Stroke in the Time of Circadian Medicine.

Time-of-day significantly influences the severity and incidence of stroke. Evidence has emerged not only for circadian governance over stroke risk factors, but also for important determinants of clinical outcome. In this review, we provide a comprehensive overview of the interplay between chronobiology and cerebrovascular disease. We discuss circadian regulation of pathophysiological mechanisms underlying stroke onset or tolerance as well as in vascular dementia. This includes cell death mechanisms, metabolism, mitochondrial function, and inflammation/immunity. Furthermore, we present clinical evidence supporting the link between disrupted circadian rhythms and increased susceptibility to stroke and dementia. We propose that circadian regulation of biochemical and physiological pathways in the brain increase susceptibility to damage after stroke in sleep and attenuate treatment effectiveness during the active phase. This review underscores the importance of considering circadian biology for understanding the pathology and treatment choice for stroke and vascular dementia and speculates that considering a patient's chronotype may be an important factor in developing precision treatment following stroke.

Magnesium Sulfate and Hematoma Expansion: An Ancillary Analysis of the FAST-MAG Randomized Trial.

BACKGROUND: Intracerebral hemorrhage (ICH) is the deadliest form of stroke. In observational studies, lower serum magnesium has been linked to more hematoma expansion (HE) and intracranial hemorrhage, implying that supplemental magnesium sulfate is a potential acute treatment for patients with ICH and could reduce HE. FAST-MAG (Field Administration of Stroke Therapy - Magnesium) was a clinical trial of magnesium sulfate started prehospital in patients with acute stroke within 2 hours of last known well enrolled. CT was not required prior to enrollment, and several hundred patients with acute ICH were enrolled. In this ancillary analysis, we assessed the effect of magnesium sulfate treatment upon HE in patients with acute ICH. METHODS: We retrospectively analyzed data that were prospectively collected in the FAST-MAG study. Patients received intravenous magnesium sulfate or matched placebo within 2 hours of onset. We compared HE among patients allocated to intravenous magnesium sulfate or placebo with a Mann-Whitney U. We used the same method to compare neurological deficit severity (National Institutes of Health Stroke Scale) and global disability (modified Rankin Scale) at 3 months. RESULTS: Among 268 patients with ICH meeting study entry criteria, mean 65.4±13/4 years, 33% were female, and 211 (79%) had a history of hypertension. Initial deficit severities were median (interquartile range) of 4 (3-5) on the Los Angeles Motor Scale in the field and National Institutes of Health Stroke Scale score of 16 (9.5-25.5) early after hospital arrival. Follow-up brain imaging was performed a median of 17.1 (11.3-22.7) hours after first scan. The magnesium and placebo groups did not statistically differ in hematoma volume on arrival, 10.1 (5.6-28.7) versus 12.4 (5.6-28.7) mL (P=0.6), or HE, 2.0 (0.1-7.4) versus 1.5 (-0.2 to 8) mL (P=0.5). There was no difference in functional outcomes (modified Rankin Scale score of 3-6), 59% versus 50% (P=0.5). CONCLUSIONS: Magnesium sulfate did not reduce HE or improve functional outcomes at 90 days. A benefit for patients with initial hypomagnesemia was not addressed. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00059332.

Association of Recent Use of Non-Vitamin K Antagonist Oral Anticoagulants With Intracranial Hemorrhage Among Patients With Acute Ischemic Stroke Treated With Alteplase.

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

The Effect of Early Treatment with Intravenous Magnesium Sulfate on the Incidence of Cardiac Comorbidities in Hospitalized Stroke Patients.

