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Background: Among the currently approved antiobesity medications, the glucagon-like-peptide-1 receptor-agonists (GLP-1 RAs) liraglutide and semaglutide, and the dual glucose-dependent-insulinotropic-polypeptide (GIP)/GLP-1 RA tirzepatide have been suggested to reduce cardiovascular-risk in overweight or obesity without diabetes. Objectives: The objective of this study was to evaluate the cardio- and neuroprotective potential of these novel agents in the nondiabetic overweight/obese adult population. Data sources and methods: A systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) was performed to estimate the risk of major adverse cardiovascular events (MACE), all-cause and cardiovascular mortality in overweight or obese adults without diabetes treated with GLP-1 or GIP/GLP-1 RAs (vs placebo). Secondary outcomes included the risk of myocardial infarction (MI) and stroke. Results: Sixteen RCTs (13 and 3 on GLP-1 RAs and tirzepatide, respectively) comprising 28,168 participants were included. GLP-1 or GIP/GLP-1 RAs reduced MACE (odds ratio (OR): 0.79; 95% confidence interval (CI): 0.71–0.89; p

Background The impact of mobile stroke units (MSUs) on outcomes in patients with large vessel occlusions eligible for endovascular thrombectomy (EVT) has yet to be characterized. Methods We completed a prespecified substudy of patients with EVT‐eligible stroke with anterior and posterior circulation large vessel occlusions on computed tomography and/or computed tomography angiography who were enrolled in BEST‐MSU (Benefits of Stroke Treatment using a Mobile Stroke Unit). Primary outcome was 90‐day utility‐weighted modified Rankin scale. Groups were compared using chi‐square or Fisher's exact tests for categorical variables, and 2‐sample t‐tests for continuous variables. Multiple logistic regression was used to assess the effect of MSU on binary outcomes after adjusting for other baseline factors. Results Of 1515 trial patients, 293 had large vessel occlusions eligible for EVT: 168 in the MSU group and 125 in the emergency medical services group. Baseline characteristics were comparable, with the exception of baseline National Institutes of Health Stroke Scale score (MSU median 19 [interquartile range 13, 23] versus emergency medical services 16 [11, 20], P = 0.002) and study site. The mean (±SD) score on the utility‐weighted modified Rankin scale at 90 days was 0.63±0.39 in MSU group and 0.51±0.41 in emergency medical services group (mean difference 0.13, 95% CI [0.03–0.22]). After adjustment, MSU had significantly higher odds of functional independence (odds ratio 2.60 [95% CI, 1.45–4.77], P = 0.002). Secondary outcomes also favored MSU: early neurologic recovery (30% improvement in National Institutes of Health Stroke Scale score at 24 hours) 68% versus 52%; adjusted odds ratio 1.98 [95% CI, 1.19–3.33]; time of tissue plasminogen activator bolus from symptom onset 65.0 minutes [50.5–92.0] versus 96.0 [79.3–130.0], P≤0.001. The groups had similar onset to arterial puncture (169.0 minutes [133.5, 210.0] versus 162.0 [135.0–207.0], P = 0.83). Conclusions In patients with EVT‐eligible large vessel occlusion stroke, MSU management was associated with better clinical outcomes compared with standard emergency medical services management. MSU management sped thrombolysis but did not expedite EVT treatment times. Future MSU processes should include efforts to capitalize on the potential of MSUs to provide earlier EVT.

Background Automatic noninvasive oscillometric blood pressure (NIBP) devices measure mean arterial pressure (MAP); systolic and diastolic blood pressure (SBP, DBP) are algorithmically derived from MAP. The most invalid NIBP measure is SBP, yet stroke practitioners use it to manage blood pressure (BP) in accordance with thrombolysis guidelines. We determined agreement between SBP, DBP, and MAP measured manually and by NIBP in patients treated with alteplase. Methods A multisite prospective observational study of NIBP and manual BP agreement was conducted in patients treated with alteplase immediately after bolus and infusion initiation using methods established in guidelines for the assessment of device agreement. Dual auscultatory stethoscopes were used by 2 investigators to ensure agreement with each manual BP variable and MAP was calculated using the standard formula for manual BP measures. Data were analyzed using Bland–Altman analyses and Lin concordance correlation coefficient. Results A total of 7 hospitals participated, collecting 5 sets of manual/NIBP BPs in 95 patients treated with alteplase (475 paired measures). Range in limits of agreement were SBP: −28.91 to 21.41 mmHg with Lin's concordance correlation coefficient 0.8; DBP: −21.0 to 19.0 mmHg with Lin's concordance correlation coefficient 0.69; and MAP: −27.5 to 16.5 mmHg with Lin's concordance correlation coefficient 0.7. There was no difference in device agreement by BP device manufacturer brand. Differences in SBP, DBP, and MAP between NIBP and manual sphygmomanometry failed to reach guideline recommendations requiring 80% of measures to fall within a 5 mmHg difference and 95% of measures to fall within a 10 mmHg difference. Conclusion NIBP devices produce significantly different BP measures then manual sphygmomanometry auscultated BP. Because NIBP devices rely on the MAP and do not directly measure SBP and DBP, definition of what constitutes safe MAP boundaries in patients treated with alteplase should be determined when automatic BP measurement is used in clinical practice.

