The blood–brain barrier (BBB) is a dynamic interface responsible for maintaining the central nervous system homeostasis. Its unique characteristics allow protecting the brain from unwanted compounds, but its impairment is involved in a vast number of pathological conditions. Disruption of the BBB and increase in its permeability are key in the development of several neurological diseases and have been extensively studied in stroke. Ischemic stroke is the most prevalent type of stroke and is characterized by a myriad of pathological events triggered by an arterial occlusion that can eventually lead to fatal outcomes such as hemorrhagic transformation (HT). BBB permeability seems to follow a multiphasic pattern throughout the different stroke stages that have been associated with distinct biological substrates. In the hyperacute stage, sudden hypoxia damages the BBB, leading to cytotoxic edema and increased permeability; in the acute stage, the neuroinflammatory response aggravates the BBB injury, leading to higher permeability and a consequent risk of HT that can be motivated by reperfusion therapy; in the subacute stage (1–3 weeks), repair mechanisms take place, especially neoangiogenesis. Immature vessels show leaky BBB, but this permeability has been associated with improved clinical recovery. In the chronic stage (>6 weeks), an increase of BBB restoration factors leads the barrier to start decreasing its permeability. Nonetheless, permeability will persist to some degree several weeks after injury. Understanding the mechanisms behind BBB dysregulation and HT pathophysiology could potentially help guide acute stroke care decisions and the development of new therapeutic targets; however, effective translation into clinical practice is still lacking. In this review, we will address the different pathological and physiological repair mechanisms involved in BBB permeability through the different stages of ischemic stroke and their role in the development of HT and stroke recovery.

IMPORTANCE The NAVIGATE ESUS randomized clinical trial found that 15 mg of rivaroxaban per day does not reduce stroke compared with aspirin in patients with embolic stroke of undetermined source (ESUS); however, it substantially reduces stroke risk in patients with atrial fibrillation (AF).OBJECTIVE To analyze whether rivaroxaban is associated with a reduction of recurrent stroke among patients with ESUS who have an increased risk of AF. DESIGN, SETTING, AND PARTICIPANTS Participants were stratified by predictors of AF, including left atrial diameter, frequency of premature atrial contractions, and HAVOC score, a validated scheme using clinical features. Treatment interactions with these predictors were assessed. Participants were enrolled between December 2014 and September 2017, and analysis began March 2018. INTERVENTION Rivaroxaban treatment vs aspirin. MAIN OUTCOMES AND MEASURES Risk of ischemic stroke.RESULTS Among 7112 patients with a mean (SD) age of 67 (9.8) years, the mean (SD) HAVOC score was 2.6 (1.8), the mean (SD) left atrial diameter was 3.8 (1.4) cm (n = 4022), and the median (interquartile range) daily frequency of premature atrial contractions was 48 (13-222). Detection of AF during follow-up increased for each tertile of HAVOC score: 2.3% (score, 0-2), 3.0% (score, 3), and 5.8% (score, >3); however, neither tertiles of the HAVOC score nor premature atrial contractions frequency impacted the association of rivaroxaban with recurrent ischemic stroke (P for interaction = .67 and .96, respectively). Atrial fibrillation annual incidence increased for each tertile of left atrial diameter (2.0%, 3.6%, and 5.2%) and for each tertile of premature atrial contractions frequency (1.3%, 2.9%, and 7.0%). Among the predefined subgroup of patients with a left atrial diameter of more than 4.6 cm (9% of overall population), the risk of ischemic stroke was lower among the rivaroxaban group (1.7% per year) compared with the aspirin group (6.5% per year) (hazard ratio, 0.26; 95% CI, 0.07-0.94; P for interaction = .02). CONCLUSIONS AND RELEVANCEThe HAVOC score, left atrial diameter, and premature atrial contraction frequency predicted subsequent clinical AF. Rivaroxaban was associated with a reduced risk of recurrent stroke among patients with ESUS and moderate or severe left atrial enlargement; however, this needs to be independently confirmed before influencing clinical practice.

Classically, the relationship between systolic BP (SBP) and clinical outcome was described as U-or J shaped, with both high and low values of BP being independent prognostic factors for poor outcome.2,3 Nonetheless, these studies did not consider the recanalization state of the affected arterial territory, which may directly influence the hemodynamic response.The main objective of this study is to determine the relationship between BP during the first 24 hours after ischemic stroke and clinical outcome in patients submitted to intravenous or intra-arterial recanalization treatments. Methods Study PopulationWe included consecutive patients with acute ischemic stroke from July 2009 to June 2015, treated with intravenous thrombolysis (IVrtPA) or intra-arterial therapies in our tertiary, university hospital in Portugal. The exclusion criteria were as follows: patients who had insufficient BP data (ie, incomplete BP readings in the first 24 hours poststroke due to patient death or early hospital transfer); unavailable information Background and Purpose-Historical stroke cohorts reported a U-or J-shaped relationship between blood pressure (BP) and clinical outcome. However, these studies predated current revascularization strategies, disregarding the recanalization state of the affected arterial territory. We aimed to investigate the relationship between BP in the first 24 hours after ischemic stroke and clinical outcome in patients submitted to intravenous or intra-arterial recanalization treatments. Methods-Consecutive patients with acute stroke treated with intravenous thrombolysis or intra-arterial therapies were enrolled in a retrospective cohort study. BP was measured on regular intervals throughout day and night during the first 24 hours after stroke onset. The mean systolic BP and diastolic BP during the first 24 hours post stroke were calculated.Recanalization was assessed at 6 hours by transcranial color-coded Doppler, angiography, or angio-computed tomography.Functional outcome was assessed at 3 months by modified Rankin Scale. Linear and quadratic multivariate regression models were performed to determine associations between BP and functional outcome for the whole population and recanalyzed and nonrecanalyzed patients. Results-We Conclusions-Systemic

