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Importance: Prehospital transfer protocols are based on rapid access to reperfusion therapies for patients with ischemic stroke. The effect of different protocols among patients receiving a final diagnosis of intracerebral hemorrhage (ICH) is unknown., Objective: To determine the effect of direct transport to an endovascular treatment (EVT)-capable stroke center vs transport to the nearest local stroke center., Design, Setting, and Participants: This was a prespecified secondary analysis of RACECAT, a multicenter, population-based, cluster-randomized clinical trial conducted from March 2017 to June 2020 in Catalonia, Spain. Patients were evaluated by a blinded end point assessment. All consecutive patients suspected of experiencing a large vessel occlusion stroke (Rapid Arterial Occlusion Evaluation Scale [RACE] score in the field >4 on a scale of 0 to 9, with lower to higher stroke severity) with final diagnosis of ICH were included. A total of 1401 patients were enrolled in RACECAT with suspicion of large vessel occlusion stroke. The current analysis was conducted in October 2022., Intervention: Direct transport to an EVT-capable stroke center (n = 137) or to the closest local stroke center (n = 165)., Main Outcomes and Measures: The primary outcome was tested using cumulative ordinal logistic regression to estimate the common odds ratio (OR) and 95% CI of the shift analysis of disability at 90 days as assessed by the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) in the intention-to-treat population. Secondary outcomes, included 90-day mortality, death or severe functional dependency, early neurological deterioration, early mortality, ICH volume and enlargement, rate of neurosurgical treatment, rate of clinical complications during initial transport, and rate of adverse events until day 5., Results: Of 1401 patients enrolled, 1099 were excluded from this analysis (32 rejected informed consent, 920 had ischemic stroke, 29 had transient ischemic attack, 12 had subarachnoid hemorrhage, and 106 had stroke mimic). Thus, 302 patients were included (204 [67.5%] men; mean [SD] age 71.7 [12.8] years; and median [IQR] RACE score, 7 [6-8]). For the primary outcome, direct transfer to an EVT-capable stroke center (mean [SD] mRS score, 4.93 [1.38]) resulted in worse functional outcome at 90 days compared with transfer to the nearest local stroke center (mean [SD] mRS score, 4.66 [1.39]; adjusted common OR, 0.63; 95% CI, 0.41-0.96). Direct transfer to an EVT-capable stroke center also suggested potentially higher 90-day mortality compared with transfer to the nearest local stroke center (67 of 137 [48.9%] vs 62 of 165 [37.6%]; adjusted hazard ratio, 1.40; 95% CI, 0.99-1.99). The rates of medical complications during the initial transfer (30 of 137 [22.6%] vs 9 of 165 patients [5.6%]; adjusted OR, 5.29; 95% CI, 2.38-11.73) and in-hospital pneumonia (49 of 137 patients [35.8%] vs 29 of 165 patients [17.6%]; OR, 2.61; 95% CI, 1.53-4.44) were higher in the EVT-capable stroke center group., Conclusions and Relevance: In this secondary analysis of the RACECAT randomized clinical trial, bypassing the closest stroke center resulted in reduced chances of functional independence at 90 days for patients who received a final diagnosis of ICH., Trial Registration: ClinicalTrials.gov Identifier: NCT02795962.

Background: We aim to compare the outcome of patients from urban areas, where the referral center is able to perform thrombectomy, with patients from nonurban areas enrolled in the RACECAT trial (Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke Patients With Suspected Large Vessel Occlusion)., Methods: Patients with suspected large vessel occlusion stroke, as evaluated by a Rapid Arterial Occlusion Evaluation score of ≥5, from urban catchment areas of thrombectomy-capable centers during RACECAT trial enrollment period were included in the Stroke Code Registry of Catalonia. Primary outcome was disability at 90 days, as assessed by the shift analysis on the modified Rankin Scale score, in patients with an ischemic stroke. Secondary outcomes included mortality at 90 days, rate of thrombolysis and thrombectomy, time from onset to thrombolysis, and thrombectomy initiation. Propensity score matching was used to assemble a cohort of patients with similar characteristics., Results: The analysis included 1369 patients from nonurban areas and 2502 patients from urban areas. We matched 920 patients with an ischemic stroke from urban areas and nonurban areas based on their propensity scores. Patients with ischemic stroke from nonurban areas had higher degrees of disability at 90 days (median [interquartle range] modified Rankin Scale score, 3 [2-5] versus 3 [1-5], common odds ratio, 1.25 [95% CI, 1.06-1.48]); the observed average effect was only significant in patients with large vessel stroke (common odds ratio, 1.36 [95% CI, 1.08-1.65]). Mortality rate was similar between groups(odds ratio, 1.02 [95% CI, 0.81-1.28]). Patients from nonurban areas had higher odds of receiving thrombolysis (odds ratio, 1.36 [95% CI, 1.16-1.67]), lower odds of receiving thrombectomy(odds ratio, 0.61 [95% CI, 0.51-0.75]), and longer time from stroke onset to thrombolysis (mean difference 38 minutes [95% CI, 25-52]) and thrombectomy(mean difference 66 minutes [95% CI, 37-95])., Conclusions: In Catalonia, Spain, patients with large vessel occlusion stroke triaged in nonurban areas had worse neurological outcomes than patients from urban areas, where the referral center was able to perform thrombectomy. Interventions aimed at improving organizational practices and the development of thrombectomy capabilities in centers located in remote areas should be pursued., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02795962.