Background We sought to determine if the National Institutes of Health Stroke Scale (NIHSS) has a greater discriminative power than Glasgow coma scale (GCS) to identify patients at risk of poor early functional outcomes and large hematoma volumes. Methods We prospectively collected clinical assessments, imaging, and outcome data in consecutive patients with intracerebral hemorrhage, and determined the ability of GCS and NIHSS to predict poor functional outcome (modified Rankin scale 3–6) and hematoma volume >30 cm3 using receiver operating characteristics analysis, C‐statistics, and the DeLong test. Results We studied 672 patients with intracerebral hemorrhage (mean age 62±14 years; 56% men; median intracerebral hemorrhage score=1, interquartile range (IQR) 0–2; median intracerebral hemorrhage volume 7 cm3, IQR 2–19) with median NIHSS of 8 (IQR 3–18) and GCS 15 (IQR 7–15). NIHSS correlated strongly to GCS (r=−0.773; P

Background Transfer times from primary stroke centers and acute stroke–ready hospitals to higher levels of care are often excessive, prompting some to suggest ambulance bypass regulations. Since barriers to rapid transfer have never been fully explored, we sought to understand stroke coordinators’ experiences with transfer of patients with hyperacute stroke from lower to higher levels of stroke centers. Methods We conducted a national focus group study with primary stroke center stroke coordinators who had recent experience overseeing transfer of a patient with hyperacute stroke to a higher‐level stroke center. Interviews were conducted using prescripted open‐ended questions; information was recorded and data were transcribed for theme identification. Results A total of 23 stroke coordinators participated representing the Northeast, Mid‐Atlantic, Southeast, Midwest, and Western United States. Findings were grouped into 3 main categories: Internal Primary Stroke Center Factors, Transport Factors, and External Comprehensive Stroke Center Factors. Within the primary stroke center group, themes slowing transfer were exclusively physician based, whereas themes emerging from the transport category were associated with poor transport company processes. Within the comprehensive stroke center category, themes were all associated with complex hospital processes and communication. Conclusion Important contributors to efficient transfer of patients with hyperacute stroke are beyond the control of stroke coordinators, requiring cross‐system collaboration and improved administrative management to resolve. Quantification of these factors is warranted to support transfer system redesign for rapid access to care for patients with stroke.

Background: Prior to the conduct of the Head Position in Stroke Trial (HeadPoST), an international survey ( n = 128) revealed equipoise for selection of head position in acute ischemic stroke. Objectives: We aimed to determine whether equipoise exists for head position in spontaneous hyperacute intracerebral hemorrhage (ICH) patients following HeadPoST. Design: This is an international, web-distributed survey focused on head positioning in hyperacute ICH patients. Methods: A survey was constructed to examine clinicians’ beliefs and practices associated with head positioning of hyperacute ICH patients. Survey items were developed with content experts, piloted, and then refined before distributing through stroke listservs, social media, and purposive snowball sampling. Data were analyzed using descriptive statistics and χ 2 test. Results: We received 181 responses representing 13 countries on four continents: 38% advanced practice providers, 32% bedside nurses, and 30% physicians; overall, participants had median 7 [interquartile range (IQR) = 3–12] years stroke experience with a median of 100 (IQR = 37.5–200) ICH admissions managed annually. Participants disagreed that HeadPoST provided ‘definitive evidence’ for head position in ICH and agreed that their ‘written admission orders include 30-degree head positioning’, with 54% citing hospital policies for this head position in hyperacute ICH. Participants were unsure whether head positioning alone could influence ICH longitudinal outcomes. Use of serial proximal clinical and technology measures during the head positioning intervention were identified by 82% as the most appropriate endpoints for future ICH head positioning trials. Conclusion: Interdisciplinary providers remain unconvinced by HeadPoST results that head position does not matter in hyperacute ICH. Future trials examining the proximal effects of head positioning on clinical stability in hyperacute ICH are warranted.

Background Mechanical thrombectomy (MT) has been shown to improve functional outcome in patients with anterior circulation strokes and emergent large‐vessel occlusion (ELVO). Despite successful recanalization, some of these patients require decompressive hemicraniectomy (DHC). We aimed to study the predictors of DHC in successfully recanalized anterior circulation ELVO patients. Methods Consecutive patients with anterior circulation ELVO treated with MT during a 6‐year period were evaluated. Only successfully recanalized patients (modified Thrombolysis in Cerebral Infarction grades 2b, 2c, or 3) after MT were included in the analysis. Baseline demographic, clinical, and procedural variables were compared between patients requiring DHC after successful recanalization versus those who did not. Results Of 453 successfully recanalized patients with ELVO, 47 who underwent DHC had higher admission blood glucose levels (170±88 versus 142±66 mg/dL; P=0.008), lower median Alberta Stroke Program Early CT Scores (9 [interquartile range, 8–10] versus 10 [interquartile range, 9–10]; P=0.002), higher prevalence of poor collaterals on pretreatment computed tomography angiogram (75% versus 26%; P

