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Background: There is increasing interest in the concept of frailty in stroke, including both physical frailty and imaging-evidence of brain frailty. We aimed to establish the prevalence of brain frailty in stroke survivors as well as the concurrent and predictive validity of various frailty measures against long-term cognitive outcomes., Methods: We included consecutively admitted stroke or transient ischaemic attack (TIA) survivors from participating stroke centres. Baseline CT scans were used to generate an overall brain frailty score for each participant. We measured frailty via the Rockwood frailty index, and a Fried frailty screening tool. Presence of major or minor neurocognitive disorder at 18-months following stroke or TIA was established via a multicomponent assessment. Prevalence of brain frailty was established based upon observed percentages within groups defined by frailty status (robust, pre-frail, frail). We assessed the concurrent validity of brain frailty and frailty scales via Spearman's rank correlation. We conducted multivariable logistic regression analyses, controlling for age, sex, baseline education and stroke severity, to evaluate association between each frailty measure and 18-month cognitive impairment., Results: Three-hundred-forty-one stroke survivors participated. Three-quarters of people who were frail had moderate-severe brain frailty and prevalence increased according to frailty status. Brain frailty was weakly correlated with Rockwood frailty (Rho: 0.336; p  < 0.001) and with Fried frailty (Rho: 0.230; p  < 0.001). Brain frailty (OR: 1.64, 95% CI = 1.17-2.32), Rockwood frailty (OR: 1.05, 95% CI = 1.02-1.08) and Fried frailty (OR: 1.93, 95% CI = 1.39-2.67) were each independently associated with cognitive impairment at 18 months following stroke., Conclusions: There appears to be value in the assessment of both physical and brain frailty in patients with ischaemic stroke and TIA. Both are associated with adverse cognitive outcomes and physical frailty remains important when assessing cognitive outcomes., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Blunt cerebrovascular injury (BCVI), defined as blunt traumatic injury to the carotid or vertebral arteries, is associated with significant risk of stroke and mortality. Cervical spine trauma is a recognized risk factor for BCVI., Objective: The objective of this study was to identify significant predictors of BCVI and its sequelae in patients with known cervical spine injury., Methods: Patients from 2007 to 2018 with blunt cervical spine injury diagnoses were identified in the National Trauma Data Bank. Multivariable logistic regression models were used to identify patient baseline and injury characteristics associated with BCVI, stroke, and mortality., Results: We identified 229,254 patients with cervical spine injury due to blunt trauma. The overall rate of BCVI was 1.6%. Factors associated with BCVI in patients with cervical spine injury included lower Glasgow Coma Scale, motor vehicle crash, higher Injury Severity Score, concomitant traumatic brain or spinal cord injury, and current smoking status. BCVI was a strong predictor of stroke (odds ratio, 8.2; 95% confidence interval, 5.7-12.0) and was associated with mortality (odds ratio, 1.7; 95% confidence interval, 1.3-2.2). Stroke occurred in 3.3% of patients with BCVI versus 0.02% for patients without BCVI., Conclusions: While BCVI is rare following cervical spine injury due to blunt trauma, it is a significant predictor of stroke and mortality. The risk factors associated with BCVI, stroke, and mortality identified here should be used in the development of more effective predictive tools to improve care., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: In a telestroke network, patients at a referring hospital (RH) with large-vessel occlusion (LVO) are transferred to a comprehensive stroke centre (CSC) for endovascular thrombectomy (EVT). However, a significant number of patients do not ultimately undergo thrombectomy after CSC arrival., Methods: Within a 17-hospital telestroke network, we retrospectively analysed patients with suspected or confirmed LVO transferred to a CSC, and characterized the reasons why these patients did not undergo EVT based on the 2019 American Heart Association guidelines., Results: Of 400 patients transferred to our hub, 68 (17%) were based on vascular imaging at RH. Time from RH arrival to neuroimaging was significantly longer in patients that underwent both computed tomography (CT) and CT angiography of the brain and neck compared to only CT of the brain (53 vs 13 minutes, p < 0.05). Accuracy of anterior circulation LVO (ACLVO) detection based on clinical suspicion was 62% (205 of 332 patients). Among 234 ACLVO patients, overall, 175 (74%) (early window group: 123 (73%) patients and late window group: 52 (80%) patients) met at least one EVT ineligibility criterion. The reasons for EVT ineligibility varied from large core infarct (aspects <6 or core volume >70 cc on perfusion imaging in late window), low National Institutes of Health Stroke Scale (<6), distal occlusion, and poor baseline modified Rankin Scale score (>1)., Discussion: Instituting rapid acquisition and interpretation of vascular imaging at RHs for LVO detection and establishing benchmarks for door to vascular imaging is urgently needed for RHs.

