intravenous thrombolysis with a low-dose of alteplase (0.6mg/kg) and whether the low-dose of alteplase could reduce the risk of intracerebral bleeding in acute ischemic stroke (AIS) remains uncertain. Aims: We aimed to investigate determinants for the utilization of intravenous thrombolysis with a low-dose of alteplase. We further assessed the association between the low-dose of alteplase and the intracerebral bleeding risk in AIS patients. Method: We included AIS patients who received intravenous thrombolysis using alteplase in this multicenter retrospective observational study. We investigated the association between baseline characteristics and the utilization of a low-dose of alteplase to identify determinants. We assessed the association of the low-dose of alteplase with the risk of symptomatic intracranial hemorrhage (sICH) using a multivariable logistic regression model. We further compared the rate of sICH and any ICH in patients in the low-dose group to those in the standard-dose group, using propensity score-matching data. Results: A total of 506 AIS patients were included in this study. The mean age was 67 (interquartile range [IQR] 59-75), and 178 (35.2%) were women. A total of 96 patients were treated with the low-dose. Age (adjusted odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00 -1.04, p = 0.042), having a previous ischemic stroke (adjusted OR 2.01, 95%CI 1.11 - 3.64 p = 0.021) and increasing baseline systolic blood pressure (adjusted OR 1.12, 95%CI 1.00 - 1.26, p = 0.049) were determinants for the utilization of the low-dose. Multivariable logistic regression analysis showed that the low-dose was significantly associated with a reduced risk of sICH (adjusted OR 0.13, 95%CI 0.03 - 0.62, p = 0.01). Propensity score analysis showed that the rate of sICH was significantly lower in the low-dose group compared to standard-dose group (2 [2.3%] vs 10 [11.4%], p = 0.032). There was no significant difference in the rate of any ICH between two groups (14 [15.9%] vs 18 [20.5%], p = 0.434). Conclusions: Patients with increasing age, a higher baseline systolic blood pressure, and previous ischemic stroke were at a higher odd of receiving a low-dose of alteplase. The low-dose was associated with a lower risk of developing symptomatic intracranial hemorrhage., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Intravenous thrombolysis (IVT) for acute brain infarctions caused by aortic dissection (AD) may lead to fatal outcomes; thus, it should be ruled out, especially if hypofibrinogenemia occurs after IVT. Successful management of AD-related acute brain infarction with hypofibrinogenemia after IVT has not been reported previously., Case Report: An 84-year-old woman developed sudden left limb weakness and aphasia for almost 4 h. Alteplase was administered intravenously immediately after cerebral hemorrhage was ruled out by emergent head computed tomography (CT). An anomaly suspected to be AD was detected during subsequent routine chest CT, which was confirmed by CT angiography to be a thoracoabdominal aortic dissecting aneurysm (DeBakey type I). Severe hypofibrinogenemia was also noted. After effective blood pressure control, intramuscular injection of vitamin K, and rehydration therapy, her brain cell metabolism improved, hemiplegia improved slightly, and hypofibrinogenemia recovered gradually. The patient's cerebral hemorrhage did not progress, there was no chest pain or no aggravation of hemiplegia, and the fibrinogen level gradually returned to normal. The condition was stable during hospitalization. At 1.5 months after discharge, the patient showed minimal change in condition., Conclusion: The symptoms of AD may be nonspecific and latent. IVT may be allowed to perform for some patients with AD related ischemical stroke, And IVT can improve the neural symptoms of AD-related ischemic stroke, but close monitoring is needed to avoid aneurysm rupture. Fibrinogen levels should also be monitored periodically after IVT for early detection of hypofibrinogenemia.

The accelerated pace of life leads to people's unhealthy living habits such as irregular diet, irregular work and rest, and fatigued work. The incidence of acute cerebral infarction (ACI) is increasing year by year. Intravenous thrombolysis is the best solution for clinical treatment of ACI, but intravenous thrombolysis increases the risk of cerebral microbleeds and even seriously damages the brain of patients. It is crucial to analyze the relationship between intravenous thrombolysis of ACI and cerebral microbleeds. Using intelligent medical methods such as BP neural network (BPNN), meta-analysis was carried out on the prognosis of ACI intravenous thrombolysis and cerebral microbleeds, and the basic data indicators, living habits indicators, and ACI intravenous thrombolysis indicators of ACI patients were analyzed. The experimental results showed that the odds ratios (OR) of systolic blood pressure before ACI intravenous thrombolysis, blood glucose concentration after ACI intravenous thrombolysis, diastolic blood pressure before ACI intravenous thrombolysis, and diastolic blood pressure after ACI intravenous thrombolysis on cerebral microbleeds after ACI intravenous thrombolysis were 0.97, 0.44, 0.13, and 0.07, respectively. Long-term intravenous thrombolysis with ACI, high systolic blood pressure after NIHSS thrombolysis with high scores, and blood glucose concentration before thrombolysis had OR >1, which were risk factors for cerebral microbleeds after intravenous thrombolysis with ACI. Therefore, paying attention to the risk factors of cerebral microbleeds during ACI intravenous thrombolysis can effectively reduce cerebral microbleeds after ACI intravenous thrombolysis and improve the treatment efficiency of ACI patients., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Kui Duan and Yufang Wu.)