Background and Purpose Although onset-to-treatment time is associated with early clinical recovery in acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (tPA), the effect of the timing of tPA-induced recanalization on functional outcomes remains debatable. Methods We conducted a multicenter, prospective observational cohort study to determine whether early (within 1-hour from tPA-bolus) complete or partial recanalization assessed during 2-hour real-time transcranial Doppler monitoring is associated with improved outcomes in patients with proximal occlusions. Outcome events included dramatic clinical recovery (DCR) within 2 and 24-hours from tPA-bolus, 3-month mortality, favorable functional outcome (FFO) and functional independence (FI) defined as modified Rankin Scale (mRS) scores of 0–1 and 0–2 respectively. Results We enrolled 480 AIS patients (mean age 66±15 years, 60% men, baseline National Institutes of Health Stroke Scale score 15). Patients with early recanalization (53%) had significantly (jos-2019-01648P

Background and Purpose Current guidelines do not provide firm directions on atrial fibrillation (AF) screening after ischemic stroke (IS). We sought to investigate the association of implantable cardiac monitoring (ICM) duration with the yield of AF detection in IS patients. Methods We included studies reporting AF detection rates by ICM in IS patients with negative initial AF screening. We excluded studies reporting prolonged cardiac monitoring with devices other than ICM, not providing AF detection rates or monitoring duration, and reporting overlapping data for the same population. The random-effects model was used for all pooled estimates and meta-regression analyses. Results We included 28 studies (4,531 patients, mean age 65 years). In meta-regression analyses, the proportion of AF detection by ICM was independently associated with monitoring duration (coefficient=0.015; 95% confidence interval [CI], 0.005 to 0.024) and mean patient age (coefficient=0.009; 95% CI, 0.003 to 0.015). No associations were detected with other patient characteristics, including IS subtype (cryptogenic vs. embolic stroke of undetermined source) or time from IS onset to CM implantation. In subgroup analyses, significant differences (P12 and ≤24 months: 26% [95% CI, 22% to 31%]; >24 months: 34% [95% CI, 29% to 39%]). Conclusions Extended duration of ICM monitoring and increased patient age are factors that substantially increase AF detection in IS patients with initial negative AF screening.

Abstract Prior studies suggest an association between Vitamin K antagonists (VKA) and cerebral microbleeds (CMBs); less is known about nonvitamin K oral anticoagulants (NOACs). In this observational study we describe CMB profiles in a multicenter cohort of 89 anticoagulation‐related intracerebral hemorrhage (ICH) patients. CMB prevalence was 51% (52% in VKA‐ICH, 48% in NOAC‐ICH). NOAC‐ICH patients had lower median CMB count [2(IQR:1–3) vs. 7(4–11); P

Background and Purpose Although arbitrary blood pressure (BP) thresholds exist for acute ischemic stroke (AIS) patients eligible for intravenous thrombolysis (IVT), current international recommendations lack clarity on the impact of mean pre- and post-IVT BP levels on clinical outcomes. Methods Eligible studies involving IVT-treated AIS patients were identified that reported the association of mean systolic BP (SBP) or diastolic BP levels before and after IVT with the following outcomes: 3-month favorable functional outcome (modified Rankin Scale [mRS] scores of 0–1) and 3-month functional independence (mRS scores of 0–2), 3-month mortality and symptomatic intracranial hemorrhage (sICH). Unadjusted analyses of standardized mean differences and adjusted analyses of studies reporting odds ratios (ORadj) per 10 mm Hg BP increment were performed using random-effects models. Results We identified 26 studies comprising 56,513 patients. Higher pre- (P=0.02) and posttreatment (P=0.006) SBP levels were observed in patients with sICH. Patients with 3-month functional independence had lower post-treatment (P

Background: We hypothesized that autotitrating bilevel positive airway pressure (auto-BPAP) favorably affects short-term clinical outcomes in hyperacute ischemic stroke.Methods: In a multicenter, randomized, controlled trial patients with large vessel steno-occlusive stroke and clinically suspected sleep apnea were allocated to auto-BPAP or standard stroke care alone. Auto-BPAP was initiated within 24 h from stroke onset and performed over 48 h during diurnal and nocturnal sleep. Sleep apnea was assessed using cardiorespiratory polygraphy. Primary endpoint was early neurological improvement on National Institutes of Health Stroke Scale (NIHSS) score at 72 h. Safety and tolerability of BPAP, functional independence [modified Rankin Scale (mRS) 0–2], stroke recurrence, and mortality at 90 days were assessed.Results: Due to low recruitment, the trial was prematurely stopped after 24 patients had been randomized (auto-BPAP, n = 14; control, n = 10): median baseline NIHSS 13 (5.5–18), 88% large vessel occlusion, and 12% large vessel stenosis. Polygraphy confirmed sleep apnea in 64% of auto-BPAP and 88% of control patients (p = 0.34). Adherence to auto-BPAP was achieved by 9 of the 14 (64%) patients. Between auto-BPAP and control patients, no differences were observed in early neurological improvement (median NIHSS change: −2.0, IQR = 7 points vs. −0.5, IQR = 3 points), 90 days functional independence (21 vs. 30%, p = 0.67), stroke recurrence (0 vs. 20%, p = 0.16), and death (14 vs. 20%, p = 1.0). No safety concerns were identified.Conclusions: In this prematurely terminated trial, auto-BPAP was safe but did not show an effect on short-term clinical outcomes in selected ischemic stroke patients. Its tolerability, however, may be limited in hyperacute stroke care and needs to be improved before larger trials are conducted.Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT01812993.