Objectives: Various informant-based questionnaires are used in clinical practice to screen for pre-stroke cognitive problems. However, there is no guidance on which tool should be preferred. We compared the validity of the two most commonly used informant-based tools., Methods: We recruited consecutively admitted stroke patients. Patients' informants completed the Informant Questionnaire for Cognitive Decline in the Elderly Short Form (IQCODE-SF, 16-item) and Ascertain Dementia 8 (AD8). We assessed construct validity (accuracy) against a semi-structured clinical interview for dementia or mild cognitive impairment (MCI), describing test accuracy metrics and comparing area under ROC curves (AUROC). We described criterion validity by evaluating associations between test scores and neuroimaging markers of dementia and overall 'brain frailty'. Finally, we described prognostic validity comparing ROC curves for 18-month clinical outcomes of dementia, death, stroke, and disability., Results: One-hundred-thirty-seven patient-informant dyads were recruited. At usual clinical cut-points, the IQCODE-SF had comparable sensitivity to the AD8 (both = 92%) for pre-stroke dementia, but superior specificity (IQCODE-SF: 82% vs. AD8: 58%). Youden index suggested that the optimal AD8 threshold for diagnosis of dementia is ≥4. The IQCODE-SF demonstrated stronger associations with markers of generalised and medial-temporal lobe atrophy, neurovascular disease, and overall brain frailty. IQCODE-SF also demonstrated greater accuracy for predicting future dementia (IQCODE-SF AUROC = 0.903, 95% CI = 0.798-1.00; AD8 AUROC = 0.821, 95% CI = 0.664-0.977)., Conclusions: Both IQCODE-SF and AD8 are valid measures of pre-stroke dementia. Higher cut points for AD8 may improve performance in the acute stroke setting. Based on consistent superiority across a range of validity analyses, IQCODE-SF may be preferable to AD8 for pre-stroke dementia screening., (© 2022 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Background: Major adverse cardiovascular events (MACE) are increasingly used as composite outcomes in randomized controlled trials (RCTs) and observational studies. However, it is unclear how observational studies most commonly define MACE in the literature when using administrative data., Methods: We identified peer-reviewed articles published in MEDLINE and EMBASE between January 1, 2010 to October 9, 2020. Studies utilizing administrative data to assess the MACE composite outcome using International Classification of Diseases 9th or 10th Revision diagnosis codes were included. Reviews, abstracts, and studies not providing outcome code definitions were excluded. Data extracted included data source, timeframe, MACE components, code definitions, code positions, and outcome validation., Results: A total of 920 articles were screened, 412 were retained for full-text review, and 58 were included. Only 8.6% (n = 5/58) matched the traditional three-point MACE RCT definition of acute myocardial infarction (AMI), stroke, or cardiovascular death. None matched four-point (+unstable angina) or five-point MACE (+unstable angina and heart failure). The most common MACE components were: AMI and stroke, 15.5% (n = 9/58); AMI, stroke, and all-cause death, 13.8% (n = 8/58); and AMI, stroke and cardiovascular death 8.6% (n = 5/58). Further, 67% (n = 39/58) did not validate outcomes or cite validation studies. Additionally, 70.7% (n = 41/58) did not report code positions of endpoints, 20.7% (n = 12/58) used the primary position, and 8.6% (n = 5/58) used any position., Conclusions: Components of MACE endpoints and diagnostic codes used varied widely across observational studies. Variability in the MACE definitions used and information reported across observational studies prohibit the comparison, replication, and aggregation of findings. Studies should transparently report the administrative codes used and code positions, as well as utilize validated outcome definitions when possible., (© 2021. The Author(s).)

Introduction: We aimed to identify factors associated with rapid infarct progression during inter-facility transfer for endovascular thrombectomy evaluation and its impact on clinical outcomes., Methods: Patients with anterior circulation large artery occlusion within 24 h of onset transferred within our 17 hospital tele-stroke network were retrospectively analyzed. Patients were divided into fast progressors and slow progressors. Fast progressors were defined as CT ASPECTS score of ≥6 at the referring hospital (RH) and <6 at the hub hospital. Good clinical outcomes were defined as modified Rankin Scale score (mRS) 0-2 at 90 days. Demographic, clinical and radiologic variables associated with fast progressors and good clinical outcomes were identified using multivariable regression models., Results: Among the 190 patients, 44 (23%) patients underwent rapid infarct progression. Higher stroke severity at presentation [aOR, 1.096, 95% CI,1.023, 1.174; p = 0.009], presence of early ischemic changes (CT ASPECT 6-9) at the RH [aOR, 2.721, 95% CI, 1.22, 6.071; p = 0.014] were positively associated, whereas prior ischemic stroke [aOR, 0.272, 95% CI, 0.078, 0.948; p = 0.04] and higher collateral score (2,3,4) [aOR, 0.138, 95%CI, 0.059, 0.324, p=<0.0001] were negatively associated with rapid infarct progression. Fifty-eight (31%) transferred patients had good outcomes. After adjusting for reperfusion status, age [aOR, 0.96, 95% CI, 0.93, 0.98; p=<0.001], initial stroke severity [aOR, 0.87, 95% CI, 0.81, 0.93; p=<0.001], absolute rate of decrease in CT ASPECTS [aOR, 0.38, 95% CI, 0.19, 0.77; p = 0.007] and internal carotid artery (ICA) occlusion [aOR, 0.34, 95 %CI, 0.12, 0.94; p = 0.038] were negatively associated with good outcome., Conclusion: Higher stroke severity, presence of early ischemic changes at the referring facility, absence of prior stroke, and poor collateral scores (CS 0-1) are the factors associated with rapid infarct progression in the telemedicine transfer cohort. Increasing age, higher stroke severity, higher absolute decrease in CT ASPECTS and ICA occlusion determine poor clinical outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Cognitive 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., Methods: We 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., Results: From 594 eligible patients, we included 587 in the final analysis (age range 26-100; 45% female). Our model explained R 2  = 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., Conclusions: We 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.

