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Background and Purpose: Preclinical stroke studies endeavor to model the pathophysiology of clinical stroke, assessing a range of parameters of injury and impairment. However, poststroke pathology is complex and variable, and associations between diverse parameters may be difficult to identify within the usual small study designs that focus on infarct size. Methods: We have performed a retrospective large-scale big data analysis of records from 631 C57BL/6 mice of either sex in which the middle cerebral artery was occluded by 1 of 5 surgeons either transiently for 1 hour followed by 23-hour reperfusion (transient middle cerebral artery occlusion [MCAO]; n=435) or permanently for 24 hours without reperfusion (permanent MCAO; n=196). Analyses included a multivariate linear mixed model with random intercept for different surgeons as a random effect to reduce type I and type II errors and a generalized ordinal regression model for ordinal data when random effects are low. Results: Analyses indicated that brain edema volume was associated with infarct volume at 24 hours (β, 0.52 [95% CI, 0.45–0.59]) and was higher after permanent MCAO than after transient MCAO ( P Conclusions: Large-scale analysis of preclinical stroke data can provide researchers in our field with insight into relationships between variables not possible if individual studies are analyzed in isolation and has identified hypotheses for future study.

Introduction: Motor deficit is common following anterior cerebral artery (ACA) stroke. This study aimed to determine the impact on the motor outcome, given the location of descending corticofugal fiber tracts (from the primary motor cortex [M1], dorsal and ventral premotor area [PMdv], and supplementary motor area [SMA]) and the regional variations in collateral support of the ACA territory. Methods: Patients with ACA vessel occlusion were included. Disruption to corticofugal fibers was inferred by overlap of tracts with a lesion on computed tomography perfusion at the onset and on magnetic resonance imaging (MRI) poststroke. The motor outcome was defined by dichotomized and combined National Institute of Health Stroke Scale (NIHSS) sub-scores for the arm and leg. Multivariate hierarchical partitioning was used to analyze the proportional contribution of the corticofugal fibers to the motor outcome. Results: Forty-seven patients with a median age of 77.5 (interquartile range 68.0–84.5) years were studied. At the stroke onset, 96% of patients showed evidence of motor deficit on the NIHSS, and the proportional contribution of the corticofugal fibers to motor deficit was M1-33%, SMA-33%, and PMdv-33%. By day 7, motor deficit was present in Conclusion: Improvements in the motor outcome seen in ACA stroke may be due to the relative sparing of M1 fiber tracts from infarction. This may occur as a consequence of the posterior location of M1 fiber tracts and the evolving topography of ACA stroke due to the compensatory capacity of leptomeningeal anastomoses.

Background and Purpose: The circle of Willis (CoW) and leptomeningeal anastomoses play an important role in transforming infarct topography following middle cerebral artery occlusion. Their role in infarct topography following anterior cerebral artery occlusion is not well understood. The aim of this study was to evaluate the role of the CoW and leptomeningeal anastomoses in modifying regional variation in infarct topography following occlusion of the anterior cerebral artery and its branches. Methods: Perfusion and magnetic resonance imaging of patients with anterior cerebral artery stroke and evidence of vessel occlusion were segmented and manually registered to standard brain template for voxel-wise comparison. Next, a computer model of the cerebral arteries was formulated as network of nodes connected by cylindrical pipes. The experiments included occlusion of successive branches of the anterior cerebral artery while the configurations of the CoW were varied. Results: Forty-seven patients with a median age of 77.5 years (interquartile range, 68.0–84.5 years) were studied. The regions with the highest probabilities of infarction were the superior frontal gyrus (probability =0.26) and anterior cingulate gyrus (probability =0.24). The regions around the posterior cingulate gyrus (probability =0.08), paracentral lobule (probability =0.05), precuneus and superior parietal lobule (probability =0.03) had a low probability of infarction. Following occlusions distal to the anterior communicating artery, the computer model demonstrated an increase in flow (>30%) in neighboring cortical arteries with leptomeningeal anastomoses. Conclusions: Traditionally the CoW has been regarded as the primary collateral system. However, our computer model shows that the CoW is only helpful in redirecting flow following proximal vessel occlusions (pre-anterior communicating artery). More important are leptomeningeal anastomoses, which play an essential role in distal vessel occlusions, influencing motor outcome by modifying the posterolateral extent of infarct topography.

Social media (YouTube) has been used to educate the public on stroke signs and the need to contact emergency hotline. We perform sentiment analysis to explore the emotional response to the 2006 North American and contrast this with the five Australian campaigns (2009-2015). The positive sentiment in the North American campaign provides insights for developing material for public health campaigns.

Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

Stroke is responsible for almost 6 million deaths and more than 10% of all mortalities each year, and two-thirds of stroke survivors remain disabled. With treatments for ischemic stroke still limited to clot lysis and/or mechanical removal, new therapeutic targets are desperately needed. In this review, we provide an overview of the complex mechanisms of innate and adaptive immune cell-mediated inflammatory injury, that exacerbates infarct development for several days after stroke. We also highlight the features of poststroke systemic immunodepression that commonly leads to infections and some mortalities, and argue that safe and effective therapies will need to balance pro- and anti-inflammatory mechanisms in a time-sensitive manner, to maximize the likelihood of an improved long-term outcome.

Despite intracerebral haemorrhage causing 5% of deaths worldwide, few evidence-based therapeutic strategies other than stroke unit care exist. Tranexamic acid decreases haemorrhage in conditions such as acute trauma and menorrhoea. We aimed to assess whether tranexamic acid reduces intracerebral haemorrhage growth in patients with acute intracerebral haemorrhage.We did a prospective, double-blind, randomised, placebo-controlled, investigator-led, phase 2 trial at 13 stroke centres in Australia, Finland, and Taiwan. Patients were eligible if they were aged 18 years or older, had an acute intracerebral haemorrhage fulfilling clinical criteria (eg, Glasgow Coma Scale score of7, intracerebral haemorrhage volume70 mL, no identified or suspected secondary cause of intracerebral haemorrhage, no thrombotic events within the previous 12 months, no planned surgery in the next 24 h, and no use of anticoagulation), had contrast extravasation on CT angiography (the so-called spot sign), and were treatable within 4·5 h of symptom onset and within 1 h of CT angiography. Patients were randomly assigned (1:1) to receive either 1 g of intravenous tranexamic acid over 10 min followed by 1 g over 8 h or matching placebo, started within 4·5 h of symptom onset. Randomisation was done using a centralised web-based procedure with randomly permuted blocks of varying size. All patients, investigators, and staff involved in patient management were masked to treatment. The primary outcome was intracerebral haemorrhage growth (33% relative or6 mL absolute) at 24 h. The primary and safety analyses were done in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT01702636).Between March 1, 2013, and Aug 13, 2019, we enrolled and randomly assigned 100 participants to the tranexamic acid group (n=50) or the placebo group (n=50). Median age was 71 years (IQR 57-79) and median intracerebral haemorrhage volume was 14·6 mL (7·9-32·7) at baseline. The primary outcome was not different between the two groups: 26 (52%) patients in the placebo group and 22 (44%) in the tranexamic acid group had intracerebral haemorrhage growth (odds ratio [OR] 0·72 [95% CI 0·32-1·59], p=0·41). There was no evidence of a difference in the proportions of patients who died or had thromboembolic complications between the groups: eight (16%) in the placebo group vs 13 (26%) in the tranexamic acid group died and two (4%) vs one (2%) had thromboembolic complications. None of the deaths was considered related to study medication.Our study does not provide evidence that tranexamic acid prevents intracerebral haemorrhage growth, although the treatment was safe with no increase in thromboembolic complications. Larger trials of tranexamic acid, with simpler recruitment methods and an earlier treatment window, are justified.National Health and Medical Research Council, Royal Melbourne Hospital Foundation.