Background: Mobile stroke units (MSUs) equipped with a CT scanner reduce time to thrombolytic treatment and improve patient outcomes. We tested the hypothesis that tenecteplase administered in an MSU would result in superior reperfusion at hospital arrival, when compared with alteplase., Methods: The TASTE-A trial is a phase 2, randomised, open-label trial at the Melbourne MSU and five tertiary hospitals in Melbourne, VIC, Australia. Patients (aged ≥18 years) with ischaemic stroke who were eligible for thrombolytic treatment were randomly allocated in the MSU to receive, within 4·5 h of symptom onset, either standard-of-care alteplase (0·9 mg/kg [maximum 90 mg], administered intravenously with 10% as a bolus over 1 min and 90% as an infusion over 1 h), or the investigational product tenecteplase (0·25 mg/kg [maximum 25 mg], administered as an intravenous bolus over 10 s), before being transported to hospital for ongoing care. The primary outcome was the volume of the perfusion lesion on arrival at hospital, assessed by CT-perfusion imaging. Secondary safety outcomes were modified Rankin Scale (mRS) score of 5 or 6 at 90 days, symptomatic intracerebral haemorrhage and any haemorrhage within 36 h, and death at 90 days. Assessors were masked to treatment allocation. Analysis was by intention-to-treat. The trial was registered with ClinicalTrials.gov, NCT04071613, and is completed., Findings: Between June 20, 2019, and Nov 16, 2021, 104 patients were enrolled and randomly allocated to receive either tenecteplase (n=55) or alteplase (n=49). The median age of patients was 73 years (IQR 61-83), and the median NIHSS at baseline was 8 (5-14). On arrival at the hospital, the perfusion lesion volume was significantly smaller with tenecteplase (median 12 mL [IQR 3-28]) than with alteplase (35 mL [18-76]; adjusted incidence rate ratio 0·55, 95% CI 0·37-0·81; p=0·0030). At 90 days, an mRS of 5 or 6 was reported in eight (15%) patients allocated to tenecteplase and ten (20%) patients allocated to alteplase (adjusted odds ratio [aOR] 0·70, 95% CI 0·23-2·16; p=0·54). Five (9%) patients allocated to tenecteplase and five (10%) patients allocated to alteplase died from any cause at 90 days (aOR 1·12, 95% CI 0·26-4·90; p=0·88). No cases of symptomatic intracerebral haemorrhage were reported within 36 h with either treatment. Up to day 90, 13 serious adverse events were noted: five (5%) in patients treated with tenecteplase, and eight (8%) in patients treated with alteplase., Interpretation: Treatment with tenecteplase on the MSU in Melbourne resulted in a superior rate of early reperfusion compared with alteplase, and no safety concerns were noted. This trial provides evidence to support the use of tenecteplase and MSUs in an optimal model of stroke care., Funding: Melbourne Academic Centre for Health., Competing Interests: Declaration of interests All authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: Delayed tissue plasminogen activator (tPA) treatment increases the risk of intracerebral hemorrhage in patients with ischemic stroke. We previously demonstrated that tPA treatment caused hemorrhagic complications in a 4-h middle cerebral artery occlusion (MCAO) mouse model when administered after reperfusion. In the present study, we administered an anti-high mobility group box 1 (αHMGB1) antibody to 4-h MCAO mice to evaluate the usability of αHMGB1 antibody treatment in the delayed phase of ischemia, beyond the therapeutic time window of tPA., Methods: αHMGB1 antibody, tPA and control IgG were dissolved in normal saline and administered intravenously into the tail vein of the mice after reperfusion. Infarct volume, hemorrhagic volume, brain swelling, functional outcomes and levels of pro-inflammatory cytokines, such as HMGB1, interleukin (IL)-6 and tumor necrosis factor (TNF)-α, were evaluated 24 h after MCAO., Results: tPA treatment was not only ineffective but also caused a massive intracerebral hemorrhage. Treatment with αHMGB1 antibody reduced the infarct volume and swelling and ameliorated neurologic impairment and motor coordination without hemorrhagic complications by inhibiting HMGB1 activity. Moreover, the αHMGB1 antibody suppressed pathways of secondary inflammatory responses, such as IL-6 and TNF-α, after cerebral ischemia., Conclusion: These results indicate that αHMGB1 antibody may be therapeutically efficient in the delayed phase of ischemia, where tPA treatment is no longer an eligible option. Treatment with an αHMGB1 antibody may be an effective therapeutic option in patients who exceed the tPA therapeutic time window., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To investigate the safety and efficacy of intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke (AIS) and cerebral microbleeds (CMBs) and analyze the risk factors for hemorrhagic transformation (HT)., Patients and Methods: The clinical data of 220 patients with CMB within the first 4.5 h after the onset of acute ischemic stroke treated in our hospital from September 2018 to December 2019 were retrospectively analyzed. Then, these patients were evenly assigned into two groups based on whether the intravenous thrombolysis with rt-PA was adopted or not. Next, the neurological deficit was scored using the National Institute of Health stroke scale (NIHSS) before and after treatment, the modified Rankin scale (mRs) score of patients was recorded at 90 d after treatment, and the incidence rate and death rate of intracranial hemorrhage (ICH) after treatment were recorded and evaluated. Additionally, the univariate and logistic regression analyses were employed for the risk factors for HT in patients after thrombolysis., Results: The NIHSS score declined to (7.08±3.75) points and (7.83±4.22) points at 24 h after treatment and (3.67±3.63) points and (4.92±3.87) points at 7 d after treatment, respectively, in Thrombolysis group and Control group, which were significantly lower than those before treatment (p<0.05). The NIHSS score displayed no statistically significant difference between the two groups at 24 h after treatment (p=0.165), whereas it was markedly lower in Thrombolysis group than that in Control group at 7 d after treatment (p=0.015). At 90 d after treatment, there were 98 (89.1%) and 79 (71.8%) cases of good prognosis in Thrombolysis group and Control group, respectively, and the difference was statistically significant between the two groups (p=0.002). Besides, the number of patients with SICH and aSICH was 3 and 2 (2.7% vs. 1.8%, p=0.651) and 9 and 4 (8.2% vs. 3.6%, p=0.152) in Thrombolysis group and Control group, respectively, and the number of deaths was 7 and 5 (6.4% vs. 4.5%, p=0.553) in the two groups, showing no statistically significant difference. The results of univariate and multivariate analyses revealed that the time from stroke onset to thrombolysis, baseline NIHSS score, and history of atrial fibrillation were independent risk factors affecting the HT of patients undergoing intravenous thrombolysis [odds ratio (OR) =1.330, 95% confidence interval (95% CI) =1.079-1.851, p=0.019; OR=1.592, 95% CI=1.025-2.767, p=0.010; OR=2.428, 95% CI=1.814-3.643, p=0.016]., Conclusions: Compared with those undergoing no intravenous thrombolysis with rt-PA, patients with acute ischemic stroke and CMB who received intravenous thrombolysis with rt-PA exhibit significantly improved short-term neurological function recovery and long-term prognosis, but the incidence and mortality rates of ICH have no statistically significant differences. Moreover, the time from stroke onset to thrombolysis, baseline NIHSS score, and history of atrial fibrillation are independent risk factors affecting the HT of patients treated with intravenous thrombolysis.

