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Background: Perinatal arterial ischemic stroke (PAIS) is a focal brain injury in term neonates, identified postnatally but presumed to occur around birth. Early risk detection and targeted treatments are limited. We developed and validated a diagnostic risk prediction model from common clinical factors to predict a term neonate’s probability of PAIS. Methods: A diagnostic prediction model was developed using multivariable logistic regression. Common pregnancy, delivery, and neonatal clinical factors were collected across four registries. Variable selection was based on peer-reviewed literature. Participant inclusion criteria were term birth and no underlying predisposition to stroke. The primary outcome was discriminative accuracy of the model predicting PAIS, measured by the concordance (C-) statistic. Results: 2571 participants (527 cases, 2044 controls) were eligible for analysis. Nine variables were included in the model – maternal age, tobacco exposure, recreational drug exposure, pre-eclampsia, chorioamnionitis, maternal fever, emergency c-section, low 5-minute Apgar score, and sex – to predict the risk of PAIS in a term neonate. This model demonstrated good discrimination between cases and controls (C-statistic 0.73) and model fit (Hosmer-Lemeshow p=0.20). Conclusions: Clinical variables can be used to develop and internally validate a model of PAIS risk prediction. Identifying high-risk neonates for early screening and treatment could reduce lifelong morbidity.
Background: Women are reported to have worse outcomes than men following ischemic stroke despite similar treatment effects for thrombolysis and endovascular treatment. Methods: We performed a post-hoc analysis of patients with acute ischemic stroke and intracranial occlusion enrolled in INTERRSeCT, an international prospective cohort study. We compared workflow times, reperfusion therapy choices, and 90-day modified Rankin scale (mRS) scores. Results: We included 575 patients, mean age 70.2 years (SD: 13.1) and 48.5% female. There were no significant sex differences in onset-to-CT (males: 115 minutes [IQR: 72-171], females: 114 minutes [IQR: 75-196] ) or CT-to-thrombolysis time (males: 24 minutes [IQR: 17-32], females: 23 minutes [IQR: 18-36]). However, female participants had a 12-minute faster CT-to-groin-puncture time, p=0.001. Reperfusion therapies did not significantly differ by sex. Reperfusion therapies included thrombolysis alone (males: 46%, females: 49%), EVT alone (males: 34%, females: 34%), thrombolysis plus EVT (males: 8%, females 9%) and conservative management (males: 12%, females: 8%). Median 90-day mRS was 2 (IQR: 1-4) in both males and females, p=0.1. Conclusions: In the INTERRSeCT cohort, rates of reperfusion therapy, workflow times and 90-day outcomes were similar between sexes, suggesting that women are not subject to any poorer performance in key quality indicators for reperfusion treatment for acute stroke.
Background: Perinatal arterial ischemic stroke (PAIS) is a leading cause of hemiparetic cerebral palsy. Multiple risk factors are associated with PAIS but studies are limited by small sample sizes and complex interactions. Unbiased machine learning applied to larger datasets may enable the development of robust predictive models. We aimed to use machine learning to identify risk factors predictive of PAIS and compare these to the existing literature. Methods: Common data elements of maternal, delivery, and neonatal factors were collected from three perinatal stroke registries and one control sample over a 7-year period. Inclusion criteria were MRI-confirmed PAIS, term birth, and idiopathic etiology. Random forest machine learning in combination with feature selection was used to develop a predictive model of PAIS. Results: Total of 2571 neonates were included (527 cases, 2044 controls). Risk factors uniquely identified through machine learning were infertility, miscarriage, primigravida, and meconium. When compared, factors identified through both literature-based selection and machine learning included maternal age, fetal tobacco exposure, intrapartum fever, and low 5-minute APGAR. Conclusions: Machine learning offers a novel, less biased method to identify PAIS predictors and complex pathophysiology. Our findings support known associations with concepts of placental disease and difficult fetal transition and may support early screening for PAIS.