ObjectiveDysregulation of iron in the cerebral motor areas has been hypothesized to occur in individuals with Amyotrophic Lateral Sclerosis (ALS). There is still limited knowledge regarding iron dysregulation in the progression of ALS pathology. Our objectives were to use magnetic resonance based Quantitative Susceptibility Mapping (QSM) to investigate the association between iron dysregulation in the motor cortex and clinical manifestations in patients with limb-onset ALS, and to examine changes in the iron concentration in the motor cortex in these patients over a six-month period.MethodsIron concentration was investigated using magnetic resonance based -QSM in the primary motor cortex and the pre-motor area in thirteen limb-onset ALS patients (including five lumbar onset, six cervical onset and two flail arm patients), and eleven age and sex-matched healthy controls. Nine ALS patients underwent follow-up scans at six months.ResultsSignificantly increased QSM was observed in the left posterior primary motor area (p = 0.02, Cohen’s d = 0.9) and right anterior primary motor area (p = 0.02, Cohen’s d = 0.92) in all individuals with limb-onset ALS compared to healthy controls. Increased QSM was observed in the primary motor and pre-motor area at baseline in patients with lumbar onset ALS patients, but not cervical limb-onset ALS patients, compared to healthy controls. No significant change in QSM was observed at the six-month follow-up scans in the ALS patients.ConclusionsThe findings suggest that iron dysregulation can be detected in the motor cortex in limb-onset ALS, which does not appreciably change over a further 6 months. Individuals with lumbar onset ALS appear to be more susceptible to motor cortex iron dysregulation compared to the individuals with cervical onset ALS. Importantly, this study highlights the potential use of QSM as a radiological indicator in disease diagnosis, and in clinical trials in limb-onset ALS and its subtypes.HighlightsSerial measurement of QSM in the motor cortex in limb-onset ALS was performedQSM changes in the motor cortex in ALS sub-groups were investigatedHigher QSM was observed in the motor cortex in Lumbar ALS relative to controlsQSM is sensitive to iron dysregulation in the motor cortex in limb-onset ALS

Background Focal brain lesions can lend insight into the causal neuroanatomical substrate of depression in the human brain. However, studies of lesion location have led to inconsistent results. Methods Five independent datasets with different lesion etiologies and measures of postlesion depression were collated (N = 461). Each 3-dimensional lesion location was mapped to a common brain atlas. We used voxel lesion symptom mapping to test for associations between depression and lesion locations. Next, we computed the network of regions functionally connected to each lesion location using a large normative connectome dataset (N = 1000). We used these lesion network maps to test for associations between depression and connected brain circuits. Reproducibility was assessed using a rigorous leave-one-dataset-out validation. Finally, we tested whether lesion locations associated with depression fell within the same circuit as brain stimulation sites that were effective for improving poststroke depression. Results Lesion locations associated with depression were highly heterogeneous, and no single brain region was consistently implicated. However, these same lesion locations mapped to a connected brain circuit, centered on the left dorsolateral prefrontal cortex. Results were robust to leave-one-dataset-out cross-validation. Finally, our depression circuit derived from brain lesions aligned with brain stimulation sites that were effective for improving poststroke depression. Conclusions Lesion locations associated with depression fail to map to a specific brain region but do map to a specific brain circuit. This circuit may have prognostic utility in identifying patients at risk for poststroke depression and therapeutic utility in refining brain stimulation targets.

Background and Purpose— The computed tomography angiographic spot sign refers to contrast leakage within intracerebral hemorrhage (ICH). It has been proposed as a surrogate radiological marker for ICH growth. We conducted a meta-analysis to study the accuracy of the spot sign for predicting ICH growth and mortality. Methods— PubMed, Medline, conference proceedings, and article references in English up to June 2017 were searched for studies reporting “computed tomography angiography” and “spot sign” or “intracerebral hemorrhage” and “spot sign.” Each study was ranked on 27 criteria resulting in a quality rating score. Bivariate random effect meta-analysis was used to calculate positive and negative likelihood ratios and area under summary receiver operating characteristics curve for ICH growth and mortality. Hematoma growth was defined using the change in ≥6 mL or ≥33% increase in volume. Results— There were 26 studies describing 5085 patients, including 15 studies not used in previous meta-analyses. Positive likelihood ratio and negative likelihood ratio for ICH growth were 4.85 (95% CI, 3.85–6.02; I 2 =76.1%) and 0.49 (95% CI, 0.40–0.58) and mortality were 4.65 (95% CI, 3.67–5.90) and 0.55 (95% CI, 0.40–0.69), respectively. For ICH growth, the pooled sensitivity was 0.57 (95% CI, 0.49–0.64) and pooled false positive rate was 0.12 (95% CI, 0.09–0.14). The post-test probability of ICH growth was 0.57. The area under the curve for ICH growth and mortality was 0.86 and 0.87 (CIs are not provided in bivariate method). Meta-regression showed sensitivity of the test to decline significantly with subsequent year of publication (β=−0.148; 95% CI, −0.295 to −0.001; P =0.05). Higher quality assessment is associated with lower false positive rate (β=−0.074; 95% CI, −0.126 to −0.022; P =0.006). Conclusions— The high area under the curve potentially suggests that the spot sign can predict hematoma growth and mortality. Caution is recommended in its application given the heterogeneity across studies, which is appropriate given the data.

Background: There is emphasis on timely administration of thrombolysis and clot retrieval but not antithrombotic therapy within 48 h for ischemic stroke (frequency of 64% in Australia and 97% in North America). We planned to assess the time metrics and variables associated with delaying antithrombotics (antiplatelet and anticoagulant therapy) administration.Methods: This was a retrospective study at Monash Health over 12 months in 2015. We plotted the cumulative event and mapped the key drivers (dimensionless variable Shapley value/SV) of antithrombotics.Results: There were 42 patients with transient ischemic attack/TIA and 483 with ischemic stroke [mean age was 71.8 ± 15.4; 56.0% male; nil by mouth (NBM) 74.5 and 49.3% of patients received “stat” (immediate and one off) dose antithrombotics]. The median time to imaging for the patients who did not have stroke code activated was 2.3 h (IQR 1.4–3.7), from imaging to dysphagia screen was 14.6 h (IQR 6.2–20.3), and from stopping NBM to antithrombotics was 1.7 h (IQR 0–16.5). TIA patients received antithrombotics earlier than those with ischemic stroke (90.5 vs. 86.5%, p = 0.01). Significant variables in regression analysis for time to antithrombotics were time to dysphagia screen (β 0.20 ± 0.03, SV = 3.2), nasogastric tube (β 19.8 ± 5.9, SV = −0.20), Alteplase (β 8.6 ± 3.6, SV = −1.9), stat dose antithrombotic (β −18.9 ± 2.9, SV = −10.8) and stroke code (β −5.9 ± 2.5, SV = 2.8). The partial correlation network showed that the time to antithrombotics increased with delay in dysphagia screen (coefficient = 0.33) and decreased if “stat” dose of antithrombotics was given (coefficient = −0.32).Conclusion: The proportion of patients receiving antithrombotics within 48 h was higher than previously reported in Australia but remained lower than the standard achieved in North American hospitals. Our process map and network analysis show avenues to shorten the time to antithrombotic.

