Reduced Stroke Severity Research Articles

Impact of vitamin D deficiency on ischemic stroke severity: Insights from a prospective study

Background. Ischemic stroke, characterized by the obstruction of blood flow to the brain, is a major cause of morbidity and mortality globally. The severity of ischemic stroke is typically assessed using the National Institutes of Health Stroke Scale (NIHSS), which predicts patient outcomes. Recent research suggests a potential link between low vitamin D levels and an increased risk of cerebrovascular events, including ischemic stroke. However, the specific relationship between vitamin D deficiency and stroke severity remains underexplored. Objective. This study aimed to investigate the correlation between serum vitamin D levels and NIHSS scores in patients with ischemic stroke to determine if vitamin D deficiency contributes to the severity of neurological deficits observed in these patients. Materials and methods. This prospective observational study was conducted at Saveetha Medical College, Chennai, involving 86 patients presenting with acute ischemic stroke. Inclusion criteria included age ≥ 18 years, confirmed diagnosis of acute ischemic stroke by neuroimaging, and presentation within 24 hours of symptom onset. Exclusion criteria included hemorrhagic stroke, conditions affecting vitamin D metabolism, and vitamin D supplementation. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured using chemiluminescence immunoassay (CLIA), and NIHSS scores were assessed within 24 hours of admission. Statistical analyses included Pearson’s correlation and multivariate linear regression to adjust for confounders. Results. The study found a significant negative correlation between serum 25(OH)D levels and NIHSS scores at admission (Pearson correlation coefficient r = -0.4081, p <0.001). Multivariate regression analysis confirmed this association (β = -0.3994, p <0.001) after adjusting for age, sex, and comorbidities. Age (β = 0.1123, p = 0.009) and comorbid conditions (β= 0.9565, p = 0.008) were also significantly associated with higher NIHSS scores. Conclusion. The study demonstrates a significant negative correlation between serum 25-hydroxyvitamin D levels and ischemic stroke severity, suggesting that higher vitamin D levels may be associated with less severe strokes. Further research is needed to explore the mechanistic pathways and therapeutic potential of vitamin D in stroke management, emphasizing the importance of maintaining adequate vitamin D levels to potentially reduce stroke severity and improve patient outcomes.

Efficacy of antiplatelet drugs combined with Argatroban in treating acute ischemic stroke and its impact on patients’ coagulation function and neurological function: a preliminary trial

This retrospective study analyzed the efficacy of combined antiplatelet therapy with Argatroban in treating acute ischemic stroke (AIS) and its impact on patients’ coagulation and neurological functions. Clinical data of 113 AIS patients admitted between January 2021 and January 2023 were retrospectively analyzed. Patients were divided into control (n = 56) and observation (n = 57) groups based on treatment interventions. The control group patients were treated with antiplatelet drugs, while the observation group patients received combination therapy with apatinib on the basis of the control group treatment. Compared to the control group, the observation group demonstrated higher clinical efficacy, improved coagulation parameters, reduced stroke severity (measured by NIHSS), enhanced daily living abilities (BI scores), and lowered inflammatory and neural injury markers post-treatment. Adverse reaction incidence was similar between groups. Combining Argatroban with antiplatelet drugs in AIS management showed superior efficacy without increasing adverse effects, suggesting its potential for clinical application.

Clinical Benefits of Oral Anticoagulants for Elderly Patients With Cardioembolic Stroke at High Bleeding Risk.

The relationship between the severity of cardioembolic stroke (CES) and oral anticoagulant (OAC) treatment before stroke onset in very elderly (≥80 years) patients with nonvalvular atrial fibrillation (NVAF) at high bleeding risk remains unknown. A total of 364 consecutive patients (≥80 years) with CES and NVAF within 48 h following stroke onset were investigated. High bleeding risk was defined as follows: Bleeding history, renal dysfunction (creatinine clearance <30 ml/min), low body weight (≤45 kg), and antiplatelet or nonsteroidal anti-inflammatory drug use. Patients were divided into two groups: High bleeding risk (n=214) and non-high bleeding risk (n=150). We assessed stroke severity and functional outcome between the two groups, and evaluated the effect of therapy with direct OAC (DOAC) on stroke severity in the high-risk group. The high-risk group had a worse modified Rankin Scale (mRS) at discharge than the non-high-risk group [median: 4 (range=2-5) vs. 3 (range=1-4); p=0.02]. Patients in the high-risk group were categorized according to OAC treatment before stroke onset: No OAC (n=148), warfarin (n=46), and DOAC (n=20). The numbers of patients with National Institutes of Health Stroke Scale score (NIHSS) ≥8 on admission in these groups were 104 (70%), 30 (65%), and 8 (40%) (p=0.03), respectively. Multivariate analysis confirmed that DOAC therapy had a lower odds ratio (OR) for severe stroke (NIHSS ≥8) on admission (OR relative to no OAC=0.22, 95% confidence interval=0.08-0.62; p=0.005) and poor functional outcome (mRS ≥4) at discharge (OR=0.31, 95% confidence interval=0.11-0.90; p=0.03). Very elderly patients with CES at high bleeding risk have unfavorable functional outcomes. DOAC administration may be associated with reduced stroke severity.