Background and Purpose- Delirium is associated with increased mortality, length of stay, and poor functional outcome following critical illness. The epidemiology of delirium in stroke is poorly described. We sought to collate evidence around occurrence (incidence or prevalence) of delirium in acute stroke. Methods- We searched multiple cross-disciplinary electronic databases using a prespecified search strategy, complemented by hand searching. Eligible studies described delirium in acute (first 6 weeks) stroke. We compared delirium occurrence using random-effects models to describe summary estimates. We assessed risk of bias using the Newcastle-Ottawa tool, incorporating this in sensitivity analyses. We performed subgroup analyses for delirium diagnostic method (confusion assessment method scoring, clinical diagnosis, other), duration and timing of delirium assessment (>1 or <1 week), and performed meta-regression based on the year of publication. Results- Of 8822 titles, we included 32 papers (6718 participants) in the quantitative analysis. Summary estimate for occurrence of delirium was 25% (95% CI, 20%-30%; moderate quality evidence). Limiting to studies at low risk of bias (22 studies, 4422 participants), the occurrence rate was 23% (95% CI, 17%-28%). Subgroup summary estimates suggest that delirium occurrence may vary with assessment method: confusion assessment method, 21% (95% CI, 16%-27%); clinical diagnosis, 27% (95% CI, 19%-38%); other, 32% (95% CI, 22%-43%) but not with duration and timing of assessment. Meta-regression suggested decline in occurrence of delirium comparing historical to more recent studies (slope, 0.03 [SE, 0.004]; P <0.0001). Conclusions- Delirium is common, affecting 1 in 4 acute stroke patients. Reported rates of delirium may be dependent on assessment method. Our estimate of delirium occurrence could be used for audit, to plan intervention studies, and inform clinical practice. Clinical Trial Registration- URL: http://www.crd.york.ac.uk/PROSPERO/. Unique identifier: CRD42015029251.

Background and Purpose- Delirium is a common and serious complication of acute illness. We describe delirium occurrence in an unselected, acute stroke population. Methods- We collected data from consecutive stroke admissions. We performed comprehensive cognitive assessment within the first week including Diagnostic Statistical Manual-5-based delirium diagnosis. We reported proportion with delirium and the clinical and demographic associations with delirium using multiple logistic regression. Results- Of 708 patients, median age of 71 years (interquartile range, 59-80), we recorded delirium in 187 of 708 (26.4%; 95% CI, 23.0-30.0). Across 395 patients with complete risk factor data (105 delirium), factors independently associated with delirium were: age (odds ratio, 1.05; 95% CI, 1.03-1.08), drug/alcohol misuse (odds ratio, 2.64; 95% CI, 1.10-6.26), and stroke severity (odds ratio, 1.22; 95% CI, 1.14-1.31). Conclusions- Delirium is common in acute stroke, affecting 1 in 4. It may be possible to predict those at risk using prestroke and stroke-specific factors. Clinical Trial Registration- URL: researchregistry.com. Protocol: 1147.