OBJECTIVE The natural history of patients with stroke and cancer remains poorly understood in the modern era of hyper-acute stroke therapies (recombinant tissue plasminogen activator (tPA) and endovascular clot retrieval (ECR)). Prior to these advances in stroke treatment, a highly cited study reported median overall survival (mOS) 4.5 months after stroke in a cohort of patients with cancer (2004, n=96). Our aim is to evaluate outcome following stroke for patients with cancer in this modern era. Our hypothesis is that patients with stroke and cancer have better outcome than in earlier studies. DESIGN AND SETTING Retrospective analysis of admission to a tertiary Stroke Unit between January 2015 and September 2017 (N=1910), evaluation of hospital records and cancer treatment records. OUTCOME MEASURES Cancer was categorised as early stage (stage I and II) and advanced stage (stage III or IV, using the RD-Staging system). Survival analysis was performed in R. RESULTS There were 143 stroke patients with cancer (62% male) with mean age 73.2 +/- 12.5 years. Ischemic stroke occurred in 74.1% and 45 of 106 patients (42.5%) received intravenous thrombolysis (34/45) and / or endovascular clot retrieval (11/45). One patient who received ECR died within 30-days of stroke. Those with early-stage disease had mOS of 19.6 months (IQR 3.1, 31.5 months) and in advanced stage cancer mOS was 2.5 months (IQR 0.4, 6.3 months, p

Background and Purpose: Severity-based assessment tools may assist in prehospital triage of patients to comprehensive stroke centers (CSCs) for endovascular thrombectomy (EVT), but criticisms regarding diagnostic inaccuracy have not been adequately addressed. This study aimed to quantify the benefits and disadvantages of severity-based triage in a large real-world paramedic validation of the Ambulance Clinical Triage for Acute Stroke Treatment (ACT-FAST) algorithm. Methods: Ambulance Victoria paramedics assessed the prehospital ACT-FAST algorithm in patients with suspected stroke from November 2017 to July 2019 following an 8-minute training video. All patients were transported to the nearest stroke center as per current guidelines. ACT-FAST diagnostic accuracy was compared with hospital imaging for the presence of large vessel occlusion (LVO) and need for CSC-level care (LVO, intracranial hemorrhage, and tumor). Patient-level time saving to EVT was modeled using a validated Google Maps algorithm. Disadvantages of CSC bypass examined potential thrombolysis delays in non-LVO infarcts, proportion of patients with false-negative EVT, and CSC overburdening. Results: Of 517 prehospital assessments, 168/517 (32.5%) were ACT-FAST positive and 132/517 (25.5%) had LVO. ACT-FAST sensitivity and specificity for LVO was 75.8% and 81.8%, respectively. Positive predictive value was 58.8% for LVO and 80.0% when intracranial hemorrhage and tumor (CSC-level care) were included. Within the metropolitan region, 29/55 (52.7%) of ACT-FAST-positive patients requiring EVT underwent a secondary interhospital transfer. Prehospital bypass with avoidance of secondary transfers was modeled to save 52 minutes (95% CI, 40.0–61.5) to EVT commencement. ACT-FAST was false-positive in 8 patients receiving thrombolysis (8.1% of 99 non-LVO infarcts) and false-negative in 4 patients with EVT requiring secondary transfer (5.4% of 74 EVT cases). CSC bypass was estimated to over-triage 1.1 patients-per-CSC-per-week in our region. Conclusions: The overall benefits of an ACT-FAST algorithm bypass strategy in expediting EVT and avoiding secondary transfers are estimated to substantially outweigh the disadvantages of potentially delayed thrombolysis and over-triage, with only a small proportion of EVT patients missed.

Introduction and PurposeChronic Disease Management (CDM) plans are used by general practitioners to manage chronic diseases such as stroke. However, there is limited evidence that being on these plans improve adherence to secondary prevention medications after stroke. We aimed to assess the association of the duration on a CDM plan in improving adherence to secondary prevention medications following stroke. MethodsAustralian survivors of stroke or transient ischaemic attack were participants from the STAND FIRM trial. Patients were individually linked with claims for CDM plans from Medicare and dispensings of secondary prevention medications from the Pharmaceutical Benefits Scheme. We estimated (1) duration on a CDM plan based on the timing and Medicare items claimed and (2) the proportion of days that patients would have been covered by these medications (PDC), while accounting for deaths and instances of over-supply. Dosage for each quantity of medication was determined by the regularity in which patients returned for a refill. Logistic regression was used to evaluate factors associated with ≥80% adherence, up to 3 years after stroke, for each of antihypertensive, antithrombotic and lipid-modifying drugs. ResultsThe median PDC for 563 patients (median age 70yrs; 36% female) ranged from 92% to 95% among the three classes of medications. Approximately 27% did not take up a CDM plan, 33% were on plans for

IntroductionEpileptic and psychogenic non-epileptic seizures (PNES) are common diagnostic problems encountered in hospital practice. This study explores the use of unsupervised machine learning in discovering themes in medical records of patients presenting with PNES. We hypothesised that themes generated by machine learning are comparable with the classification by human experts.MethodsThis is a retrospective analysis of the medical records in the emergency department of patients (age >18 years) with PNES who underwent inpatient video-electroencephalography monitoring from May 2009 to June 2014 and received a final diagnosis of PNES. Prior to machine learning of written text, we applied a standardised approach in natural language processing to create a document-term matrix (removal of numbers, stop-words and punctuations, transforming fonts to lower case). The words were separated into tokens and treated as if existing within a bag-of-words. A probability of each word existing within a topic (theme) was modelled on multivariate Dirichlet distribution (R Foundation, V.3.5.0). Next, we asked four experts to independently provide a clinical interpretation of the generated topics. When the majority of (≥3) experts agreed, it was regarded as highly congruent. Interactive data are available on the web at (https://gntem2.github.io/PNES/%23topic=1&lambda=0.6&term=).ResultsThere were 39 patients (74.4% women, median age 35 years with range 20–82). A total of 121 documents were converted to text files for text mining. There were 15 generated topics with 12/15 topics rated as highly congruent. The main themes were about descriptors of seizures and medication use.ConclusionsThe findings from machine learning on PNES-related documentation provides evidence for the feasibility of applying machine-learning methodology to analyse large volumes of medical records. The topics generated by machine learning were congruent with interpretations by clinicians indicating this method can be used for screening of medical conditions among large volumes of medical records.

BackgroundThe emergence of the COVID-19 pandemic has significantly impacted global healthcare systems and this may affect stroke care and outcomes. This study examines the changes in stroke epidemiology and care during the COVID-19 pandemic in Zanjan Province, Iran.MethodsThis study is part of the CASCADE international initiative. From February 18, 2019, to July 18, 2020, we followed ischemic and hemorrhagic stroke hospitalization rates and outcomes in Valiasr Hospital, Zanjan, Iran. We used a Bayesian hierarchical model and an interrupted time series analysis (ITS) to identify changes in stroke hospitalization rate, baseline stroke severity [measured by the National Institutes of Health Stroke Scale (NIHSS)], disability [measured by the modified Rankin Scale (mRS)], presentation time (last seen normal to hospital presentation), thrombolytic therapy rate, median door-to-needle time, length of hospital stay, and in-hospital mortality. We compared in-hospital mortality between study periods using Cox-regression model.ResultsDuring the study period, 1,026 stroke patients were hospitalized. Stroke hospitalization rates per 100,000 population decreased from 68.09 before the pandemic to 44.50 during the pandemic, with a significant decline in both Bayesian [Beta: -1.034; Standard Error (SE): 0.22, 95% CrI: -1.48, -0.59] and ITS analysis (estimate: -1.03, SE = 0.24, p&nbsp

Background and PurposeThe novel severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), now named coronavirus disease 2019 (COVID-19), may change the risk of stroke through an enhanced systemic inflammatory response, hypercoagulable state, and endothelial damage in the cerebrovascular system. Moreover, due to the current pandemic, some countries have prioritized health resources towards COVID-19 management, making it more challenging to appropriately care for other potentially disabling and fatal diseases such as stroke. The aim of this study is to identify and describe changes in stroke epidemiological trends before, during, and after the COVID-19 pandemic.MethodsThis is an international, multicenter, hospital-based study on stroke incidence and outcomes during the COVID-19 pandemic. We will describe patterns in stroke management, stroke hospitalization rate, and stroke severity, subtype (ischemic/hemorrhagic), and outcomes (including in-hospital mortality) in 2020 during COVID-19 pandemic, comparing them with the corresponding data from 2018 and 2019, and subsequently 2021. We will also use an interrupted time series (ITS) analysis to assess the change in stroke hospitalization rates before, during, and after COVID-19, in each participating center.ConclusionThe proposed study will potentially enable us to better understand the changes in stroke care protocols, differential hospitalization rate, and severity of stroke, as it pertains to the COVID-19 pandemic. Ultimately, this will help guide clinical-based policies surrounding COVID-19 and other similar global pandemics to ensure that management of cerebrovascular comorbidity is appropriately prioritized during the global crisis. It will also guide public health guidelines for at-risk populations to reduce risks of complications from such comorbidities.