Intravenous thrombolysis (IVT) represents the only systemic reperfusion therapy able to reverse neurological deficit in patients with acute ischemic stroke (AIS). Despite its effectiveness in patients with or without large vessel occlusion, it can be offered only to a minority of them, because of the short therapeutic window and additional contraindications derived from stringent but arbitrary inclusion and exclusion criteria used in landmark randomized controlled clinical trials. Many absolute or relative contraindications lead to disparities between the official drug label and guidelines or expert recommendations. Based on recent advances in neuroimaging and evidence from cohort studies, off-label use of IVT is increasingly incorporated into the daily practice of many stroke centers. They relate to extension of therapeutic time windows, and expansion of indications in co-existing conditions originally listed in exclusion criteria, such as use of alternative thrombolytic agents, pre-treatment with antiplatelets, anticoagulants or low molecular weight heparins. In this narrative review, we summarize recent randomized and real-world data on the safety and efficacy of off-label use of IVT for AIS. We also make some practical recommendations to stroke physicians regarding the off-label use of thrombolytic agents in complex and uncommon presentations of AIS or other conditions mimicking acute cerebral ischemia. Finally, we provide guidance on the risks and benefits of IVT in numerous AIS subgroups, where equipoise exists and guidelines and treatment practices vary.

Neurological manifestations are not uncommon during infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A clear association has been reported between cerebrovascular disease and coronavirus disease 2019 (COVID-19). However, whether this association is causal or incidental is still unknown. In this narrative review, we sought to present the possible pathophysiological mechanisms linking COVID-19 and cerebrovascular disease, describe the stroke syndromes and their prognosis and discuss several clinical, radiological, and laboratory characteristics that may aid in the prompt recognition of cerebrovascular disease during COVID-19. A systematic literature search was conducted, and relevant information was abstracted. Angiotensin-converting enzyme-2 receptor dysregulation, uncontrollable immune reaction and inflammation, coagulopathy, COVID-19-associated cardiac injury with subsequent cardio-embolism, complications due to critical illness and prolonged hospitalization can all contribute as potential etiopathogenic mechanisms leading to diverse cerebrovascular clinical manifestations. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been described in case reports and cohorts of COVID-19 patients with a prevalence ranging between 0.5% and 5%. SARS-CoV-2-positive stroke patients have higher mortality rates, worse functional outcomes at discharge and longer duration of hospitalization as compared with SARS-CoV-2-negative stroke patients in different cohort studies. Specific demographic, clinical, laboratory and radiological characteristics may be used as ‘red flags’ to alarm clinicians in recognizing COVID-19-related stroke.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China and rapidly spread worldwide, with a vast majority of confirmed cases presenting with respiratory symptoms. Potential neurological manifestations and their pathophysiological mechanisms have not been thoroughly established. In this narrative review, we sought to present the neurological manifestations associated with coronavirus disease 2019 (COVID-19). Case reports, case series, editorials, reviews, case-control and cohort studies were evaluated, and relevant information was abstracted. Various reports of neurological manifestations of previous coronavirus epidemics provide a roadmap regarding potential neurological complications of COVID-19, due to many shared characteristics between these viruses and SARS-CoV-2. Studies from the current pandemic are accumulating and report COVID-19 patients presenting with dizziness, headache, myalgias, hypogeusia and hyposmia, but also with more serious manifestations including polyneuropathy, myositis, cerebrovascular diseases, encephalitis and encephalopathy. However, discrimination between causal relationship and incidental comorbidity is often difficult. Severe COVID-19 shares common risk factors with cerebrovascular diseases, and it is currently unclear whether the infection per se represents an independent stroke risk factor. Regardless of any direct or indirect neurological manifestations, the COVID-19 pandemic has a huge impact on the management of neurological patients, whether infected or not. In particular, the majority of stroke services worldwide have been negatively influenced in terms of care delivery and fear to access healthcare services. The effect on healthcare quality in the field of other neurological diseases is additionally evaluated.