Objective: This study was undertaken to investigate whether adjunct alteplase improves brain reperfusion following successful thrombectomy., Methods: This single-center, randomized, double-blind, placebo-controlled study included 36 patients (mean [standard deviation] = 70.8 [13.5] years old, 18 [50%] women) with large vessel occlusion undergoing thrombectomy resulting in near-normal (expanded Thrombolysis in Cerebral Infarction [eTICI] b50/67/2c, n = 23, 64%) or normal angiographic reperfusion (eTICI 3, n = 13, 36%). Seventeen patients were randomized to intra-arterial alteplase (0.225mg/kg), and 19 received placebo. At 48 hours, patients had brain perfusion/diffusion-weighted magnetic resonance imaging (MRI) and MRI-spectroscopy. The primary outcome was the difference in the proportion of patients with areas of hypoperfusion on MRI. Secondary outcomes were the infarct expansion ratio (final to initial infarction volume), and the N-acetylaspartate (NAA) peak relative to total creatine as a marker of neuronal integrity., Results: The prevalence of hypoperfusion was 24% with intra-arterial alteplase, and 58% with placebo (adjusted odds ratio = 0.20, 95% confidence interval [CI] = 0.04-0.91, p = 0.03). Among 14 patients with final eTICI 3 scores, hypoperfusion was found in 1 of 7 (14%) in the alteplase group and 3 of 7 (43%) in the placebo group. Abnormal brain perfusion was associated with worse functional outcome at day 90. Alteplase significantly reduced the infarct expansion ratio compared with placebo (median [interquartile range (IQR)] = 0.7 [0.5-1.2] vs 3.2 [1.8-5.7], p = 0.01) and resulted in higher NAA peaks (median [IQR] = 1.13 [0.91-1.36] vs 1.00 [0.74-1.22], p < 0.0001)., Interpretation: There is a high prevalence of areas of hypoperfusion following thrombectomy despite successful reperfusion on angiography. Adjunct alteplase enhances brain reperfusion, which results in reduced expansion of the infarction and improved neuronal integrity. ANN NEUROL 2022;92:860-870., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Purpose: Previous studies suggest that mechanisms and outcomes in patients with COVID-19-associated stroke differ from those in patients with non-COVID-19-associated strokes, but there is limited comparative evidence focusing on these populations. The aim of this study, therefore, was to determine if a significant association exists between COVID-19 status with revascularization and functional outcomes following thrombectomy for large vessel occlusion (LVO), after adjustment for potential confounding factors., Methods: A cross-sectional, international multicenter retrospective study was conducted in consecutively admitted COVID-19 patients with concomitant acute LVO, compared to a control group without COVID-19. Data collected included age, gender, comorbidities, clinical characteristics, details of the involved vessels, procedural technique, and various outcomes. A multivariable-adjusted analysis was conducted., Results: In this cohort of 697 patients with acute LVO, 302 had COVID-19 while 395 patients did not. There was a significant difference (p &lt; 0.001) in the mean age (in years) and gender of patients, with younger patients and more males in the COVID-19 group. In terms of favorable revascularization (modified Thrombolysis in Cerebral Infarction [mTICI] grade 3), COVID-19 was associated with lower odds of complete revascularization (odds ratio 0.33, 95% confidence interval [CI] 0.23-0.48; p &lt; 0.001), which persisted on multivariable modeling with adjustment for other predictors (adjusted odds ratio 0.30, 95% CI 0.12-0.77; p = 0.012). Moreover, endovascular complications, in-hospital mortality, and length of hospital stay were significantly higher among COVID-19 patients (p &lt; 0.001)., Conclusion: COVID-19 was an independent predictor of incomplete revascularization and poor functional outcome in patients with stroke due to LVO. Furthermore, COVID-19 patients with LVO were more often younger and had higher morbidity/mortality rates., (© 2022 European Academy of Neurology.)