Purpose: Intracerebral hemorrhage (ICH) can be a fatal complication of intravenous thrombolysis (IVT) for acute ischemic stroke. An early coagulopathy can develop after IVT, in relation to a significant fibrinogen depletion, increasing the risk of ICH. This systematic review and meta-analysis aimed at defining the role of fibrinogen depletion after IVT on the risk of ICH after IVT., Methods: Protocol was registered with PROSPERO (CRD42020124241) and followed PRISMA and MOOSE guidelines. We systematically searched English studies reporting rates of post-IVT ICH depending on fibrinogen depletion until 7/1/2021. Primary outcome was symptomatic ICH (sICH). Meta-analysis followed random-effects model to account for heterogeneity in design and timing of ascertainments. Biases were assessed via the Newcastle-Ottawa Scale., Results: Overall, among 352 records identified, 5 observational studies were eligible for quantitative synthesis (n = 2142), all of fair quality. Considering sICH within 24-36 h post-IVT, pooling data from 4 studies (n = 1753), fibrinogen depletion consistently increased the risk of sICH (OR 3.67, 95%CI 2.28-5.90, p heterogeneity  = 0.55). Pooling adjusted estimated for age, gender, and NIHSS from 3 studies (n = 723), fibrinogen depletion was confirmed to significantly increase the risk of ICH after IVT (OR 5.41, 95%CI 2.96-9.89)., Conclusions: Fibrinogen depletion significantly increases the risk of ICH after IVT for acute ischemic stroke. Routine fibrinogen assessment might be considered to identify people at higher risk of ICH. As fibrinogen repletion is feasible, trials should investigate its efficacy in preventing ICH, potentially increasing the net benefit profile of IVT in acute ischemic stroke., (© 2021. Fondazione Società Italiana di Neurologia.)

Acute ischemic stroke is the leading cause of morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) is the only agent clinically approved by FDA for patients with acute ischemic stroke. However, delayed treatment of rtPA (e.g., more than 3 h after stroke onset) exacerbates ischemic brain damage by causing intracerebral hemorrhage and increasing neurotoxicity. In the present study, we investigated whether the neuroprotant otaplimastat reduced delayed rtPA treatment-evoked neurotoxicity in male Sprague Dawley rats subjected to embolic middle cerebral artery occlusion (eMCAO). Otaplimastat reduced cerebral infarct size and edema and improved neurobehavioral deficits. In particular, otaplimastat markedly reduced intracerebral hemorrhagic transformation and mortality triggered by delayed rtPA treatment, consequently extending the therapeutic time window of rtPA. We further found that ischemia-evoked extracellular matrix metalloproteases (MMPs) expression was closely correlated with cerebral hemorrhagic transformation and brain damage. In ischemic conditions, delayed rtPA treatment further increased brain injury via synergistic expression of MMPs in vascular endothelial cells. In oxygen-glucose-deprived endothelial cells, otaplimastat suppressed the activity rather than protein expression of MMPs by restoring the level of tissue inhibitor of metalloproteinase (TIMP) suppressed in ischemia, and consequently reduced vascular permeation. This paper shows that otaplimastat under clinical trials is a new drug which can inhibit stroke on its own and extend the therapeutic time window of rtPA, especially when administered in combination with rtPA.

Background: Stroke is one of the most common causes of morbidity and mortality. The need for additional objective parameters as well as the existing criteria continues for eligible patients. The objective of this study is to determine whether the baseline neutrophil/lymphocyte ratio (NLR) predicts symptomatic intracranial hemorrhage (SICH) due to intravenous thrombolytic therapy., Material and Methods: One hundred thirty-three consecutive patients aged 18 years and over who were admitted to the emergency department of a training and research hospital for acute ischemic stroke and underwent intravenous thrombolytic therapy were retrospectively analyzed. For the definition of SICH, European Cooperative Acute Stroke Study III (ECASS III) classification was accepted., Results: When the groups with and without intracranial hemorrhage were compared, there was a significant difference in terms of the initial National Institutes of Health Stroke Scale (NIHSS) score (p < 0.006), glucose level (p < 0.018), and systolic blood pressure (SBP) (p < 0.050). The NLR value of the patients ranged from 0.47 to 13.74. In the group with SICH, NLR was found to be higher but not statistically significant. (p = 0.125)., Conclusion: For predicting SICH, NLR did not provide strong specificity and sensitivity. A precise cut-off value could not be found to predict the hemorrhagic transformation., (© 2021. Fondazione Società Italiana di Neurologia.)