Sex Differences in Severity and Risk Factors for Ischemic Stroke in Patients With Hyperlipidemia.

This study aims to determine sex differences in poststroke hypertriglyceridemia (serum triglyceride levels ⩾ 200 mg/dl) and high stroke severity in ischemic stroke patients. Our study analyzed data from 392 males and 373 females with hypertriglyceridemia. Stroke severity on admission was measured using the National Institute of Health Stroke Scale (NIHSS) with a value ⩽7 indicating a more favorable post-stroke prognosis while a score of >7 indicates poorer post-stroke outcomes. Logistic regression models adjusted for demographic and risk factors. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for each clinical risk factor were used to predict the increasing odds of an association of a specific clinical baseline risk factor with the male or female AIS with hypertriglyceridemia. In the adjusted analysis, male patients with hypertriglyceridemia, diastolic blood pressure (OR = 1.100, 95% CI, 1.034-1.171, P = .002), and Ischemic stroke mortality (OR = 6.474, 95% CI, 3.262-12.847, P < .001) were significantly associated with increased stroke severity. In female patients with hypertriglyceridemia, age (OR = 0.920, 95% CI, 0.866-0.978, P = .008) was associated with reduced stroke severity, while ischemic stroke mortality score (OR = 37.477, 95% CI, 9.636-145.756, P < .001) was associated with increased stroke severity. Increased ischemic stroke mortality risk score was associated with increased severity in both male and female AIS patients with hypertriglyceridemia. Our findings provide information about sex differences in specific risk factors that can be managed to improve the care of male and female ischemic stroke patients with hypertriglyceridemia.

The effectiveness of direct oral anticoagulant therapy on stroke severity and functional prognosis for very elderly cardioembolic stroke patients at high bleeding risk

Abstract Background The All Nippon AF In the Elderly (ANAFIE) Registry showed that taking any DOACs was associated with reduced stroke/systemic embolisms and was not associated with increased major bleeding in very elderly (≥80 years) patients with nonvalvular atrial fibrillation (NVAF) at high bleeding risk (1). However, the relationship between very elderly (≥80 years) cardioembolic stroke (CES) patients with NVAF at high bleeding risk and direct oral anticoagulant (DOAC) therapy before stroke onset remains unknown. Methods During a 10-year period from April 2011 to March 2021, 364 CES patients (≥80 years) with NVAF admitted to our hospital within 48 hours after stroke onset and with a modified Rankin Scale (mRS) score of 0 or 1 before onset were studied. High bleeding risk was defined as having any following factors; a bleeding history, renal dysfunction (creatinine clearance &amp;lt;30 ml/min), low body weight (≤45 kg), use of antiplatelet or nonsteroidal anti-inflammatory drugs. They were divided into two groups: high bleeding risk group (H group) (n=214; median 85 years [82-88]; 144 women [67%]) and non-high bleeding risk group (Non-H group) (n=150; median 84 years [82-87]; 69 women [46%]). We compared stroke severity between the two groups and evaluated effect of DOAC treatment on stroke severity and functional outcome. Results CHADS₂ score was significantly higher in the H group than in the Non-H group (median 4 [3-4] versus 3 [2-4], p=0.002). NIHSS (National Institutes of Health Stroke Scale) score on admission and proportion of mortality (mRS:6) were relatively higher in H group than in Non-H group, but there were no significant differences among the two groups. However, mRS score at discharge was worse in the H group than in the Non-H group (median 4 [2-5] versus 3 [1-4], p=0.002). The patients in the H group were further divided into three groups based on the treatment with OAC before stroke onset: DOAC therapy (n=20), no-OAC (n=148) and warfarin therapy (n=46). The number of patients with NIHSS (≥8) on admission and mRS (≥5) at discharge were 8 (40%), 104 (70%), and 30 (65%) (p=0.03) and 3 (15%), 60 (41%) and 23 (50%) (p=0.03), respectively. Multivariate analysis confirmed that DOAC therapy had a lower odds ratio (OR) for severe stroke (NIHSS ≥8) on admission (OR to no-OAC=0.22; 95% confidence interval [CI]=0.08-0.62; p=0.005) and poor functional outcome (mRS ≥5) at discharge (OR=0.20; 95% CI=0.05-0.80; p=0.02), when no-OAC was used as a reference after adjusting for confounders. Conclusion Very elderly (≥80 years) CES patients with NVAF at high bleeding risk have severe CES than those at non-high bleeding risk. However, DOAC therapy before stroke onset may be associated with reduced stroke severity on admission and poor functional outcome at discharge in very elderly (≥80 years) CES patients with NVAF at high bleeding risk.