T h e ne w e ngl a nd jou r na l o f m e dicine n engl j med 371;5 nejm.org july 31, 2014 478 CRT-D between patients with ischemic cardiomyopathy with NYHA class I or class II and patients with nonischemic cardiomyopathy. Hazard ratios were similar in these groups (0.66, 0.65, and 0.57, respectively), which denoted a similar effect size.We do, however, agree with the correspondents that because of sample-size limitations, more prospective data are necessary to corroborate the beneficial effects of CRT-D among patients with asymptomatic ischemic cardiomyopathy.To the Editor: Zhou et al. 1 and Navon Elkan et al. 2 (both in the March 6 issue) speculate that hematopoietic stem-cell transplantation (HSCT) or enzyme-replacement therapy may be beneficial in patients with adenosine deaminase 2 (ADA2) deficiency. We report the clinical course of two brothers with recently diagnosed ADA2 deficiency resulting from a homozygous mutation in CECR1 (p.R169Q). One sibling underwent HSCT in 2003. (CECR1 encodes the protein ADA2.)One brother presented in 1999, at 6 months of age, with livedo reticularis, hepatosplenomegaly, hypercoagulability, granulocytopenia, and complete red-cell aplasia. He underwent HSCT in 2003 for a presumed diagnosis of atypical Diamond-Blackfan anemia; the transplant was obtained from a matched unrelated donor after myeloablative conditioning. The patient showed rapid immune reconstitution, with resolution of cytopenias, skin lesions, hepatosplenomegaly, and hypercoagulability. He has had 100% donor chimerism in peripheral blood and has been not been taking medications for any of these conditions for 9 years. Serum ADA2 levels are now within the normal range for his age. A recent magnetic resonance image of the brain was negative for vasculopathic changes. HSCT corrected the CECR1 mutation in blood cells, but not in (somatic) buccal mucosa cells.This patient's younger brother presented in 2009, at 6 years of age, with hepatosplenomegaly, hypogammaglobulinemia, and profound lymphopenia. He also had unexplained fever, livedo reticularis, and stroke at the age of 10, which prompted us to sequence CECR1. Treatment with a tumor necrosis factor (TNF) inhibitor (etanercept) has stabilized his clinical condition, al-though he has persisting profound lymphopenia and low-grade inflammation. HSCT is being considered.The absence of vasculopathy and the resolution of hypercoagulability after HSCT in the older brother suggests that the correction of ADA2 blood levels reduces macrophage activation and endothelial disruption, both of which probably cause vasculitis and stroke in patients with ADA2 deficiency.

The reported associations of cerebral microbleeds with recurrent stroke and intracerebral hemorrhage have raised concerns regarding antithrombotic treatment in patients with a history of stroke and microbleeds on magnetic resonance imaging.OBJECTIVE To characterize microbleeds in embolic strokes of undetermined source (ESUS) and report interactions between microbleeds and the effects of random assignment to anticoagulant vs antiplatelet therapy.DESIGN, SETTING, AND PARTICIPANTS Subgroup analyses of the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) international, double-blind, randomized, event-driven phase 3 clinical trial. Participants were enrolled between December 2014 and September 2017 and followed up for a median of 11 months. The study setting included 459 stroke recruitment centers in 31 countries. Patients aged 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of these 7213 NAVIGATE ESUS participants, 3699 (51%) had information on cerebral microbleeds reported on their baseline clinical magnetic resonance imaging and were eligible for these analyses. Patients with a prior history of symptomatic intracerebral hemorrhage were excluded from the NAVIGATE ESUS trial.INTERVENTIONS Rivaroxaban, 15 mg, compared with aspirin, 100 mg, daily. MAIN OUTCOMES AND MEASURESThe primary outcome was recurrent stroke. Secondary outcomes were ischemic stroke, intracerebral hemorrhage, and all-cause mortality.RESULTS Microbleeds were present in 395 of 3699 participants (11%). Of patients with cerebral microbleeds, mean (SD) age was 69.5 (9.4) years, 241 were men (61%), and 201 were White (51%). Advancing age (odds ratio [OR] per year, 1.03; 95% CI, 1.01-1.04), East Asian race/ethnicity (OR, 1.57; 95% CI, 1.04-2.37), hypertension (OR, 2.20; 95% CI,, multiterritorial infarcts (OR, 1.95; 95% CI, 1.42-2.67), chronic infarcts (OR, 1.78; 95% CI, 1.42-2.23), and occult intracerebral hemorrhage (OR, 5.23; 95% CI, 2.76-9.90) were independently associated with microbleeds. The presence of microbleeds was associated with a 1.5-fold increased risk of recurrent stroke (hazard ratio [HR], 1.5; 95% CI, 1.0-2.3), a 4-fold risk of intracerebral hemorrhage (HR, 4.2; 95% CI, 1.3-13.9), a 2-fold risk of all-cause mortality (HR, 2.1; 95% CI, 1.1-4.3), and strictly lobar microbleeds with an approximately 2.5-fold risk of ischemic stroke (HR, 2.3; 95% CI, 1.3-4.3). There were no interactions between microbleeds and treatment assignments for recurrent stroke, ischemic stroke, or all-cause mortality. The HR of intracerebral hemorrhage on rivaroxaban was similar between persons with microbleeds (HR, 3.1; 95% CI, 0.3-30.0) and persons without microbleeds (HR, 3.0; 95% CI, 0.6-14.7; interaction P = .97). CONCLUSIONS AND RELEVANCEMicrobleeds mark an increased risk of recurrent stroke, ischemic stroke, intracerebral hemorrhage, and mortality in ESUS but do not appear to influence effects of rivaroxaban on clinical out...