Objective: We aimed to determine prevalence of pre-stroke frailty in acute stroke and describe validity of a Frailty Index-based assessment., Design: Cross-sectional., Setting: Single UK urban teaching hospital., Subjects: Consecutive acute stroke unit admissions, recruited in four waves (May 2016-August 2018). We performed the assessments within first week and attempted to include all admissions., Main Measures: Our primary measure was a Frailty Index, based on cumulative disorders. A proportion of participants were also assessed with the 'Frail non-disabled' questionnaire. We evaluated concurrent validity of Frailty Index against variables associated with frailty in non-stroke populations. We described predictive validity of Frailty Index for stroke severity and delirium. We described convergent validity, quantifying agreement between frailty assessments and a measure of pre-stroke disability (modified Rankin Scale) using kappa statistics and correlations., Results: We included 546 patients. A Frailty Index-defined frailty syndrome was observed in 427 of 545 patients (78%), of whom, 151 (28%) had frank frailty and 276 (51%) were pre-frail. Phenotypic frailty was observed in 72 of 258 patients (28%). We demonstrated concurrent validity via significant associations with all variables (all p  < 0.01). We demonstrated predictive validity for stroke severity and delirium ( p  < 0.01). Agreement between the frailty measures was poor (kappa = -0.06) and convergent validity was moderate (Frail non-disabled 'Cramer's V' = 0.25; modified Rankin Scale 'Cramer's V' = 0.47)., Conclusion: Frailty is present in around one in four patients with acute stroke; if pre-frailty is included, then a frailty syndrome is seen in three out of four patients. The Frailty Index is a valid measure of frailty in stroke; however, there is little agreement between this scale and other measurements of frailty.

Objective: Post-stroke cognitive impairment is common, but mechanisms and risk factors are poorly understood. Frailty may be an important risk factor for cognitive impairment after stroke. We investigated the association between pre-stroke frailty and acute post-stoke cognition., Methods: We studied consecutively admitted acute stroke patients in a single urban teaching hospital during three recruitment waves between May 2016 and December 2017. Cognition was assessed using the Mini-Montreal Cognitive Assessment (min=0; max=12). A Frailty Index was used to generate frailty scores for each patient (min=0; max=100). Clinical and demographic information were collected, including pre-stroke cognition, delirium, and stroke-severity. We conducted univariate and multiple-linear regression analyses with covariates forced in (covariates included were: age, sex, stroke severity, stroke-type, pre-stroke cognitive impairment, delirium, previous stroke/transient ischemic attack) to investigate the association between pre-stroke frailty and post-stroke cognition., Results: Complete data were available for 154 stroke patients. Mean age was 68 years (SD=11; range=32-97); 93 (60%) were male. Median mini-Montreal Cognitive Assessment score was 8 (IQR=4-12). Mean Frailty Index score was 18 (SD=11). Pre-stroke cognitive impairment was apparent in 13/154 (8%) patients. Pre-stroke frailty was significantly associated with lower post-stroke cognition (Standardized-Beta=-0.40; p&lt;0.001) and this association was independent of covariates (Unstandardized-Beta=-0.05; p=0.005). Additional significant variables in the multiple regression model were age (Unstandardized-Beta=-0.05; p=0.002), delirium (Unstandardized-Beta=-2.81; p&lt;0.001), pre-stroke cognitive impairment (Unstandardized-Beta=-2.28; p=0.001), and stroke-severity (Unstandardized-Beta=-0.20; p&lt;0.001)., Conclusions: Pre-stroke frailty may be a moderator of post-stroke cognition, independent of other well-established post-stroke cognitive impairment risk factors. (JINS, 2019, 25, 501-506).

Background: Randomized controlled trials (RCTs) have compared mechanical endovascular therapy (MET) in addition to intravenous tissue plasminogen activator (IVtPA) to IVtPA alone for the management of acute ischemic stroke (AIS). Direct comparative studies between individual METs are not available. In lieu of head-to-head randomized control trials, we performed an adjusted indirect treatment comparison (ITC) meta-analysis to assess the comparative efficacy and safety of different METs, Solitaire+IVtPA and Penumbra+IVtPA in AIS patients., Methods and Findings: We searched MEDLINE, the Cochrane Central Register of Controlled Trials and Embase from January 1, 2005 through April 1, 2017 for RCTs in AIS patients, comparing a single MET+IVtPA to IVtPA alone and reporting shift in ordinal modified Rankin Scale (mRS) score at 90 days. Secondary endpoints included 90 day mortality and symptomatic intracranial hemorrhage (sICH). Endpoints were pooled using traditional random effects meta-analysis methods, producing odds ratios and 95% confidence intervals. Adjusted ITCs using pooled estimates were then performed. Three studies (SWIFT PRIME, EXTEND-IA, THERAPY) were included; two evaluating the Solitaire stent retriever and one the Penumbra system. Traditional meta-analysis demonstrated that each MET+IVtPA resulted in increased odds of improving ordinal mRS score vs. IVtPA alone, but did not alter the odds of death or sICH. Adjusted ITC showed no significant difference between the METs for any outcome., Conclusion: No significant difference in efficacy or safety between the Solitaire and Penumbra devices was observed.