Background and Purpose: Intravenous recombinant tissue plasminogen activator (rt-PA) remains the only FDA approved pharmacological therapy for acute ischemic stroke (AIS), but this treatment is associated with symptomatic intracerebral haemorrhage (SICH). The aim of this study was to derive and validate an accurate measure of SICH risk in ischemic stroke patients treated with rt-PA using data readily available from patient clinical records., Methods: Demographics, physiological parameters, and clinical data were obtained from 1,270 ischemic stroke patients treated with thrombolysis at 20 hospitals. This included age, sex, weight, blood pressure, glucose levels, smoking preferences, and presence of previous clinical conditions. Using a bivariate analysis on a training dataset of 890 patients, SICH cases were compared against SICH-free patients and key risk factors associated with SICH were identified. Continuous variables were stratified using k-means clustering, and odds ratios computed for each of the categorical risk factors employed in the risk score. The SICH risk score, which was assessed using an independent validation dataset comprising 380 patients, was defined between 0 and 53, and stratified into 4 categories: very low risk (0-6), low risk (7-12), moderate risk (13-19), and high risk (>20)., Results: Older age (age > 75 years), higher blood pressure, higher severity of stroke, pre-treatment antithrombotic and history of hypertension and hyperlipidaemia, were shown to be significant risk factors for SICH following rt-PA treatment (p < 0.05). A number of interaction effects with age produced greater overall SICH risk than that of individual variables alone, including age*weight, age*NIHSS, age*diastolic blood pressure, and age*hypertension. The SICH prediction tool demonstrated a C-statistic of 0.75 for continuous risk scoring (0-53) and 0.71 for stratified risk levels., Conclusion: A novel, computationally efficient risk score utilising data readily available from patient clinical records was shown to predict SICH risk following thrombolysis treatment with high accuracy. This tool may be useful for pre-screening patients for SICH risk to reduce the morbidity and mortality associated with thrombolysis treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to analyze the effect of tirofiban on new cerebral microhemorrhage after mechanical thrombectomy in patients with acute ischemic stroke., Methods: In total, 203 patients with acute ischemic stroke treated by mechanical thrombectomy in our department of neurology were enrolled as the research objects. The patients were divided into two groups: the patients who used tirofiban within 24 h after surgery were assigned to the study group (78 subjects), while patients who did not use tirofiban were assigned to the conventional group (125 subjects). Magnetic resonance imaging was used to detect new-onset cerebral microbleeds in patients with stroke after surgery. The National Institute of Health Stroke Scale, modified ranking scale, and activity of daily living scale were used to assess the prognosis of patients, and the general data and the occurrence of adverse effects between two groups were compared to comprehensively evaluate the efficacy and safety of tirofiban., Results: The proportion of atrial fibrillation in the research group was significantly lower than that in the conventional group. The research group had a much lower rate of new-onset cerebral microbleeds than the conventional group (p<0.001). There was no significant difference in the proportion of adverse reactions between the two groups (p>0.05)., Conclusion: The application of tirofiban in mechanical thrombectomy of patients with acute ischemic stroke has high safety, effectively reduces the occurrence of new cerebral microhemorrhage, and provides a guarantee for patient safety.

Background: There is contradicting evidence on the outcome of emergency patients treated during weekends versus weekdays. We studied if outcome of ischemic stroke patients receiving intravenous thrombolysis (IVT) differs according to the treatment time., Methods: Our retrospective study included consecutive patients receiving IVT within 4.5 h of stroke onset between June 1995 and December 2018 at the Helsinki University Hospital. The patients were compared based on the treatment initiation either during weekdays (Monday to Friday) or weekend (Saturday and Sunday). The primary outcome was 3-month mortality and secondary outcomes comprised 3-month modified Rankin Scale (mRS) and incidence of symptomatic intracerebral hemorrhage (sICH). Additional analyses studied the effect of IVT treatment according to non-office hours, time of day, and season., Results: Of the 3980 IVT-treated patients, 28.0% received treatment during weekends. Mortality was similar after weekend (10.0%) and weekday (10.6%) admissions in the multivariable regression analysis (OR 0.78; 95% CI 0.59-1.03). Neither 3-month mRS (OR 0.98; 95% CI 0.86-1.12), nor the occurrence of sICH (4.2% vs 4.6%; OR 0.87; 95% CI 0.60-1.26) differed between the groups. No outcome difference was observed between the office vs non-office hours or by the time of day. However, odds for worse outcome were higher during autumn (OR 1.19; 95% CI 1.04-1.35) and winter (OR 1.15; 95% CI 1.01-1.30)., Conclusion: We did not discover any weekend effect for IVT-treated stroke patients. This confirms that with standardized procedures, an equal quality of care can be provided to patients requiring urgent treatment irrespective of time., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Intracerebral hemorrhage (ICH) is a devastating disease with the high mortality. The poor outcome of ICH is partially due to a combination of various secondary insults, including in the ischemic area. Xuemaitong capsule (XMT), a kind of traditional Chinese medicine, has been applied to clinic practice. The purpose of this study is to explore the mechanism of XMT in alleviating secondary damage in the ischemic area after ICH. We screened XMT target, compound components, and ICH-related targets using network pharmacology, cluster analysis, and enrichment analysis. We found that the tumor necrosis factor (TNF) signaling pathway might be the key signaling pathway for XMT treatment of ICH. An ICH rat model was established, as demonstrated by poor neurologic score. In the ICH rats, Western blot analysis and immunofluorescence indicated the upregulated expression of TNF receptor 1 (TNFR1), mitogen-activated protein kinase (MAPK), nuclear factor- κ B (NF- κ B), and caspase-3 (CASP3). Importantly, administration of XMT alleviated inflammation, edema, and increased perfusion in the ischemic area, whereas the expression of TNFR1, MAPK, NF- κ B, and CASP3 was decreased. Furthermore, Fluoro-Jade B and terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining revealed that XMT application also inhibited apoptosis and degradation of ischemic area neurons. In conclusion, this evidence elucidates that XMT alleviates neuron apoptosis, ischemic area inflammation, edema, and perfusion through the TNFR1-mediated CASP3/NF- κ B/MAPK axis. SIGNIFICANCE STATEMENT: Tumor necrosis factor (TNF) is the key signaling pathway of Xuemaitong (XMT) to intervention during intracerebral hemorrhage. Fourteen key targets [intercellular adhesion molecule 1, interleukin (IL) 6, TNF, C-C motif chemokine ligand 2, prostaglandin-endoperoxide synthase 2, v-rel reticuloendotheliosis viral oncogene homolog A, matrix metalloproteinase 9, endothelin-1 (EDN1), mitogen-activated protein kinase (MAPK) 1, fos proto-oncogene protein, caspase-3 (CASP3), jun proto-oncogene, IL1B, MAPK8] are retrieved from the data base. XMT can inhibit neuron apoptosis in the ischemic area via regulating TNF receptor 1 (TNFR1)/CASP3. XMT alleviates inflammation and edema through regulating TNFR1/nuclear factor- κ B and TNFR1/MAPK signaling pathways. XMT alleviates hypoperfusion in the cerebral ischemic area through mediating TNFR1/MAPK/EDN1., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Symptomatic intracranial hemorrhage (sICH) is a serious hemorrhagic complication after intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients. Most existing predictive scoring systems were derived from Western countries., Objective: The objective of this study is to develop a nomogram to predict the possibility of sICH after IVT in Asian population., Methods: This retrospective cohort study included AIS patients treated with recombinant tissue plasminogen activator (rt-PA) in a tertiary hospital in Shenzhen, China, from January 2014 to December 2020. The endpoint was sICH within 36 hours of IVT treatment. Multivariable logistic regression was used to identify risk factors of sICH, and a predictive nomogram was developed. Area under the curve of receiver operating characteristic curves (AUC), calibration curve, and decision curve analyses were performed. The nomogram was validated by bootstrap resampling., Results: Data on a total of 462 patients were collected, of whom 20 patients (4.3 %) developed sICH. In the multivariate logistic regression model, the National Institute of Health stroke scale scores (NIHSS) (odds ratio (OR), 1.14; 95 % confidence interval (CI), 1.06-1.23, P < 0.001), onset to treatment time (OTT) (OR, 1.02; 95 % CI, 1.01-1.03, P < 0.001), neutrophil to lymphocyte ratio (NLR) (OR, 1.22; 95 % CI, 1.09-1.35, P < 0.001), and cardioembolism (OR, 3.74; 95 % CI, 1.23-11.39, P = 0.020) were independent predictors for sICH and were used to construct a nomogram. Our nomogram exhibited favorable discrimination ability (AUC, 0.878; specificity, 87.35 %; and sensitivity, 73.81 %). Bootstrapping for 500 repetitions was performed to further validate the nomogram. The AUC of the bootstrap model was 0.877 (95 % CI: 0.823-0.922). The calibration curve exhibited good fit and calibration. The decision curve revealed good positive net benefits and clinical effects., Conclusion: The nomogram consisting of the predictors NIHSS, OTT, NLR, and cardioembolism could be used as an auxiliary tool to predict the individual risk of sICH in Chinese AIS patients after IVT. Further external verification among more diverse patient populations is needed to demonstrate the accuracy of the model's predictions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: It remains unclear whether thrombolysis outcomes can be influenced by the affected vascular territory (i.e. anterior circulation stroke vs. posterior circulation stroke) in stroke patients owing to the lack of randomized controlled trials., Aims: Using multiple comprehensive databases, we searched for observational studies of the safety and efficacy of intravenous thrombolytics and intra-arterial treatment with or without intravenous thrombolytics in accordance with the affected vascular territory. We performed a systematic review and meta-analysis. We evaluated symptomatic intracerebral hemorrhage, all-type intracerebral hemorrhage, mortality, and functional outcomes at three months. The recanalization rate was assessed in the intra-arterial treatment group., Summary of Review: Twenty-one studies including a report from our own stroke registry were included through quantitative synthesis. Compared with the anterior circulation stroke group, the posterior circulation stroke group had a lower risk of ICH, including symptomatic intracerebral hemorrhage and all-type intracerebral hemorrhage, after intravenous thrombolytics and tended to have favorable functional outcomes at three months. Mortality was similar between the two groups. Regarding intra-arterial treatment, the symptomatic intracerebral hemorrhage and post-procedural recanalization rates were comparable between the two groups, although the posterior circulation stroke group had a higher mortality risk and lower tendency for a favorable functional outcome., Conclusions: Safety and efficacy of thrombolysis in posterior circulation stroke depends on involvement of large vessel occlusion and reperfusion modality such that intravenous thrombolytics is more effective and safer than in anterior circulation stroke; the safety and efficacy of intra-arterial treatment is comparable or lower than anterior circulation stroke. Considering the limitations of our meta-analysis, further studies are needed to provide high level evidence of a beneficial effect of intra-arterial treatment, and to identify patients' profiles associated with benefit of treatment.