Background: Sex differences in treatment response to intravenous thrombolysis (IVT) are poorly characterized. We compared sex-disaggregated outcomes in patients receiving IVT for acute ischemic stroke in the Alteplase compared to Tenecteplase (AcT) trial, a Canadian multicentre, randomised trial. Methods: In this post-hoc analysis, the primary outcome was excellent functional outcome (modified Rankin Score [mRS] 0-1) at 90 days. Secondary and safety outcomes included return to baseline function, successful reperfusion (eTICI≥2b), death and symptomatic intracerebral hemorrhage. Results: Of 1577 patients, there were 755 women and 822 men (median age 77 [68-86]; 70 [59-79]). There were no differences in rates of mRS 0-1 (aRR 0.95 [0.86-1.06]), return to baseline function (aRR 0.94 [0.84-1.06]), reperfusion (aRR 0.98 [0.80-1.19]) and death (aRR 0.91 [0.79-1.18]). There was no effect modification by treatment type on the association between sex and outcomes. The probability of excellent functional outcome decreased with increasing onset-to-needle time. This relation did not vary by sex (pinteraction 0.42). Conclusions: The AcT trial demonstrated comparable functional, safety and angiographic outcomes by sex. This effect did not differ between alteplase and tenecteplase. The pragmatic enrolment and broad national participation in AcT provide reassurance that there do not appear to be sex differences in outcomes amongst Canadians receiving IVT.
Background: Respiratory infection can be an immediate precursor to stroke and myocardial infarction (MI). Influenza vaccination is associated with reduced risk of MI. This relationship has also been suggested for stroke although it is unclear if the effect is consistent across age and risk groups. Methods: Using administrative data in Alberta from September 2009 – December 2018 we modelled the hazard of any stroke for individuals recently exposed (< 182 days) to the influenza vaccine compared to those without recent exposure adjusted for age, sex, anticoagulant use, atrial fibrillation, COPD, diabetes, hypertension, income quintile, and rural/urban home location. Results: 4,141,209 adults (29,687,899 person-years) were included; 1,769,565 (43%) received at least one vaccination in the 10-year time span. 38,126 stroke events were recorded. Adjusted for demographics and comorbidities, recent influenza vaccination significantly reduced the hazard of stroke (HR: 0.77; 95% CI: 0.76 – 0.79). This effect persisted across all stroke subtypes and across all ages and risk profiles. Conclusions: There is a 23% reduction in hazard of stroke among those recently vaccinated against influenza compared to those who were not. Protection extended to the entire adult population and was not limited to high-risk groups only.
Background: Pandemics may promote hospital avoidance among patients with emergencies, and added precautions may exacerbate treatment delays. Methods: We used linked administrative data and data from the Quality Improvement and Clinical Research Alberta Stroke Program – a registry capturing stroke-related data on the entire Albertan population (4.3 million) – to identify all patients hospitalized with stroke in the pre-pandemic (01/01/2016-27/02/2020) and COVID-19 pandemic (28/02/2020-30/08/2020) periods. We examined changes in stroke presentation rates and use of thrombolysis and endovascular therapy (EVT), adjusted for age, sex, comorbidities, and pre-admission care needs; and in workflow, stroke severity (National Institutes of Health Stroke Scale/NIHSS), and in-hospital outcomes. Results: We analyzed 19,531 patients with ischemic stroke pre-pandemic versus 2,255 during the pandemic. Hospitalizations/presentations dropped (weekly adjusted-incidence-rate-ratio[aIRR]:0.48,95%CI:0.46-0.50), as did population-level incidence of thrombolysis (aIRR:0.49,0.44-0.56) or EVT (aIRR:0.59,0.49-0.69). However, proportions of presenting patients receiving thrombolysis/EVT did not decline (thrombolysis:11.7% pre-pandemic vs 13.1% during-pandemic, aOR:1.02,0.75-1.38). For out-of-hospital strokes, onset-to-door times were prolonged(adjusted-coefficient:37.0-minutes, 95%CI:16.5-57.5), and EVT recipients experienced greater door-to-reperfusion delays (adjusted-coefficient:18.7-minutes,1.45-36.0). NIHSS scores and in-hospital mortality did not differ. Conclusions: The first COVID-19 wave was associated with a halving of presentations and acute therapy utilization for ischemic stroke at a population level, and greater pre-/in-hospital treatment delays. Our data can inform public health messaging and stroke care in future pandemic waves.