Background and Purpose: Intravenous tissue-type plasminogen activator (tPA) is a proven treatment for acute ischemic stroke, but there has been limited evaluation among patients aged ≥90 years., Methods: We analyzed data from the Get With The Guidelines-Stroke national quality improvement registry from January 2009 to April 2013. Frequency, determinants, and outcomes of tPA use were compared among patients aged ≥90 and 3 younger age groups (18-64, 65-79, and 80-89 years)., Results: Among 35 708 patients from 1178 sites who arrived within 2 hours of time last known well and received tPA, 2585 (7.2%) were ≥90 years. Compared with younger patients, the rate of tPA use among patients without a documented contraindication was lower among patients aged ≥90 years (67.4% versus 84.1% in 18-89-year olds; P<0.0001). Discharge outcomes among individuals aged ≥90 years included discharge to home or acute rehabilitation in 31.4%, independent ambulation at discharge in 13.4%, symptomatic hemorrhage in 6.1%, and in-hospital mortality or hospice discharge in 36.4%. On multivariable analysis, good functional outcomes generally occurred less often and mortality more often among patients aged ≥90 years. The risk of symptomatic hemorrhage was increased compared with patients <65 years but was not significantly different than the risk in 66- to 89-year olds., Conclusions: The use of intravenous tPA among those aged ≥90 years is lower than in younger patients. When fibrinolytic therapy is used, the risk of symptomatic hemorrhage is not higher than in 66- to 89-year olds; however, mortality is higher and functional outcomes are lower., (© 2016 American Heart Association, Inc.)

Background: The "drip-and-ship" paradigm is an important treatment modality for acute ischemic stroke (AIS) patients who do not have immediate access to a comprehensive stroke center (CSC). Intravenous thrombolysis is initiated at a primary stroke center followed by expeditious transfer to a CSC. We sought to determine factors associated with poor outcomes in drip-and-ship AIS patients transferred to a CSC., Methods: This study is a retrospective analysis of 130 consecutive drip-and-ship patients transferred by ambulance to a single CSC between July 2012 and June 2014. Multiple patient and transport factors were analyzed. Transport blood pressure (BP) control was considered inadequate if the systolic BP was greater than 180 mmHg and/or diastolic BP was greater than 105 mmHg upon CSC arrival. Poor patient outcome was defined as discharge to hospice or expiry, a discharge modified Rankin Scale (mRS) score higher than 2, or symptomatic intracerebral hemorrhage (ICH)., Results: There was a significant association between inadequate BP control upon CSC arrival and in-hospital mortality or discharge to hospice (P < .0007). Arrival BP was not associated with the risk of post-thrombolysis symptomatic ICH. Longer transport time was significantly associated with a poorer mRS score at discharge (P < .0174) and death (P < .0351)., Conclusions: Post-thrombolysis BP guideline violations and longer transport times during drip-and-ship transfers were significantly associated with poor outcome. Guidelines for strict transport BP management and alternative modes of transfer for longer-distance transports may be warranted., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: We report a case of ischemic and hemorrhagic strokes occurring almost simultaneously in a patient diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) previously known as Churg-Strauss vasculitis. To our knowledge, this is the first known case., Methods: A 59-year-old man presented with a 2-month history of bilateral leg weakness, difficulty ambulating, and dyesthesias. While in the hospital, he developed acute right hand weakness, and magnetic resonance imaging of the brain revealed multiple, bilateral ischemic infarcts. After a few days, he acutely became unresponsive and was found to have a large left frontal hematoma and underwent emergent hematoma evacuation. His weakness was unexplained by the infarcts based on location and so a peripheral process was suspected., Results: Nerve conduction studies showed severe axonal sensorimotor neuropathy. A sural nerve biopsy showed necrotizing vasculitis, consistent with EGPA., Conclusions: EGPA is the rarest of the antineutrophilic cytoplasmic antibody vasculitides. The peripheral nervous system is frequently involved, but the central nervous system can also be affected. The vasculitis damages the vessel walls, which leads either to stenosis or to dilatation, resulting in ischemic or bleeding consequences which can occur simultaneously, such as in this case. Caution should be exercised when prescribing antiplatelet therapy to such patients., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background Aims: After ischemic or hemorrhagic stroke, neurons in the penumbra surrounding regions of irreversible injury are vulnerable to delayed but progressive damage as a result of ischemia and hemin-induced neurotoxicity. There is no effective treatment to rescue such dying neurons. Mesenchymal stem cells (MSCs) hold promise for rescue of these damaged neurons. In this study, we evaluated the efficacy and mechanism of MSC-induced neuro-regeneration and immune modulation., Methods: Oxygen-glucose deprivation (OGD) was used in our study. M17 neuronal cells were subjected to OGD stress then followed by co-culture with MSCs. Rescue effects were evaluated using proliferation and apoptosis assays. Cytokine assay and quantitative polymerase chain reaction were used to explore the underlying mechanism. Antibody and small molecule blocking experiments were also performed to further understand the mechanism., Results: We showed that M17 proliferation was significantly decreased and the rate of apoptosis increased after exposure to OGD. These effects could be alleviated via co-culture with MSCs. Tumor necrosis factor-α was found elevated after OGD stress and was back to normal levels after co-culture with MSCs. We believe these effects involve interleukin-6 and vascular endothelial growth factor signaling pathways., Discussion: Our studies have shown that MSCs have anti-inflammatory properties and the capacity to rescue injured neurons., (Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: In ARISTOTLE, apixaban resulted in a 21% reduction in stroke, a 31% reduction in major bleeding, and an 11% reduction in death. However, approval of apixaban was delayed to investigate a statement in the clinical study report that "7.3% of subjects in the apixaban group and 1.2% of subjects in the warfarin group received, at some point during the study, a container of the wrong type.", Methods: Rates of study medication dispensing error were characterized through reviews of study medication container tear-off labels in 6,520 participants from randomly selected study sites. The potential effect of dispensing errors on study outcomes was statistically simulated in sensitivity analyses in the overall population., Results: The rate of medication dispensing error resulting in treatment error was 0.04%. Rates of participants receiving at least 1 incorrect container were 1.04% (34/3,273) in the apixaban group and 0.77% (25/3,247) in the warfarin group. Most of the originally reported errors were data entry errors in which the correct medication container was dispensed but the wrong container number was entered into the case report form. Sensitivity simulations in the overall trial population showed no meaningful effect of medication dispensing error on the main efficacy and safety outcomes., Conclusions: Rates of medication dispensing error were low and balanced between treatment groups. The initially reported dispensing error rate was the result of data recording and data management errors and not true medication dispensing errors. These analyses confirm the previously reported results of ARISTOTLE., (© 2013.)