Highlights • Globally, there was a significant correlation between healthy life expectancy (HALE), non-communicable disease DALYs and mortality, with COVID-19 caseload and deaths. • There was a positive independent association between HALE and COVID-19 cases. • The number of tourists was also associated with COVID-19 mortality. • Our integrated model of global data is valuable for health policymakers, allowing for the implementation of optimal preventative measures at national and global scales., Background The interaction between coronavirus disease 2019 (COVID-19) and non-communicable diseases may increase the global burden of disease. We assessed the association of COVID-19 with ageing and non-communicable diseases. Methods We extracted data regarding non-communicable disease, particularly cardiovascular disease, deaths, disability-adjusted life years (DALYs), and healthy life expectancy (HALE) from the Global Burden of Disease Study (GBD) 2017. We obtained data of confirmed COVID-19 cases, deaths, and tests from the Our World in Data database as of May 28, 2020. Potential confounders of pandemic outcomes analyzed include institutional lockdown delay, hemispheric geographical location, and number of tourists. We compared all countries according to GBD classification and World Bank income level. We assessed the correlation between independent variables associated with COVID-19 caseload and mortality using Spearman's rank correlation and adjusted mixed model analysis. Findings High-income had the highest, and the Southeast Asia, East Asia, and Oceania region had the least cases per million population (3050.60 vs. 63.86). Sub-saharan region has reported the lowest number of COVID-19 mortality (1.9). Median delay to lockdown initiation varied from one day following the first case in Latin America and Caribbean region, to 34 days in Southeast Asia, East Asia, and Oceania. Globally, non-communicable disease DALYs were correlated with COVID-19 cases (r = 0.32, p

Objectives Age and female sex are risk factors for dementia, and menopause is associated with cognitive dysfunction. Previous work largely considered the effects of sex and menopause as being independent of age. We studied whether age interacts with sex or menopause in explaining imaging biomarkers of dementia during midlife. Methods In this cross-sectional study of UK Biobank participants with brain magnetic resonance imaging (MRI), we explored the interaction of age with sex or menopausal status in explaining total brain volume (TBV), gray matter volume (GMV), white matter volume (WMV), white matter hyperintensity volume (WMHV), regional cortical volume , and subcortical volume. Results Data were available for 1827 postmenopausal women, 230 pre/perimenopausal women and 2165 men (median age 63.3 years). There was a significant interaction between age and sex (P = .024) for TBV, where the inverse association age with TBV was steeper in women (β = –5.35 mL/year) than in men (β = –4.77 mL/year). Similar age–sex interactions were also observed for GMV and WMV. In women, there was a significant interaction between age and menopausal status (P = .007) where the inverse association of age with TBV was steeper in postmenopausal (β = –5.89 mL/year) than in pre/perimenopausal women (β = –1.61 mL/year). Similar age–menopause interactions were found in predicting lower GMV and higher WMHV. Differences in the direction of these age–sex and age–menopause interactions were found for regional cortical and subcortical brain volumes. Conclusion Sex and menopause both interact with age during midlife in explaining MRI biomarkers of dementia. Further work is required to understand the mechanisms driving these interactions to develop strategies for delaying dementia.

Endovascular clot retrieval, often referred to as mechanical thrombectomy, has transformed the treatment of patients with ischemic stroke based on an underlying large cerebral vessel occlusion, ranging from the extracranial internal carotid artery (ICA) to the M1 (proximal) segment of the middle cerebral artery (MCA). The aim of this study was to evaluate the effect of a progressive occlusion of the extracranial portion of the ICA on the cerebral blood flow either with a conventional guiding catheter or a balloon-guiding catheter, which enables the operator to completely occlude the parent artery by inflating the balloon around the tip of this type of guiding catheter. We evaluated the impact of flow reduction in the ICA in the setting of ipsilateral MCA occlusion given the different configurations of the circle of Willis (CoW). The computer model of cerebral arteries was based on anatomical works by Rhoton (1) and van der Eecken (2). The interactive experimental results are available on the web at https://gntem3.shinyapps.io/ecrsim. In the setting of left MCA occlusion, compensation from the anterior and posterior communicating artery preserved the flow in the left anterior cerebral artery (ACA) but not the left MCA branches. Under selected CoW configurations, such as classic, missing Acom, or missing A1 segment of the ACA and concurrent right ICA occlusion, there was a progressive decrease of flow in the left ACA to a minimum of 78% when the simulated catheter fully occluded the left ICA. Flow collapsed (

Objective: We aimed to utilize the data on lifetime risk of stroke, from Global Burden of Disease (GBD) 2016, in combination with open data platforms to create an interactive map for use by clinicians and members of the public. Further, we explore the relationship between life expectancy and lifetime risk of stroke. Design: Enhancing visual display of large volume of data. Setting: Worldwide estimates of the lifetime risk of stroke obtained from the GBD 2016. Participants: None. Intervention: None. Methods: Data were extracted from a portable document format (pdf) copy of the GBD article on the lifetime risk of stroke and exported into the R programming environment (version 3.4.4). These data were merged with (i) the world map boundary, (ii) open data platforms from the World Bank (life expectancy and income), and (ii) open data from the United Nation Population Prospects 2017. Further we plotted the relationship between the adjusted lifetime risk of stroke and life expectancy. Outcomes: The map of the global burden of stroke shows a higher lifetime risk of stroke among high-income countries than in low-income countries (https://gntem3.shinyapps.io/strokeglobal/). The greatest risk was among upper-middle-income countries such as China and Eastern and Central European countries such as Latvia and Romania. The lifetime risk of stroke increased in countries with higher life expectancy (β = 0.48 ± 0.047, 95% confidence interval = 0.390–0.574, R2 = 0.38, p < 0.01). Conclusion: Overall life expectancy is a major driver of the lifetime risk of stroke. The interactive map enables clinicians to search information about the lifetime risk of stroke interactively and navigate by zooming in and out, while still retaining high resolution.

ObjectiveWe investigated differences in the anatomical distribution of cerebral microbleeds (CMBs) on MRI, hypothesized to indicate the type of underlying cerebral small vessel disease (SVD), between Eastern and Western general populations.MethodsWe analyzed data from 11 studies identified by a PubMed search between 1996 and April 2014 according to the Preferred Reporting Items for a Systematic Review and Meta-analysis of Individual Participant Data. Study quality measures indicated low or medium risk of bias. We included stroke-free participants from populations aged between 55 and 75 years, categorized by geographic location (Eastern or Western). We categorized CMB distribution (strictly lobar, deep and/or infratentorial [D/I], or mixed [i.e., CMBs located in both lobar and D/I regions]). We tested the hypothesis that Eastern and Western populations have different anatomical distributions of CMBs using multivariable mixed effects logistic regression analyses adjusted for age, sex, and hypertension and clustering by institution.ResultsAmong 8,595 stroke-free individuals (mean age [SD] 66.7 [5.6] years; 48% male; 42% from a Western population), 624 (7.3%) had CMBs (strictly lobar in 3.1%; D/I or mixed in 4.2%). In multivariable mixed effects models, Eastern populations had higher odds of D/I or mixed CMBs (adjusted odds ratio 2.78, 95% confidence interval [CI] 1.77–4.35) compared to Western populations. Eastern populations had a higher number of D/I or mixed CMBs (adjusted prevalence ratio 2.83, 95% CI 1.27–6.31).ConclusionsEastern and Western general populations have different anatomical distributions of CMBs, suggesting differences in the spectrum of predominant underlying SVDs, with potential implications for SVD diagnosis and treatment.