Objectives: After an acute ischemic stroke, patients with a large CT perfusion (CTP) predicted infarct core (pIC) have poor clinical outcome. However, previous research suggests that this relationship may be relevant for subgroups of patients determined by pretreatment and treatment-related variables while negligible for others. We aimed to identify these variables., Methods: We included a cohort of 828 patients with acute proximal carotid arterial occlusions imaged with a whole-brain CTP within 8 h from stroke onset. pIC was computed on CTP Maps (cerebral blood flow < 30%), and poor clinical outcome was defined as a 90-day modified Rankin Scale score > 2. Potential mediators of the association between pIC and clinical outcome were evaluated through first-order and advanced interaction analyses in the derivation cohort (n = 654) for obtaining a prediction model. The derived model was further validated in an independent cohort (n = 174)., Results: The volume of pIC was significantly associated with poor clinical outcome (OR = 2.19, 95% CI = 1.73 - 2.78, p < 0.001). The strength of this association depended on baseline National Institute of Health Stroke Scale, glucose levels, the use of thrombectomy, and the interaction of age with thrombectomy. The model combining these variables showed good discrimination for predicting clinical outcome in both the derivation cohort and validation cohorts (area under the receiver operating characteristic curve 0.780 (95% CI = 0.746-0.815) and 0.782 (95% CI = 0.715-0.850), respectively)., Conclusions: In patients imaged within 8 h from stroke onset, the association between pIC and clinical outcome is significantly modified by baseline and therapeutic variables. These variables deserve consideration when evaluating the prognostic relevance of pIC., Key Points: •The volume of CT perfusion (CTP) predicted infarct core (pIC) is associated with poor clinical outcome in acute ischemic stroke imaged within 8 h of onset. •The relationship between pIC and clinical outcome may be modified by baseline clinical severity, glucose levels, thrombectomy use, and the interaction of age with thrombectomy. •CTP pIC should be evaluated in an individual basis for predicting clinical outcome in patients imaged within 8 h from stroke onset., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background: The mechanisms and outcomes in coronavirus disease (COVID-19)-associated stroke are unique from those of non-COVID-19 stroke., Objective: To describe the efficacy and outcomes of acute revascularization of large vessel occlusion (LVO) in the setting of COVID-19 in an international cohort., Methods: We conducted an international multicenter retrospective study of consecutively admitted patients with COVID-19 with concomitant acute LVO across 50 comprehensive stroke centers. Our control group constituted historical controls of patients presenting with LVO and receiving a mechanical thrombectomy between January 2018 and December 2020., Results: The total cohort was 575 patients with acute LVO; 194 patients had COVID-19 while 381 patients did not. Patients in the COVID-19 group were younger (62.5 vs 71.2; P < .001) and lacked vascular risk factors (49, 25.3% vs 54, 14.2%; P = .001). Modified thrombolysis in cerebral infarction 3 revascularization was less common in the COVID-19 group (74, 39.2% vs 252, 67.2%; P < .001). Poor functional outcome at discharge (defined as modified Ranklin Scale 3-6) was more common in the COVID-19 group (150, 79.8% vs 132, 66.7%; P = .004). COVID-19 was independently associated with a lower likelihood of achieving modified thrombolysis in cerebral infarction 3 (odds ratio [OR]: 0.4, 95% CI: 0.2-0.7; P < .001) and unfavorable outcomes (OR: 2.5, 95% CI: 1.4-4.5; P = .002)., Conclusion: COVID-19 was an independent predictor of incomplete revascularization and poor outcomes in patients with stroke due to LVO. Patients with COVID-19 with LVO were younger, had fewer cerebrovascular risk factors, and suffered from higher morbidity/mortality rates., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Background and Objectives: The presence of postinterventional subarachnoid hyperdensities (SA-HD) is a relatively common finding after mechanical thrombectomy (MT). We aimed to assess the incidence, characteristics, clinical relevance, and predictors of SA-HD after MT as categorized through the use of postinterventional dual-energy CT (DE-CT)., Methods: A single-center consecutive series of patients with acute stroke treated with MT was retrospectively reviewed. Posttreatment SA-HD were defined as incident extraaxial hyperdensities in a follow-up DE-CT performed within a median of 8 hours after MT. SA-HD were further classified according to their content (isolated contrast extravasation vs blood extravasation) and extension (diffuse [hyperdensities in more than one extraparenchymal compartment] vs nondiffuse). Adjusted logistic regression models assessed the association of SA-HD with pretreatment and procedural variables and with poor clinical outcome (shift towards worse categories in the ordinal Rankin Scale at 90 days)., Results: SA-HD were observed in 120 (28%) of the 424 included patients (isolated contrast extravasation n = 22, blood extravasation n = 98). In this group, SA-HD were diffuse in 72 (60%) patients (isolated contrast extravasation n = 7, blood extravasation n = 65) and nondiffuse in 48 (40%) patients (isolated contrast extravasation n = 15, blood extravasation n = 33). Diffuse SA-HD were significantly associated with worse clinical outcome in adjusted models (common odds ratio [cOR] 2.3, 95% confidence interval [CI] 1.36-4.00, p = 0.002), unlike the specific SA-HD content alone. In contrast with the absence of SA-HD, only the diffuse pattern with blood extravasation was significantly associated with worse clinical outcome (cOR 2.4, 95% CI 1.36-4.15, p = 0.002). Diffuse SA-HD patterns were predicted by M2 occlusions, more thrombectomy passes, and concurrent parenchymal hematomas., Discussion: In our cohort of patients imaged within a median of 8 hours after MT, postinterventional SA-HD showed a diffuse pattern in 17% of thrombectomies and were associated with more arduous procedures. Diffuse SA-HD but not local collections of blood or contrast extravasations were associated with an increased risk of poor outcome and death. These findings reinforce the need for improvement in reperfusion strategies., Classification of Evidence: This study provides Class IV evidence that in individuals with proximal carotid artery territory occlusions treated with MT, diffuse postinterventional SA-HD on imaging 8 hours postprocedure are associated with worse clinical outcomes at 90 days., (© 2021 American Academy of Neurology.)

Background: Single-center studies have suggested that the early clinical course after mechanical thrombectomy (MT) in patients with ischemic stroke is a clinical predictor of long-term outcome., Objective: To analyze the prognostic value of clinical improvement within 24 hours in a population-based multicenter cohort., Methods: From a total of 3792 patients with acute ischemic stroke in Catalonia (CICAT registry), 1951 patients were treated with MT. The National Institutes of Health Stroke Scale (NIHSS) score within 24 hours, and follow-up was available in 1666 patients. Percentage variation in the NIHSS score was calculated in relation to a baseline assessment. Good outcome was defined as a modified Rankin Scale score ≤2 at 90 days. Predictive values of clinical improvement and adjusted OR to predict good outcomes were assessed in the whole cohort and the subgroup of patients with posterior circulation stroke (n=166)., Results: Good outcome was achieved in 656/1666 patients (39%) overall. Percentage improvements both at the end of MT and at 24 hours predicted good outcome, with higher predictive capacity at 24 hours (C-statistic, 0.85 vs 0.73, p<0.001). Positive and negative predictive values were 70% and 74% for the >30% cut-off point at the end of MT, and 69% and 84% for the >50% cut-off point at 24 hours, respectively. The adjusted OR for good outcome was 5.8 (95% CI 4.2 to 8.1) and 12.9 (95% CI 9.7 to 17.1), respectively. In patients with posterior circulation stroke, the predictive value of the improvement at 24 hours was similar (C-statistic 0.90)., Conclusion: Clinical improvement of patients within 24 hours of MT is a reliable and robust predictor of long-term prognosis, including patients with posterior circulation occlusions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: The potential value of rescue intraarterial thrombolysis in patients with large vessel occlusion stroke treated with mechanical thrombectomy has not been assessed in randomized trials., Aim: The CHemical OptImization of Cerebral Embolectomy trial aims to establish whether rescue intraarterial thrombolysis is more effective than placebo in improving suboptimal reperfusion scores in patients with large vessel occlusion stroke treated with mechanical thrombectomy., Sample Size Estimates: A sample size of 200 patients allocated 1:1 to intraarterial thrombolysis or intraarterial placebo will have >95% statistical power for achieving the primary outcome (5% in the control versus 60% in the treatment group) for a two-sided (5% alpha, and 5% lost to follow-up)., Methods and Design: We conducted a multicenter, randomized, placebo-controlled, double blind, phase 2b trial. Eligible patients are 18 or older with symptomatic large vessel occlusion treated with mechanical thrombectomy resulting in a modified treatment in cerebral ischemia score 2b at end of the procedure. Patients will receive 20-30 min intraarterial infusion of recombinant tissue plasminogen activator or placebo (0.5 mg/ml, maximum dose limit 22.5 mg)., Study Outcome(s): The primary outcome is the proportion of patients with an improved modified treatment in cerebral ischemia score 10 min after the end of the study treatment. Secondary outcomes include the shift analysis of the modified Rankin Scale, the infarct expansion ratio, the proportion of excellent outcome (modified Rankin Scale 0-1), the proportion of infarct expansion, and the infarction volume. Mortality and symptomatic intracerebral bleeding will be assessed., Discussion: The study will provide evidence whether rescue intraarterial thrombolysis improves brain reperfusion in patients with large vessel occlusion stroke and incomplete reperfusion (modified treatment in cerebral ischemia 2b) at the end of mechanical thrombectomy.