Background: Subcutaneous heparin at a prophylactic dose (SHPD) is a rather common treatment in ischemic stroke, but whether it confers an increased risk of hemorrhagic transformation of cerebral infarct (HT) and whether its reduction or discontinuation favors HT regression are presently poorly understood., Methods: Two samples of ischemic stroke patients with a cerebral lesion diameter ≥ 3 cm on brain CT scan, admitted over 7 years to our stroke unit, were retrospectively examined: (1) patients treated or not treated with SHPD (enoxaparin 4000 U/day), with subsequent assessment of possible HT appearance (N = 267, mean age 75.9 ± 12.8 years) and (2) patients treated with SHPD, with HT and subsequent reduction/discontinuation or maintenance of the initial dose, and subsequent assessment of HT evolution (N = 116, mean age 75.7 ± 11.1 years). HT severity was quantified according to the ECASS study (HT score)., Results: In the first sample, after adjustment for age, sex, stroke severity, cerebral lesion diameter, and other possible confounders, SHPD was inversely associated with HT appearance (hazard ratio 0.62, 95% CI 0.39-0.98, P = 0.04). In the second sample, after adjustment for age, sex, stroke severity, cerebral lesion diameter, and initial HT severity, SHPD reduction/discontinuation had an inverse effect on both HT score improvement (odds ratio 0.42, 95% CI 0.18-0.99, P = 0.049) and HT improvement according to neuroradiological reports (odds ratio 0.34, 95% CI 0.14-0.82, P = 0.015)., Conclusions: This retrospective study suggests that SHPD may play a protective role in HT appearance and evolution, which requires verification by a randomized clinical trial.

Background and Purpose- Although cilostazol has shown less hemorrhagic events than aspirin, only marginal difference was observed in hemorrhagic stroke events among patients at high risk for cerebral hemorrhage. To identify patients who would most benefit from cilostazol, this study analyzed interactions between treatment and subgroups of the PICASSO trial (Prevention of Cardiovascular Events in Asian Ischemic Stroke Patients With High Risk of Cerebral Hemorrhage). Methods- Ischemic stroke patients with a previous intracerebral hemorrhage or multiple microbleeds were randomized to treatment with cilostazol or aspirin and followed up for a mean 1.8 years. Efficacy, defined as the composite of any stroke, myocardial infarction, and vascular death, and safety, defined as the incidence of hemorrhagic stroke, were analyzed in the 2 groups. Interactions between treatment and age, sex, presence of hypertension and diabetes mellitus, index of high-risk cerebral hemorrhage, and white matter lesion burden were analyzed for primary and key secondary outcomes. Changes in vital signs and laboratory results were compared in the 2 groups. Results- Among all 1534 patients enrolled, a significant interaction between treatment group and index of high risk for cerebral hemorrhage on hemorrhagic stroke ( P for interaction, 0.03) was observed. Hemorrhagic stroke was less frequent in the cilostazol than in the aspirin group in patients with multiple microbleeds (1 versus 13 events; hazard ratio, 0.08 [95% CI, 0.01-0.61]; P =0.01). A marginal interaction between treatment group and white matter change on any stroke ( P for interaction, 0.08) was observed. Cilostazol reduced any stroke significantly in patients with mild (5 versus 16 events; hazard ratio, 0.36 [95% CI, 0.13-0.97]; P =0.04)-to-moderate (16 versus 32 events; hazard ratio, 0.50 [95% CI, 0.29-0.92]; P =0.03) white matter changes. Heart rate and HDL (high-density lipoprotein) cholesterol level were significantly higher in the cilostazol group than in the aspirin group at follow-up. Conclusions- Cilostazol may be more beneficial for ischemic stroke patients with multiple cerebral microbleeds and before white matter changes are extensive. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01013532.