Atherosclerosis is a major cause of ischemic stroke that can be effectively prevented with appropriate lifestyle modifications and control of cardiovascular risk factors. Medical advances in recent years along with aggressive cardiovascular risk factor modifications have resulted in decreased recurrence rates of atherosclerotic stroke. Non-statin lipid-lowering molecules have recently shown clinical benefit and are recommended for very high-risk patients to reduce their risk of stroke. Aggressive hypertension treatment is crucial to reduce atherosclerotic stroke risk. Advances in antithrombotic treatments include combinations of antiplatelets and new antiplatelet agents in the acute phase post-stroke, which carries a high risk of recurrence. Intensive medical treatment has also limited the indications for carotid interventions, especially for asymptomatic disease. Intracranial atherosclerotic disease may provoke stroke through various mechanisms; it is increasingly recognized as a cause of ischemic stroke with advanced imaging and is best managed with lifestyle modifications and medical therapy. The diagnostic search for the vulnerable culprit atherosclerotic plaque is an area of intense research, from the level of the intracranial arteries to that of the aortic arch. Ultrasonography and novel magnetic resonance imaging techniques (high-resolution vessel-wall imaging) may assist in the identification of vulnerable atherosclerotic plaques as the underlying cause in cryptogenic or misdiagnosed non-atherosclerotic ischemic stroke. Vertebrobasilar atherosclerotic disease is less common than carotid artery disease; thus, high-quality data on effective prevention strategies are scarcer. However, aggressive medical treatment is also the gold standard to reduce cerebrovascular disease located in posterior circulation.

Background Recent randomized controlled clinical trials have provided solid evidence that mechanical thrombectomy (MT) coupled with best medical therapy (BMT) improve functional outcomes of acute ischemic stroke patients with large vessel occlusion compared with BMT alone. However, they provided inconclusive evidence on the benefit of MT on mortality. Methods and Results We evaluated the association of MT+BMT compared with BMT with the risk of 3‐month mortality using aggregate data from all available randomized controlled clinical trials. We also sought to identify potential predictors on the mortality risk and performed univariate meta‐regression analyses. Our literature search identified 11 eligible randomized controlled clinical trials, including a total of 2460 patients. The pooled rates of 3‐month mortality were 15% (95% CI:12%–19%) and 19% (95% CI:16%–23%), respectively, in the MT+BMT and BMT groups. In the overall analysis MT+BMT was associated with a significantly lower risk for 3‐month mortality compared with BMT (risk ratio=0.83, 95% CI:0.69–0.99; P=0.04), without heterogeneity across included studies (I2=3%, P for Cochran Q=0.41). No evidence of publication bias was present in funnel plot inspection and Egger statistical test (P=0.762). In meta‐regression analyses no moderating effect on the aforementioned association was detected with patient age (P=0.254), sex (P=0.702), admission systolic blood pressure (P=0.601), admission glucose (P=0.277), onset‐to‐groin puncture time (P=0.985), administration of intravenous alteplase before MT (P=0.804), MT under general anesthesia (P=0.735), and successful reperfusion following MT (P=0.663). Conclusions Our meta‐analysis provides evidence that MT+BMT reduces the risk of 3‐month mortality compared with BMT alone. This association appears not to be moderated by individual patient or procedural characteristics.

Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p

In 2014, the definition of embolic strokes of undetermined source (ESUS) emerged as a new clinical construct to characterize cryptogenic stroke (CS) patients with complete vascular workup to determine nonlacunar, nonatherosclerotic strokes of presumable embolic origin. NAVIGATE ESUS, the first phase III randomized-controlled, clinical trial (RCT) comparing rivaroxaban (15 mg daily) with aspirin (100 mg daily), was prematurely terminated for lack of efficacy after enrollment of 7213 patients. Except for the lack of efficacy in the primary outcome, rivaroxaban was associated with increased risk of major bleeding and hemorrhagic stroke compared with aspirin. RE-SPECT ESUS was the second phase III RCT that compared the efficacy and safety of dabigatran (110 or 150 mg, twice daily) to aspirin (100 mg daily). The results of this trial have been recently presented and showed similar efficacy and safety outcomes between dabigatran and aspirin. Indirect analyses of these trials suggest similar efficacy on the risk of ischemic stroke (IS) prevention, but higher intracranial hemorrhage risk in ESUS patients receiving rivaroxaban compared to those receiving dabigatran (indirect HR = 6.63, 95% CI: 1.38–31.76). ESUS constitute a heterogeneous group of patients with embolic cerebral infarction. Occult AF represents the underlying mechanism of cerebral ischemia in the minority of ESUS patients. Other embolic mechanisms (paradoxical embolism via patent foramen ovale, aortic plaque, nonstenosing unstable carotid plaque, etc.) may represent alternative mechanisms of cerebral embolism in ESUS, and may mandate different management than oral anticoagulation. The potential clinical utility of ESUS may be challenged since the concept failed to identify patients who would benefit from anticoagulation therapy. Compared with the former diagnosis of CS, ESUS patients required thorough investigations; more comprehensive diagnostic work-up than is requested in current ESUS diagnostic criteria may assist clinicians in uncovering the source of brain embolism in CS patients and individualize treatment approaches.