Abstract 18826: Atrial Fibrillation, Atrial Myopathy, and the Risk of Recurrent Stroke or Transient Ischemic Attack After Cryptogenic Stroke

Background: The annual risk of recurrent stroke after cryptogenic stroke (CS) is estimated at 3-6%. Atrial myopathy, characterized by left atrial structural and electrophysiological remodeling, is associated with atrial fibrillation (AF) and stroke. Hypothesis: Atrial myopathy is associated with an increased risk of recurrent stroke or transient ischemic attack (rCVA) within one year. Methods: Patients with interpretable echocardiograms who received an implantable loop recorder for CS at a tertiary care medical center (2015-22) were included and followed for at least 1 year. Left atrial emptying fraction (LAEF) and reservoir strain (LARS) were calculated from two-dimensional transthoracic echocardiograms. Covariates including congestive heart failure, hypertension, age, diabetes, sex, stroke/transient ischemic attack, vascular disease, carotid artery stenosis, and rCVA were ascertained by review of hospital medical records. Incident AF post CS was obtained from review of loop recorder data. Odds ratios were calculated using logistic regression models. Two-sided student's T-test was used to compare means of continuous variables. Results: 159 patients (mean age 74.4 years, 52.1% female) were followed for at least one-year post CS. Patients with rCVA had significantly lower LAEF (p=0.012) and near-significantly lower LARS (p=0.088) compared to those who did not. The odds of rCVA were 4.82 (2.22, 7.11)-fold greater in those found to have new AF independent of LAEF, LARS, and remaining covariates including carotid artery stenosis. Patients on anticoagulation at time of rCVA had trends towards reduced stroke severity (p=0.184). Conclusions: Atrial myopathy characterized by AF or reduced LA function is associated with rCVA post CS.

Effect of prior anticoagulation therapy on stroke severity and in-hospital outcomes in patients with acute ischemic stroke and atrial fibrillation

BackgroundWe aimed to assess the prevalence of prior anticoagulation therapy (warfarin or non-vitamin K antagonist oral anticoagulants [NOACs]) among patients with acute ischemic stroke (AIS) and atrial fibrillation (AF) in China and investigate the associations between prior anticoagulation therapy and initial stroke severity and in-hospital outcomes. MethodsWe included consecutive patients with AIS and known history of AF admitted to hospitals in the China Stroke Center Alliance (CSCA) program from January 2019 to July 2019. Multivariate logistic regression analyses were performed to determine the associations between prior anticoagulation therapy and initial stroke severity and in-hospital outcomes. ResultsOf 7181 patients (median [IQR] age, 75.0 [68.0–81.0] years; 48.7% men), 700 (9.7%), 129 (1.8%), and 255 (3.6%) patients received prior subtherapeutic warfarin (international normalized ratio [INR] <2.0), therapeutic warfarin (INR ≥2.0), and NOACs therapy, respectively. A total of 6499 patients had a preadmission CHA2DS2-VASc score ≥ 2, among whom 94.6% were not adequately anticoagulated. Compared with no prior anticoagulation therapy, prior NOACs therapy was associated with reduced risk of moderate or severe stroke at admission (odds ratio [95% CI], 0.64 [0.43–0.94], P = 0.023) and in-hospital mortality or discharge against medical advice (DAMA) (0.46 [0.24–0.86], P = 0.015). However, no significant association was observed between prior therapeutic warfarin therapy and stroke severity or in-hospital mortality or DAMA. ConclusionsAmong patients with AIS and AF in China, the proportion of patients with inadequate anticoagulation prior to stroke remained substantially high. Prior NOACs therapy was associated with reduced stroke severity and less in-hospital mortality or DAMA.

Post-stroke periodic estrogen receptor-beta agonist improves cognition in aged female rats