To advance our understanding about the emotional and cognitive deficits of patients with frontotemporal dementia with behavioral variant (bvFTD), the current study examined comprehension and expression of emotions from prosodic and facial cues in a 66-year-old woman. The patient diagnosed with bvFTD is compared to six patients with acute right hemisphere stroke. Recognition of emotion from prosodic cues was assessed using an identification task in four conditions with decreasing verbal demands (neutral sentences, language-like pseudo sentences, monosyllables, and asyllabic vowel sounds). Repetition of utterances with emotional connotations and self-generated conversations were analyzed to measure relative changes in mean fundamental frequency (f0), f0 variance, speech rate, and intensity along with the facial musculature pattern. The patient showed a marked deficit in identifying emotions in all four prosody conditions; and she did not show much variation in modulating mean f0, f0 variance, speech rate and intensity for all emotion categories when compared to neutral utterances. In addition, this patient demonstrated little to no facial expressions during emotionally provoking tasks, but demonstrated no difficulty recognizing emotions from facial expressions or verbal scenarios. Results show that the patient seems to have selective impairment in recognition of emotions from prosody and expression of emotions using both prosodic and facial features. Impaired processing of emotional prosody and facial expressions could be important for detecting bvFTD with greater right hemisphere atrophy.

Sickle cell disease (SCD) is associated with increased risk of stroke and cognitive impairment. This study describes a retrospective review of 65 patients who underwent routine neuropsychological testing and MRI during treatment at a comprehensive sickle cell center. It was hypothesized that (1) children with no evidence of CVA would perform lower than expected on cognitive tasks compared to population-based normative data, (2) children with strokes and children with silent infarcts would perform lower on cognitive tasks and motor skills as compared to patients with no evidence of CVA, and (3) children with evidence of silent infarcts would perform better than children with known overt strokes. This final hypothesis has not been studied previously, as children with known overt stroke and silent infarct were grouped together. Sixty-five children with SCD who were sent for routine neuropsychological testing and brain MRI were identified via retrospective chart review. Patients had been administered neuropsychological tests to assess cognitive, executive and motor function. Brain MRI was obtained from each patient and was analyzed for evidence of cerebrovascular accident (CVA). Based on MRI analysis, 27% of patients with SCD had experienced a stroke and 13% a silent infarct. The majority (59%) of patients diagnosed with stroke or infarct sustained cortical damage to the frontal lobe. Patients with SCD and no evidence of CVA functioned normally on tests of cognitive ability and achievement, but patients with CVA displayed impairments in cognitive function and comparatively lower scores on verbal and performance scales. Neuropsychological testing can identify impairments in patients with SCD with no known cerebrovascular accident. Investigations of neurocognitive functioning will help characterize patterns of deficits and can inform the ability to implement comprehensive care strategies for patients with SCD and cognitive impairment.