About half of acute stroke patients treated with mechanical thrombectomy (MT) do not show clinical improvement despite successful recanalization. Early arterial reocclusion (EAR) may be one of the causes that explain this phenomenon. We aimed to analyze the incidence and clinico-radiological correlations of EAR after successful MT. A consecutive series of patients treated with MT between 2010 and 2018 at a single-center included in a prospective registry was retrospectively reviewed. Specific inclusion criteria for the analysis were (1) successful recanalization after MT and (2) availability of pretreatment CT perfusion and follow-up MRI. EAR was evaluated in the follow-up MR angiography. Adjusted regression models were used to analyze the association of EAR with pretreatment variables, infarct growth, final infarct volume, and clinical outcome at 90 days (ordinal distribution of the modified Rankin Scale scores). Out of 831 MT performed, 218 (26%) patients fulfilled inclusion criteria, from whom 13 (6%) suffered EAR. In multivariate analysis controlled by confounders, EAR was independently associated with poor clinical outcome (aOR = 3.2, 95%CI = 1.16-9.72, p = 0.039), greater final infarct volume (aOR = 3.8, 95%CI = 1.93-7.49, p < 0.001), and increased infarct growth (aOR = 8.5, CI95% = 2.04-34.70, p = 0.003). According to mediation analyses, the association between EAR and poor clinical outcome was mainly explained through its effects on final infarct volume and infarct growth. Additionally, EAR was associated with non-cardioembolic etiology (adjusted Odds Ratio (aOR) = 10.1, 95%CI = 1.25-81.35, p = 0.030) and longer procedural time (aOR = 2.6, 95%CI = 1.31-5.40, p = 0.007). Although uncommon, EAR hampers the benefits of successful recanalization after MT resulting in increased infarct growth and larger final lesions.

Background and Aims: Emergent stent placement may be required during neurothrombectomy. Our aim was to investigate the incidence, predictors and clinical relevance of early extracranial carotid stent occlusion following neurothrombectomy., Methods: We retrospectively analyzed a cohort of 761 consecutive neurothrombectomies performed at our center between May 2010 and August 2018, from whom a total of 106 patients had acute internal carotid artery occlusions. Early stent occlusion was defined as complete vessel occlusion within 24 h of neurothrombectomy. Clinical outcome was evaluated at day 90 with the modified Rankin Score scale (mRS). Pretreatment, procedural and outcome variables were recorded and analyzed using logistic regression., Results: Carotid stenting was performed in 99 (13%) patients. Of those, 22 (22%) had early stent occlusion at follow-up. Stent occlusion was associated with a lower use of post-stenting angioplasty [adjusted OR (aOR) = 11.2, 95%CI = 2.49-50.78, p = 0.002)], increased residual intrastent stenosis (aOR = 2.1, 95%CI = 1.38-3.06, p < 0.001) and unsuccesful intracranial recanalization (modified TICI score 0-2a) (aOR = 13.5, 95%CI = 1.97-92.24, p = 0.008). Stent occlusion was associated with poor clinical outcome at day 90 (poorer mRS shift, aOR = 3.9, 95%CI = 1.3-11.3, p = 0.014; mRS>2, aOR = 6.3, 95%CI = 1.8-22.7, p = 0.005), and with an increased rate of symptomatic intracranial hemorrhage at 24 h (14% versus 1%, p = 0.033)., Conclusions: Early carotid stent occlusion occurred in one out of five neurothrombectomies and was associated with periprocedural factors that included increased residual intrastent stenosis, a lower use of post-stenting angioplasty and unsuccessful intracranial recanalization. Further investigation is warranted for the evaluation of strategies aimed to prevent carotid stent occlusion., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Hemichorea and other hyperkinetic movement disorders are a rare presentation of stroke, usually secondary to deep infarctions affecting the basal ganglia and the thalamus. Chorea can also result from lesions limited to the cortex, as shown in recent reports. Still, the pathophysiology of this form of cortical stroke-related chorea remains unknown. We report 4 cases of acute ischemic cortical strokes presenting as hemichorea, with the infarction being limited to the parietal and insular cortex in perfusion computed tomography scans and magnetic resonance imaging. These cases suggest potential dysfunction of pathways connecting these cortical regions with the basal ganglia., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: Reliable recognition of large vessel occlusion (LVO) on noncontrast computed tomography (NCCT) may accelerate identification of endovascular treatment candidates. We aim to validate a machine learning algorithm (MethinksLVO) to identify LVO on NCCT., Methods: Patients with suspected acute stroke who underwent NCCT and computed tomography angiography (CTA) were included. Software detection of LVO (MethinksLVO) on NCCT was tested against the CTA readings of 2 experienced radiologists (NR-CTA). We used a deep learning algorithm to identify clot signs on NCCT. The software image output trained a binary classifier to determine LVO on NCCT. We studied software accuracy when adding National Institutes of Health Stroke Scale and time from onset to the model (MethinksLVO+)., Results: From 1453 patients, 823 (57%) had LVO by NR-CTA. The area under the curve for the identification of LVO with MethinksLVO was 0.87 (sensitivity: 83%, specificity: 71%, positive predictive value: 79%, negative predictive value: 76%) and improved to 0.91 with MethinksLVO+ (sensitivity: 83%, specificity: 85%, positive predictive value: 88%, negative predictive value: 79%)., Conclusions: In patients with suspected acute stroke, MethinksLVO software can rapidly and reliably predict LVO. MethinksLVO could reduce the need to perform CTA, generate alarms, and increase the efficiency of patient transfers in stroke networks.