Women have a higher risk of having an ischemic stroke and increased cognitive decline after stroke as compared to men. The female sex hormone 17β-estradiol (E2) is a potent neuro- and cognitive-protective agent. Periodic E2 or estrogen receptor subtype-beta (ER-β) agonist pre-treatments every 48 h before an ischemic episode ameliorated ischemic brain damage in young ovariectomized or reproductively senescent (RS) aged female rats. The current study aims to investigate the efficacy of post-stroke ER-β agonist treatments in reducing ischemic brain damage and cognitive deficits in RS female rats. Retired breeder (9–10 months) Sprague–Dawley female rats were considered RS after remaining in constant diestrus phase for more than a month. The RS rats were exposed to transient middle cerebral artery occlusion (tMCAO) for 90 min and treated with either ER-β agonist (beta 2, 3-bis(4-hydroxyphenyl) propionitrile; DPN; 1 mg/kg; s.c.) or DMSO vehicle at 4.5 h after induction of tMCAO. Subsequently, rats were treated with either ER-β agonist or DMSO vehicle every 48 h for ten injections. Forty-eight hours after the last treatment, animals were tested for contextual fear conditioning to measure post-stroke cognitive outcome. Neurobehavioral testing, infarct volume quantification, and hippocampal neuronal survival were employed to determine severity of stroke. Periodic post-stroke ER-β agonist treatment reduced infarct volume, improved recovery of cognitive capacity by increasing freezing in contextual fear conditioning, and decreased hippocampal neuronal death in RS female rats. These data suggest that periodic post-stroke ER-β agonist treatment to reduce stroke severity and improve post-stroke cognitive outcome in menopausal women has potential for future clinical investigation.

Age Stratification in Acute Ischemic Stroke Patients with Heart Failure.

Background and Purpose. Heart failure (HF) is considered one of the major risk factors associated with the severity of acute ischemic stroke(AIS). The risk factors associated with stroke severity in AIS with a history of HF is not fully understood. Methods. A prospectively maintained database from comprehensive stroke centers in PRISMA Health Upstate Sc, was analyzed for patients with AIS and a history of HF from January 2010 to 30 June 2016. The primary outcome was risk factors associated with a National Institute of Health Stroke Scale score (NIHSS) < 7 indicating lower severity and a score ≥ 7 indicating high severity for 65−74 age category and ≥75 years age category for AIS-HF patients. Univariate analysis was used to determine risk factors based on age categories and stroke severities, while multivariable analysis was used to adjust for the effect of confounding variables. Results: A total 367 AIS-HF patients were identified in this study, 113 patients were between 65−74 years old, while 254 patients were in the ≥75 years old age category. In the adjusted analysis for 65−74 age category, history of smoking (OR = 0.105, 95% Confidence interval (CI): 0.018−0.614, p = 0.012), triglycerides (Odd ratio(OR) = 0.993, 95% (CI): 0.987−0.999, p = 0.019), and International Normalized Ratio (INR) (OR = 0.454, 95% CI: 0.196−1.050, p = 0.045), and direct admission treatment (OR = 0.355, 95% CI: 0.137−0.920, p = 0.033) were associated with a lower stroke severity, elevated heart rate (OR = 1.032, 95% CI: 1.009−1.057, p = 0.007) was associated with a higher stroke severity. For the ≥75 years old age category, previous stroke (OR = 2.297, 95% CI: 1.171−9.852, p = 0.024), peripheral vascular disease (OR = 6.784, 95% CI: 1.242−37.065, p = 0.027), heart rate (OR = 1.035, 95% CI: 1.008−1.063, p = 0.012), and systolic blood pressure (OR = 1.023, 95% CI: 1.005−1.041, p = 0.012) were associated with a higher severe stroke severity. Conclusions: After adjusting for the effect of potential confounders, more risk factors were associated with a high severity of stroke among ≥75 years old compared with 65−74 years old AIS-HF patients. Elevated heart rate was an independent risk factor associated with stroke severity in 65−74 and ≥75 years old AIS-HF patients. Elevated heart rate and other identified risk factors should be managed to reduce stroke severity among elderly AIS-HF patients.

Tonic extracellular glutamate and ischaemia: glutamate antiporter system xc - regulates anoxic depolarization in hippocampus.

In stroke, the sudden deprivation of oxygen to neurons triggers a profuse release of glutamate that induces anoxic depolarization (AD) and leads to rapid cell death. Importantly, the latency of the glutamate-driven AD event largely dictates subsequent tissue damage. Although the contribution of synaptic glutamate during ischaemia is well-studied, the role of tonic (ambient) glutamate has received far less scrutiny. The majority of tonic, non-synaptic glutamate in the brain is governed by the cystine/glutamate antiporter, system xc - . Employing hippocampal slice electrophysiology, we showed that transgenic mice lacking a functional system xc - display longer latencies to AD and altered depolarizing waves compared to wild-type mice after total oxygen deprivation. Experiments which pharmacologically inhibited system xc - , as well as those manipulating tonic glutamate levels and those antagonizing glutamate receptors, revealed that the antiporter's putative effect on ambient glutamate precipitates the ischaemic cascade. As such, the current study yields novel insight into the pathogenesis of acute stroke and may direct future therapeutic interventions. KEY POINTS: Ischaemic stroke remains the leading cause of adult disability in the world, but efforts to reduce stroke severity have been plagued by failed translational attempts to mitigate glutamate excitotoxicity. Elucidating the ischaemic cascade, which within minutes leads to irreversible tissue damage induced by anoxic depolarization, must be a principal focus. Data presented here show that tonic, extrasynaptic glutamate supplied by system xc - synergizes with ischaemia-induced synaptic glutamate release to propagate AD and exacerbate depolarizing waves. Exploiting the role of system xc - and its obligate release of ambient glutamate could, therefore, be a novel therapeutic direction to attenuate the deleterious effects of acute stroke.