The aims of the study were to examine whether type 2 diabetes mellitus is associated with greater brain atrophy and cognitive decline, and whether brain atrophy mediates associations between type 2 diabetes and cognitive decline. Participants without dementia aged 55–90 years from the Cognition and Diabetes in Older Tasmanians (CDOT) study underwent brain MRI (ventricular and total brain volume) and neuropsychological measures (global function and seven cognitive domains) at three time points over 4.6 years. Mixed models were used to examine longitudinal associations of type 2 diabetes with cognitive and MRI measures, adjusting for covariates. A test of mediation was used to determine whether brain atrophy explained associations between type 2 diabetes and cognitive decline. A total of 705 participants (diabetes: n = 348, mean age 68.2 years [SD 7.0]; no diabetes: n = 357, mean age 72.5 years [SD 7.1]) were available at baseline. Adjusting for age, sex, education and vascular risk factors, there were significant diabetes × time interactions for verbal memory (β −0.06; 95% CI −0.09, −0.02) and verbal fluency (β −0.03; 95% CI −0.06, −0.00). Although people with diabetes had lower brain (β −14.273; 95% CI −21.197, −6.580) and greater ventricular (β 2.672; 95% CI 0.152, 5.193) volumes at baseline, there were no significant diabetes × time interactions (p > 0.05) or evidence of mediation of the diabetes–cognition relationship by brain atrophy. In older community-dwelling people, type 2 diabetes is associated with decline in verbal memory and fluency over ~5 years. The effect of diabetes on brain atrophy may begin earlier (midlife).

Background and Purpose— Human amnion epithelial cells (hAECs) are nonimmunogenic, nontumorigenic, anti-inflammatory cells normally discarded with placental tissue. We reasoned that their profile of biological features, wide availability, and the lack of ethical barriers to their use could make these cells useful as a therapy in ischemic stroke. Methods— We tested the efficacy of acute (1.5 hours) or delayed (1–3 days) poststroke intravenous injection of hAECs in 4 established animal models of cerebral ischemia. Animals included young (7–14 weeks) and aged mice (20–22 months) of both sexes, as well as adult marmosets of either sex. Results— We found that hAECs administered 1.5 hours after stroke in mice migrated to the ischemic brain via a CXC chemokine receptor type 4-dependent mechanism and reduced brain inflammation, infarct development, and functional deficits. Furthermore, if hAECs administration was delayed until 1 or 3 days poststroke, long-term functional recovery was still augmented in young and aged mice of both sexes. We also showed proof-of-principle evidence in marmosets that acute intravenous injection of hAECs prevented infarct development from day 1 to day 10 after stroke. Conclusions— Systemic poststroke administration of hAECs elicits marked neuroprotection and facilitates mechanisms of repair and recovery.

It has been 40 years since the ischemic penumbra was first conceptualized through work on animal models. The topography of penumbra has been portrayed as an infarcted core surrounded by penumbral tissue and an extreme rim of oligemic tissue. This picture has been used in many review articles and textbooks before the advent of modern imaging. In this paper, we review our understanding of the topography of the ischemic penumbra from the initial experimental animal models to current developments with neuroimaging which have helped to further define the temporal and spatial evolution of the penumbra and refine our knowledge. The concept of the penumbra has been successfully applied in clinical trials of endovascular therapies with a time window as long as 24 h from onset. Further, there are reports of “good” outcome even in patients with a large ischemic core. This latter observation of good outcome despite having a large core requires an understanding of the topography of the penumbra and the function of the infarcted regions. It is proposed that future research in this area takes departure from a time-dependent approach to a more individualized tissue and location-based approach.

Background and Purpose— Many guidelines for secondary prevention of stroke focus on controlling cardiometabolic risk factors. We investigated the effectiveness of a management program for attaining cardiometabolic targets in survivors of stroke/transient ischemic attack. Methods— Randomized controlled trial of survivors of stroke/transient ischemic attack aged ≥18 years. General practices were randomized to usual care (control) or an intervention comprising specialist review of care plans and nurse education in addition to usual care. The outcome is attainment of pre-defined cardiometabolic targets based on Australian guidelines. Multivariable regression was undertaken to determine efficacy and identify factors associated with attaining targets. Results— Overall, 283 subjects were randomized to the intervention and 280 to controls. Although we found no between-group difference in overall cardiometabolic targets achieved at 12 months, the intervention group more often achieved control of low-density lipoprotein cholesterol (odds ratio, 1.97; 95% confidence interval, 1.18–3.29) than controls. At 24 months, no between-group differences were observed. Medication adherence was ≥80% at follow-up, but uptake of lifestyle/behavioral habits was poor. Older age, being male, being married/living with partner, and having greater functional ability or a history of diabetes mellitus were associated with attaining targets. Conclusions— The intervention in this largely negative trial only had a detectable effect on attaining target for lipids but not for other factors at 12 months or any factor at 24 months. This limited effect may be attributable to inadequate uptake of behavioral/lifestyle interventions, highlighting the need for new or better approaches to achieve meaningful behavioral change. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: ACTRN12608000166370.

Frailty is a prevalent geriatric condition associated with poor health outcomes. The pathogenesis of frailty is incompletely understood. We aimed to evaluate the relationship between cerebral small vessel disease (SVD) and frailty.People aged between 60 and 85 years were randomly selected from the electoral roll into the Tasmanian Study of Cognition and Gait. Participants completed standardized questionnaires regarding medical history and underwent objective sensorimotor, gait, and cognitive testing. These data were used to calculate a frailty index score. Magnetic resonance imaging was performed on all participants to measure SVD. Automated quantification was used to measure white matter hyperintensities (WMH), with manual consensus for subcortical infarction (SI) and cerebral microbleeds (CMB). Multivariable linear regression was used to determine the association between SVD and frailty.The mean age of the sample (n = 388) was 72.0 years (SD 7.0), 44% (172/388) were female and the median Frailty Index was 0.20 (interquartile range 0.12, 0.27). WMH, SI, and CMB in unadjusted models were positively associated with higher frailty scores (p.05). In final models including all brain variables, higher burden of WMH (β = 2.16; 95% confidence interval [CI] 0.75, 3.57; p = .003), but not SI (β = 2.96; 95% CI -0.44, 6.35; p = .09) or CMB (β = -0.46; 95% CI -4.88, 3.96; p = .84), was independently associated with a higher frailty score.We provide cross-sectional evidence for a positive association between larger burden of WMH and frailty. Longitudinal design is required to determine the temporality of this relationship.

Diabetes mellitus is associated with an elevated risk of cognitive impairment and dementia. Cerebrovascular disease and neurodegeneration are two major pathways that may explain the effect of diabetes on the brain and therefore deserve investigation. Neuroimaging provides an effective way to investigate the contribution of these pathways in vivo, guiding further mechanistic research and providing biomarkers for clinical correlation or interventional studies. In this paper, we present a narrative review of the state of play with neuroimaging evidence in studies of people with diabetes mellitus, how these data are useful in understanding mechanistic links between diabetes and brain impairment, and possible ways that the field may develop in the future.