Background and Purpose- There are scarce data regarding the safety of intravenous thrombolysis (IVT) in acute ischemic stroke among patients on direct oral anticoagulants (DOACs). Methods- We performed a systematic review and meta-analysis of the current literature. Data regarding all adult patients pretreated with DOAC who received IVT for acute ischemic stroke were recorded. Meta-analysis was performed by comparing the rate of symptomatic intracerebral hemorrhage in these patients with (1) stroke patients without prior anticoagulation therapy and (2) patients on warfarin with international normalized ratio <1.7. Meta-analyses were further conducted in subgroups as follows: (1) administration of DOAC within 48 hours versus an unknown interval before IVT, (2) consideration of symptomatic intracerebral hemorrhage outcome according to the National Institute of Neurological Disorders (NINDS) versus the European Cooperative Acute Stroke Study II (ECASS-II) criteria. Results- After reviewing 13 392 reports and communicating with certain authors of 12 published studies, a total of 52 823 acute ischemic stroke patients from 6 studies were enrolled in the present meta-analysis: DOACs: 366, warfarin: 2133, and 503 241 patients without prior anticoagulation. We detected no additional risk of symptomatic intracerebral hemorrhage following IVT among patients taking DOACs within 48 hours-DOACs-warfarin: NINDS (odds ratio [OR], 0.55 [95% CI, 0.19-1.59]), ECASS-II (OR, 0.77 [95% CI, 0.28-2.16]); DOACs-no-anticoagulation: NINDS (OR, 1.23 [95% CI, 0.46-3.31]), ECASS-II (OR, 0.87 [95% CI, 0.32-2.41]). Similarly, no additional risk was detected with no time limit between last DOAC intake-DOACs warfarin: NINDS (OR, 0.85 [95% CI, 0.49-1.45]), ECASS-II (OR, 1.11 [95% CI, 0.67-1.85]); DOACs-no-anticoagulation: NINDS (OR, 1.17 [95% CI, 0.43-3.15]), ECASS-II (OR, 0.87 [95% CI, 0.33-2.41]). There was no evidence of heterogeneity across included studies ( I 2 =0%). We also provided the details of 123 individual cases with or without reversal agents before IVT. There was no significant increase in the risk of hemorrhagic transformation (OR, 1.48 [95% CI, 0.50-4.38]), symptomatic hemorrhagic transformation (OR, 0.47 [95% CI, 0.09-2.55]), or early mortality (OR, 0.60 [95% CI, 0.11-3.43]) between cohorts who did or did not receive prethrombolysis idarucizumab. Conclusions- The results of our study indicated that prior intake of DOAC appears not to increase the risk of symptomatic intracerebral hemorrhage in selected AIS patients treated with IVT.

Treatment with recombinant tissue plasminogen activator (rt-PA) is the most effective therapeutic option against brain ischemic stroke at the present time. However, elevated incidence of symptomatic intracerebral hemorrhage (SIH) greatly hinders ideal treatment outcome of rt-PA. We sought to assess the impacts of hesperidin on SIH following rt-PA therapies. Patients with ischemic stroke were assigned into two groups in a random fashion, to receive either rt-PA + placebo (Pc) or rt-PA + hesperidin. Treatment outcome was evaluated 24 h after the initial reperfusion using the transcranial Doppler ultrasonography (TCD) and the NIH Stroke Scale (NIHSS). Further, serum concentrations of transforming growth factor (TGF)-β1, matrix metalloproteinase (MMP)-2, and MMP-9 were examined. Following the initial administration, stroke patients continued to receive either daily Pc or daily hesperidin, and the treatment outcome after 7 days was examined using the TCD, NIHSS, Glasgow Outcome Scale (GOS), and the Modified Rankin Scale (MRS). Combined treatment of rt-PA with hesperidin yielded significant improvement of outcomes, as revealed by better TCD and NIHSS scores as well as decreased SIH incidences, which could be attributable to elevation of TGF-β1 and reduction in serum levels of both MMP-2 and MMP-9 caused by hesperidin. Follow-up hesperidin treatment for 7 consecutive days also markedly enhanced the recovery of stroke patients, as indicated by TCD, MRS, GOS, and NIHSS. Findings of the present study strongly suggested potential clinical application of hesperidin supplement in rt-PA therapies to reduce SIH and thereby improve the treatment outcomes of rt-PA in patients with ischemic stroke.