Stroke Severity in Ischemic Stroke Patients with a History of Diastolic Blood Pressure Treated in a Telestroke Network.

Background: The relationship between diastolic blood pressure (DBP), risk factors, and stroke severity in acute ischemic stroke (AIS) patients treated in a telestroke network is not fully understood. The present study aims to determine the effect of risk factors on stroke severity in AIS patients with a history of elevated DBP. Material and Methods: We retrospectively analyzed data on stroke severity for AIS patients treated between January 2014 and June 2016 treated in the PRISMA Health telestroke network. Data on the severity of stroke on admission were evaluated using NIHSS scores ≤7 for reduced, and >7 for increased, stroke severity. DBP was stratified as ≤80 mmHg for reduced DBP and >80 mmHg for elevated DBP. The study’s primary outcomes were risk factors associated with improving neurologic functions or reduced stroke severity and deteriorating neurologic functions or increased stroke severity. The associations between risk factors and stroke severity for AIS with elevated DBP were determined using multi-level logistic and regression models. Results: In the adjusted analysis, AIS patients with a DBP ≤ 80 mmHg, obesity (OR = 0.388, 95% Cl, 0.182–0.828, p = 0.014) was associated with reduced stroke severity, while an increased heart rate (OR = 1.025, 95% Cl, 1.001–1.050, p = 0.042) was associated with higher stroke severity. For AIS patients with a DBP > 80 mmHg, hypertension (OR = 3.453, 95% Cl, 1.137–10.491, p = 0.029), history of smoking (OR = 2.55, 95% Cl, 1.06–6.132, p = 0.037), and heart rate (OR = 1.036, 95% Cl, 1.009–1.064, p = 0.009) were associated with higher stroke severity. Caucasians (OR = 0.294, 95% Cl, 0.090–0.964, p = 0.002) and obesity (OR = 0.455, 95% Cl, 0.207–1.002, p = 0.05) were more likely to be associated with reduced stroke severity. Conclusions: Our findings reveal specific risk factors that can be managed to improve the care of AIS patients with elevated DBP treated in the telestroke network.

Effect of metformin on outcome after acute ischemic stroke in patients with type 2 diabetes mellitus

IntroductionDiabetes mellitus is a well-known risk factor for ischemic stroke and is associated with unfavorable outcome after stroke. Metformin is recommended as first-line treatment in these patients. Pre-stroke metformin use might have neuroprotective properties resulting in reduced stroke severity. However, results of the effects of pre-stroke metformin use on functional outcome are conflicting and has not been previously described in patients with type 2 diabetes mellitus regardless of stroke severity or revascularization treatment. In this study, we aimed to assess the association between metformin use and functional outcome in patients with type 2 diabetes mellitus and acute ischemic stroke. MethodsWe used data from patients with known type 2 diabetes mellitus who were admitted with acute ischemic stroke between 2017 and 2021 in the Isala Hospital Zwolle and Medisch Spectrum Twente (MST) Enschede, the Netherlands. The association between pre-stroke metformin use and favorable functional outcome at 3 months (defined as modified Rankin Scale (mRS) < 3) was expressed as Odds Ratios (ORs) with corresponding confidence intervals (CIs). Adjustments were made for age, sex, hyperglycemia on admission and revascularization treatment by means of multiple logistic regression. ResultsNine hundred thirty seven patients were included of whom 592 patients (63%) used metformin. Six hundred seventy eight (74%) patients were hyperglycemic on admission. Median mRS was 3 (IQR 2–6) and 593 patients (63%) had a favorable outcome. Pre-stroke metformin use was associated with favorable outcome (aOR of 1.94 (95%- CI 1.45–2.59)). ConclusionIn this study, we showed that pre-stroke metformin use was associated with favorable outcome after acute ischemic stroke in patients with diabetes mellitus type 2.

Admission Severity of Atrial-Fibrillation-Related Acute Ischemic Stroke in Patients under Anticoagulation Treatment: A Systematic Review and Meta-Analysis.