Background: Some patients do poorly despite small infarcts after endovascular therapy(EVT) whilst others with large infarcts do well. We validated exploratory findings from the ESCAPE trial regarding factors associated with such discrepancies, in the ESCAPE-NA1 trial(NCT02930018). Methods: We identified “discrepant cases” with modified Rankin Scale(mRS)≥3 despite small follow-up infarct volume(FIV≤25th-percentile) on 24-hour CT/MRI or mRS≤2 despite large FIV(volume≥75th-percentile). We compared area-under-the-curve(AUC) of pre-specified logistic models containing (a)pre-treatment factors(age/cancer/vascular risk-factors) and (b)treatment-related/post-treatment factors(serious adverse events/SAEs) in identifying small-FIV/mRS≥3 and large-FIV/mRS≤2, with stepwise regression-derived models. Results: Among 1,091 patients, 42/287(14.6%) with FIV≤7mL(25th-percentile) had mRS≥3; 65/275(23.6%) with FIV≥92mL(75th-percentile) had mRS≤2. Pre-specified pre-treatment factors(age/cancer/vascular risk-factors) were associated with FIV≤7mL/mRS≥3; stepwise models selected similar variables(similar AUCs:0.92-0.93,p=0.42). SAEs(infarct-in-new-territory/recurrent stroke/pneumonia/heart failure) were strongly associated with FIV≤7mL/mRS≥3; stepwise models also identified onset-to-needle time and hemoglobin(24-hours) as treatment-related/post-treatment factors(similar AUCs:0.92-0.94,p=0.14). Younger age was associated with FIV≥92mL/mRS≤2; stepwise models also selected diabetes absence and baseline hemoglobin(similar AUCs:0.76-0.77,p=0.82). Absence of SAEs(stroke progression/pneumonia/intracerebral hemorrhage) was strongly associated with FIV≥92mL/mRS≤2; stepwise models also identified 24-hour hemoglobin, glucose, and BP(similar AUCs:0.79-0.80,p=0.030). Conclusions: FIV-mRS discrepancies are associated with pre-treatment factors like age/comorbidities; and post-treatment complications related to stroke evolution, secondary prevention, and post-acute care quality. Optimizing thrombolysis speed, BP, glucose, and hemoglobin are modifiable factors meriting further study.
Background: Pandemics may promote hospital avoidance among patients with emergencies, and added precautions may exacerbate treatment delays. Methods: We used linked administrative data and data from the Quality Improvement and Clinical Research Alberta Stroke Program – a registry capturing stroke-related data on the entire Albertan population(4.3 million) – to identify all patients hospitalized with stroke in the pre-pandemic(01/01/2016-27/02/2020) and COVID-19 pandemic(28/02/2020-30/08/2020) periods. We examined changes in stroke presentation rates and use of thrombolysis and endovascular therapy(EVT), adjusted for age, sex, comorbidities, and pre-admission care needs; and in workflow, stroke severity(National Institutes of Health Stroke Scale/NIHSS), and in-hospital outcomes. Results: We analyzed 19,531 patients with ischemic stroke pre-pandemic versus 2,255 during the pandemic. Hospitalizations/presentations dropped(weekly adjusted-incidence-rate-ratio[aIRR]:0.48,95%CI:0.46-0.50), as did population-level incidence of thrombolysis(aIRR:0.49,0.44-0.56) or EVT(aIRR:0.59,0.49-0.69). However, proportions of presenting patients receiving thrombolysis/EVT did not decline (thrombolysis:11.7% pre-pandemic vs 13.1% during-pandemic, aOR:1.02,0.75-1.38). For out-of-hospital strokes, onset-to-door times were prolonged(adjusted-coefficient:37.0-minutes, 95%CI:16.5-57.5), and EVT recipients experienced greater door-to-reperfusion delays(adjusted-coefficient:18.7-minutes,1.45-36.0). NIHSS scores and in-hospital mortality did not differ. Conclusions: The first COVID-19 wave was associated with a halving of presentations and acute therapy utilization for ischemic stroke at a population level, and greater pre-/in-hospital treatment delays. Our data can inform public health messaging and stroke care in future pandemic waves.