Objective: The rate of progression of the ischemic lesion is variable in patients with stroke. We tested the hypothesis that the tissue saving effect of mechanical thrombectomy (MT) is greater in fast progressors., Methods: A single-center cohort of consecutive patients (n=242) with occlusions of the terminal internal carotid or M1 segment of the middle cerebral artery treated with MT (n=195) or best medical treatment (n=47), known time from onset, and full imaging (baseline CT perfusion and follow-up MRI) available was studied. The estimated infarct progression rate (eIPR) was calculated at baseline and patients were categorized as fast/slow progressors according to the median eIPR of 4.8 mL/hour. The primary outcome measure was the interaction between eIPR category and MT on infarct growth. The secondary outcomes assessed the effect of MT on final infarct volume and functional status in relation to the eIPR category. The safety outcomes were mortality and symptomatic intracranial hemorrhage., Results: The eIPR category had a modifying effect (Pi=0.017) of MT on infarct growth that was significantly reduced with MT only in fast progressors (median (IQR) 3.8 mL (-11-55) vs 41 mL (11-107) with medical treatment; p=0.009, adjusted p=0.045). There was also a significant interaction on final infarct volume (Pi=0.005), with a greater reduction after MT in fast progressors. The functional status improved with MT both in fast and slow progressors, with no significant modifying effect of eIPR category (Pi=0.201). There were also no significant interactions on safety outcomes., Conclusion: MT in stroke patients with large vessel occlusion limits infarct growth more significantly in fast progressors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose- The clinical course in patients with ischemic stroke treated with mechanical thrombectomy (MT) is heterogeneous. We aimed to study the relevance of the timing of clinical improvement in the prediction of long-term outcome in patients treated with MT. Methods- We studied a cohort of 423 patients with anterior circulation stroke treated with MT, of whom 334 patients (79.0%) achieved good outcome (modified Rankin Scale score of 0-2 at 90-day follow-up). National Institutes of Health Stroke Scale scores were assessed before MT, at the end of MT (d0), at day 1 (d1), and at day 7 or discharge (d7). We explored the predictive value for good outcome of different cutoffs based on absolute and percentage changes in the National Institutes of Health Stroke Scale at each assessment (d0, d1, and d7) and selected the corresponding most informative cutoffs to define substantial clinical improvement (SCI) over time. Then, we classified patients in SCI subgroups according to the delay from MT to SCI (SCI-d0, SCI-d1, and SCI-d7) and analyzed their adjusted odds ratio for good outcome compared with patients not presenting SCI (no-SCI). Additionally, we identified the independent factors predicting SCI-d0 in multivariate models. Results- The most informative cutoffs were 30% at d0, 40% at d1, and 70% at d7. The adjusted odds ratios (95% CI) for good outcome were 47.4 (22.1-101.7, n=172) for SCI-d0, 27.7 (11.8-65.0, n=76) for SCI-d1, and 12.6 for SCI-d7 (95% CI, 3.8-41.4, n=17) compared with no-SCI (n=158). The independent factors predicting SCI-d0 were successful reperfusion (odds ratio, 25.79; 95% CI, 12.92-51.47) and shorter time to treatment (odds ratio per hour 0.90; 95% CI, 0.85-0.96). Conclusions- Shorter delay to clinical improvement is strongly related to better chances of a long-term good outcome, and an improvement >30% in National Institutes of Health Stroke Scale score at the end of MT represents a reliable prognostic marker for clinicians and also for clinical research.

Background: Collateral circulation may modify the effect of neuroprotective therapies. We report a post hoc analysis of the URICO-ICTUS trial (NCT00860366) assessing the modifying treatment effect of pretreatment collaterals on clinical and radiological outcomes in patients with large-vessel acute ischemic stroke receiving uric acid therapy or placebo., Methods: URICO-ICTUS was a randomized clinical trial where 411 alteplase-treated patients also received uric acid 1,000 mg (n = 211) or placebo (n = 200) before the end of alteplase infusion. Herein, we included a nested study of 84 patients (placebo = 40, uric acid = 44) who had a pretreatment CT-angiography (CTA) showing a proximal arterial occlusion in the carotid territory. Excellent collaterals were defined as 100% collateral supply on pretreatment CTA. Regression models assessed the interaction between therapy (uric acid/placebo) and collaterals on the main outcome (ordinal modified Rankin Scale [mRS] shift at 90 days)., Results: Overall, excellent collaterals were associated with improved outcome. There was a significant interaction between therapy and pretreatment collaterals (p interaction = 0.02) for the prediction of improved mRS shift. The largest treatment contrast in favor of uric acid was found in patients with excellent collaterals (adjusted OR 9.2; 95% CI 1.23-68.6; p = 0.03)., Conclusions: Collectively, the study found that collaterals were associated with the neuroprotective effect of uric acid therapy highlighting the importance of assessing collateral status in neuroprotection trials., (© 2019 S. Karger AG, Basel.)

Intravenous thrombolysis is contraindicated in acute ischemic stroke secondary to infective endocarditis. We report our initial experience in 6 cases of proximal vessel occlusion treated with mechanical thrombectomy, which was safe (no bleeding) and effective (significant early neurological improvement) and might be useful in this clinical setting.