Background: In non-valvular-associated atrial fibrillation (AF), direct oral anticoagulants (DOAC) are as effective as vitamin K antagonists (VKA) for the prevention of acute ischemic stroke (AIS). DOAC are associated with decreased risk and severity of intracranial hemorrhage. It is unknown if different pre-admission anticoagulants impact the prognosis of AF related AIS (AF-AIS). We sought to analyze the literature to assess the association between pre-admission anticoagulation (VKA or DOAC) and admission severity of AF-AIS. Methods: A Systematic literature search (PubMed and ScienceDirect) between January 2011 to April 2021 was undertaken to identify studies describing the outcome of AF-AIS. Results: A total of 128 articles were identified. Of 9493 patients, 1767 were on DOAC, 919 were on therapeutical VKA, 792 were on non-therapeutical VKA and 6015 were not anticoagulated. In comparison to patients without anticoagulation, patients with therapeutical VKA and under DOAC presented with less severe stroke (MD −1.69; 95% CI [−2.71, −0.66], p = 0.001 and MD −2.96; 95% Cl [−3.75, −2.18], p < 0.00001, respectively). Patients with non-therapeutical VKA presented with more severe stroke (MD 1.28; 95% Cl [0.45, 2.12], p = 0.003). Conclusions: In AF-AIS, patients under therapeutical VKA or DOAC have reduced stroke severity on admission in comparison to patients without any anticoagulation, with higher magnitude of protection for DOAC.

Opioid Antagonist Nanodrugs Successfully Attenuate the Severity of Ischemic Stroke.

The United States is in the midst of an opioid epidemic that is linked to a number of serious health issues, including an increase in cerebrovascular events, namely, stroke. Chronic prescription opioid use exacerbates the risk and severity of ischemic stroke, contributing to stroke as the fifth overall cause of death in the United States and costing the US health care system over $30 billion annually. Pathologically, opioids challenge the integrity of the blood–brain barrier (BBB), resulting in a dysregulation of tight junction (TJ) proteins that are crucial in maintaining barrier homeostasis. Despite this, treatment options for ischemic stroke are limited, and there are no pharmacological options to attenuate TJ damage, including in incidents that are linked to opioid use. Herein, we have generated carrier-free, pure “nanodrugs” or nanoparticles of naloxone and naltrexone with enhanced therapeutic properties compared to the original (parent) drugs. The generated nanoformulations of both opioid antagonists exhibited successful attenuation of morphine- or oxycodone-induced alterations of TJ protein expression and reduced oxidative stress to a greater extent than the parent drugs (non-nano). As a proof of concept, we then proceeded to evaluate the therapeutic effectiveness of the generated nanodrugs in an ischemic stroke model of mice exposed to morphine or oxycodone. Our results demonstrate that the opioid antagonist nanoformulations reduced stroke severity in mice. Overall, this research implements advances in nanotechnology-based repurposing of FDA-approved therapeutics, and the obtained results also suggest underlying pharmacological mechanisms of opioid antagonists, further supporting these opioid antagonists and their respective nanoformulations as potential therapeutic agents for ischemic stroke.

Underdosed Direct Oral Anticoagulants in Atrial Fibrillation Patients Reduce Stroke Severity and Improve Outcome

Background and Purpose: Anticoagulant drugs, including vitamin K antagonist (VKA) and direct oral anticoagulants (DOACs), can reduce stroke severity and are associated with good functional outcomes. Some patients are prescribed lower-than-recommended doses of DOACs; whether these have similar effects has not been clarified. Methods: We retrospectively evaluated 1,139 consecutive ischemic stroke and transient ischemic attack patients with atrial fibrillation. Patients were divided into 5 groups according to their preceding anticoagulant drug therapies: no anticoagulant therapy (ACn), undercontrolling VKA doses (VKAuc), recommended, controlling VKA doses (VKArec), prescribed underdoses of DOAC (DOACud), and recommended doses of DOAC (DOACrec). We investigated the associations between these anticoagulant drug therapies and patients’ initial stroke severity and 3-month outcomes. Results: Median National Institutes of Health Stroke Scale scores at admission were as follows: ACn: 16, VKAuc: 15, VKArec: 9, DOACud: 5, and DOACrec: 7. When the ACn group was used as a reference, regression analysis showed that VKArec (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.01–2.21), DOACud (OR 2.84, 95% CI: 1.47–5.66), and DOACrec (OR 1.83, 95% CI: 1.23–2.74) were associated with milder stroke severity, while VKAuc was not. Median 3-month modified Rankin Scale scores were 2 in the DOACud and DOACrec groups and 4 in all other groups. After adjusting for confounding factors, DOACud (OR 3.14, 95% CI: 1.50–6.57) and DOACrec (OR 1.67, 95% CI: 1.05–2.64) were associated with good 3-month outcomes while VKAuc and VKArec were not. Conclusions: In patients with atrial fibrillation, recommended doses and underdoses of DOACs reduced stroke severity on admission and were associated with good 3-month outcomes.

Pre-stroke physical activity and admission stroke severity: A systematic review.