BackgroundMagnesium (Mg) has potential hemostatic properties. We sought to investigate the potential association of serum Mg levels (at baseline and at 48 hours) with outcomes in patients with acute spontaneous intracerebral hemorrhage (ICH). Methods and ResultsWe reviewed data on all patients with spontaneous ICH with available Mg levels at baseline, over a 5‐year period. Clinical and radiological outcome measures included initial hematoma volume, admission National Institutes of Health Stroke Scale and ICH scores, in‐hospital mortality, favorable functional outcome (modified Rankin Scale scores, 0–1), and functional independence (modified Rankin Scale scores, 0–2) at discharge. Our study population consisted of 299 patients with ICH (mean age, 61±13 years; mean admission serum Mg, 1.8±0.3 mg/dL). Increasing admission Mg levels strongly correlated with lower admission National Institutes of Health Stroke Scale score (Spearman's r, −0.141; P=0.015), lower ICH score (Spearman's r, −0.153; P=0.009), and lower initial hematoma volume (Spearman's r, −0.153; P=0.012). Higher admission Mg levels were documented in patients with favorable functional outcome (1.9±0.3 versus 1.8±0.3 mg/dL; P=0.025) and functional independence (1.9±0.3 versus 1.8±0.3 mg/dL; P=0.022) at discharge. No association between serum Mg levels at 48 hours and any of the outcome variables was detected. In multiple linear regression analyses, a 0.1‐mg/dL increase in admission serum Mg was independently and negatively associated with the cubed root of hematoma volume at admission (regression coefficient, −0.020; 95% confidence interval, −0.040 to −0.000; P=0.049) and admission ICH score (regression coefficient, −0.053; 95% confidence interval, −0.102 to −0.005; P=0.032). ConclusionsHigher admission Mg levels were independently related to lower admission hematoma volume and lower admission ICH score in patients with acute spontaneous ICH.

BackgroundWe sought to assess the risk of acute kidney injury (AKI) and mortality associated with intensive systolic blood pressure reduction in acute intracerebral hemorrhage. Methods and ResultsPatients with acute intracerebral hemorrhage had spontaneous cause and symptom onset within 24 hours. We excluded patients with structural causes, coagulopathy, thrombocytopenia, and preexisting end‐stage renal disease. We defined AKI using the Acute Kidney Injury Network criteria. Chronic kidney disease status was included in risk stratification and was defined by Kidney Disease Outcomes Quality Initiative staging. Maximum systolic blood pressure reduction was defined over a 12‐hour period and dichotomized using receiver operating characteristic curve analysis. Descriptive statistics were done using independent sample t tests, χ2 tests, and Mann‐Whitney U tests, whereas multivariable logistic regression analysis was used to evaluate for predictors for AKI and mortality. A total of 448 patients with intracerebral hemorrhage met inclusion criteria. Maximum systolic blood pressure reduction was dichotomized to 90 mm Hg and found to increase the risk of AKI in patients with normal renal function (odds ratio, 2.1; 95% confidence interval, 1.19–3.62; P=0.010) and chronic kidney disease (odds ratio, 3.91; 95% confidence interval, 1.26–12.15; P=0.019). The risk of AKI was not significantly different in normal renal function versus chronic kidney disease groups when adjusted for demographics, presentation characteristics, and medications associated with AKI. AKI positively predicted mortality for patients with normal renal function (odds ratio, 2.41; 95% confidence interval, 1.11–5.22; P=0.026) but not for patients with chronic kidney disease (odds ratio, 3.13; 95% confidence interval, 0.65–15.01; P=0.154). ConclusionsThese results indicate that intensive systolic blood pressure reduction with a threshold >90 mm Hg in patients with acute intracerebral hemorrhage may be an independent predictor for AKI.

Objectives: Current recommendations advocate that pretreatment with intravenous thrombolysis (IVT) should first be offered to all eligible patients with emergent large vessel occlusion (ELVO) before an endovascular thrombectomy (ET) procedure. However, there are observational data that question the safety and efficacy of IVT pretreatment in patients with ELVO. Methods: We performed a meta-analysis of the included subgroups from ET randomized controlled trials (RCTs) to evaluate the comparative efficacy between direct ET without IVT pretreatment and bridging therapy (IVT and ET) in patients with ELVO. Results: We included a total of seven RCTs, including 1764 patients with ELVO (52.8% men). Patients receiving bridging therapy (IVT followed by ET) had lower rates ( p = 0.041) of 90-day death/severe dependency (modified Rankin Scale-score of 5–6; 19.0%, 95% CI: 14.1–25.1%) compared with patients receiving only ET (31.0%, 95% CI: 21.2–42.9%). Moreover, patients receiving IVT and ET had a nonsignificant ( p = 0.389) trend towards higher 90-day functional independence rates (51.4%, 95% CI: 42.5–60.1%) compared with patients undergoing only ET (41.7%, 95% CI: 24.1–61.7%). Finally, shift-analysis uncovered a nonsignificant trend towards functional improvement at 90 days for bridging therapy over ET (cOR = 1.28, 95% CI: 0.91–1.89; p = 0.155). It should be noted that patients included in the present meta-analysis were not randomized to receive IVT, and thus the two groups (bridging therapy versus ET monotherapy) may differ in terms of baseline characteristics and, in particular, in terms of onset to groin puncture time and thus the risk of confounding bias cannot be ruled out. Conclusion: Despite the limitations and the risk of confounding bias, our findings contradict the recent notion regarding potential equality between ET and bridging therapy in ELVO patients and suggest that IVT and ET are complementary therapies that should be pursued in a parallel and noncompeting fashion.