BACKGROUND: Cardiac adverse events are common among patients presenting with acute stroke and contribute to overall morbidity and mortality. Prophylactic measures for the reduction of cardiac adverse events in hospitalized stroke patients have not been well understood. We sought to investigate the effect of early initiation of high-dose intravenous magnesium sulfate on cardiac adverse events in stroke patients. METHODS: This is a secondary analysis of the prehospital Field Administration of Stroke Therapy-Magnesium (FAST-MAG) randomized phase-3 clinical trial, conducted from 2005-2013. Consecutive patients with suspected acute stroke and a serum magnesium level within 72 hours of enrollment were selected. Twenty grams of magnesium sulfate or placebo was administered in the ambulance starting with a 15-minute loading dose intravenous infusion followed by a 24-hour maintenance infusion in the hospital. RESULTS: Among 1126 patients included in the analysis of this study, 809 (71.8%) patients had ischemic stroke, 277 (24.6%) had hemorrhagic stroke, and 39 (3.5%) with stroke mimics. The mean age was 69.5 (SD13.4) and 42% were female. 565 (50.2%) received magnesium treatment, and 561 (49.8%) received placebo. 254 (22.6%) patients achieved the target, and 872 (77.4%) did not achieve the target, regardless of their treatment group. Among 1126 patients, 159 (14.1%) had at least one CAE. Treatment with magnesium was not associated with fewer cardiac adverse events. A multivariate binary logistic regression for predictors of CAEs showed a positive association of older age and frequency of CAEs (R = 1.04, 95% CI 1.03-1.06, p < 0.0001). Measures of early and 90-day outcomes did not differ significantly between the magnesium and placebo groups among patients who had CAEs. CONCLUSION: Treatment of acute stroke patients with magnesium did not result in a reduction in the number or severity of cardiac serious adverse events.

Refined Sphenopalatine Ganglion Stimulator Placement and Intensity Setting to Augment Blood Flow and Neurologic Function.

Background and Purpose- Two large, randomized trials indicated that sphenopalatine ganglion (SPG) stimulation improves final disability outcome in acute anterior circulation patients with ischemic stroke with confirmed cortical involvement. This study evaluated 2 refinements in SPG stimulation treatment technique: (1) SPG electrode placement with real-time optical tracking guidance; and (2) stimulation intensity comfortable tolerance level selection using non-noxious facial physiological markers. Methods- This study was a single, active arm trial at 4 centers, enrolling patients with anterior circulation ischemic stroke, National Institutes of Health Stroke Scale 1 to 6 including arm weakness subitem score ≥1, not receiving recanalization therapies, and within 24 hours of onset. Stimulation level was set based on ipsilateral facial tingling sensation or lacrimation. SPG stimulation effects were assessed by measuring volumetric blood flow in the ipsilateral common carotid artery by ultrasound and grasp and pinch strength in the affected hand before and during stimulation, and by change in National Institutes of Health Stroke Scale from day 1 to 7. Results- Among 50 enrolled patients, age was median 66 years (interquartile range, 60-74), 44% were female, National Institutes of Health Stroke Scale median was 5 (interquartile range, 4-5), and median onset-to-screening time was 18 hours (interquartile range, 9-20). Median implantation skin-to-skin time was 4 minutes (interquartile range, 3-7), and all 50 implants were placed correctly. Comfortable tolerance level was found based on physiological biomarkers in 96% of patients, including 86% in the optimal, low-medium intensity range. SPG stimulation significantly increased common carotid artery peak systolic and end-diastolic blood flow (44%, P<0.0001; and 52%, P<0.0001) and improved pinch strength (42%, P<0.0001) and grasp strength (26%, P<0.0001). Degree of National Institutes of Health Stroke Scale recovery by day 7 was greater than in matched historic controls, median 75% versus 50%, P=0.0003. Conclusions- SPG stimulator placement with real-time optical tracking guidance was fast and accurate, and selection of stimulation intensity levels based on non-noxious facial tingling and lacrimation was feasible in nearly all patients. SPG stimulation led to cervico-cranial blood flow augmentation and improved hand motor function. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03551093.

An injectable implant to stimulate the sphenopalatine ganglion for treatment of acute ischaemic stroke up to 24 h from onset (ImpACT-24B): an international, randomised, double-blind, sham-controlled, pivotal trial.