Admission stroke severity is an important clinical predictor of stroke outcomes. Pre-stroke physical activity contributes to stroke prevention and may also be associated with reduced stroke severity. Summarizing the evidence to date will inform strategies to reduce burden after stroke. To summarize the published evidence for the relationship between pre-stroke physical activity and admission stroke severity and to provide recommendations for future research. MEDLINE, Embase, Emcare, CENTRAL, and gray literature databases were searched on 14 February 2020 using search terms related to stroke and pre-stroke physical activity in adult stroke survivors. We screened 8,152 references and assessed 172 full-text references for eligibility. We included seven studies (n = 41,800 stroke survivors). All studies were observational, assessed pre-stroke physical activity using self-reported questionnaires, and assessed admission stroke severity using the National Institute of Health Stroke Scale. Analyses were categorized as the presence of pre-stroke physical activity (four studies) or dose-response (five studies). In three studies, presence of pre-stroke physical activity was associated with milder stroke severity, and no association in one study. Greater pre-stroke physical activity duration and intensity (two studies) or amount (three studies) were associated with milder stroke severity. Studies ranged between moderate to critical risk of bias, primarily due to confounding factors. Pre-stroke physical activity may be associated with reduced risk factors for severe stroke, distal occlusion, smaller infarcts, and shorter time-to-treatment delivery. Pre-stroke physical activity may be associated with reduced admission stroke severity. Lack of randomized controlled trials limited causality conclusions. Future research recommendations were provided.

Effects of dabigatran and rivaroxaban on stroke severity according to the results of routine coagulation tests.

IntroductionPrior use of direct oral anticoagulants has been associated with reduced stroke severity in patients with non-valvular atrial fibrillation (NVAF). The aim of this study was to investigate the impact of prothrombin time (PT) and activated partial thromboplastin time (aPTT) on stroke severity in patients who were receiving dabigatran or rivaroxaban at the time of stroke onset.Materials and methodsWe enrolled 107 patients with NVAF who developed acute ischemic stroke while on dabigatran or rivaroxaban and presented within 24 hours to nine hospitals between January 2014 and December 2018. The results of PT and aPTT assays were obtained within 24 hours of stroke onset in all patients. We analyzed PT and aPTT in relation to stroke severity and ischemic lesion volume using correlation and multivariable regression analyses.ResultsOf the 107 patients included, 46 (43.0%) were on dabigatran and 61 (57.0%) were on rivaroxaban. In patients with prior dabigatran use, while aPTT was inversely correlated with admission National Institutes of Health Stroke Scale (NIHSS) score (r = -0.369, p = 0.012) and ischemic lesion volume (r = -0.480, p = 0.005), there was no correlation between PT and either of these variables. Multivariable analysis confirmed the existence of a significant independent inverse relationship between aPTT and NIHSS score at admission (B, -0.201; 95% confidence interval [CI], -0.370 to -0.032; p = 0.005) and between aPTT and ischemic lesion volume (B, -0.076; 95% CI, -0.130 to -0.023; p = 0.007). In patients with prior rivaroxaban use, neither PT nor aPTT was associated with admission NIHSS score or ischemic lesion volume in the correlation and multivariable analyses.ConclusionsIn patients with NVAF who were receiving dabigatran, prolonged aPTT was associated with reduced stroke severity.

Cardiovascular risk factors indirectly affect acute post-stroke cognition through stroke severity and prior cognitive impairment: a moderated mediation analysis

BackgroundCognitive impairment is an important consequence of stroke and transient ischaemic attack, but its determinants are not fully understood. Simple univariable or multivariable models have not shown clinical utility for predicting cognitive impairment. Cardiovascular risk factors may influence cognition through multiple, direct, and indirect pathways, including effects on prior cognition and stroke severity. Understanding these complex relationships may help clinical teams plan intervention and follow-up strategies.MethodsWe analysed clinical and demographic data from consecutive patients admitted to an acute stroke ward. Cognitive assessment comprised Abbreviated Mental Test and mini-Montreal Cognitive Assessment. We constructed bias-corrected confidence intervals to test indirect effects of cardiovascular risk factors (hypertension, vascular disease, atrial fibrillation, diabetes mellitus, previous stroke) on cognitive function, mediated through stroke severity and history of dementia, and we assessed moderation effects due to comorbidity.ResultsFrom 594 eligible patients, we included 587 in the final analysis (age range 26–100; 45% female). Our model explained R2 = 62.10% of variance in cognitive test scores. We found evidence for an indirect effect of previous stroke that was associated with increased risk of prevalent dementia and in turn predicted poorer cognitive score (estimate = − 0.39; 95% bias-corrected CI, − 0.75 to − 0.13; p = 0.02). Atrial fibrillation was associated with greater stroke severity and in turn with a poorer cognitive score (estimate = − 0.27; 95% bias-corrected CI, − 0.49 to − 0.05; p = 0.02). Conversely, previous TIA predicted decreased stroke severity and, through that, lesser cognitive impairment (estimate = 0.38; 95% bias-corrected CI, 0.08 to 0.75; p = 0.02). Through an association with reduced stroke severity, vascular disease was associated with lesser cognitive impairment, conditional on presence of hypertension and absence of diabetes mellitus (estimate = 0.36; 95% bias-corrected CI, 0.03 to 0.68; p = 0.02), although the modelled interaction effects did not reach statistical significance.ConclusionsWe have shown that relationships between cardiovascular risk factors and cognition are complex and simple multivariable models may be overly reductionist. Including direct and indirect effects of risk factors, we constructed a model that explained a substantial proportion of variation in cognitive test scores. Models that include multiple paths of influence and interactions could be used to create dementia prognostic tools for use in other healthcare settings.