Background and PurposeSickle cell disease (SCD) is strongly linked to stroke across all haplotypes in the pediatric population. Transcranial Doppler (TCD) ultrasound is known to identify the highest risk group in African-Americans who need to receive and stay on blood transfusions, but it is unclear if the same flow velocity cut-offs can be applied to the Iranian population. We aimed to evaluate baseline TCD findings in Iranian children with SCD and no prior strokes.MethodsChildren with genetically confirmed SCD (Arabian haplotype, homozygote) and without SCD (controls) were prospectively recruited from pediatric outpatient clinic over a period of 9 months. We performed TCD in both groups to determine flow velocities in the middle cerebral (MCA) and terminal internal carotid arteries (TICA).ResultsOf 74 screened children, 60 met the inclusion/exclusion criteria (62% female; mean age 10±4 years). Baseline characteristics did not differ between the cases and controls, except hemoglobin (Hb) which was significantly lower in the SCD group (P

Objectives: The cumulative safety and efficacy measures of percutaneous transluminal angioplasty and stenting (PTAS) for secondary stroke prevention in patients with symptomatic intracranial arterial stenosis (sICAS) have not previously been evaluated using a meta-analytical approach. Methods: We conducted a systematic review and random effects meta-analysis of all available randomized controlled trials (RCTs) evaluating the safety and efficacy of PTAS (in comparison with medical therapy) for sICAS. Results: Three RCTs (678 total patients) were included in the quantitative analysis. PTAS was associated with a higher risk of recurrent ischemic stroke in the territory of qualifying artery both within 30 days [risk ratio (RR) = 2.21, 95% confidence interval (CI) 1.10–4.43] and 1 year (RR = 1.92, 95% CI 1.10–3.36). PTAS was also related to a higher risk of any ischemic stroke within 30 days from the index event (RR = 2.08, 95% CI 1.17–3.71). The risk for intracranial hemorrhage was found to be higher in PTAS patients both within 30 days (RR = 10.60, 95% CI 1.98–56.62) and 1 year (RR = 8.15, 95% CI 1.50–44.34). The composite outcome of any stroke or death within 1 year (RR = 2.29, 95% CI 1.13–4.66) and 2 years (RR = 1.52, 95% CI 1.04–2.21) was higher in PTAS than in medical therapy. PTAS was associated with a higher risk of any stroke or death within 2 years in the sICAS subgroup located in posterior circulation (RR = 2.37, 95% CI 1.27–4.42). Conclusions: PTAS is associated with adverse early and long-term outcomes and should not be recommended in patients with sICAS. Further research to identify subgroups of patients who could also serve as candidates for future interventional trials along with efforts to reduce procedure-related complications are needed.

Background: Novel oral anticoagulants (NOACs) have shown to be both safe and effective for ischemic stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). We conducted a network meta-analysis (NMA) using published data from secondary prevention subgroups of different phase III randomized clinical trials (RCTs) comparing individual NOACs with warfarin. Methods: Eligible studies were identified by searching MEDLINE and SCOPUS and the Cochrane Central Register of Controlled Trials databases. First, we conducted a pairwise meta-analysis for each pairwise comparison, and then we performed NMA to combine direct and indirect evidence for any given pair of treatments. The comparative effects of all NOACs against warfarin were ranked with the surface under the cumulative ranking (SUCRA) curve for each outcome. Results: We identified four RCTs (including 15,240 patients) comparing individual NOACs (apixaban, dabigatran, rivaroxaban) with warfarin. Using indirect evidence, dabigatran was related to a significantly lower risk of hemorrhagic stroke compared with rivaroxaban [risk ratio (RR) 0.28; 95% confidence interval (CI) 0.11–0.75], while rivaroxaban was associated with a significantly lower risk of major gastrointestinal bleeding compared with dabigatran (RR 0.14; 95% CI 0.03–0.74). We also performed clustered ranking plot for the primary efficacy and safety endpoints to identify the treatment with the probably best benefit-to-risk ratio profile. Conclusions: The three NOACs showed differences in terms of safety and efficacy for secondary stroke prevention in NVAF. Our findings can serve only as hypothesis generation and require independent confirmation in head-to-head RCTs, owing to the sparse available evidence and increased uncertainty in both indirect effect estimates and ranking of treatments.