Introduction Lacunes are defined morphologically by size and location, but radiological characteristics alone may be unable to distinguish small vessel disease aetiology from alternative mechanisms. We investigated the branching order of arterial vessels associated with basal ganglia lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in order to improve the understanding of their pathogenesis in pure cerebral small vessel disease. Patients and methods Adults with a confirmed diagnosis of CADASIL were included. A pilot study was conducted in a Scottish CADASIL cohort. The Paris–Munich CADASIL cohort was used for independent validation. Lacunes identified on T1-weighted magnetic resonance imaging scans were registered to a standard brain template. A microangiographic template of the basal ganglia vasculature was automatically overlaid onto coronal slices, and raters estimated the vessel branching order related to each lacune. Results Of 179 lacunes, 150 (84%) were associated with third-order vessels. In 14 incident lacunes, 11 (79%) were associated with third-order vessels. In the pilot study, lacune volume was significantly lower in lacunes associated with third-order vessels (0.04 ml ± 0.04 ml) compared to second-order vessels (0.48 ± 0.16 ml; p Discussion In this study of CADASIL patients, most lacunes were small and associated with third-order vessel disease. This suggests that these are the vessels primarily affected in cerebral small vessel disease. Microangiographic template techniques could be used to further investigate in a general stroke population whether finding large lacunes originating from higher order vessels indicates an alternative cause of stroke. Conclusion Lacunes in pure small vessel disease are associated with the smallest vessels in the basal ganglia.

Objective:To extensively investigate long-term unmet needs in survivors of stroke or TIA and to identify factors associated with these unmet needs.Methods:Community-dwelling adults were invited to participate in a survey ≥2 years after discharge for stroke/TIA. Unmet needs were assessed across 5 domains: activities and participation, environmental factors, body functions, post–acute care, and secondary prevention. Factors associated with unmet needs were determined with multivariable negative binomial regression.Results:Of 485 participants invited to complete the survey, 391 (81%) responded (median age 73 years, 67% male). Most responders (87%) reported unmet needs in ≥1 of the measured domains, particularly in secondary prevention (71%). Factors associated with fewer unmet needs included older age (incident rate ratio [IRR] 0.62, 95% confidence interval [CI] 0.50–0.77), greater functional ability (IRR 0.33, 95% CI 0.17–0.67), and reporting that the general practitioner was the most important in care (IRR 0.69, 95% CI 0.57–0.84). Being depressed (IRR 1.61, 95% CI 1.23–2.10) and receiving community services after stroke (IRR 1.45, 95% CI 1.16–1.82) were associated with more unmet needs.Conclusions:Survivors of stroke/TIA reported considerable unmet needs ≥2 years after discharge, particularly in secondary prevention. The factors associated with unmet needs could help guide policy decisions, particularly for tailoring care and support services provided after discharge.

Background and Purpose— There is great interest in how endovascular clot retrieval hubs provide services to a population. We applied a computational method to objectively generate service boundaries for such endovascular clot retrieval hubs, defined by traveling time to hub. Methods— Stroke incidence data merged with population census to estimate numbers of stroke in metropolitan Melbourne, Australia. Traveling time from randomly generated addresses to 4 endovascular clot retrieval–capable hubs (Royal Melbourne Hospital [RMH], Monash Medical Center [MMC], Alfred Hospital [ALF], and Austin Hospital [AUS]) estimated using Google Map application program interface. Boundary maps generated based on traveling time at various times of day for combinations of hubs. Results— In a 2-hub model, catchment was best distributed when RMH was paired with MMC (model 1a, RMH 1765 km 2 and MMC 1164 km 2 ) or with AUS (model 1c, RMH 1244 km 2 and AUS 1685 km 2 ), with no statistical difference between models ( P =0.20). Catchment was poorly distributed when RMH was paired with ALF (model 1b, RMH 2252 km 2 and ALF 676 km 2 ), significantly different from both models 1a and 1c (both P P Conclusions— We provide proof of concept for a novel computational method to objectively designate service boundaries for endovascular clot retrieval hubs.

A 39-year-old woman presented with vertigo and difficulty controlling her right side. She had a right-sided Horner’s syndrome, gaze-evoked horizontal nystagmus with the fast-beating phase to the left, and right upper and lower limb ataxia with reduced temperature sensation to the left side of her face, arm and leg. MR scan of brain showed a right lateral medullary infarct secondary to a dissection of the right vertebral artery (figure 1). A week after her stroke, she noticed increased sweating on the left side of …

Summary Background S44819, a selective GABAA α5 receptor antagonist, reduces tonic post-ischaemic inhibition of the peri-infarct cortex. S44819 improved stroke recovery in rodents and increased cortical excitability in a transcranial magnetic stimulation study in healthy volunteers. The Randomized Efficacy and Safety Trial of Oral GABAA α5 antagonist S44819 after Recent ischemic Event (RESTORE BRAIN) aimed to evaluate the safety and efficacy of S44819 for enhancing clinical recovery of patients with ischaemic stroke. Methods RESTORE BRAIN was an international, randomised, double-blind, parallel-group, placebo-controlled, multicentre phase 2 trial that evaluated the safety and efficacy of oral S44189 in patients with recent ischaemic stroke. The study was done in specialised stroke units in 92 actively recruiting centres in 14 countries: ten were European countries (Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, and the UK) and four were non-European countries (Australia, Brazil, Canada, and South Korea). Patients aged 18–85 years with acute ischaemic stroke involving cerebral cortex (National Institute of Health Stroke Scale [NIHSS] score 7–20) without previous disability were eligible for inclusion. Participants were randomly assigned to receive 150 mg S44819 twice a day, 300 mg S44819 twice a day, or placebo twice a day by a balanced, non-adaptive randomisation method with a 1:1:1 ratio. Treatment randomisation and allocation were centralised via the interactive web response system using computer-generated random sequences with a block size of 3. Blinding of treatment was achieved by identical appearance and taste of all sachets. Patients, investigators and individuals involved in the analysis of the trial were masked to group assignment. The primary endpoint was the modified Rankin Scale (mRS) score 90 days from onset of treatment, evaluated by shift analysis (predefined main analysis) or by dichotomised analyses using 0–1 versus 2–6 and 0–2 versus 3–6 cutoffs (predefined secondary analysis). Secondary endpoints were the effects of S44819 on the NIHSS and Montreal Cognitive Assessment (MoCA) scores, time needed to complete parts A and B of the Trail Making Test, and the Barthel index. Efficacy analyses were done on all patients who received at least one dose of treatment and had at least one mRS score taken after day 5 (specifically, on or after day 30). Safety was compared across treatment groups for all patients who received at least one dose of treatment. The study was registered at ClinicalTrials.gov , NCT02877615 . Findings Between Dec 19, 2016, and Nov 16, 2018, 585 patients were enrolled in the study. Of these, 197 (34%) were randomly assigned to receive 150 mg S44819 twice a day, 195 (33%) to receive 300 mg S44819 twice a day, and 193 (33%) to receive placebo twice a day. 189 (96%) of 197 patients in the 150 mg S44819 group, 188 (96%) of 195 patients in the 300 mg S44819 group, and 191 (99%) patients in the placebo group received at least one dose of treatment and had at least one mRS score taken after day 5, and were included in efficacy analyses. 195 (99%) of 197 patients in the 150 mg S44819 group, 194 (99%) of 195 patients in the 300 mg S44819 group, and 193 (100%) patients in the placebo group received at least one dose of treatment, and were included in safety analyses. The primary endpoint of mRS at day 90 did not differ between each of the two S44819 groups and the placebo group (OR 0·91 [95% CI 0·64–1·31]; p=0·80 for 150 mg S44819 compared with placebo and OR 1·17 [95% CI 0·81–1·67]; p=0·80 for 300 mg S44819 compared with placebo). Likewise, dichotomised mRS scores at day 90 (mRS 0–2 vs 3–6 or mRS 0–1 vs 2–6) did not differ between groups. Secondary endpoints did not reveal any significant group differences. The median NIHSS score at day 90 did not differ between groups (4 [IQR 2–8] in 150 mg S44819 group, 4 [2–7] in 300 mg S44819 group, and 4 [2–6] in placebo group), nor did the number of patients at day 90 with an NIHSS score of up to 5 (95 [61%] of 156 in 150 mg S44819 group, 106 [66%] of 161 in 300 mg S44819 group, and 104 [66%] of 157 in placebo group) versus more than 5 (61 [39%] in 150 mg S44819 group, 55 [34%] in 300 mg S44819 group, and 53 [34%] in placebo group). Likewise, the median MoCA score (22·0 [IQR 17·0–26·0] in 150 mg S44819 group, 23·0 [19·0–26·5] in 300 mg S44819 group, and 22·0 [17·0–26·0] in placebo group), time needed to complete parts A (50 s [IQR 42–68] in 150 mg S44819 group, 49 s [36–63] in 300 mg S44819 group, and 50 s [38–68] in placebo group) and B (107 s [81–144] in 150 mg S44819 group, 121 s [76–159] in 300 mg S44819 group, and 130 s [86–175] in placebo group) of the Trail Making Test, and the Barthel index (90 [IQR 60–100] in 150 mg S44819 group, 90 [70–100] in 300 mg S44819 group, and 90 [70–100] in placebo group) were similar in all groups. Number and type of adverse events were similar between the three groups. There were no drug-related adverse events and no drug-related deaths. Interpretation There was no evidence that S44819 improved clinical outcome in patients after ischaemic stroke, and thus S44819 cannot be recommended for stroke therapy. The concept of tonic inhibition after stroke should be re-evaluated in humans. Funding Servier.