Background and Purpose: Ischemic stroke occurs in at least 11% of patients with homozygous sickle cell anemia (SCD) by the time they turn 20 years old. High risk associated with distal intracranial internal carotid (ICA) and proximal middle cerebral artery (MCA) stenosis can be detected by transcranial Doppler (TCD). TCD screening offers the possibility of reducing the risk of first stroke significantly based on a paradigm tested and proven to be effective in a stroke prevention trial in sickle cell anemia (STOP). Children with high flow velocity in the ICA and MCA of 200 cm/s time average mean of the maximum (TAMM) or higher had a 10% per year risk of first stroke that was reduced to <1% with regular red cell transfusion (reduction of hemoglobin S <30%). The clinical application of the STOP results could be enhanced if criteria for treatment could be found that are based on peak systolic velocity (PSV), the measure more commonly used in vascular ultrasound practice., Objective: To compare PSV and end diastolic velocity (EDV) with TAMM for prediction of stroke and to derive PSV cutpoints for STOP protocol definitions of conditional and abnormal TCD. Using the STOP TCD and stroke outcome data to compare PSV and TAMM in terms of stroke prediction, PSV cutpoints comparable to those based on TAMM and used in STOP were derived. Because of their familiarity to the vascular ultrasound community, PSV cutpoints should be an important alternative to TAMM and may increase availability of screening and risk stratification for children with this disease., Materials and Methods: Data from 1,937 baseline TCD studies from STOP were correlated with stroke outcome in those not treated with transfusion. Stroke prediction was assessed with survival analysis using TAMM, PSV and EDV as continuous variables individually and then pair-wise in the same model, which contained 53 stroke events., Results: PSV and EDV were highly correlated to the TAMM velocity (r=0.94). The multivariate model for prediction indicated that TAMM velocity was a better predictor than EDV, and PSV and TAMM were approximately equivalent. PSV cutpoints defining the two relevant STOP risk categories--"conditional," which should lead to increased TCD surveillance, and "abnormal," which should lead to strong consideration for treatment according to STOP--were derived taking into consideration known differences in measurements between the dedicated Doppler systems (TCD) used in STOP and the transcranial Doppler imaging (TCDI) systems commonly used in clinical practice. The recommended PSV cutpoint for conditional TCD is 200 cm/s, and for abnormal TCD triggering consideration for treatment is 250 cm/s., Conclusion: Assuming TCDI equipment is used and the STOP protocol is applied, a PSV cutpoint of 200 cm/s is recommended as the threshold for increased TCD surveillance (comparable to a TCD TAMM of 170 cm/s in STOP); a PSV of 250 cm/s is recommended as the cutpoint at which, if confirmed in a second examination, chronic transfusion should be considered. Assuming the STOP scanning protocol is used, PSV is at least as good as TAMM and can be used to select children with SCD for treatment or increased surveillance to prevent first stroke.

The Stroke Prevention Trial in Sickle Cell Anemia (STOP) was a randomized multicenter controlled trial comparing prophylactic blood transfusion with standard care in sickle cell anemia (SCA) children aged 2 to 16 years selected for high stroke risk by transcranial Doppler (TCD). More than 2000 children were screened with TCD to identify the 130 high-risk children who entered the randomized trial. A total of 5613 TCD studies from 2324 children were evaluated. We also collected information on stroke. We describe the changes in TCD with repeated testing and report the outcome without transfusion in the STOP screened cohort. Risk of stroke was higher with abnormal TCD than with normal or conditional TCD (P <.001) or inadequate TCD (P =.002), and risk with conditional TCD was higher than with normal TCD (P <.001). Repeated TCD in 1215 children showed that the condition of 9.4% of children became abnormal during observation. Younger patients and those with higher initial flow velocities were most likely to convert to abnormal TCDs. Screening in STOP confirmed the predictive value of TCD for stroke. Substantial differences in the probability of conversion to abnormal TCD were observed, with younger children and those with higher velocity more likely to have an abnormal TCD with rescreening.

Stroke is a devastating complication of sickle cell anemia (SCA), affecting up to 30% of children with the disease. Despite the relative frequency of stroke in SCA, few predictors of risk exist. Because stroke in SCA is likely a multifactorial disease, analysis of the combined effect of multiple genetic variants may prove more successful than evaluation of individual candidate genes. We genotyped 230 children with SCA for 104 polymorphisms among 65 candidate vascular genes to identify risk associations with stroke. Patients were phenotyped based on magnetic resonance imaging/angiography (MRI/MRA) findings into large-vessel (LV) versus small-vessel (SV) disease stroke subgroups. Specific polymorphisms in the IL4R 503, TNF (-308), and ADRB2 27 genes were independently associated with stroke susceptibility in the LV stroke subgroup, while variants in the VCAM1 (-1594) and LDLR NcoI genes were associated with SV stroke risk. The combination of TNF (-308)GG homozygosity and the IL4R 503P variant carrier status was associated with a particularly strong predisposition to LV stroke (odds ratio [OR] = 5.5; 95% confidence interval [CI] = 2.3-13.1). We show that several candidate genes may play a role in predisposition to specific stroke subtypes in children with SCA. If confirmed, these results provide a basis for population screening and targeted intervention to prevent stroke in SCA.