Background: In the USA, stable intravenous tissue plasminogen activator (IV tPA) patients have traditionally been cared for in an intensive care unit (ICU). We examined the safety of using an acuity-adaptable stroke unit (SU) to manage IV tPA patients. Methods: We conducted an observational study of consecutive patients admitted to our acuity-adaptable SU over the first 3 years of operation. Safety was assessed by symptomatic intracerebral hemorrhage (sICH) rates, systemic hemorrhage (SH) rates, tPA-related deaths, and transfers from SU to ICU; cost savings and length of stay (LOS) were determined. Results: We admitted 333 IV tPA patients, of which 302 were admitted directly to the SU. A total of 31 (10%) patients had concurrent systemic hemodynamic or pulmonary compromise warranting direct ICU admission. There were no differences in admission National Institutes of Health Stroke Scale scores between SU and ICU patients (9.0 versus 9.5, respectively). Overall sICH rate was 3.3% ( n = 10) and SH rate was 2.9 ( n = 9), with no difference between SU and ICU patients. No tPA-related deaths occurred, and no SU patients required transfer to the ICU. Estimated hospital cost savings were US$362,400 for ‘avoided’ ICU days, and hospital LOS decreased significantly ( p = 0.001) from 9.8 ± 15.6 days (median 5) in year 1, to 5.2 ± 4.8 days (median 3) by year 3. Conclusions: IV tPA patients may be safely cared for in a SU when nurses undergo extensive education to ensure clinical competence. Use of the ICU solely for monitoring may constitute significant overuse of system resources at an expense that is not associated with additional safety benefit.

Background: There are growing concerns for the side effects of dabigatran etexilate (dabigatran), including higher incidence of dyspepsia and gastrointestinal bleeding. We conducted a multicenter early implementation study to prospectively evaluate the safety, efficacy and adherence to dabigatran for secondary stroke prevention. Methods: Consecutive atrial fibrillation (AF) patients with ischemic stroke (IS) or transient ischemic attack (TIA) received dabigatran for secondary stroke prevention during their hospital stay according to American Heart Association recommendations at five tertiary care stroke centers. The study population was prospectively followed and outcomes were documented. The primary and secondary safety outcomes were major hemorrhage and all other bleeding events respectively defined according to RE-LY trial methodology. Results: A total of 78 AF patients (mean age 71 ± 9years; 54% men; 81% IS, 19% TIA; median CHADS 2 (Congestive heart failure, Hypertension, diabetes mellitus, age >75 years, prior stroke or TIA); range 2–5) score 4 were treated with dabigatran [(110mg bid (74%); 150mg bid (26%)]. During a mean follow-up period of 7 ± 5 months (range 1–18) we documented no cases of IS, TIA, intracranial hemorrhage, systemic embolism or myocardial infarction in AF patients treated with dabigatran. There were two (2.6%) major bleeding events (lower gastrointestinal bleeding) and two (2.6%) minor bleedings [hematuria ( n = 1) and rectal bleeding ( n = 1)]. Dabigatran was discontinued in 26% of the study population with high cost being the most common reason for discontinuation (50%). Discussion: Our pilot data indicate that dabigatran appears to be safe for secondary stroke prevention during the first year of implementation of this therapy. However, high cost may limit the long-term treatment of AF patients with dabigatran, leading to early discontinuation.

Background. Obstructive sleep apnea (OSA) is a common condition in patients with acute ischemic stroke and associated with early clinical deterioration and poor functional outcome. However, noninvasive ventilatory correction is hardly considered as a complementary treatment option during the treatment phase of acute ischemic stroke. Summary of Case. A 55-year-old woman with an acute middle cerebral artery (MCA) occlusion received intravenous tissue plasminogen activator (tPA) and enrolled into a thrombolytic research study. During tPA infusion, she became drowsy, developed apnea episodes, desaturated and neurologically deteriorated without recanalization, re-occlusion or intracerebral hemorrhage. Urgent noninvasive ventilatory correction with biphasic positive airway pressure (BiPAP) reversed neurological fluctuation. Her MCA completely recanalized 24 hours later. Conclusions. Noninvasive ventilatory correction should be considered more aggressively as a complementary treatment option in selected acute stroke patients. Early initiation of BiPAP can stabilize cerebral hemodynamics and may unmask the true potential of other therapies.

With majority of ischemic strokes attributable to atherothrombosis and many being predictable after transient ischemic attacks (TIA), the role of early secondary prevention with antiplatelet agents is under renewed investigation. Prior major clinical trials of various secondary stroke prevention regimens pointed to a greater efficacy of dual antiplatelet agents if initiated early from symptom onset. This paper examines data and rationale behind dual antiplatelet regimens across the completed clinical trials. The safety of dual antiplatelets approach is of concern, but it could be outweighed, at least in early management, by a greater reduction in recurrence of ischemic events since this risk is “front loaded” after minor stroke or TIA. Aspirin monotherapy, though considered standard of care, is compared to aspirin-extended release dipiridamole and its combination with clopidogrel in early-phase completed and efficacy-phase ongoing clinical trials.