Background: General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care., Methods: For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered., Findings: Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1·52, 95% CI 1·09-2·11, p=0·014) and in those who did not have GA (adjusted cOR 2·33, 95% CI 1·75-3·10, p<0·0001) versus standard care. However, outcomes were significantly better for patients who did not receive GA versus those who received GA (covariate-adjusted cOR 1·53, 95% CI 1·14-2·04, p=0·0044). The risk of bias and variability between studies was assessed to be low., Interpretation: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons., Funding: Medtronic., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background Numerous neuroprotective drugs have failed to show benefit in the treatment of acute ischemic stroke, making the search for new treatments imperative. Uric acid is an endogenous antioxidant making it a drug candidate to improve stroke outcomes. Aim To report the effects of uric acid therapy in stroke patients receiving intravenous thrombolysis and mechanical thrombectomy. Methods Forty-five patients with proximal vessel occlusions enrolled in the URICO-ICTUS trial received intravenous recombinant tissue plasminogen activator within 4.5 h after stroke onset and randomized to intravenous 1000 mg uric acid or placebo (NCT00860366). These patients also received mechanical thrombectomy because a brain computed tomogaphy angiography confirmed the lack of proximal recanalization at the end of systemic thrombolysis. The primary outcome was good functional outcome at 90 days (modified Rankin Score 0-2). Safety outcomes included mortality, symptomatic intracerebral bleeding, and gout attacks. Results The rate of successful revascularization was >80% in the uric acid and the placebo groups but good functional outcome was observed in 16 out of 24 (67%) patients treated with uric acid and 10 out of 21 (48%) treated with placebo (adjusted Odds Ratio, 6.12 (95% CI 1.08-34.56)). Mortality was observed in two out of 24 (8.3%) patients treated with uric acid and one out of 21 (4.8%) treated with placebo (adjusted Odds Ratio, 3.74 (95% CI 0.06-226.29)). Symptomatic cerebral bleeding and gout attacks were similar in both groups. Conclusions Uric acid therapy was safe and improved stroke outcomes in stroke patients receiving intravenous thrombolysis followed by thrombectomy. Validation of this simple strategy in a larger trial is urgent.

A 29-year-old male patient with aphasia and mild weakness of the right arm arrived at the emergency room 4 hours after symptom onset. The computed tomography perfusion showed a typical delay in the time-based maps in the left occipital lobe and another hyperperfused area in the left frontal lobe. The follow-up magnetic resonance imaging confirmed cortical ischemic lesions in both areas. This case shows that besides hypoperfusion, hyperperfusion can also be found in the first stages of acute stroke, and it is highly suggestive of established ischemic lesions., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Less than half of acute ischemic stroke patients treated with mechanical thrombectomy obtain permanent clinical benefits. Consequently, there is an urgent need to identify mechanisms implicated in the limited efficacy of early reperfusion. We evaluated the predictors and prognostic significance of vessel wall permeability impairment and its association with blood-cerebrospinal fluid barrier (BCSFB) disruption after acute stroke treated with thrombectomy., Methods: A prospective cohort of acute stroke patients treated with stent retrievers was analyzed. Vessel wall permeability impairment was identified as gadolinium vessel wall enhancement (GVE) in a 24- to 48-hour follow-up contrast-enhanced magnetic resonance imaging, and severe BCSFB disruption was defined as subarachnoid hemorrhage or gadolinium sulcal enhancement (present across >10 slices). Infarct volume was evaluated in follow-up magnetic resonance imaging, and clinical outcome was evaluated with the modified Rankin Scale at day 90., Results: A total of 60 patients (median National Institutes of Health Stroke Scale score, 18) were analyzed, of whom 28 (47%) received intravenous alteplase before mechanical thrombectomy. Overall, 34 (57%) patients had GVE and 27 (45%) had severe BCSFB disruption. GVE was significantly associated with alteplase use before thrombectomy and with more stent retriever passes, along with the presence of severe BCSFB disruption. GVE was associated with poor clinical outcome, and both GVE and severe BCSFB disruption were associated with increased final infarct volume., Conclusions: These findings may support the clinical relevance of direct vessel damage and BCSFB disruption after acute stroke and reinforce the need for further improvements in reperfusion strategies. Further validation in larger cohorts of patients is warranted., (© 2017 American Heart Association, Inc.)

Background and Purpose: Identification of neuroprotective therapies in acute ischemic stroke is imperative. We report a predefined analysis of the URICO-ICTUS trial (Efficacy Study of Combined Treatment With Uric Acid and r-tPA in Acute Ischemic Stroke) assessing the efficacy of uric acid (UA) compared with placebo to prevent early ischemic worsening (EIW) and the relevance of collateral circulation., Methods: URICO-ICTUS was a double-blind, placebo-controlled, phase 2b trial where a total of 411 patients treated with alteplase within 4.5 hours of stroke onset were randomized (1:1) to receive UA 1000 mg (n=211) or placebo (n=200) before the end of alteplase infusion. EIW defined an increment ≥4 points in the National Institutes of Health Stroke Scale score within 72 hours of treatment in the absence of hemorrhage or recurrent stroke. Logistic regression models assessed the interaction between therapy and the collateral circulation in 112 patients who had a pretreatment computed tomographic angiography., Results: EIW occurred in 2 of 149 (1%) patients with good outcome and 23 of 262 (9%) patients with poor outcome (χ 2 ; P=0.002). EIW occurred in 7 of 204 (3%) patients treated with UA and in 18 of 200 (9%) patients treated with placebo (χ 2 ; P=0.01). There was a significant interaction between the efficacy of UA to prevent EIW and collaterals (P=0.029), with lower incidence in patients with good collaterals treated with UA compared with placebo (2% versus 15%, respectively; P=0.048)., Conclusions: UA therapy may prevent EIW after acute stroke in thrombolysed patients. Optimal access of UA to its molecular targets through appropriate collaterals may modify the magnitude of the neuroprotective effect., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00860366., (© 2016 American Heart Association, Inc.)