BACKGROUND: Sphenopalatine ganglion stimulation increased cerebral collateral blood flow, stabilised the blood-brain barrier, and reduced infarct size, in preclinical models of acute ischaemic stroke, and showed potential benefit in a pilot randomised trial in humans. The pivotal ImpACT-24B trial aimed to determine whether sphenopalatine ganglion stimulation 8-24 h after acute ischaemic stroke improved functional outcome. METHODS: ImpACT-24B is a randomised, double-blind, sham-controlled, pivotal trial done at 73 centres in 18 countries. It included patients (men aged 40-80 years and women aged 40-85 years) with anterior-circulation acute ischaemic stroke, not undergoing reperfusion therapy. Enrolled patients were randomly assigned via web-based randomisation to receive active sphenopalatine ganglion stimulation (intervention group) or sham stimulation (sham-control group) 8-24 h after stroke onset. Patients, clinical care providers, and all outcome assessors were masked to treatment allocation. The primary efficacy endpoint was the difference between active and sham groups in the proportion of patients whose 3-month level of disability improved above expectations. This endpoint was evaluated in the modified intention-to-treat (mITT) population (defined as all patients who received one active or sham treatment session) and the population with confirmed cortical involvement (CCI) and was analysed using the Hochberg multi-step procedure (significance in both populations if p<0·05 in both, and in one population if p<0·025 in that one). Safety endpoints at 3 months were all serious adverse events (SAEs), SAEs related to implant placement or removal, SAEs related to stimulation, neurological deterioration, and mortality. All patients who underwent an attempted sphenopalatine ganglion stimulator or sham stimulator placement procedure were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00826059. FINDINGS: Between June 10, 2011, and March 7, 2018, 1078 patients were enrolled and randomly assigned to either the intervention or the sham-control group. 1000 patients received at least one session of sphenopalatine ganglion stimulation or sham stimulation and entered the mITT population (481 [48%] received sphenopalatine ganglion stimulation, 519 [52%] were sham controls), among whom 520 (52%) patients had CCI on imaging. The proportion of patients in the mITT population whose 3-month disability level was better than expected was 49% (234/481) in the intervention group versus 45% (236/519) in the sham-control group (odds ratio 1·14, 95% CI 0·89-1·46; p=0·31). In the CCI population, the proportion was 50% (121/244) in the intervention group versus 40% (110/276) in the sham-control group (1·48, 1·05-2·10; p=0·0258). There was an inverse U-shaped dose-response relationship between attained sphenopalatine ganglion stimulation intensity and the primary outcome in the CCI population: the proportion with favourable outcome increased from 40% to 70% at low-midrange intensity and decreased back to 40% at high intensity stimulation (p=0·0034). There were no differences in mortality or SAEs between the intervention group (n=536) and the sham-control group (n=519) in the safety population. INTERPRETATION: Sphenopalatine ganglion stimulation is safe for patients with acute ischaemic stroke 8-24 h after onset, who are ineligible for thrombolytic therapy. Although not reaching significance, the trial's results support that, among patients with imaging evidence of cortical involvement at presentation, sphenopalatine ganglion stimulation is likely to improve functional outcome. FUNDING: BrainsGate Ltd.

The Frequency of Substantial Salvageable Penumbra in Thrombectomy-ineligible Patients with Acute Stroke.

BACKGROUND AND PURPOSE: Endovascular therapy (ET) has become the standard of care for selected patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). However, many LVO or medium vessel occlusion (MVO) patients are ineligible for ET, including some who harbor salvageable tissues. To develop complementary therapies for these patients, it is important to delineate their prevalence, clinical features, and outcomes. METHODS: In a prospectively maintained database, we reviewed consecutive AIS patients between December 2015 and September 2016. Based on the first multimodal computed tomography or magnetic resonance imaging, patients were categorized as having substantial penumbra if perfusion lesion volume (Tmax >6 seconds) exceeded ischemic core volume (relative cerebral blood flow <30% on CT perfusion or apparent diffusion coefficient <620 on diffusion weighted image) by ≥20%. RESULTS: Among 174 consecutive AIS patients presenting within 24 hours of last known well time, 29 (17%) had LVO or MVO and substantial penumbra, but were deemed ET ineligible. Among these patients, mean age was 81 (±13), 45% were female, and median National Institute of Health Stroke Scale score was 11 (interquartile range [IQR]: 5-19). The most common reasons for not pursuing ET were: distal occlusion (28%), mild neurologic deficit (16%), and temporally advanced core injury (16%). Ischemic core volume was 20 mL (±31), penumbral volume was 54 mL (±63), and mismatch ratio median was 5.6 (IQR: 2-infinite). Severe disability or death at discharge (modified Rankin scale: 4-6) occurred in 72% of the patients. CONCLUSION: Even in the modern stent retriever era, 1 in 6 AIS patients presents with substantial penumbra judged not appropriate for ET. This population may benefit from the development of alternative therapies, including collateral enhancement, neuroprotection, and thrombectomy devices deployable in distal arteries.