Background and Purpose- The risk of arterial ischemic events after intracerebral hemorrhage (ICH) is poorly understood given the lack of a control group in prior studies. This study aimed to evaluate the risk of acute ischemic stroke and myocardial infarction (MI) among patients with and without ICH. Methods- We performed a retrospective cohort study using claims data from Medicare beneficiaries from 2008 to 2014. Our exposure was acute ICH, identified using validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Our primary outcome was a composite of acute ischemic stroke and MI, whereas secondary outcomes were ischemic stroke alone and MI alone. We used Cox regression analysis to compute hazard ratios during 1-month intervals after ICH. Sensitivity analyses entailed exclusion of patients with atrial fibrillation and valvular heart disease. Results- Among 1 760 439 Medicare beneficiaries, 5924 had ICH. The 1-year cumulative incidence of an arterial ischemic event was 5.7% (95% CI, 4.8-6.8) in patients with ICH and 1.8% (95% CI, 1.7-1.9) in patients without ICH. After adjusting for potential confounders, the risk of an arterial ischemic event remained significantly increased for the first 6 months after ICH and was especially high in the first month (hazard ratio, 6.7 [95% CI, 5.0-8.6]). In secondary analysis, the risk of ischemic stroke was increased in the first 6 months after ICH (hazard ratio, 6.1 [95% CI, 3.5-9.3]) but the risk of MI was not (hazard ratio, 1.6 [95% CI, 0.3-2.9]). In sensitivity analyses excluding patients with atrial fibrillation and valvular heart disease, the association between ICH and arterial ischemic events was similar to that of the primary analysis. Conclusions- In a large population-based cohort, we found that elderly patients with ICH had a substantially increased risk of ischemic stroke in the first 6 months after diagnosis. Further exploration of this risk is needed to determine optimal secondary prevention strategies for these patients.

Background and Purpose- Cerebral microbleeds (CMBs) are a risk factor for intracranial hemorrhage. Whether intravenous thrombolysis (IVT) improves functional outcome in acute ischemic stroke patients with CMBs is unknown. We aimed to estimate the treatment effect of IVT in patients with acute ischemic stroke and a high burden (>10) of CMBs. Methods- We devised a multistep algorithm to model 90-day modified Rankin Scale scores in patients with ≤10 versus >10 CMBs who do or do not receive IVT. Parameters were extracted from recently published meta-analyses and included pairwise relationships between CMBs, IVT, 3-month functional outcome, and intracranial hemorrhage. Uncertainty was quantified in probabilistic sensitivity analyses. Results- In patients with >10 CMBs as compared with ≤10 CMBs, point estimates of the odds ratios for favorable outcome (modified Rankin Scale ≤2) associated with IVT were 7% to 10% lower but still >1 (range, 1.03-1.51). On the other hand, IVT in patients with >10 CMBs significantly increased the odds of mortality. The point estimates for the net treatment effect of IVT (change in the utility-weighted modified Rankin Scale score) in patients with >10 CMBs were in favor of withholding IVT in older patients with more severe strokes and longer treatment delays. However, because the general pretest probability of >10 CMBs is low (0.6%-2.7%), pretreatment magnetic resonance imaging to quantify CMB burden would be justified only if it delayed IVT by <10 minutes. Conclusions- High CMB burden modifies the treatment effect of IVT. In patients with >10 CMBs, IVT is associated with higher mortality and, in older patients with severe strokes and longer treatment delays, a net utility loss. Patients with higher-than-average pretest probability of >10 CMB might profit from magnetic resonance imaging screening if it does not increase the treatment time.

Background and Purpose- Despite evidence to support the prescription of antihypertensive medications before hospital discharge to promote medication adherence and prevent recurrent events, many patients with stroke miss out on these medications at discharge. We aimed to examine patient, clinical, and system-level differences in the prescription of antihypertensive medications at hospital discharge after stroke. Methods- Adults with acute ischemic stroke or intracerebral hemorrhage alive at discharge were included (years 2009-2013) from 39 hospitals participating in the Australian Stroke Clinical Registry. Patient comorbidities were identified using the International Statistical Classification of Diseases and Related Health Problems (Tenth Edition, Australian Modification ) codes from the hospital admissions and emergency presentation data. The outcome variable and other system factors were derived from the Australian Stroke Clinical Registry dataset. Multivariable, multilevel logistic regression was used to examine factors associated with the prescription of antihypertensive medications at hospital discharge. Results- Of the 10 315 patients included, 79.0% (intracerebral hemorrhage, 74.1%; acute ischemic stroke, 79.8%) were prescribed antihypertensive medications at discharge. Prescription varied between hospital sites, with 6 sites >2 SDs below the national average for provision of antihypertensives at discharge. Prescription was also independently associated with patient and clinical factors including history of hypertension, diabetes mellitus, management in an acute stroke unit, and discharge to rehabilitation. In patients with acute ischemic stroke, females (odds ratio, 0.85; 95% CI, 0.76-0.94), those who had greater stroke severity (odds ratio, 0.81; 95% CI 0.72-0.92), or dementia (odds ratio, 0.65; 95% CI, 0.52-0.81) were less likely to be prescribed. Conclusions- Prescription of antihypertensive medications poststroke varies between hospitals and according to patient factors including age, sex, stroke severity, and comorbidity profile. Implementation of targeted quality improvement initiatives at local hospitals may help to reduce the variation in prescription observed.

Background and Purpose: Standardized registries may provide valuable data to further improve stroke care. Our aim was to obtain updated information about characteristics of stroke patients and management of stroke across the Ibero-American countries, using a common in-hospital registry (Safe Implementation of Treatments in Stroke–Sociedad Iberoamericana de Enfermedades Cerebrovasculares) as a basis for further quality improvement., Methods: Data for this study were entered into the Safe Implementation of Treatments in Stroke registry from September 2009 to December 2013 by 58 centers in 14 countries. Data included demographics, risk factors, onset-to-door time, National Institutes of Health Stroke Scale score, stroke subtype, ischemic stroke etiology, treatments, 3-month mortality, and modified Rankin Scale score. Time to treatment was also recorded for patients treated with thrombolysis., Results: Five thousand four hundred one patients were registered; median age, 65 years; 46% women; 3915 (72.5%) ischemic strokes; 686 (13.7%) hemorrhagic strokes; 213 (4.3%) subarachnoid hemorrhages; 414 (8.3%) transient ischemic attacks; and 31 (0.6%) cerebral vein thrombosis. The most prevalent risk factors were hypertension (71.3%), dyslipidemia (35.2%), and diabetes mellitus (23.6%). Atrial fibrillation was present in 15.1%. Three hundred one ischemic strokes were treated with intravenous thrombolysis (IVT; 7.7%). Patients undergoing IVT were more severely affected (median baseline National Institutes of Health Stroke Scale score, 11 versus 6). The rate of symptomatic intracerebral hemorrhages after IVT was 5.7%. At 3 months, 60.3% of IVT-treated patients and 59.1% of untreated patients were independent (modified Rankin Scale score, 0–2). Mortality was 11.4% in treated and 12.8% in untreated patients., Conclusions: Safe Implementation of Treatments in Stroke–Sociedad Iberoamericana de Enfermedades Cerebrovasculares is the largest registry of a general stroke population and the first study to evaluate the level of IVT use in Ibero-America. It provides valuable information that may help to improve the quality of stroke care in the Ibero-American region., (© 2019 American Heart Association, Inc.)