Children with sickle cell anemia (SCA) carry a 200-fold increased risk for cerebral infarction. Stroke can be the result of small-vessel (SV) or large-vessel (LV) disease. However, it is unknown whether these subtypes result from the same pathophysiologic processes. Complete HLA genotyping was performed on 231 eligible children previously enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD). Cerebral infarction on magnetic resonance imaging (MRI) was documented in 71 patients, and 160 patients had negative findings on MRI. Based on MRI/magnetic resonance angiography (MRA) findings, infarct size, and location, 36 patients were classified as having LV stroke and 35 as having SV stroke. When comparing the total MRI+ group with the MRI- group, HLA DPB1*0401 was associated with increased stroke risk (P =.01), whereas DPB1*1701 (P =.02) conferred protection from stroke. These DPB1 associations with stroke were attributed to the SV stroke group, in whom DPB1*0401 was associated with susceptibility (P =.003) and DPB1*1701 with protection from stroke (P =.06). In the LV stroke subgroup, HLA-A*0102 (P =.02) and -A*2612 (P =.007) conferred susceptibility, whereas -A*3301(P =.04) protected from stroke. These results suggest that specific HLA alleles influence stroke risk and appear to contribute differently to SV and LV stroke subtypes. The distinct HLA associations with SV and LV stroke suggest that different pathologic processes may be involved in the development of stroke in children with SCA. If these results are confirmed in a larger study, HLA type may serve as a useful marker for the early identification of SCA patients at high risk for stroke.

Background: Half-dose aprotinin (HDA) appears to be equivalent to full-dose aprotinin (FDA) in its ability to prevent bleeding. However, data regarding the potential effect of aprotinin use and dosage on other outcomes such as the occurrence of perioperative stroke are limited. It has been postulated that the higher level of kallikrein inhibition obtained with FDA dosing may be required for end-organ protection. Therefore, we performed a retrospective study in cardiac surgery patients at high risk for developing stroke to determine the relative effects of FDA and HDA regimens on the incidence of postoperative stroke., Methods: Records of 1,524 patients undergoing cardiac surgery over a 15-month period were reviewed. Patients at high risk for stroke were selected if they met all of the following predefined criteria: age greater than 70 years, history of hypertension, history of diabetes mellitus, history of stroke or transient ischemic attack, and presence of aortic atheroma. A validated preoperative stroke risk index was calculated for each patient. Postoperative stroke required confirmation by computed tomography or magnetic resonance imaging. Patients were divided into three groups according to whether they were administered no aprotinin, HAD, or FDA., Results: A total of 149 patients fulfilled the criteria for being at high risk for stroke. Stroke risk index was very similar (p = 0.56) in the three groups: those who received no aprotinin and served as a control group (124 +/- 15, n = 56), those who were given HDA (123 +/- 12, n = 67), and those who received FDA (122 +/- 11 n = 26). Preoperative and intraoperative characteristics were also similar between the three study groups. Overall, the incidence of stroke was 16% (24/149). The incidence of stroke differed (p < 0.05) among the three groups: no aprotinin 16% (9/56), HDA 22% (15/67), and FDA 0% (0/26)., Conclusions: In this retrospective study of cardiac surgery patients at high risk for postoperative stroke, the administration of FDA but not HDA was associated with a lower incidence of stroke.

Purpose: Chronic red cell transfusion has been used for prevention of recurrent stroke in patients with sickle cell disease for three decades, and its effectiveness in primary prevention was recently shown. Iron overload, the inevitable result of chronic transfusion, is commonly monitored with serum ferritin concentration., Patients and Methods: Sixty-one patients at high risk for stroke received chronic transfusion in a clinical trial of stroke prevention. A serum ferritin level of less than 500 ng/mL was required for study entry. Ferritin levels were obtained quarterly. Fifty patients who had four or more ferritin measurements were included in this analysis. Transfusions were administered as exchange or simple, with washed, reconstituted, or packed red blood cells, at the discretion of the site investigator., Results: Serum ferritin levels increased linearly with cumulative transfusion volume during the first four ferritin measurements, but the rate of increase varied widely among patients. Rates of increase varied similarly among 23 patients who received exclusively simple transfusion with packed red cells and in five patients who received exchange transfusions. Thirty-two patients received a total transfusion volume of more than 250 mL/kg. Ferritin continued to increase linearly after the first four measurements in 14, but the remaining 18 experienced a plateau before the level reached 3,000 ng/mL. Six of those with a linear increase never reached a ferritin level of 3,000 ng/dL., Conclusions: There was strong intrapatient correlation between serum ferritin levels and volume transfused but wide interpatient variability early during chronic transfusion therapy. Intrapatient correlation declined at transfusion volumes of more than 250 mL/kg. Direct iron store assessment is needed to determine the clinical significance of serum ferritin variability.