Background and Purpose: A progressive decline in the odds of favorable outcome as time to reperfusion increases is well known. However, the impact of specific workflow intervals is not clear., Methods: We studied the mechanical thrombectomy group (n=103) of the prospective, randomized REVASCAT (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset) trial. We defined 3 workflow metrics: time from symptom onset to reperfusion (OTR), time from symptom onset to computed tomography, and time from computed tomography (CT) to reperfusion. Clinical characteristics, core laboratory-evaluated Alberta Stroke Program Early CT Scores (ASPECTS) and 90-day outcome data were analyzed. The effect of time on favorable outcome (modified Rankin scale, 0-2) was described via adjusted odds ratios (ORs) for every 30-minute delay., Results: Median admission National Institutes of Health Stroke Scale was 17.0 (14.0-20.0), reperfusion rate was 66%, and rate of favorable outcome was 43.7%. Mean (SD) workflow times were as follows: OTR: 342 (107) minute, onset to CT: 204 (93) minute, and CT to reperfusion: 138 (56) minute. Longer OTR time was associated with a reduced likelihood of good outcome (OR for 30-minute delay, 0.74; 95% confidence interval [CI], 0.59-0.93). The onset to CT time did not show a significant association with clinical outcome (OR, 0.87; 95% CI, 0.67-1.12), whereas the CT to reperfusion interval showed a negative association with favorable outcome (OR, 0.72; 95% CI, 0.54-0.95). A similar subgroup analysis according to admission ASPECTS showed this relationship for OTR time in ASPECTS<8 patients (OR, 0.56; 95% CI, 0.35-0.9) but not in ASPECTS≥8 (OR, 0.99; 95% CI, 0.68-1.44)., Conclusions: Time to reperfusion is negatively associated with favorable outcome, being CT to reperfusion, as opposed to onset to CT, the main determinant of this association. In addition, OTR was strongly associated to outcome in patients with low ASPECTS scores but not in patients with high ASPECTS scores., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379., (© 2016 American Heart Association, Inc.)

Acute stroke induces a local inflammatory reaction causing leukocyte infiltration. Circulating monocytes are recruited to the ischemic brain and become tissue macrophages morphologically indistinguishable from reactive microglia. However, monocytes are a heterogeneous population of cells with different functions. Herein, we investigated the infiltration and fate of the monocyte subsets in a mouse model of focal brain ischemia by permanent occlusion of the distal portion of the middle cerebral artery. We separated two main subtypes of CD11b(hi) monocytes according to their expression of the surface markers Ly6C and CD43. Using adoptive transfer of reporter monocytes and monocyte depletion, we identified the pro-inflammatory Ly6C(hi)CD43(lo)CCR2(+) subset as the predominant monocytes recruited to the ischemic tissue. Monocytes were seen in the leptomeninges from where they entered the cortex along the penetrating arterioles. Four days post-ischemia, they had invaded the infarcted core, where they were often located adjacent to blood vessels. At this time, Iba-1(-) and Iba-1(+) cells in the ischemic tissue incorporated BrdU, but BrdU incorporation was rare in the reporter monocytes. The monocyte phenotype progressively changed by down-regulating Ly6C, up-regulating F4/80, expressing low or intermediate levels of Iba-1, and developing macrophage morphology. Moreover, monocytes progressively acquired the expression of typical markers of alternatively activated macrophages, like arginase-1 and YM-1. Collectively, the results show that stroke mobilized immature pro-inflammatory Ly6C(hi)CD43(lo) monocytes that acutely infiltrated the ischemic tissue reaching the core of the lesion. Monocytes differentiated to macrophages with features of alternative activation suggesting possible roles in tissue repair during the sub-acute phase of stroke., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Purpose: It is unknown whether women and men with acute ischemic stroke respond similar to an antioxidant regimen administered in combination with thrombolysis. Here, we investigated the independent effect of sex on the response to uric acid (UA) therapy in patients with acute stroke treated with alteplase., Methods: In the Efficacy Study of Combined Treatment With Uric Acid and rtPA in Acute Ischemic Stroke (URICO-ICTUS) trial, 206 women and 205 men were randomized to UA 1000 mg or placebo. In this reanalysis of the trial, the primary outcome was the rate of excellent outcome at 90 days (modified Rankin Scale, 0-1, or 2, if premorbid score of 2) in women and men using regression models adjusted for confounders associated with sex. The interaction of UA levels by treatment on infarct growth was assessed in selected patients., Results: Excellent outcome occurred in 47 of 111 (42%) women treated with UA, and 28 of 95 (29%) treated with placebo, and in 36 of 100 (36%) men treated with UA and 38 of 105 (34%) treated with placebo. Treatment and sex interacted significantly with excellent outcome (P=0.045). Thus, UA therapy doubled the effect of placebo to attain an excellent outcome in women (odd ratio [95% confidence interval], 2.088 [1.050-4.150]; P=0.036), but not in men (odd ratio [95% confidence interval], 0.999 [0.516-1.934]; P=0.997). The interactions between treatment and serum UA levels (P<0.001) or allantoin/UA ratio (P<0.001) on infarct growth were significant only in women., Conclusions: In women with acute ischemic stroke treated with alteplase, the administration of UA reduced infarct growth in selected patients and was better than placebo to reach excellent outcome., Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00860366., (© 2015 American Heart Association, Inc.)

Background and Purpose: Computed tomographic (CT) high attenuation (HA) areas after endovascular therapy for acute ischemic stroke are a common finding indicative of blood-brain barrier disruption. Dual-energy CT allows an accurate differentiation between HA areas related to contrast staining (CS) or to brain hemorrhage (BH). We sought to evaluate the prognostic significance of the presence of CS and BH after endovascular therapy., Methods: A prospective cohort of 132 patients treated with endovascular therapy was analyzed. According to dual-energy CT findings, patients were classified into 3 groups: no HA areas (n=53), CS (n=32), and BH (n=47). The rate of new hemorrhagic transformations was recorded at follow-up neuroimaging. Clinical outcome was evaluated at 90 days with the modified Rankin Scale (poor outcome, 3-6)., Results: Poor outcome was associated with the presence of CS (odds ratio [OR], 11.3; 95% confidence interval, 3.34-38.95) and BH (OR, 10.4; 95% confidence interval, 3.42-31.68). The rate of poor outcome despite complete recanalization was also significantly higher in CS (OR, 9.7; 95% confidence interval, 2.55-37.18) and BH (OR, 15.1; 95% confidence interval, 3.85-59.35) groups, compared with the no-HA group. Patients with CS disclosed a higher incidence of delayed hemorrhagic transformation at follow-up (OR, 4.5; 95% confidence interval, 1.22-16.37) compared with no-HA patients., Conclusions: Blood-brain barrier disruption, defined as CS and BH on dual-energy CT, was associated with poor clinical outcomes in patients with stroke treated with endovascular therapies. Moreover, isolated CS was associated with delayed hemorrhagic transformation. These results support the clinical relevance of blood-brain barrier disruption in acute stroke., (© 2015 American Heart Association, Inc.)