BACKGROUND Type 2 diabetes (T2D) is associated with an increased risk of cognitive impairment and dementia with poorly understood underlying mechanisms. OBJECTIVE We examined the role of blood pressure (BP), aortic stiffness, and hemodynamics in this association. METHODS Cross-sectional sample of late middle-aged twins discordant for T2D from the Australian Twin Registry. Measurements included neuropsychological battery and brain MRI including arterial spin labelling (ASL) to measure cerebral perfusion. Mobil-o-Graph devices were used to non-invasively obtain 24-hour BP, aortic stiffness, and hemodynamic measures. Using mixed modelling, we studied associations of T2D with cognition, MRI measures, BP, aortic stiffness, and hemodynamics. RESULTS There were 23 twin pairs with mean age 63.7 (SD = 6.1) years. T2D (β=-0.45, p

Background: There are interests in the use geospatial data for development of acute stroke services given the importance of timely acess to acute reperfusion therapy. This paper aims to introduce clinicians and citizen scientists to the possibilities offered by open source softwares (R and Python) for analyzing geospatial data. It is hope that this introduction would stimulate interest in the field as well as generate ideas for improving stroke services. Method: Instructions on installation of libraries for R and Python, source codes and links to census data are provided in a notebook format to enhance experience with running these softwares. These codes illustrate different aspects of using geospatial analysis: 1)- creation of choropleth (thematic) map which depicts estimate of stroke cases per post codes; 2) use of map to help define service regions for rehabilitation after stroke. Results: Choropleth map showing estimate of stroke per post codes and service boundary map for rehabilitation after stroke. Conclusions The examples in this article illustrate the use of a range of components that underpin geospatial analysis. By providing an accessible introduction to these areas, clinicians and researchers can create code to answer clinically relevant questions on topics such as service delivery and service demand.

Contains fulltext : 208975.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. METHODS: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. FINDINGS: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1.34 years [IQR 0.19-2.44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1.35 (95% CI 1.20-1.50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2.45 (1.82-3.29) for intracranial haemorrhage and 1.23 (1.08-1.40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4.55 [95% CI 3.08-6.72] for intracranial haemorrhage vs 1.47 [1.19-1.80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5.52 [3.36-9.05] vs 1.43 [1.07-1.91]; and for >/=20 cerebral microbleeds, aHR 8.61 [4.69-15.81] vs 1.86 [1.23-1.82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for >/=20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years). INTERPRETATION: In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. FUNDING: British Heart Foundation and UK Stroke Association.

Stroke is the second leading cause of death and physical disability, with a global lifetime incidence rate of 1 in 6. Currently, the only FDA approved treatment for ischemic stroke is the administration of tissue plasminogen activator (tPA). Stem cell clinical trials for stroke have been underway for close to two decades, with data suggesting that cell therapies are safe, feasible, and potentially efficacious. However, clinical trials for stroke account for

Infection is a leading cause of death in patients with stroke; however, the impact of cerebral infarct size or location on infectious outcome is unclear. To examine the effect of infarct size on post-stroke infection, we utilised the intraluminal middle-cerebral artery occlusion (MCAO) mouse model of ischemic stroke and adjusted the duration of arterial occlusion. At 1 day following stroke onset, the proportion of mice with infection was significantly greater in mice that had larger infarct sizes. Additionally, the presence of lung infection in these mice with severe strokes extended past 2 days, suggestive of long-term immune impairment. At the acute phase, our data demonstrated an inverse relationship between infarct volume and the number of circulating leukocytes, indicating the elevated risk of infection in more severe stroke is associated with reduced cellularity in peripheral blood, owing predominately to markedly decreased lymphocyte numbers. In addition, the stroke-induced reduction of lymphocyte-to-neutrophil ratio was also evident in the lung of all post-stroke animals. To investigate the effect of infarct location on post-stroke infection, we additionally performed a photothrombotic (PT) model of stroke and using an innovative systematic approach of analysis, we found the location of cerebral infarct does not impact on the susceptibility of post-stroke infection, confirming the greater role of infarct volume over infarct location in the susceptibility to infection. Our experimental findings were validated in a clinical setting and reinforced that stroke severity, and not infarct location, influences the risk of infection after stroke.

We read with interest the disorders of consciousness guideline1 but found issues with the recommendations. Some of the recommendations are classified as level A (recommendations 3, 9, and 11). For example, “When prognosis is poor, long-term care must be discussed (level A)….”1 The references cited did not come from a randomized control trial.

Transient Ischaemic Attack (TIA) if untreated carries a high risk of early stroke and is associated with poorer long-term survival [1]. There is emerging evidence of a reduction in stroke risk following TIA. Time critical investigations and management, as well as service organisation remain key to achieving good outcomes. Patients are diagnosed with TIA if they have transient, sudden-onset focal neurological symptoms which usually completely and rapidly resolve by presentation. The tissue based definition of TIA guides the fact that patients with residual symptoms should be considered as potentially having a stroke, with urgent evaluation regarding eligibility for thrombolysis and/or endovascular clot retrieval (ECR). Essential investigations for all patients with TIA should include early brain imaging, ECG, and carotid imaging in patients with anterior circulation symptoms. After brain imaging, exclusion of high risk indicators and immediate administration of an antiplatelet agent, subsequent attention to other mechanistic factors can be managed safely as part of a structured clinical pathway supervised by stroke specialists. This is in line with the recently revised Stroke Foundation Clinical Guidelines for Stroke Management (2017).

The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging.We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline.After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days.Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group. (Funded by the Australian National Health and Medical Research Council and others; EXTEND ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).

Background The contribution of cerebral small vessel disease (cSVD) to the pathogenesis of frailty remains uncertain. We aimed to examine the associations between cSVD with progression of frailty in a population-based study of older people. Methods People aged between 60 and 85 years were randomly selected form the electoral roll to participate in the Tasmanian Study of Cognition and Gait. Participants underwent self-reported questionnaires, objective gait, cognitive and sensorimotor testing over three phases ranging between 2005 and 2012. These data were used to calculate a 41-item frailty index (FI) at three time points. Baseline brain magnetic resonance imaging was performed on all participants to measure cSVD. Generalized mixed models were used to examine associations between baseline cSVD and progression of frailty, adjusted for confounders of age, sex, level of education, and total intracranial volume. Results At baseline (n = 388) mean age was 72 years (SD = 7.0), 44% were female, and the median FI score was 0.20 (interquartile range [IQR] 0.12, 0.27). In fully adjusted models higher burden of baseline white matter hyperintensity (WMH) was associated with frailty progression over 4.4 years (β = 0.03, 95% CI: 0.01, 0.05; p = .004) independent of other SVD markers. Neither baseline infarcts (p = .23), nor microbleeds at baseline (p = .65) were associated with progression of frailty. Conclusions We provide evidence for an association between baseline WMHs and progression of frailty. Our findings add to a growing body of literature suggesting WMH is a marker for frailty.