Folic Acid in Stroke Prevention in Countries without Mandatory Folic Acid Food Fortification: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND PURPOSE: Additional folic acid (FA) treatment appears to have a neutral effect on reducing vascular risk in countries that mandate FA fortification of food (e.g., USA and Canada). However, it is uncertain whether FA therapy reduces stroke risk in countries without FA food fortification. The purpose of this study was to comprehensively evaluate the efficacy of FA therapy on stroke prevention in countries without FA food fortification. METHODS: PubMed, EMBASE, and clinicaltrials.gov from January 1966 to August 2016 were searched to identify relevant studies. Relative risk (RR) with 95% confidence interval (CI) was used as a measure of the association between FA supplementation and risk of stroke, after pooling data across trials in a random-effects model. RESULTS: The search identified 13 randomized controlled trials (RCTs) involving treatment with FA that had enrolled 65,812 participants, all of which stroke was reported as an outcome measure. After all 13 RCTs were pooled, FA therapy versus control was associated with a lower risk of any future stroke (RR, 0.85; 95% CI, 0.77 to 0.95). FA alone or combination of FA and minimal cyanocobalamin (≤0.05 mg/day) was associated with a lower risk of future stroke (RR, 0.75; 95% CI, 0.66 to 0.86) whereas combination of FA and cyanocobalamin (≥0.4 mg/day) was not associated with a lower risk of future stroke (RR, 0.95; 95% CI, 0.86 to 1.05). CONCLUSIONS: FA supplement reduced stroke in countries without mandatory FA food fortification. The benefit was found mostly in patients receiving FA alone or combination of FA and minimal cyanocobalamin.

The American Heart Association's Get With the Guidelines (GWTG)-Stroke development and impact on stroke care.

The American Heart Association's Get With the Guidelines (GWTG)-Stroke programme has changed stroke care delivery in the USA since its establishment in 2003. GWTG is a voluntary registry and continuous quality improvement initiative that collects data on patient characteristics, hospital adherence to guidelines and inpatient outcomes. Implementation of the programme saw increased provision of evidence-based care and improved patient outcomes. This review will describe the development of the programme and discuss the impact on stroke outcomes and transformation of stroke care delivery that followed its implementation.

Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials.

BACKGROUND: In observational studies, lower serum homocysteine levels are associated with a lower incidence of cardiovascular disease (CVD). However, individual randomized controlled trials (RCTs) have yielded mixed findings regarding the efficacy of therapeutic homocysteine in lowering cardiovascular risk. Our aim was to perform an updated meta-analysis of relevant RCTs to assess the efficacy of folic acid supplementation in the prevention of CVD, coronary heart disease (CHD), and stroke. METHODS: We performed systematic search to identify RCTs reported at least one of the CVD, CHD, or stroke as outcomes. Relative risk (RR) with 95% confidence interval was used as a measure of the association between folic acid supplementation and risk of CVD, CHD, stroke, and all-cause mortality. The analysis was further stratified by factors that could affect the treatment effects. RESULTS: The systematic search identified 26 RCTs enrolling 58,804 participants. Pooling the RRs showed that folic acid supplementation was not associated with any significant change in the risk of CVD (RR 0.98, 0.95 to 1.02; p=0.36), CHD (RR 1.03, 0.98 to 1.08; p=0.23), and all-cause mortality (RR 1.00, 0.96 to 1.04; p=0.92), but was linked to a decreasing trend in stroke risk (RR 0.93, 0.86 to 1.00; p=0.05). In stratified analyses, the only heterogeneity was found for stroke risk reduction among groups with (RR 1.07, 0.92 to 1.25) vs. without (RR 0.88, 0.81 to 0.96) mandatory grain fortification (P for heterogeneity=0.03). CONCLUSIONS: This meta-analysis suggests that there might be a potentially modest benefit of folic acid supplementation in stroke prevention.

Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis.

BACKGROUND AND PURPOSE: Although a lower serum homocysteine concentration is associated with a reduced risk of stroke in epidemiologic studies, randomized, controlled trials have yielded mixed findings regarding the effect of therapeutic homocysteine lowering on stroke prevention. We performed a meta-analysis of randomized, controlled trials to assess the efficacy of folic acid supplementation in the prevention of stroke. METHODS: Salient trials were identified by formal literature search. Relative risk (RR) with 95% CI was used as a measure of the association between folic acid supplementation and risk of stroke, after pooling data across trials in a fixed-effects model. RESULTS: The search identified 13 randomized, controlled trials that had enrolled 39 005 participants for folic acid therapy to reduce homocysteine in which stroke was reported as an outcome measure. Across all trials, folic acid supplementation was associated with a trend toward mild benefit that did not reach statistical significance in reducing the risk of stroke (RR=0.93; 95% CI, 0.85-1.03; P=0.16). The RR for nonsecondary prevention trials was 0.89 (95% CI, 0.79-0.99; P=0.03). In stratified analyses, a greater beneficial effect was seen in the trials testing combination therapy of folic acid plus vitamins B6 and B12 (RR=0.83; 95% CI, 0.71-0.97; P=0.02) and in the trials that disproportionately enrolled male patients (men:women >2; RR=0.84; 95% CI, 0.74-0.94; P=0.003). CONCLUSIONS: Folic acid supplementation did not demonstrate a major effect in averting stroke. However, potential mild benefits in primary stroke prevention, especially when folate is combined with B vitamins and in male patients, merit further investigation.

A care pathway to boost influenza vaccination rates among inpatients with acute ischemic stroke and transient ischemic attack.

BACKGROUND: Although influenza-related morbidity and mortality is high, and influenza can be a trigger for recurrent stroke, only about half of stroke survivors receive yearly influenza vaccination. Identifying new avenues through which to optimize influenza vaccination among stroke survivors is a public health need. We assessed the feasibility of integrating influenza vaccination into routine inpatient stroke care. METHODS: We designed a quality improvement project incorporating influenza vaccination into care administered to hospitalized patients with ischemic stroke and transient ischemic attack that included a standardized order and discharge checklist. Data were then prospectively collected on consecutively encountered patients with ischemic stroke and transient ischemic attack admitted to a university hospital stroke service during the influenza season of October 2007 to February 2008. Successful influenza treatment use was based on optimal rather than actual treatment, with credit for optimal treatment given if an acceptable reason for nonadministration of the vaccine was documented. RESULTS: Of 103 patients admitted during the study period, 75 (73%) were eligible for influenza vaccination (mean age 72.8 years; 51% women). Among vaccination-eligible patients, 65 (87%) received optimal influenza vaccination treatment, whereas 14 (21%) actually received the vaccination during hospitalization. Leading reason (90%) for suboptimal influenza vaccination treatment among eligible patients was that the vaccination was inadvertently not ordered on admission or at discharge. CONCLUSIONS: Influenza vaccination can be systematically incorporated into stroke hospitalization and may be a viable avenue for promptly enhancing short-term clinical outcomes among hospitalized patients with stroke during peak influenza season.

Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair.

Choline precursors promote repair and growth of cell membranes and hold promise in a variety of neurologic diseases, including ischemic and hemorrhagic stroke. Citicoline, the most well-studied choline agent precursor, is widely prescribed throughout the world and recently became available in the United States as a dietary supplement. In experimental stroke models, citicoline conferred acute neuroprotection and enhanced neuroplasticity and neurorepair in the subacute period. Although individual human stroke trials have been inconclusive, meta-analysis of 10 trials enrolling 2279 patients suggests patients receiving citicoline had substantially reduced frequencies of death and disability. Reinvestigation of citicoline with modern neuroimaging and clinical trial methods are underway and will provide more definitive information regarding the mechanistic and clinical effects of this promising neurotherapeutic agent.