Neutrophils are rapidly recruited in response to local tissue infection or inflammation. Stroke triggers a strong inflammatory reaction but the relevance of neutrophils in the ischemic brain is not fully understood, particularly in the absence of reperfusion. We investigated brain neutrophil recruitment in two murine models of permanent ischemia induced by either cauterization of the distal portion of the middle cerebral artery (c-MCAo) or intraluminal MCA occlusion (il-MCAo), and three fatal cases of human ischemic stroke. Flow cytometry analyses revealed progressive neutrophil recruitment after c-MCAo, lesser neutrophil recruitment following il-MCAo, and absence of neutrophils after sham operation. Confocal microscopy identified neutrophils in the leptomeninges from 6 h after the occlusion, in the cortical basal lamina and cortical Virchow-Robin spaces from 15 h, and also in the cortical brain parenchyma at 24 h. Neutrophils showed signs of activation including histone-3 citrullination, chromatin decondensation, and extracellular projection of DNA and histones suggestive of extracellular trap formation. Perivascular neutrophils were identified within the entire cortical infarction following c-MCAo. After il-MCAo, neutrophils prevailed in the margins but not the center of the cortical infarct, and were intraluminal and less abundant in the striatum. The lack of collaterals to the striatum and a collapsed pial anastomotic network due to brain edema in large hemispheric infarctions could impair neutrophil trafficking in this model. Neutrophil extravasation at the leptomeninges was also detected in the human tissue. We concluded that neutrophils extravasate from the leptomeningeal vessels and can eventually reach the brain in experimental animal models and humans with prolonged arterial occlusion.

Background and Purpose: We sought to explore the safety and efficacy of the new TREVO stent-like retriever in consecutive patients with acute stroke., Methods: We conducted a prospective, single-center study of 60 patients (mean age, 71.3 years; male 47%) with stroke lasting <8 hours in the anterior circulation (n=54) or <12 hours in the vertebrobasilar circulation (n=6) treated if CT perfusion/CT angiography confirmed a large artery occlusion, ruled out a malignant profile, or showed target mismatch if symptoms >4.5 hours. Successful recanalization (Thrombolysis In Cerebral Infarction 2b-3), good outcome (modified Rankin Scale score 0-2) and mortality at Day 90, device-related complications, and symptomatic hemorrhage (parenchymal hematoma Type 1 or parenchymal hematoma Type 2 and National Institutes of Health Stroke Scale score increment ≥ 4 points) were prospectively assessed., Results: Median (interquartile range) National Institutes of Health Stroke Scale score on admission was 18 (12-22). The median (interquartile range) time from stroke onset to groin puncture was 210 (173-296) minutes. Successful revascularization was obtained in 44 (73.3%) of the cases when only the TREVO device was used and in 52 (86.7%) when other devices or additional intra-arterial tissue-type plasminogen activator were also required. The median time (interquartile range) of the procedure was 80 (45-114) minutes. Good outcome was achieved in 27 (45%) of the patients and the mortality rate was 28.3%. Seven patients (11.7%) presented a symptomatic intracranial hemorrhage. No other major complications were detected., Conclusions: The TREVO device was reasonably safe and effective in patients with severe stroke. These results support further investigation of the TREVO device in multicentric registries and randomized clinical trials.

Background: The complement system is a major effector of innate immunity that has been involved in stroke brain damage. Complement activation occurs through the classical, alternative and lectin pathways. The latter is initiated by mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs). Here we investigated whether the lectin pathway contributes to stroke outcome in mice and humans., Methodology/principal Findings: Focal cerebral ischemia/reperfusion in MBL-null mice induced smaller infarctions, better functional outcome, and diminished C3 deposition and neutrophil infiltration than in wild-type mice. Accordingly, reconstitution of MBL-null mice with recombinant human MBL (rhMBL) enhanced brain damage. In order to investigate the clinical relevance of these experimental observations, a study of MBL2 and MASP-2 gene polymorphism rendering the lectin pathway dysfunctional was performed in 135 stroke patients. In logistic regression adjusted for age, gender and initial stroke severity, unfavourable outcome at 3 months was associated with MBL-sufficient genotype (OR 10.85, p = 0.008) and circulating MBL levels (OR 1.29, p = 0.04). Individuals carrying MBL-low genotypes (17.8%) had lower C3, C4, and CRP levels, and the proinflammatory cytokine profile was attenuated versus MBL-sufficient genotypes., Conclusions/significance: In conclusion, genetically defined MBL-deficiency is associated with a better outcome after acute stroke in mice and humans.

Background and Purpose: Infection after experimental focal ischemia may result from brain-induced immunodepression, but it is unsettled whether a similar syndrome occurs in human stroke., Summary of Review: Many patients develop infections shortly after acute stroke regardless of optimal management. Mortality is higher in these patients and the severity of stroke is the strongest determinant of the infectious risk. However, it is controversial whether infections promote neurological worsening or alternatively represent a marker of severe disease. The brain and the immune system are functionally linked through neural and humoral pathways, and decreased immune competence with higher incidence of infections has been demonstrated in several acute neurological conditions. In experimental brain ischemia, infections are associated with the activation of the autonomous nervous system and neuroendocrine pathways, which increase the strength of anti-inflammatory signals. A strong cytokine-mediated anti-inflammatory response was recently observed in stroke patients at higher risk of infection, although infection could not demonstrate an independent association with the progression of the symptoms., Conclusions: The appearance of infection in patients with acute stroke obeys in part to immunological mechanisms triggered by acute brain injury. An excessive anti-inflammatory response is a key facilitating factor for the development of infection, and it is likely that this immunological response represents an adaptive mechanism to brain ischemia. Contrarily, it is unclear whether infection contributes independently to poor outcome in human stroke. Overall, a better understanding of the cross-talk between the brain and the immune system might lead to more effective therapies in patients with acute stroke.