Background: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy., Methods: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627., Findings: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08-1·13] vs 0·77 [0·13-4·61]; p interaction =0·41), cerebral microbleed number 0-1 versus 2-4 versus 5 or more (HR 0·77 [0·13-4·62] vs 0·32 [0·03-3·66] vs 0·33 [0·07-1·60]; p interaction =0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004-6·79] vs 0·37 [0·09-1·28]; p interaction =0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all p interaction >0·05)., Interpretation: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision., Funding: British Heart Foundation., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose- We aimed to determine incidences and predictors of major vascular events in intracerebral hemorrhage (ICH) survivors. Methods- We did a prospective observational cohort study in patients with spontaneous ICH from the Prognosis of Intracerebral Hemorrhage cohort in Lille, France. We studied incidences and predictors of long-term vascular events (cerebral and extracerebral, ischemic and hemorrhagic) in patients alive at 30 days with a prespecified subgroup analysis according to ICH location. We performed multivariable analyses (competing risk analyses, with death during follow-up as a competing event). Results- From the 560 patients with spontaneous ICH enrolled between November 2004 and March 2009, we included 310 patients (median age, 70 years). Eighty-two patients presented at least 1 major vascular event leading to an incidence rate of 20.0% (95% CI, 15.7-24.7) at 5 years after ICH. In the overall cohort, ischemic events were more frequent than hemorrhagic events. However, the incidence strikingly differed according to ICH location: deep ICH was associated with future ischemic events (subhazard ratio, 1.85; 95% CI, 1.01-3.40), whereas lobar ICH with hemorrhagic events (subhazard ratio, 2.38; 95% CI, 1.17-4.86). In deep ICH, the incidence of ischemic events at 5 years was 6× higher than the incidence of hemorrhagic events. Conclusions- ICH survivors are at high risk of both cerebral and extracerebral vascular events. The ischemic or hemorrhagic risk profile varies according to the index ICH location with a stronger ischemic risk in deep ICH. Secondary prevention, tailored on ICH location, should target not only cerebral recurrences but also extracerebral vascular events.

Background: Measuring anti-Xa activity (AXA) has been reported as useful for predicting future risk of hemorrhagic and ischemic events in stroke patients taking direct factor Xa inhibitors. We evaluated AXA levels of rivaroxaban or apixaban in acute stroke patients with non-valvular atrial fibrillation. Methods and Results: This was a single-center, prospective, observational study. Consecutive patients with acute ischemic stroke or transient ischemic attack who were admitted within 7 days of onset and started taking rivaroxaban or apixaban for NVAF between January 2012 and April 2017 were enrolled. AXA was measured at 2 time points: just before (AXA trough ) and 4 h after (AXA peak ) taking rivaroxaban or apixaban on the 2nd day or later of administration. Of 156 patients taking rivaroxaban, hemorrhagic events occurred in 13. Patients with hemorrhagic events had higher AXA peak than those without [median (interquartile range): 1.93 (1.11-3.75) vs. 1.35 (0.80-2.00) IU/mL; P<0.01]. Multivariable-adjusted Cox models showed that AXA peak was independently related to the incidence of hemorrhagic events. Of 169 patients taking apixaban, hemorrhagic events occurred in 11. Patients with hemorrhagic events had higher AXA trough [2.78 (1.90-3.53) vs. 1.42 (0.93-2.08) IU/mL, P<0.01] and AXA peak [4.05 (3.44-4.72) vs. 2.43 (1.79-3.35) IU/mL, P<0.01] than those without. Both AXA trough and AXA peak were independently related to the incidence of hemorrhagic events., Conclusions: In these patients who started rivaroxaban or apixaban early after stroke, AXA levels in the early period were related to future hemorrhagic events.

Purpose of Review: The management of patients with acute stroke has been revolutionized in recent years with the advent of new effective treatments. In this rapidly evolving field, we provide an update on the management of acute stroke excluding thrombectomy, looking to recent, ongoing, and future trials., Recent Findings: Large definitive trials have provided insight into acute stroke care including broadening the therapeutic window for thrombolysis, alternatives to standard dose alteplase, the use of dual antiplatelet therapy early after minor ischemic stroke, and treating elevated blood pressure in intracerebral hemorrhage. Further ongoing and future trials are eagerly awaited in this ever-expanding area. Although definitive trials have led to improvements in acute stroke care, there remains a need for further research to improve our understanding of pathophysiological mechanisms underlying different stroke types with the potential for treatments to be tailored to the individual.

Polymorphonuclear neutrophil granulocytes (PMN) orchestrate the removal of cell debris in ischemic stroke and intracerebral hemorrhage. In both pathologies, high neutrophil to lymphocyte ratios in peripheral blood are predictive of poor outcome in human stroke patients. Following earlier studies indicating that the cerebral microvasculature forms an efficient barrier that impedes neutrophil brain entry, intravital microscopy and immunohistochemistry in the meantime unequivocally revealed the accumulation of PMN in the ischemic and hemorrhagic brain parenchyma. These studies provide definite evidence that PMN contribute to the degradation of the blood-brain barrier, predisposing the brain to secondary injury, edema, hemorrhage formation, hemorrhage growth and poor neurological recovery. Recent studies demonstrated the role of pro-inflammatory N1 neutrophils in brain edema and neurotoxicity, whereas anti-inflammatory N2 neutrophils were found to limit this excessive immune response, promoting neuronal survival and successful brain remodeling. In view of the recent failure of anti-inflammatory immunotherapies in clinical trials, strategies specifically modulating the brain accumulation, differentiation and action of PMN may open promising perspectives for stroke treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)