Evaluation and treatment of acute ischemic stroke has undergone significant advancement since the 1990s, when acute systemic reperfusion with intravenous alteplase became the first approved method for achieving reperfusion. Until recently, 4.5 h after stroke onset appeared to be the maximum time window in which positive results from thrombolysis can be achieved. However, the advent of advanced imaging modalities, including multimodal magnetic resonance imaging and computed tomography perfusion has allowed clinicians to refine the evaluation of these patients by delineating areas of infarcted tissue, areas of potentially salvageable tissue given timely reperfusion, and areas of benign oligemia. Early work in extending the time window beyond this historical limit of 4.5 h has culminated in four positive trials that demonstrate the benefit of acute mechanical or systemic reperfusion therapy in an extended time window of up to 24 h, using advanced imaging criteria for patient selection. The implications of the success of advanced imaging suggest use of these modalities for disposition decisions and selection of greater numbers of patients for reperfusion but add complexity to individual patient evaluation. Despite this, many questions remain unanswered, including the best choice of thrombolysis agent, whether we can extend the time window further to 24 h, and the optimal combination of mechanical thrombectomy and bridging therapy in the late time window in patients with or without large vessel occlusion.

Background This report aims to describe changes that centres providing transient ischaemic attack (TIA) pathway services have made to stay operational in response to the SARS-CoV-2 pandemic. Methods An international cross-sectional description of the adaptions of TIA pathways between 30th March and 6th May 2020. Experience was reported from 18 centres with rapid TIA pathways in seven countries (Australia, France, UK, Canada, USA, New Zealand, Italy, Canada) from three continents. Results All pathways remained active (n = 18). Sixteen (89%) had TIA clinics. Six of these clinics (38%) continued to provide in-person assessment while the majority (63%) used telehealth exclusively. Of these, three reported PPE use and three did not. Five centres with clinics (31%) had adopted a different vascular imaging strategy. Conclusion The COVID pandemic has led TIA clinics around the world to adapt and move to the use of telemedicine for outpatient clinic review and modified investigation pathways. Despite the pandemic, all have remained operational.

Background: Chronic Disease Management (CDM) plans are usually administered by general practitioners (GPs) to assist those with a chronic medical condition, such as stroke, and provide better management of risk factors. Despite the prevalent use of CDM plans, its comprehensiveness and the fact that there is a government commitment to fund it, there is limited evidence of its effectiveness in Australian survivors of stroke. We aimed to assess the effectiveness of CDM plans on preventing the recurrence of CVD-related serious adverse events. Methods: Patients comprised survivors of stroke/TIA who participated in the Shared Team Approach between Nurses and Doctors For Improved Risk factor Management (STAND FIRM) trial (n = 563). We used standardised anthropometric, biochemical and blood pressure data, collected at baseline, to evaluate risk factors for stroke/TIA. Poisson regression models were used to determine the incidence rate ratio (IRRs) of increasing exposure to being on a CDM plan over 3 years, while adjusting for confounding factors. We used the total count of CVD-related events and deaths within 3 years after stroke/TIA, based on either hospital discharge codes or adjudication by two independent stroke specialists. Results: Five hundred and sixty-three patients were included (median age 70; 36% female). There were 305 CVD-related events over the three years (mean 0.54), in which a third (104) were adjudicated and two-thirds (201) were derived from hospital discharge codes alone. Nearly a quarter (27%) did not take up a CDM plan over the three years, a third (33%) were on plans for less than 1.5 years and 40% were on plans from 1.5 years to 3 years. The factors most strongly associated with decreased incidence of CVD-related events were duration on a CDM plan (Adjusted IRR (aIRR) 0.85, 95% confidence interval (95%CI) 0.77-0.93; p Conclusion: Being on a CDM plan for a longer duration appeared to reduce the occurrence of CVD-related events within 3 years after stroke, potentially via more closely controlled risk factors. Patients should be encouraged to return for regular reviews of their CDM plans to enhance secondary prevention strategies, and maintain a better quality of life.

Background: Prognostic performances of models predicting risk of recurrent events of cardiovascular disease (CVD) are not adequate for use in clinical settings. We aimed to determine whether adapting the Framingham Risk Score (FRS) to an Australian population could effectively predict recurrent cardiovascular outcomes. Methods: Patients comprised survivors of stroke/TIA who participated in the Shared Team Approach between Nurses and Doctors For Improved Risk factor Management (STAND FIRM) trial (n = 563). We used standardised anthropometric, biochemical and blood pressure data, collected at baseline, to evaluate risk factors for stroke/TIA. Cox proportional hazards regression models were used to determine the risk of recurrence of CVD-related events and deaths within 3 years after stroke/TIA; adjudicated by two independent stroke specialists. Regression estimates were then used to recalibrate the coefficients used by the FRS, and performance of the model assessed. Results: In women, the recalibrated FRS model had poor discrimination (C-statistic = 0.634) and appeared to better predict CVD recurrence (AUC = 0.664) than the original FRS model (AUC = 0.598). However in men, the recalibrated FRS model had poor discrimination (C-statistic = 0.604) and prediction of CVD recurrence (AUC = 0.632) similar to the original FRS model (AUC = 0.606). Conclusion: The original FRS and recalibrated FRS models appeared to perform poorly in Australian men and women with stroke. The identification of relevant risk factors, easily measured in a clinical setting, may help clinicians better monitor the risks of their patients and enhance secondary prevention strategies.

Background: Hospital, emergency presentation and death databases are frequently used to research outcomes after stroke. The reliability of diagnostic coding for cardiovascular disease (CVD) in these administrative data remains uncertain. We aimed to determine the reliability of these data in Australia using an existing clinical trial cohort. Methods: Patients with stroke/TIA who participated in the Shared Team Approach between Nurses and Doctors For Improved Risk factor Management (STAND FIRM) trial (n = 563, recruited from 4 hospitals within Victoria). We used diagnostic ICD-10-AM coded data from hospital, emergency department and death databases within 2 years after stroke/TIA. Medical records for these potential CVD-related events were reviewed by two independent stroke specialists and adjudicated according to strict criteria. We then estimated sensitivity and specificity of using either primary or both primary and secondary diagnoses fields (obtained for all adjudicated records), against the events adjudicated by the specialists (gold standard). False positives were CVD-events defined by ICD-10-AM diagnostic codes that were adjudicated as not being a CVD-event. False negatives were true CVD-events that were misclassified as not being CVD-related when using ICD-10-AM codes. Results: We identified 261 events for medical review. After adjudication, 65 were classified as CVD-events (cases) and 196 were not CVD-events. Using both primary and secondary diagnoses, 55 true positives were correctly identified among the cases (sensitivity = 84.6%) and 129 true negatives among the non-cases (specificity = 65.8%). Using only primary diagnoses, 48 true positives were identified (sensitivity = 73.9%) and 171 true negatives (specificity = 87.2%). Using both primary and secondary diagnoses had an increased sensitivity, but decreased specificity (area under the Receiver Operating Characteristic curve (AUC) = 0.75; 95% CI, 0.70, 0.81) when compared with using only primary diagnoses (AUC = 0.81; 95% CI, 0.75, 0.86; p = 0.028). Conclusion: Both primary and secondary diagnoses should be used to identify true CVD-events and minimise misclassifying these in administrative databases.

Stroke thrombolysis with alteplase is currently recommended 0-4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis.In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036.We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15-2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23-76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81-2·96, p=0·66).Patients with ischaemic stroke 4·5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis.None.