Abstract WP466: Optimism Reduces Stroke Severity and Inflammation

Introduction: Post-stroke inflammation is detrimental to the brain and leads to impaired recovery. Optimism has been associated with lower inflammation and better health outcomes among people with medical conditions, but no studies have assessed this association in stroke population. The overall goals were to examine the relationship between optimism, stroke severity, physical disability, and inflammation during hospitalization and to evaluate this relationship over the three-month post-stroke period. Hypothesis: Patients with higher levels of optimism have lower stroke severity on presentation, less physical disability, decreased inflammation, and better recovery during the first three months after stroke compared to those with lower levels of optimism. Methods: This pilot study is a secondary analysis of data prospectively collected from the BioRepository of Neurological Diseases biobank. Outcomes included optimism level measured by the revised Life Orientation Test (LOT-R), stroke severity evaluated via the NIHSS, physical recovery defined by the mRS, and levels of inflammatory markers (IL-6, TNFα, and CRP) assessed by ELISA. Spearman’s correlation, Wilcoxon signed-rank test, multiple linear regression, and mixed-effect regression model were used to determine the relationship among the variables. Results: The sample consisted of 49 subjects at baseline and 13 subjects at 3-month follow-up. LOT-R scores were negatively correlated with NIHSS (ρ= -.41, p=.003), mRS (ρ= -.30, p=.05), and inflammatory markers IL-6 (ρ= -.44, p=.008) and CRP (ρ= -.40, p=.02), but not with TNFα. After adjusting for potential confounders, NIHSS and CRP remained negatively correlated with the optimism level. For every unit increase of LOT-R, subject’s NIHSS scores decreased by .27 point (p=.001), mRS decreased by .11 point (p=.03), and level of CRP decreased 148.6 ng/ml (p=.02). However, LOT-R was not correlated with mRS the three-month follow-up. Conclusion: Optimistic stroke survivors showed lower inflammation, less stroke severity, and less physical disability. Although the number of patients was low in this initial cohort, understanding this relationship may provide a scientific framework whereby new strategies for stroke recovery can be developed.

Effect of non-vitamin-K oral anticoagulants on stroke severity compared to warfarin: a meta-analysis of randomized controlled trials.

In addition to lowering stroke risk, warfarin use is also associated with reduced stroke severity in patients with atrial fibrillation and acute ischaemic stroke. It was sought to determine whether the effect of non-vitamin-K oral anticoagulants (NOACs), compared to warfarin, differed by stroke severity. Phase III randomized controlled trials with participants who were randomized to receive NOACs or warfarin for stroke prevention in the setting of non-valvular atrial fibrillation were identified. Stroke was classified into two categories, fatal or disabling stroke and non-disabling stroke, and meta-analyses were completed for both outcomes and for comparative case fatality of stroke amongst trials. Five randomized controlled trials met our inclusion criteria. In clinical trials evaluating the NOACs usually prescribed in clinical practice (four trials), acute stroke was reported in 1403 (1.86%) participants, 787 (1.04%) in the NOAC group [386 (0.51%) fatal or disabling, 401 (0.53%) non-disabling] and 616 (0.82%) in the warfarin group [367 (0.49%) fatal or disabling, 249 (0.33%) non-disabling]. On meta-analysis NOACs were significantly superior to warfarin for fatal or disabling stroke (odds ratio [OR] 0.77; 95% confidence interval [CI] 0.66-0.89, I2 =21%) and non-disabling stroke (OR 0.85; 95% CI 0.73-0.98, I2 =2%). The case fatality of stroke was no different between groups (OR 0.90, 95% CI 0.75-1.13, I2 =0%), but the point estimate favoured NOACs. In phase III trials of NOACs, for prevention of stroke in atrial fibrillation, NOACs are associated with a lower risk of both fatal/disabling and non-disabling stroke compared to warfarin.