Background: Small brain infarcts are often seen on diffusion-weighted MRI(DWI) following surgical/endovascular procedures. Little is known about their clinical effects. We examined the association of iatrogenic infarcts with outcomes in the ENACT(Evaluating Neuroprotection in Aneurysm Coiling Therapy) trial of nerinetide in endovascular aneurysm repair. Methods: In this post-hoc analysis, we used multi-variable models to evaluate the association of presence/number of DWI iatrogenic infarcts with NIHSS(National Institutes of Health Stroke Scale), mRS(modified Rankin Scale), and cognitive/neuropsychological scores(30-minute battery) at 1-4 and 30-days post-procedure. We also related infarct number to a Z-score-derived composite outcome score(quantile regression). Results: Among 185 patients(median age:56,IQR:50-64), 124(67.0%) had iatrogenic infarcts(median:4,IQR:2-10.5). Nerinetide resulted in fewer infarcts. Patients with infarcts had lower Mini-Mental State Exam(MMSE) scores at 2-4 days(median:28 vs 29, adjusted-coefficient[acoef] per additional infarct:-1.11,95%CI:-1.88 to -0.34,p=0.005). Infarct number was associated with worse day-1 NIHSS(aOR for NIHSS≥1:1.07,1.02-1.12,p=0.009), day 2-4 mRS(adjusted common odds-ratio[aOR]:1.05,1.01-1.09,p=0.005) and MMSE(acoef:-0.07,-0.13 to -0.003,p=0.040), 30-day mRS(aOR:1.04,1.01-1.07,p=0.016) and Hopkins Verbal Learning Test scores(acoef:-0.21,-0.39 to -0.03,p=0.020), as well as worse composite scores at 1-4 and 30-days(acoef:-0.09,-0.15 to -0.03,p=0.006). Conclusions: Iatrogenic infarcts were associated with subtle differences in post-procedural(1-4 days) and 30-day outcomes in this middle-aged cohort. Future studies should use batteries of similar/greater granularity to validate optimal measures for short- versus long-term manifestations.
Background: Decisions to treat large-vessel occlusion with endovascular therapy(EVT) or intravenous alteplase depend on how physicians weigh benefits against risks when considering patients’ pre-stroke comorbidities. Methods: In an international survey, experts chose treatment approaches under current resources and under assumed ideal conditions for 10 of 22 randomly assigned case-scenarios. Five included comorbidities(metastatic/non-metastatic cancer, cardiac/respiratory/renal disease, non-disabling/mild cognitive impairment[MCI], physical dependence). We examined scenario/respondent characteristics associated with EVT/alteplase decisions using multivariable logistic regressions. Results: Among 607 physicians(38 countries), EVT was favoured in 1,097/1,379(79.6%) responses for comorbidity-related scenarios under current resources versus 1,510/1,657(91.1%,OR:0.38, 95%CI.0.31-0.47) for six “level-1A” scenarios (assuming ideal conditions:82.7% vs 95.1%,OR:0.25,0.19-0.33). However, this was reversed on including all other scenarios(e.g. under current resources:3,489/4,691[74.4%], OR:1.34,1.17-1.54). Responses favouring alteplase for comorbidity-related(e.g.75.0% under current resources) scenarios were comparable to level-1A scenarios(72.2%) and higher than all others(60.4%). No comorbidity-related factor independently diminished EVT-odds. MCI and dependence carried higher alteplase-odds; cancer and cardiac/respiratory/renal disease had lower odds. Relevant respondent characteristics included performing more EVT cases/year (higher EVT, lower alteplase-odds), practicing in East-Asia (higher EVT-odds), and in interventional neuroradiology(lower alteplase-odds vs neurology). Conclusions: Moderate-to-severe comorbidities did not consistently deter experts from EVT, suggesting equipoise about withholding EVT based on comorbidities. However, alteplase was often foregone when respondents chose EVT.
Background: Atrial fibrillation (AF) is associated with increased risk of ischemic stroke. In Canada, the contemporary burden of AF-related stroke is incompletely characterized. Our objective was to determine temporal trends in hospital admissions and in-hospital mortality for AF-related stroke in Canada from 2007 to 2015. Methods: We conducted a retrospective cohort study using Canadian national administrative data to identify admissions to hospital for stroke with comorbid AF between 2007 and 2015. We analyzed temporal trends in age- and sex-standardized proportion of admissions with comorbid AF and associated in-hospital mortality. Results: There were 222,100 admissions to hospital for ischemic (182,990) or hemorrhagic (39,110) stroke. The age-sex adjusted proportion of ischemic stroke admissions with comorbid AF increased from 16.2% to 20.5% (p for trend = 0.02) between 2007 and 2015, and was stable among hemorrhagic stroke. In-hospital mortality for ischemic stroke with comorbid AF decreased from 21.6% to 15.0% (p for trend = 0.001). Conclusions: Rates of hospital admission for ischemic stroke with comorbid AF have increased, while associated in-hospital mortality has decreased. These results identify AF as an important continued focus for stroke prevention. Our findings provide insight into current trends and highlight the need for continued focus on AF-related stroke.